Oregon Drug Use Review / Pharmacy & Therapeutics Committee

Drug Use Research & Management Program OHA Division of Medical Assistance Programs 500 Summer Street NE, E35; Salem, OR 97301‐1079 Phone 503‐947‐5220 | Fax 503‐947‐1119

Oregon Drug Use Review / Pharmacy & Therapeutics Committee Thursday, October 1st, 2020 1:00 ‐ 5:00 PM Remote Meeting via Zoom platform MEETING AGENDA

I. CALL TO ORDER

1:00 PM A. Roll Call & Introductions R. Citron (OSU) B. Conflict of Interest Declaration R. Citron (OSU) C. Approval of Agenda and Minutes R. Citron (OSU) D. Department Update T. Douglass (OHA)

1:15 PM II. CONSENT AGENDA TOPICS J. Slater (Chair)

A. Orphan Drug Policy Update B. Oncology Policy Update 1. Public Comment

III. DUR NEW BUSINESS

1:20 PM A. Bipolar Drug Use Evaluation D. Nagarkatti‐ 1. Mental Health Clinical Advisory Group Algorithms Gude & N. Kashey 2. Drug Use Evaluation (MHCAG) 3. Public Comment S. Servid (OSU) 4. Discussion of Clinical Recommendations to OHA

IV. PREFERRED DRUG LIST NEW BUSINESS

1:40 PM A. Parkinson’s Disease Class Update with New Drug Evaluations A. Gibler (OSU) 1. Class Update/Prior Authorization Criteria 2. Nourianz™ (istradefylline) New Drug Evaluation 3. Ongentys® (opicapone) New Drug Evaluation 4. Kynmobi™ (apomorphine) New Drug Evaluation 5. Public Comment 6. Discussion of Clinical Recommendations to OHA

2:00 PM B. Asthma/COPD Class Update K. Sentena (OSU) 1. Class Update/Prior Authorization Criteria 2. Public Comment 3. Discussion of Clinical Recommendations to OHA

2:20 PM C. Antiepileptics (non‐injectable) Class Update and New Drug D. Moretz (OSU) Evaluation 1. Class Update/Prior Authorization Criteria 2. Fintepla® (fenfluramine) New Drug Evaluation 3. Public Comment 4. Discussion of Clinical Recommendations to OHA

2:35 PM D. Antacids (Proton Pump Inhibitors and H2 Receptor Antagonists) K. Sentena (OSU) Class Update 1. Class Update/Prior Authorization Criteria 2. Public Comment 3. Discussion of Clinical Recommendations to OHA

2:50 PM E. Atopic Dermatitis Literature Scan D. Moretz (OSU) 1. Literature Scan/Prior Authorization Criteria 2. Public Comment 3. Discussion of Clinical Recommendations to OHA

3:05 PM BREAK

3:20 PM F. Biologics for Autoimmune Conditions DERP Summary and Policy Evaluation 1. DERP Summary D. Moretz (OSU) 2. Policy Evaluation S. Servid (OSU) 3. Public Comment 4. Discussion of Clinical Recommendations to OHA

V. DUR NEW BUSINESS (Continued)

3:40 PM B. Modafinil/armodafinil Drug Use Evaluation D. Engen (OSU) 1. Drug Use Evaluation/Safety Edit 2. Public Comment 3. Discussion of Clinical Recommendations to OHA

3:55 PM C. Drug Discontinuation Case Management Policy Proposal S. Servid (OSU) 1. Policy Proposal 2. Public Comment 3. Discussion of Clinical Recommendations to OHA

4:05 PM D. Consultation for Antipsychotics in Kids Policy Evaluation S. Servid (OSU) 1. Policy Evaluation 2. Public Comment 3. Discussion of Clinical Recommendations to OHA

4:20 PM V. EXECUTIVE SESSION

4:50 PM VI. RECONVENE for PUBLIC RECOMMENDATIONS

VII. ADJOURN

3 Drug Use Research & Management Program OHA Health Systems Division 500 Summer Street NE, E35; Salem, OR 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Oregon Pharmacy and Therapeutics Committee – Appointed members

Name Title Profession Location Term Expiration

Tracy Klein, PhD, FNP Public Nurse Practitioner Portland December 2020

Caryn Mickelson, PharmD Pharmacist Pharmacy Director Coos Bay December 2020

William Origer, MD Physician Residency Faculty Albany December 2020

James Slater, PharmD Pharmacist Pharmacy Director Beaverton December 2020

Mark Helm, MD, MBA, FAAP Physician Pediatrician Salem December 2021

Russell Huffman, DNP, PMHNP Public Mental Health Nurse Practitioner Salem December 2021

Jim Rickards, MD, MBA Physician Radiologist / Medical Director McMinnville December 2021

Cathy Zehrung, RPh Pharmacist Pharmacy Manager Silverton December 2021

Patrick DeMartino, MD, MPh Physician Pediatrician Portland December 2022

Dave Pass, MD Physician Medical Director West Linn December 2022

Stacy Ramirez, PharmD Pharmacist Ambulatory Care Pharmacist Corvallis December 2022

Oregon Pharmacy and Therapeutics Committee Appointments Last updated 1/9/2020 4

Drug Use Research & Management Program OHA Health Systems Division 500 Summer Street NE, E35; Salem, OR 97301‐1079 Phone 503‐947‐5220 | Fax 503‐947‐1119

Oregon Drug Use Review / Pharmacy & Therapeutics Committee Thursday, August 06, 2020 1:00 - 5:00 PM Via Zoom webinar MEETING MINUTES

NOTE: Any agenda items discussed by the DUR/P&T Committee may result in changes to utilization control recommendations to the OHA. Timing, sequence and inclusion of agenda items presented to the Committee may change at the discretion of the OHA, P&T Committee and staff. The DUR/P&T Committee functions as the Rules Advisory Committee to the Oregon Health Plan for adoption into Oregon Administrative Rules 410- 121-0030 & 410-121-0040 in accordance with Oregon Revised Statute 183.333 Members Present: Mark Helm, MD, MBA, FAAP; Caryn Mickelson, PharmD; Russell Huffman, DNP, PMHNP; William Origer, MD, James Slater, PharmD; Patrick DeMartino, MD, MPh; Stacy Ramirez, PharmD; Cathy Zehrung RPh; Jim Rickards, MD, MBA

Staff Present: Roger Citron, RPh; David Engen, PharmD; Megan Herink, PharmD; Richard Holsapple, RPh; Deanna Moretz, PharmD; Sarah Servid, PharmD; Sara Fletcher, PharmD; Kathy Sentena, PharmD; Dee Weston, JD; Brandon Wells; Jennifer Bowen

Audience: Aimee Weems, Acorda Therapeutics Inc; Amy Burns, AllCare CCO; Andrea Wilcuts, Takeda; Anthony Wheeler, Eli Lilly*; Baylee Mayfield Salud Inter/OSU intern; Bill McDOugall, Biogen; Bruce Wallace, Azurity; Camille Kerr, Regeneron; Carmen Oliver, Biohaven; Carrie Johnson, Amgen*; Chelsea Leroue, Biohaven*; Chi Kohlhoff, Viela Bio; Chris DeSimone, Akcea Therapeutics; Daksha Bogdon GNE; Dan Allen, Sanofi-Genzyme; Dave Beecham, Amgen; David Large, Biohaven; Dennis Schaffner, Sanofi Genzyme; Deron Grothe, Teva; Danielle Shannon, WVP Health; Emma Selm; Garth Wright, Genentech; Herbert Alexander Krob, MD*; Hiten Patadia, Otsuka; Ian D’Souza Intra-Cellular Therapies Inc*; Jean Harris; Novo Nordisk Inc; Jean Ritter, Zealand Pharm; John Sekab, Akcea Therapeutics; Julie Baker, Deciphera Pharmaceuticals*; Katie Scheelar, EOCCO/Moda Helath; Kelly Wright, Immunomedics NAD; Jennifer Shear, Teva Pharmaceuticals*; Lisa Dunn, Amgen; Lori Howarth, Bayer; Lori McDermott, Supernus; Lynda Finch, Biogen*; Mae Kwong, Janssen*; Margaret Olmon, Abbvie; Mark Duerre, Intra-Cellular Therapies Inc; Mark Friedrich; Mark Kantor, Allcare; Melissa Bailey-Hall, Eli Lilly; Michael Foster, BMS; Nicohle Robling, Ostuka; Paul Thompson, Alkermes; Rick Frees, Vertex; Robin Traver, Umpqua Health; Roy Lindfield, Sunvion Pharmaceuticals; Sarah Day, Redhill Biopharma; Shirley

Drug Use Research & Management Program OHA Health Systems Division 500 Summer Street NE, E35; Salem, OR 97301‐1079 Phone 503‐947‐5220 | Fax 503‐947‐1119

Quach, Norvartis; Stacy Finkebeiner, Teva; Stephanie Lattig, Novo Nordisk; Suzanne Gauen, Providence Health Plans; Tiffany Jones, Pacific Source; Trent Taylor, J & J; Wendy Bibeau, BMS; Wendy Borgersen, RedHill Biopharma*

(*) Provided verbal testimony

Written testimony: Posted to OSU Website

I. CALL TO ORDER

A. The meeting was called to order at approximately 1:05 pm. Introductions were made by Committee members and staff B. Conflict of Interest Declaration ‐ No new conflicts of interest were declared C. Approval of June 2020 minutes presented by Mr. Citron ACTION: Motion to approve, 2nd, all in favor D. Department Update provided by Dee Weston

II. CONSENT AGENDA TOPICS

A. Quarterly Utilization Reports B. Antipsychotic Class Update with Caplyta™ (lumateperone) New Drug Evaluation (NDE) C. Vascular Endothlial Growth Factors (VEGF) Class Update with Beovu® (Brolucizumab‐dbll) NDE D. ADHD Literature Scan E. Immune Globulin Drug Use Evaluation (DUE) F. Oncology Policy Update G. Orphan Drug Policy Update 1. Public Comment ACTION: Motion to approve, 2nd, all in favor

III. DUR ACTIVITIES

A. ProDUR Report ‐ Mr. Holsapple presented the ProDUR report B. RetroDUR Report – Dr. Engen presented the RetroDUR Report C. Oregon State Drug Reviews 1. Biosimilar Medications: Key Considerations Providers 2. Coronavirus management: Evidence for Treatment and Drug Shortage Updates Dr. Sentena presented two recently published newsletters, thanked the Committee for reviewing the draft versions and solicited ideas for future newsletters

Drug Use Research & Management Program OHA Health Systems Division 500 Summer Street NE, E35; Salem, OR 97301‐1079 Phone 503‐947‐5220 | Fax 503‐947‐1119

IV. PREFERRED DRUG LIST NEW BUSINESS

A. Cardiovascular Outcomes of Newer Diabetes Drugs DERP Summary Dr. Sentena presented the proposal to: 1. Remove the requirement for step therapy ‐ other than metformin ‐ for DPP‐4 inhibitors, GLP‐1 receptor agonists and SGLT‐2 inhibitors 2. Evaluate comparative costs in executive session

ACTION: The Committee amended question #7 in the SGLT‐2 Inhibitor criteria to approve for 12 months Motion to approve, 2nd, all in favor

B. Non‐statin Drugs for Dyslipidemia Class Update Dr. Herink presented the proposal to: 1. Maintain Nexletol™ (bempedoic acid) and Nexlizet™ (bempedoic acid/ezetimibe) as non‐preferred 2. Implement proposed Bempedoic Acid PA criteria 3. Update Omega‐3 Fatty Acid PA criteria to include new FDA approved indication for icosapent ethyl 4. Evaluate comparative costs in executive session

ACTION: Motion to approve, 2nd, all in favor

C. Multiple Sclerosis DERP Summary Dr. Moretz presented the proposal to: 1. Revise the Oral Multiple Sclerosis Drugs PA criteria to include newly approved drugs ‐ monomethyl fumarate, diroximel fumarate, ozanimod, cladribine, and siponimod – and to add safety monitoring metrics, and the same renewal criteria outlined in Ocrelizumab critiera 2. Revise the Natalizumab PA critiera to reflect the expanded indication for all forms of relapsing MS: clinically isolated syndrome; relapsing‐remitting multiple sclerosis; and secondary progressive multiple sclerosis 3. Evaluate costs in executive session

ACTION: Motion to approve, 2nd, all in favor

D. Serotonin Agonists (formerly Triptans) Class Update Dr. Sentena presented the proposal to: 1. Rename the Triptan class Serotonin Agonists 2. Evaluate comparative costs in executive session

ACTION: Motion to approve, 2nd, all in favor

Drug Use Research & Management Program OHA Health Systems Division 500 Summer Street NE, E35; Salem, OR 97301‐1079 Phone 503‐947‐5220 | Fax 503‐947‐1119

E. Calcitonin Gene‐Related Peptide (CGRP) Inhibitors DERP Summary Dr. Sentena presented the proposal to: 1. Update the CGRP Antagonists PA criteria to include acute migraine treatments ‐ rimegepant and ubrogepant ‐ and the expanded indication for cluster headache prevention for galcanezumab 2. Evaluate costs in executive session

ACTION: Motion to approve, 2nd, all in favor

F. Topical Analgesics and Anesthetics Class Update Dr. Moretz presented the proposal to: 1. Rename the topical analgesic class as “topical pain medications” and add topical anesthetics to this new PDL class 2. Designate at least one topical anesthetic with an indication for a funded condition on the HERC prioritized list as a preferred agent based on cost 3. Add class to PDL and evaluate costs in executive session

ACTION: Motion to approve, 2nd, all in favor

V. EXECUTIVE SESSION

Members Present: Mark Helm, MD, MBA, FAAP; Caryn Mickelson, PharmD; Russell Huffman, DNP, PMHNP; William Origer, MD, James Slater, PharmD; Patrick DeMartino, MD, MPh; Stacy Ramirez, PharmD; Cathy Zehrung RPh; Jim Rickards, MD, MBA

VI. RECONVENE for PUBLIC RECOMMENDATIONS

A. Antipsychotic Class Update Recommendation: Make Abilify® (aripiprazole tablets) and Geodon® (ziprasidone capsules) and their generic alternatives preferred ACTION: Motion to approve, 2nd, all in favor

Drug Use Research & Management Program OHA Health Systems Division 500 Summer Street NE, E35; Salem, OR 97301‐1079 Phone 503‐947‐5220 | Fax 503‐947‐1119

B. VEGF Class Update Recommendation: make no changes to the PMPDP ACTION: Motion to approve, 2nd, all in favor

C. ADHD literature scan: Recommendation: Make Vyvanse® (lisdexamphetamine) chewable tablets preferred

ACTION: Motion to approve, 2nd, 7 in‐favor, 2 opposed

D. Cardiovascular Outcomes of Newer Diabetes Drug DERP Summary: Recommendation: Make Onglyza® (saxagliptin HCl), Trulicity® (dulaglutide), Farxiga® (dapagliflozin propanediol), Jardiance® (empagliflozin) and Invokana® (canagliflozin) preferred ACTION: Motion to approve, 2nd, all in favor

E. Non‐statin Drugs for Dyslipidemia Class Update Recommendation: Make generic omega‐3 fatty acids preferred and to no longer require clinical PA criteria based on that decision; and to make Triglide™/Tricor® (fenofibrate nanocrystalized tablets), Antara® (fenofibrate micronized capsules), Trilipix® (choline fenofibrate capsules) and their generic alternatives preferred ACTION: Motion to approve, 2nd, all in favor

F. Multiple Sclerosis DERP Summary Recommendation: make no changes to the PMPDP ACTION: Motion to approve, 2nd, all in favor

G. Serotonin Agonists Class Update Recommendation: Make Tosymra® (sumatriptan nasal spray) non‐preferred ACTION: Motion to approve, 2nd, all in favor

H. CGRP inhibitors Recommendation: Make Emgality® (galcanezumab‐gnlm) preferred but still subject to clinical PA criteria ACTION: Motion to approve, 2nd, all in favor

I. Topical Analgesics and Anesthetics Recommendation: Make lidocaine‐prilocaine cream, diclofenac gel, viscous lidocaine, lidocaine cream, solution and jelly w/applicator preferred; and to make everything else non‐preferred ACTION: Motion to approve, 2nd, all in favor

Drug Use Research & Management Program OHA Health Systems Division 500 Summer Street NE, E35; Salem, OR 97301‐1079 Phone 503‐947‐5220 | Fax 503‐947‐1119

IX. ADJOURN

X. OHA Rules Advisory Committee

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Orphan Drug Policy: Prior Authorization Update

Purpose of the Update: This update identifies 2 candidates for addition to the orphan drug policy due to lack of utilization in FFS since FDA approval (Table 1). See Appendix 1 for Highlights of Prescribing Information from the manufacturer, including indications, dosage and administration, formulations, contraindications, warnings and precautions, adverse reactions, drug interactions and use in specific populations.

Table 1. Candidates for Addition to the Orphan Drug Policy Generic Name Diagnosis Year of FFS Utilization Relevant ICD-10 FFS patients with (Brand) Approval Since Approval codes claims for relevant ICD-10 codes* givosiran adults with acute hepatic porphyria 2019 0 E80.21 5 (Givlaari™) REVCOVI pediatric and adult patients with adenosine deaminase 2018 0 D81.31 0 (elapegademase- severe combined immune deficiency (ADA-SCID) lvlr) * Estimated based on number of patients with FFS medical claims with the indicated diagnosis over a 1 year period (1/01/2019 to 12/31/2019). Diagnoses are based on ICD-10 codes associated with medical claims data, may not exactly match the FDA-approved indication, and may not reflect members currently enrolled in FFS.

Recommendation:  Implement PA to support medically appropriate use of givosiran and elapegademase-lvlr based on FDA labeling.

Author: Sarah Servid, PharmD October 2020 11

Appendix 1. Prescribing Information Highlights

Author: Servid October 2020 12

Author: Servid October 2020 13

Appendix 2. Proposed Prior Authorization Criteria Orphan Drugs Goal(s):  To support medically appropriate use of orphan drugs (as designated by the FDA) which are indicated for rare conditions  To limit off-label use of orphan drugs

Length of Authorization:  Up to 6 months

Requires PA:  See Table 1 (pharmacy and physician administered claims)

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Table 1. Indications for orphan drugs based on FDA labeling Drug Indication Age Dose Recommended Monitoring Burosumab-twza X-linked XLH Pediatric <18 years: Baseline and Ongoing Monitoring (CRYSVITA) hypophosphatemia ≥ 6 Initial (administered  Use of active vitamin D analogues or oral (XLH) months SC every 2 weeks): phosphate within prior week; concurrent XLH use is contraindicated FGF23-related TIO  <10 kg: 1mg/kg  Fasting serum phosphorous: do not hypophosphatemia in ≥ 2 years  ≥10 mg: 0.8 mg/kg administer if serum phosphorous is within or tumor-induced TIO above normal range osteomalacia (TIO)  0.4 mg/kg  Renal function: use is contraindicated in Max dose of 2 mg/kg ESRD or with severe renal impairment (not to exceed 90 mg (CrCl <30 mL/min for adults or eGFR <30 for XLH or 180 for mL/min/1.73m2 for pediatric patients) TIO)  25-hydroxy vitamin D levels: supplementation with vitamin D Adult: (cholecalciferol or ergocalciferol) is XLH 1 mg/kg monthly recommended as needed. (rounded to nearest Additional baseline monitoring for TIO only: 10 mg; max 90 mg)

Author: Servid October 2020 14

TIO: 0.5 mg/kg  Documentation that tumor cannot be monthly initially (Max located or is unresectable 2 mg/kg or 180mg  Elevated FGF-23 levels every 2 weeks)  Documentation indicating concurrent treatment for the underlying tumor is not planned (i.e., surgical or radiation) Cerliponase alfa To slow the loss of 3-17 300 mg every other Baseline Monitoring (BRINEURA) ambulation in years week via  Enzymatic or genetic testing to confirm symptomatic Batten intraventricular route tripeptidyl peptidase 1 deficiency or CLN2 Disease (late infantile gene mutation neuronal ceroid  Baseline motor symptoms (e.g., ataxia, lipofuscinosis type 2 or motor function, etc) TPP1 deficiency)  ECG in patients with a history of bradycardia, conduction disorders or structural heart disease Ongoing Monitoring  Disease stabilization or lack of decline in motor symptoms compared to natural history elapegademase-lvlr adenosine deaminase N/A Initial: 0.2mg/kg twice Baseline Monitoring (REVCOVI) severe combined immune weekly; No max dose  CBC or platelet count deficiency (ADA-SCID) Ongoing Monitoring  trough plasma ADA activity  trough erythrocyte dAXP levels (twice yearly)  total lymphocyte counts Givosiran acute hepatic porphyria ≥ 18 years 2.5 mg/kg monthly Baseline and ongoing monitoring (GIVLAARI)  Liver function tests Luspatercept Anemia (Hg <11 g/dL) ≥ 18 years Initial: 1 mg/kg Baseline Monitoring/Documentation (REBLOZYL) due to beta thalassemia subcutaneously  Number of red blood cell transfusions in the in patients requiring prior 2 months; minimum of 2 RBC units regular red blood cell Max dose of 1.25 over the prior 8 weeks in patients with transfusions mg/kg every 3 weeks myelodysplastic syndromes for beta thalassemia  Trial and failure of an erythropoiesis Anemia (Hg <11 g/dL) stimulating agent in patients with due to myelodysplastic myelodysplastic syndromes Author: Servid October 2020 15

syndromes with ring Max dose of 1.75  Hemoglobin level sideroblasts or mg/kg every 3 weeks  Blood pressure myelodysplastic/ for myelodysplastic myeloproliferative syndromes Ongoing Monitoring neoplasm with ring  Discontinue if there is not a decrease in sideroblasts and transfusion burden after 3 maximal doses thrombocytosis (about 9-15 weeks)  Hemoglobin level  Blood pressure

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Is the diagnosis funded by OHP? Yes: Go to #3 No: Pass to RPh. Deny; not funded by the OHP.

3. Is the request for a drug FDA-approved for the indication, Yes: Go to #4 No: Pass to RPh. Deny; age, and dose as defined in Table 1? medical appropriateness.

4. Is the request for continuation of therapy in a patient Yes: Go to Renewal Criteria No: Go to #5 previously approved by FFS?

5. Is baseline monitoring recommended for efficacy or safety Yes: Go to #6 No: Pass to RPh. Deny; (e.g., labs, baseline symptoms, etc) AND has the provider medical appropriateness. submitted documentation of recommended monitoring parameters?

6. Is this medication therapy being prescribed by, or in Yes: Go to #7 No: Pass to RPh. Deny; consultation with, an appropriate medical specialist? medical appropriateness.

Author: Servid October 2020 16

Approval Criteria

7. Have other therapies been tried and failed? Yes: Approve for up to 3 months No: Approve for up to 3 months (or length of treatment) (or length of treatment) whichever is less whichever is less

Document therapies which have Document provider rationale for been previously tried use as a first-line therapy

Renewal Criteria

1. Is there documentation based on chart notes that the Yes: Go to #2 No: Go to #3 patient experienced a significant adverse reaction related to treatment?

2. Has the adverse event been reported to the FDA Adverse Yes: Go to #3 No: Pass to RPh. Event Reporting System? Deny; medical Document provider appropriateness attestation

3. Is baseline efficacy monitoring available? Yes: Go to #4 No: Go to #5

4. Is there objective documentation of improvement from Yes: Approve for up to 6 months No: Pass to RPh. Deny; baseline OR for chronic, progressive conditions, is there medical appropriateness documentation of disease stabilization or lack of decline Document benefit compared to the natural disease progression?

5. Is there documentation of benefit from the therapy as Yes: Approve for up to 6 months No: Pass to RPh. Deny; assessed by the prescribing provider (e.g., improvement in medical appropriateness symptoms or quality of life, or for progressive conditions, a Document benefit and provider lack of decline compared to the natural disease attestation progression)?

P&T/DUR Review: 8/20 (SS); 6/20; 2/20 Implementation: 9/1/20; 7/1/20

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Prior Authorization Criteria Update: Oncology

Purpose of the Update: This update identifies antineoplastic drugs recently approved by the FDA to add to the oncology policy (see Table 1).

Table 1. New oncology drugs

Brand Name Generic Name BLENREP belantamab mafodotin‐blmf TECARTUS brexucabtagene autoleucel INQOVI decetabine and cedazuridine MONJUVI tafasitamab‐cxix

Recommendation: • Modify PA to include new, recently approved antineoplastic drugs.

Author: Sarah Servid, PharmD October 2020 18

Appendix 1. Proposed Prior Authorization Criteria

Oncology Agents Goal(s): • To ensure appropriate use for oncology medications based on FDA-approved and compendia-recommended (i.e., National Comprehensive Cancer Network® [NCCN]) indications.

Length of Authorization: • Up to 1 year

Requires PA: • Initiation of therapy for drugs listed in Table 1 (applies to both pharmacy and physician administered claims). This does not apply to oncologic emergencies administered in an emergency department or during inpatient admission to a hospital.

Covered Alternatives: • Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org • Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Is the request for treatment of an oncologic emergency (e.g., Yes: Approve for length of No: Go to #3 superior vena cava syndrome [ICD-10 I87.1] or spinal cord therapy or 12 months, whichever compression [ICD-10 G95.20]) administered in the is less. emergency department?

3. Is the request for any continuation of therapy? Yes: Approve for length of No: Go to #4 therapy or 12 months, whichever is less.

4. Is the diagnosis funded by OHP? Yes: Go to #5 No: Pass to RPh. Deny; not funded by the OHP.

Author: Servid October 2020 19 Approval Criteria

5. Is the indication FDA-approved for the requested drug? Yes: Pass to RPh. Approve for No: Go to #6 length of therapy or 12 months, Note: This includes all information required in the FDA- whichever is less. approved indication, including but not limited to the following as applicable: diagnosis, stage of cancer, biomarkers, place in therapy, and use as monotherapy or combination therapy.

6. Is the indication recommended by National Comprehensive Yes: Pass to RPh. Approve for No: Go to #7 Cancer Network (NCCN) Guidelines® for the requested length of therapy or 12 months, drug? whichever is less.

Note: This includes all information required in the NCCN recommendation, including but not limited to the following as applicable: diagnosis, stage of cancer, biomarkers, place in therapy, and use as monotherapy or combination therapy.

7. Is there documentation based on chart notes that the patient Yes: Pass to RPh. Deny; medical No: Go to #8 is enrolled in a clinical trial to evaluate efficacy or safety of appropriateness. the requested drug? Note: The Oregon Health Authority is statutorily unable to cover experimental or investigational therapies.

8. Is the request for a rare cancer which is not addressed by Yes: Go to #9 No: Pass to RPh. Deny; medical National Comprehensive Cancer Network (NCCN) appropriateness. Guidelines® and which has no FDA approved treatment options?

Author: Servid October 2020 20 Approval Criteria

9. All other diagnoses must be evaluated for evidence of clinical benefit.

The prescriber must provide the following documentation: y medical literature or guidelines supporting use for the condition, y clinical chart notes documenting medical necessity, and y documented discussion with the patient about treatment goals, treatment prognosis and the side effects, and knowledge of the realistic expectations of treatment efficacy.

RPh may use clinical judgement to approve drug for length of treatment or deny request based on documentation provided by prescriber. If new evidence is provided by the prescriber, please forward request to Oregon DMAP for consideration and potential modification of current PA criteria.

Table 1. Oncology agents which apply to this policy (Updated 10/01/2020) New Antineoplastics are immediately subject to the policy and will be added to this table at the next P&T Meeting

Generic Name Brand Name abemaciclib VERZENIO abiraterone acet,submicronized YONSA abiraterone acetate ZYTIGA acalabrutinib CALQUENCE ado-trastuzumab emtansine KADCYLA afatinib dimaleate GILOTRIF alectinib HCl ALECENSA Alpelisib PIQRAY apalutamide ERLEADA asparaginase (Erwinia chrysan) ERWINAZE atezolizumab TECENTRIQ avapritinib AYVAKIT avelumab BAVENCIO axicabtagene ciloleucel YESCARTA axitinib INLYTA belinostat BELEODAQ bendamustine HCl BENDAMUSTINE HCL bendamustine HCl BENDEKA bendamustine HCl TREANDA binimetinib MEKTOVI belantamab mafodotin-blmf BLENREP

Author: Servid October 2020 21 blinatumomab BLINCYTO bosutinib BOSULIF brentuximab vedotin ADCETRIS brexucabtagene autoleucel TECARTUS brigatinib ALUNBRIG cabazitaxel JEVTANA cabozantinib s-malate CABOMETYX cabozantinib s-malate COMETRIQ Calaspargase pegol-mknl ASPARLAS Capmatinib TABRECTA carfilzomib KYPROLIS cemiplimab-rwlc LIBTAYO ceritinib ZYKADIA cobimetinib fumarate COTELLIC copanlisib di-HCl ALIQOPA crizotinib XALKORI dabrafenib mesylate TAFINLAR dacomitinib VIZIMPRO daratumumab DARZALEX Daratumumab/hyaluronidase-fihj DARZALEX FASPRO Darolutamide NUBEQA decitabine and cedazuridine INQOVI degarelix acetate FIRMAGON dinutuximab UNITUXIN durvalumab IMFINZI duvelisib COPIKTRA elotuzumab EMPLICITI enasidenib mesylate IDHIFA encorafenib BRAFTOVI Enfortumab vedotin-ejfv PADCEV Entrectinib ROZLYTREK enzalutamide XTANDI erdafitinib BALVERSA eribulin mesylate HALAVEN everolimus AFINITOR everolimus AFINITOR DISPERZ fam-trastuzumab deruxtecan-nxki ENHERTU fedratinib INREBIC gilteritinib XOSPATA glasdegib DAURISMO ibrutinib IMBRUVICA idelalisib ZYDELIG ingenol mebutate PICATO

Author: Servid October 2020 22 inotuzumab ozogamicin BESPONSA ipilimumab YERVOY Isatuximab SARCLISA ivosidenib TIBSOVO ixazomib citrate NINLARO larotrectinib VITRAKVI lenvatinib mesylate LENVIMA lorlatinib LORBRENA Lurbinectedin ZEPZELCA Lutetium Lu 177 dotate LUTATHERA midostaurin RYDAPT moxetumomab pasudotox-tdfk LUMOXITI necitumumab PORTRAZZA neratinib maleate NERLYNX niraparib tosylate ZEJULA nivolumab OPDIVO obinutuzumab GAZYVA ofatumumab ARZERRA olaparib LYNPARZA olaratumab LARTRUVO omacetaxine mepesuccinate SYNRIBO osimertinib mesylate TAGRISSO palbociclib IBRANCE panobinostat lactate FARYDAK pazopanib HCl VOTRIENT pembrolizumab KEYTRUDA pemigatinib PEMAZYRE pertuzumab PERJETA Pertuzumab/trastuzumab/haluronidase- zzxf PHESGO Pexidartinib TURALIO Polatuzumab vedotin-piiq POLIVY pomalidomide POMALYST ponatinib HCl ICLUSIG pralatrexate FOLOTYN ramucirumab CYRAMZA regorafenib STIVARGA ribociclib succinate KISQALI KISQALI FEMARA CO- ribociclib succinate/letrozole PACK Ripretinib QINLOCK romidepsin ISTODAX romidepsin ROMIDEPSIN rucaparib camsylate RUBRACA Author: Servid October 2020 23 ruxolitinib phosphate JAKAFI Sacitizumab govitecan-hziy TRODELVY Selinexor XPOVIO Selpercatinib RETEVMO siltuximab SYLVANT sipuleucel-T/lactated ringers PROVENGE sonidegib phosphate ODOMZO tafasitamab-cxix MONJUVI Tagraxofusp-erzs ELZONRIS talazoparib TALZENNA talimogene laherparepvec IMLYGIC Tazemetostat TAZVERIK tisagenlecleucel KYMRIAH trabectedin YONDELIS trametinib dimethyl sulfoxide MEKINIST trastuzumab-pkrb HERZUMA trastuzumab-anns KANJINTI trastuzumab-dkst OGIVRI trastuzumab-dttb ONTRUZANT trastuzumab-qyyp TRAZIMERA trastuzumab-hyaluronidase-oysk HERCEPTIN HYLECTA trifluridine/tipiracil HCl LONSURF Tucatinib TUKYSA vandetanib CAPRELSA vandetanib VANDETANIB vemurafenib ZELBORAF venetoclax VENCLEXTA VENCLEXTA STARTING venetoclax PACK vismodegib ERIVEDGE zanubrutinib BRUKINSA ziv-aflibercept ZALTRAP

P&T/DUR Review: 6/2020 (JP) Implementation: 10/1/2020

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-2596

Drug Use Evaluation: Bipolar Disorders

Research Questions: 1. How frequently are patients with bipolar disorder prescribed FDA-approved or guideline recommended medication regimens for bipolar disorder? 2. Which prescriber types and specialties are associated with prescription of pharmacotherapy for patients with bipolar disorder? 3. What comorbid mental health diagnosis are most common in Medicaid patients with bipolar disorder? 4. What is the average duration of therapy for patients with bipolar disorder? 5. What proportion of patients have claims for counseling services? 6. How often do patients with bipolar disorder have hospitalizations or emergency department visits for psychiatric illnesses? Does frequency of visits vary based on treatment experience, medication adherence, or with utilization of non-pharmacological therapy?

Conclusions: 1. Use of FDA-approved medication regimens for bipolar disorder: o About 73% of patients with bipolar disorder diagnosis based on ICD-10 diagnosis codes had a claim for a bipolar medication in the one-year timeframe reviewed (6/1/17 – 5/31/18). o About 54% of patients with a bipolar diagnosis were prescribed a second-generation antipsychotic. The most commonly prescribed antipsychotics were quetiapine (15%), aripiprazole (13%) and olanzapine (9%). o Mood stabilizers were prescribed in 45% of the population. Use of lamotrigine (28%) was significantly more common than lithium (10%) or valproic acid derivatives (8%). o Twenty percent of patients with bipolar disorder were prescribed combination treatment with 2 or more agents for at least 8 weeks. i. The most common combination treatment regimens were an antipsychotic and mood stabilizer; this combination is consistent with guideline recommendations for patients who continue to have symptoms with monotherapy alone. ii. Almost 3% of patients (n=422) were prescribed combination therapy with 3 or more bipolar medications which is not consistent with current Mental Health Clinical Advisory Group (MHCAG) algorithms for first- or second-line therapy for acute bipolar mania or depression. 2. Prescriber types: o In the 6 months following an initial prescription for bipolar medication, the majority of patients had both specialists and primary care providers involved in their care (Table 5). Prescriber type varied slightly depending on the class of medication. Psychiatric mental health nurse practitioners or psychiatrists were identified as writing prescriptions for about 60% of patients. General practitioners (primarily nurse practitioners, advanced practice nurses, family practitioners, and physician assistants) were involved in care for approximately 75% of patients. 3. Common comorbid mental health diagnosis: o Approximately 86% of the population had at least one other psychiatric diagnosis. The most common concurrent conditions were panic or anxiety disorders (66% of patients), major depressive disorder (56%), and post-traumatic stress or adjustment disorders (52%). 4. Duration of bipolar medication therapy:

25 o About 40% of patients were adherent to long-term maintenance therapy, which was defined as the proportion of days covered (PDC) of more than 75% within the 6 months following the first prescription claim for a bipolar disorder medication. About 40% of patients had a PDC of 26- 75% which may indicate intermittently prescribed therapy or poor adherence. o The PDC was 25% or less in 20% of patients within the 6 months following the first prescription claim for a bipolar disorder medication, which is likely indicative of short-term treatment (45 days). Specifically in new start patients, more patients (36%) had a PDC of less than 25%. 5. Use of counseling services: o About 63% of patients with bipolar disorder diagnosis had at least one non-pharmacological treatment claim in the one-year timeframe reviewed (6/1/17 – 5/31/18). o In the 6 months following prescription of a bipolar medication, most patients had claims for non-pharmacological treatment such as psychotherapy (44%), other counseling (24%), and family or skills training (8%). The duration of non-pharmacotherapy or frequency of visits was not evaluated. 6. Frequency of hospitalizations or emergency department (ED) visits: o Only 10% of patients prescribed a bipolar medication had a hospitalization from any cause in the 6 months following prescription of a bipolar medication (6.5% with a psychiatric diagnosis). o Forty percent of patients visited the ED (11% with a psychiatric diagnosis) over the same 6-month period. o There was no apparent difference in visit frequency between new start patients or all patients with bipolar disorder in the 6 months following prescription of a bipolar medication. o Patients with hospitalizations and ED visits had a higher utilization of non-pharmacological services compared to patients without medical visits. o Overall differences in hospitalization or ED visits due to psychiatric conditions were small (<5%) between patients with high versus low PDC. o A small proportion of patients had more than 3 psychiatric ED visits (n=333) or hospitalizations (n=85) over the first 6 months following the first prescription for a bipolar disorder medication. In this population, patients with a PDC greater than 75% was similar to the broader population.

Recommendations:  Recommend implementation of a targeted profile review of patients with bipolar disorder who have frequent hospitalizations or ED visits for psychiatric reasons to identify areas for optimization of medications. Notify prescribers if opportunities to improve care are identified.  Prioritize patients with 3 or more hospitalizations or ED visits over 6 months for psychiatric reasons and who 1) appear non- adherent to current therapy or 2) are prescribed regimens not recommended by the OHA and MHCAG. Non-recommended regimens may include patients with 3 or more bipolar medications, patients prescribed antidepressant monotherapy, or patients who use aripiprazole for bipolar depression.

Current Policy: Under the Oregon Health Plan (OHP), antipsychotic medications are primarily carved-out of CCOs and are paid for by FFS. Antipsychotic medications and mood stabilizers for mental health conditions are exempt from traditional preferred drug list (PDL) and prior authorization (PA) requirements. While OHP uses a voluntary PDL, non-preferred medications do not currently require PA. However, clinical PA criteria which address safety concerns or medically inappropriate use may be implemented. Currently, a safety edit is implemented for quetiapine to support medically appropriate use and discourage use for insomnia. Historical initiatives for mental health medications have focused on provider education surrounding monitoring recommendations, dose consolidation initiatives, and safety programs for patients who are non-adherent to antipsychotic therapy.

Background: Author: Servid October 2020 26 Bipolar disorder is characterized by episodes of mania and episodes of depression or hypomania and is estimated to occur in approximately 2% of the world population.1 Initial diagnosis usually occurs prior to 25 years of age.1 Diagnosis is based primarily on presence of symptoms and differential diagnosis can include a wide variety of other mental and physical health conditions. Other psychiatric disorders which may present with similar symptoms include attention deficit hyperactivity disorder (ADHD), personality disorders, cyclothymia, schizophrenia, schizoaffective disorders, and unipolar depression. Additionally, bipolar disorder is frequently associated with other comorbid mental health conditions including anxiety disorder, ADHD, and substance use disorders.1 Bipolar disorder is classified as bipolar I disorder (characterized by at least one manic episode) or bipolar II disorder (primarily characterized by history of depressive and hypomanic episodes).1 It can be further classified as rapid cycling with at least 4 episodes of mania, hypomania or depression per year, mania with mixed features, or mania with psychotic features (including hallucinations or delusions).1

First-line treatment for bipolar disorder is medication therapy; preferred drug choices include antipsychotics (primarily second-generation antipsychotics or haloperidol) or mood stabilizers such as lithium, divalproex, or lamotrigine.2,3 Goals of treatment include resolution of acute symptoms and long-term prevention of recurrent mania or depressive episodes. If acute symptoms do not resolve with initial treatment, the patient may be switched to an alternative medication or an additional medication is added.2,3 Non-pharmacologic treatments include electroconvulsive therapy (ECT), psychoeducational therapy, cognitive behavioral therapy and social therapy.2,3 Recent guidelines from the National Institute for Health and Clinical Excellence (NICE) recommend ECT as an option for patients with life-threatening suicidality, psychosis or refusal to eat.1,2 ECT may also be considered with severe or treatment-resistant bipolar depression and as a first- line option for pregnant women with severe depression.

Recent resources from the Oregon Mental Health Clinical Advisory Group (MHCAG) provide treatment algorithms for acute bipolar depression and mania.4,5 Current medication algorithms focus on therapy for the current symptoms (acute mania or depression) and do not differentiate between patients with bipolar type I or II disorder. For patients with bipolar disorder, medication treatment is always recommended in combination with psychosocial treatment based on patient preference, interest and service availability. For treatment of acute bipolar depression, first-line medications include lamotrigine, lithium, or quetiapine.4 Aripiprazole or antidepressant monotherapy should be avoided for acute bipolar depression due to evidence of ineffectiveness.4 For continued symptoms, second-line medication therapy includes the following:4  Switching to a different first-line agent as monotherapy  Switching to cariprazine, divalproex, or lurasidone as monotherapy  Combination therapy with any of the following: o lamotrigine and another bipolar medication o lurasidone plus lithium or divalproex o olanzapine and fluoxetine o SSRI or bupropion plus another bipolar medication

Lithium and quetiapine are recommended as first-line medication options by MHCAG for treatment of acute bipolar mania.5 Anxiety or insomnia may be managed with short-term use of lorazepam as needed, and agitation may be improved by use of olanzapine as needed.5 If symptoms continue despite monotherapy treatment, combination treatment with quetiapine and either lithium or divalproex is recommended.5 If symptoms persist despite combination treatment, monotherapy with a different second-generation antipsychotic may be considered based on patient-specific factors and adverse effects. Recommended second-generation antipsychotics include aripiprazole, asenapine, cariprazine, risperidone, or ziprasidone. Recommendations are made to avoid use of lamotrigine in patients with acute mania.5

Methods:

Author: Servid October 2020 27 This analysis included 2 distinct populations of patients. The first population included any patient with a diagnosis of bipolar disorder based on ICD-10 codes. This population provides estimates of patients prescribed medication and frequency of medical visits. However, because over 85% of the population have at least one comorbid psychiatric indication which may present with similar symptoms, it is difficult to estimate the accuracy of this diagnostic data. Therefore, in order to more accurately identify patients who may actually have a diagnosis of bipolar disorder, the primary analysis focused on patients with a paid claim for a bipolar medication AND an ICD-10 code associated with bipolar disorder. Specific methods for each population are described below.

Bipolar Population based on Diagnosis Patients with an ICD-10 code indicating a bipolar disorder diagnosis between 6/1/2017 to 5/31/2018 were identified. Patients were excluded if they had Medicare part D coverage or had 75% or less Medicaid eligibility for the reporting period. Patients were stratified by presence or absence of a paid claim for a bipolar medication in that timeframe as described above in methods section. Hospitalizations, emergency department (ED) visits, and visits for non- pharmacological services were documented for the same timeframe in patients with at least one paid prescription for bipolar medication compared to patients without a paid claim for a bipolar medication. This data describes estimated frequency and rates for patients with a bipolar disorder diagnosis. However, temporal relationships between diagnosis, medication use, and medical visits cannot be determined from this data.

Patients with Bipolar Diagnosis and Medication Therapy The primary analysis included current Medicaid patients (enrolled in fee-for-service [FFS] and coordinated care organizations [CCOs]) with an index event from 6/1/2017 to 5/31/2018. The index event was defined as the first paid FFS pharmacy claim for medications recommended for maintenance treatment of bipolar disorder such as lithium, valproic acid (or its derivatives), lamotrigine, second-generation antipsychotics, or other bipolar medications (see Appendix 2 Table A2). Patients were included if they had medical claims with a diagnosis of bipolar disorder identified based on ICD-10 diagnosis codes in the 1.5 years before or 6 months after the index event (see Table A1). Type of bipolar disorder was classified according to the medical claim temporally closest to the index event. Comorbid mental health conditions were also evaluated using ICD-10 diagnosis codes in the 1.5 years before or 6 months after the index event. Categories of comorbid medical conditions are shown in Table A1. Data in the most recent 6 months may not capture all patients with a diagnosis of bipolar disorder as medical claims may be incomplete. Patients were excluded if they had Medicare part D coverage or had 75% or less Medicaid eligibility in the year prior to the index event in order to ensure complete medical records for diagnoses.

New start patients were defined as patients without any claims for bipolar medications in the year prior year to the index event. In some cases, patients may have a remote history of antipsychotic use. In new start patients, a remote history of bipolar medication use was defined as patients with paid claims for bipolar therapy at greater than 12 months before the index event. These data may be incomplete as many patients may not have a history of Medicaid eligibility. In addition, these patients may have been prescribed medications for conditions other than bipolar disorder.

The number of patients prescribed 2 or more concomitant bipolar medications was evaluated in the 6 months following the index event. There is little evidence to support long-term use of multiple drugs in the same drug class (e.g., 2 antipsychotics), but combination use of a mood stabilizer and an antipsychotic is recommended for patients not controlled on a single agent. Utilization of concomitant bipolar therapy was defined as paid claims for at least 2 distinct drugs (based on HSN) with a duration of 8 weeks or longer of continuous treatment, 8 weeks or longer of overlapping therapy, and no more than one week gap in concomitant therapy. Utilization of other medications for mental health conditions were also examined using the same parameters. Other mental health medications were categorized according to criteria in Table A3.

Adherence to bipolar medications was evaluated using the PDC and duration of continuous therapy. PDC was calculated based on days covered as a proportion of outpatient eligible days (which excludes any days in which the patient was hospitalized). Continuous therapy was defined as the time after the index event to

Author: Servid October 2020 28 the first 3-week gap in coverage for any bipolar medication. As defined here, short-term therapy over a period of 6 months would correspond to a PDC of up to 25% (≤45 days), intermittent therapy corresponds to PDC of 25-75%, and long-term therapy corresponds to a PDC of 75% or more (>135 days).

The most common providers who prescribe bipolar drug therapy to patients with bipolar disorder were evaluated. Prescriptions for bipolar therapy were evaluated in the 6 months following the index event and were stratified according to the primary provider specialty. If a patient was prescribed more than one therapy or prescribed therapy from more than one provider, they may be listed more than once.

Patients were also evaluated for medical claims for non-pharmacological counseling services, hospitalizations and ED visits in the 6 months following the index event. Codes used to identify non-pharmacological counseling services are shown in Table A4. In addition, the total number of ED visits and hospitalizations as well as visits specifically associated with a psychiatric illness (ICD 10 codes F01.5-F99) were identified for several subgroups of patients, including new start patients, patients with non-pharmacological services, and patients with PDC less than or equal to 25% or greater than 75%.

Results: Bipolar Population based on Diagnosis In total, 18,707 patients were identified with an ICD-10 diagnosis of bipolar disorder. Most of the identified patients (73.7%) had at least one paid claim for a bipolar medication in the same period and about 86% of patients had at least one other psychiatric diagnosis. The proportion of patients with a hospitalization or ED visit was similar in patients with and without bipolar disorder medication. Visits for non-pharmacological counseling services, as well as hospitalizations or ED visits due to psychiatric diagnoses were slightly lower in patients without bipolar medication. Because populations are not matched based on baseline characteristics, these data should be interpreted with caution. Differences may be explained by variation in disease severity, comorbidities, or diagnostic accuracy between groups. On average patients without a paid claim for a bipolar medication had fewer medical visits associated with that diagnosis (mean visits per year of 5.0; median of 2) compared to patients prescribed medication (mean visits per year of 9.7; median of 4).

Table 1. Incidence of hospitalizations, ED visits, non-pharmacological services and other psychiatric diagnoses in patients with a bipolar disorder diagnosis. Patients with a paid claim Patients without a paid claim for bipolar medication for bipolar medication 13,783 4,924

Hospitalization 2,574 18.7% 856 17.4% ED visit 8,263 60.0% 3,142 63.8% Hospitalization due to psychiatric diagnosis 1,853 13.4% 490 10.0% ED visit due to psychiatric diagnosis 2,792 20.3% 694 14.1% Patients with any non-pharmacological counseling services 9,207 66.8% 2,573 52.3% Patients with at least one other psychiatric diagnosis 11,926 86.5% 4,145 84.2%

Author: Servid October 2020 29 Bipolar Medication Trends Over the last several years there has been a slight increase in utilization of medications indicated for bipolar disorder. Figure 1 describes trends in utilization for second-generation antipsychotics and mood stabilizers (lithium, lamotrigine, or valproic acid) in the Medicaid population from 2015 through 2018. Second- generation antipsychotics are prescribed more commonly than mood stabilizers in the Medicaid population. Utilization is not specific to patients with bipolar disorder diagnoses and likely includes medications prescribed for conditions other than bipolar disorder (e.g., schizophrenia or seizure disorders).

Figure 1. Trend of drug utilization (per member per month [PMPM]) based on unique patient count for members over the last 3 years.

Unique Patients PMPM with FFS Bipolar Medication Claims (x100)

Total 15 Antipsychotics Mood Stabilizers

10 Patients PMPM (x100) PMPMPatients

0 Jul-15 Jul-16 Jul-17 Jul-18 Jan-15 Jan-16 Jan-17 Jan-18 Mar-15 Mar-16 Mar-17 Mar-18 Sep-15 Nov-15 Sep-16 Nov-16 Sep-17 Nov-17 Sep-18 Nov-18 May-15 May-16 May-17 May-18

Author: Servid October 2020 30 Patients with Bipolar Diagnosis and Medication Therapy Most patients prescribed bipolar disorder medications were white, female adult patients. Approximately 29% of patients had a diagnosis of bipolar I with a current episode, 23% of patients were classified as having other bipolar disorders (including bipolar II disorder), and 43% of patients had an unspecified bipolar diagnosis. In almost 90% of patients, the time from the first diagnosis in medical claims to initial pharmacological treatment was less than 6 months.

Table 2. Baseline demographics for patients with bipolar disorders N= 14,763 % Age Average (min - max) 38.2 (4-74) <13 168 1.1% 13-18 826 5.6% 19-59 13,102 88.7% >=60 667 4.5%

Female 9,552 64.7%

Race White 8,990 60.9% Hispanic 172 1.2% African American 313 2.1% Native American 821 5.6% Other/Unknown 4,467 30.2%

Average time between first diagnosis and index event >=1 year 609 4.1% >=6 months 995 6.7% <6 months 13,159 89.1%

Type of Bipolar Bipolar, current episode (F310x-F316x) 4,323 29.3% Bipolar, in remission (F317x) 745 5.0% Bipolar, other (F318x) 3,385 22.9% Bipolar, unspecified (F319x) 6,310 42.7%

Author: Servid October 2020 31 Table 3 describes utilization of medications for bipolar disorder based on the first claim in the reporting period. Overall, more than 14,700 patients met inclusion criteria for the analysis and 22% of patients were classified as new start patients with no utilization of bipolar disorder medications in the year prior to the index event. In new start patients, 37% had a remote history of bipolar disorder medication use with paid claims for bipolar therapy longer than 12 months before the index event. Approximately 54% of patients with a bipolar disorder diagnosis were prescribed a second-generation antipsychotic. The most commonly prescribed antipsychotics were quetiapine (15%), aripiprazole (13%) and olanzapine (9%). Mood stabilizers were prescribed in 45% of the entire population; use of lamotrigine (28%) was more common than use of lithium (10%) or valproic acid derivatives (8%). These trends were also consistent in new start patients.

Table 3. Utilization of bipolar disorder medications for all patients with bipolar disorders based on the Index Event. All Bipolar Patients Index Drug 14,763 %

Mood Stabilizers 6,703 45.4% Lithium* 1,414 9.6% Divalproex or valproic acid* 1,170 7.9% Lamotrigine* 4,119 27.9%

2nd generation oral antipsychotics (or LAIs when specified) 7,984 54.1% Aripiprazole (oral or injectable)* 1,951 13.2% Asenapine* 137 0.9% Brexpiprazole 82 0.6% Clozapine 49 0.3% Cariprazine* 75 0.5% Iloperidone 0.0% Lurasidone* 874 5.9% Olanzapine* or Olanzapine/fluoxetine* 1,340 9.1% Paliperidone 128 0.9% Pimavanserin 0.0% Quetiapine* 2,245 15.2% <= 50 mg 633 4.3% Risperidone (oral or injectable)* 762 5.2% Ziprasidone* 341 2.3%

Other bipolar medications 76 0.5% Carbamazepine* 31 0.2% Chlorpromazine (oral or injectable) * 45 0.3%

*Medications which are FDA-approved as monotherapy or adjunct therapy for bipolar disorder Of the 14,763 bipolar patients who are prescribed bipolar disorder medications, 2,925 (20%) were prescribed combination bipolar disorder therapy for at least 8 weeks (Table 4). Most patients with combination therapy (86%) were prescribed only 2 bipolar disorder drugs at any given time. The most commonly prescribed

Author: Servid October 2020 32 medications were a mood stabilizer and an antipsychotic. See Table 4 for a list of the most commonly prescribed drugs used in combination. In 44% of patients, the duration of combined therapy was short-term (8-12 weeks) before the patient had a break in therapy of at least one week. In most cases, duration of combination therapy was long-term and 27% of patients were prescribed combination therapy for the entire 6-month evaluation period indicating good adherence with guideline recommendations for maintenance therapy.

Table 4. Concomitant therapy in patients with ≥2 bipolar disorder medications (duration of overlap ≥ 8 weeks) in the 6 months after the Index Event. All Bipolar Patients New Start Patients N= 2,925 % 218 % Duration of overlap 8-12 weeks 1,295 44.3% 128 58.7% 13-24 weeks 1,318 45.1% 91 41.7% >24 weeks 800 27.4% 11 5.0%

Number of drugs 2 2,503 85.6% 210 96.3% 3 379 13.0% 8 3.7% 4 41 1.4% 0.0% 5 2 0.1% 0.0%

Concomitant Medications ≥2 antipsychotics 568 19.4% 30 13.8% At least 1 antipsychotic and 1 mood stabilizer 2,430 83.1% 180 82.6% ≥2 mood stabilizers 369 12.6% 14 6.4% Other 50 1.7% 1 0.5%

Top 20 commonly prescribed concomitant bipolar medications 1 Lamotrigine Quetiapine 428 14.6% 27 12.4% 2 Lamotrigine Aripiprazole 336 11.5% 33 15.1% 3 Lithium Lamotrigine 241 8.2% 10 4.6% 4 Lithium Quetiapine 220 7.5% 11 5.0% 5 Lamotrigine Lurasidone 218 7.5% 13 6.0% 6 Divalproex or valproic acid Quetiapine 193 6.6% 12 5.5% 7 Lamotrigine Olanzapine 171 5.8% 20 9.2% 8 Lamotrigine Risperidone 168 5.7% 9 4.1% 9 Divalproex or valproic acid Olanzapine 149 5.1% 9 4.1% 10 Lithium Olanzapine 128 4.4% 19 8.7% 11 Lithium Aripiprazole 119 4.1% 5 2.3% 12 Divalproex or valproic acid Risperidone 106 3.6% 4 1.8% 13 Divalproex or valproic acid Aripiprazole 106 3.6% 6 2.8% 14 Quetiapine Aripiprazole 94 3.2% 4 1.8% 15 Lamotrigine Ziprasidone 89 3.0% 2 0.9% 16 Lithium Lurasidone 79 2.7% 5 2.3% Author: Servid October 2020 33 17 Lithium Risperidone 77 2.6% 8 3.7% 18 Divalproex or valproic acid Lamotrigine 72 2.5% 0 0.0% 19 Lithium Divalproex or valproic acid 70 2.4% 4 1.8% 20 Quetiapine Lurasidone 64 2.2% 6 2.8%

The most common prescribers of bipolar disorder medications included psychiatric mental health nurse practitioners and psychiatrists. These mental health specialists were involved in care for about 60% of all patients with bipolar disorder in the 6 months following an initial prescription (Table 5). There was little variance between provider specialty and the type of bipolar disorder medication prescribed. Nurse practitioners, advanced practice nurses and family practitioners also commonly prescribe medications in patients with bipolar disorder.

Table 5. The 10 most common prescriber types for bipolar disorder medications assessed 6 months after the Index Event. Patients prescribed medication from multiple providers will be counted more than once. Divalproex or 2nd generation Other Bipolar Lithium Valproic Acid Lamotrigine antipsychotic Therapy All Bipolar Patients 2,309 1,871 5,711 10,294 169 1 Psychiatric Mental Health Nurse Practitioner 662 28.7% 488 26.1% 1,679 29.4% 3,643 35.4% 49 29.0% 2 Psychiatrist 752 32.6% 533 28.5% 1,337 23.4% 3,009 29.2% 67 39.6% 3 Nurse Practitioner (default Spec) 431 18.7% 318 17.0% 1,088 19.1% 2,134 20.7% 21 12.4% 4 Advance Practice Nurse 351 15.2% 257 13.7% 844 14.8% 1,779 17.3% 25 14.8% 5 Family Practitioner 381 16.5% 373 19.9% 1,072 18.8% 1,735 16.9% 23 13.6% 6 Family Nurse Practitioner 259 11.2% 242 12.9% 731 12.8% 1,346 13.1% 11 6.5% 7 Physician Assistants 208 9.0% 190 10.2% 552 9.7% 965 9.4% 18 10.7% 8 Internist 126 5.5% 155 8.3% 344 6.0% 711 6.9% 6 3.6% 9 Physician (Default Spec) 68 2.9% 65 3.5% 126 2.2% 310 3.0% 21 12.4% 10 Neurologist 33 1.4% 67 3.6% 146 2.6% 148 1.4% 5 3.0%

Adherence to bipolar therapy was evaluated using PDC and the time to the first 3-week gap in coverage (Table 6). About 40% of patients were adherent to long- term therapy with a PDC more than 75% in the 6 months following the index event. In 20% of patients, PDC was less than 25% (≤45 days) indicating only short- term treatment or poor adherence therapy. Forty percent of patients had PDC of 26-75% which may indicate intermittent use of long-term maintenance therapy or multiple short-term treatments. In new start patients, a larger proportion received short-term or intermittent therapy. Similar trends were observed when evaluating adherence based on the time to the first 3-week gap in coverage.

Author: Servid October 2020 34 Table 6. Adherence to any bipolar disorder therapy in the 6 months following the Index Event. All Bipolar Patients New Start Patients N= 14,763 % 3,322 %

Proportion of Days Covered <=25% 2,963 20.1% 1,204 36.2% 26-75% 5,912 40.0% 1,371 41.3% >75% 5,888 39.9% 747 22.5%

Duration of continuous therapy (time to first 3 week gap in coverage) <= 30 days 3,284 22.2% 1,163 35.0% 31-90 days 2,382 16.1% 742 22.3% 91-150 days 1,684 11.4% 440 13.2% >= 151 days 7,413 50.2% 977 29.4%

A significant proportion of patients with a bipolar disorder had other comorbid medical conditions. Table 7 describes comorbid mental health conditions in patients with a diagnosis of bipolar disorder. The most common concurrent conditions were panic or anxiety disorders (66% of patients), major depressive disorder (56%), and post-traumatic stress or adjustment disorders (52%). Substance use disorders (for stimulants, cannabis, alcohol or opioids) were documented in 15% to 26% of the population. Patients with a diagnosis of bipolar disorder in remission (ICD-10 F317x) were less likely to have other comorbid mental health diagnoses.

Table 7. Concomitant diagnosis for common mental health conditions. If patients have multiple diagnoses, they will be counted more than once. Bipolar Diagnosis All bipolar N= 14,763 % Panic or Anxiety 9,812 66.5% Major Depressive Disorder 8,250 55.9% Post-traumatic Stress or Adjustment Disorders 7,650 51.8% Stimulant Abuse 3,828 25.9% Cannabis Abuse 3,532 23.9% Alcohol Abuse 3,393 23.0% Other Mood Disorders 2,731 18.5% Attention Deficit Hyperactivity Disorder 2,659 18.0% Opioid Abuse 2,173 14.7% Single Manic Episode 572 3.9% Developmental Disorder 534 3.6%

Utilization of concurrent therapy with other drugs for mental health conditions in the 6 months following the index event was limited (Table 8). About 37% of patients with a bipolar disorder diagnosis were prescribed an antidepressant in addition to bipolar disorder medication. A small proportion of patients were Author: Servid October 2020 35 prescribed stimulants or ADHD medications (6%), long-acting injectable antipsychotics (8%) or benzodiazepines (9%). Similar trends were observed in new start patients: only 24% of new start patients were prescribed a concurrent antidepressant medication.

Table 8. Concomitant medications for mental health conditions were evaluated in the 6 months after the Index Event. Concomitant therapy was defined as a duration of overlap ≥ 8 weeks with the bipolar medications specified above. Evaluation of concomitant therapy included both CCO and FFS claims.

All Bipolar Patients Other concomitant mental health medications 14,763 %

ADHD Drugs and Other Stimulants 894 6.1% Antidepressants 5,491 37.2% Antipsychotics, 1st generation 240 1.6% Antipsychotics, parenteral (all) 1,217 8.2% Benzodiazepines 1,278 8.7%

More than half of patients had claims for non-pharmacological treatment such as psychotherapy, other counseling, and family or skills training in the 6 months following the index event (Table 9). Rates of non-pharmacological services were slightly higher in new start patients but were consistent with the overall population.

Table 9. Proportion of patients with claims for non-pharmacological services in the 6 months following the Index Event.

All Bipolar Patients New Start Patients N= 14,763 % 3,322 %

Counseling or Other Therapy 3,611 24.5% 887 26.7% Education 103 0.7% 23 0.7% Family or Skills Training 1,151 7.8% 228 6.9% Psychotherapy 6,553 44.4% 1,681 50.6%

Author: Servid October 2020 36 The rate of hospitalizations and ED visits for patients with bipolar disorder are listed in Table 10. Only 10% of patients prescribed a bipolar disorder medication had a hospitalization in the 6 months following the index event. In about 6.5% of these patients, admission was associated with a psychiatric diagnosis. Only a small proportion of patients had multiple hospitalizations. Forty percent of patients visited the ED over the 6-month period, but ED visits due to a psychiatric condition were less frequent (11%). In 333 patients, visits to the ED for psychiatric conditions occurred more than 3 times over the 6-month period. Similar trends were observed in a subgroup of new start patients (data not shown). The most common primary psychiatric diagnoses for patients with more than 3 ED visits were bipolar disorder (10%), major depressive disorder (10%), anxiety disorders (9%), and alcohol related disorders (9%).

Table 10. Number of hospitalizations or ED visits in the 6 months following the Index Event

All Bipolar Patients N= 14,763 %

Hospitalizations All hospitalizations 1,398 9.5% 0 13,365 90.5% 1-2 1,245 8.4% 3-4 124 0.8% ≥5 29 0.2%

Hospitalizations associated with psychiatric diagnosis 954 6.5% 0 13,809 93.5% 1-2 869 5.9% 3-4 73 0.5% ≥5 12 0.1%

Emergency Department Visits All ED visits 5,985 40.5% 0 8,778 59.5% 1-2 4,035 27.3% 3-4 1,099 7.4% ≥5 851 5.8%

ED visits associated with psychiatric diagnosis 1,636 11.1% 0 13,127 88.9% 1-2 1,303 8.8% 3-4 199 1.3% ≥5 134 0.9%

Author: Servid October 2020 37 To identify potential reasons for psychiatric hospitalization admissions and ED visits, patients were evaluated based on treatment characteristics (use of non- pharmacological services and PDC; Table 11). Patients with hospitalizations and ED visits for psychiatric reasons had a higher utilization of non-pharmacological services compared to patients without medical visits. Overall differences in hospitalization or ED visits due to psychiatric conditions were small (<5%) between patients with high versus low PDC.

Table 11. Treatment characteristics of patients with psychiatric hospital admissions or ED visits in the 6 months following the Index Event. Hospitalization Emergency Department Visits Psychiatric Hospitalization No hospitalization Psychiatric ED Visit No ED visit

N= 954 13,809 1,636 13,127

Patients with Non-Pharmacological Services 700 73.4% 7,612 55.1% 1,191 72.8% 7,121 54.2% Patients with PDC >75% 411 43.1% 5,477 39.7% 584 35.7% 5,304 40.4% Patients with PDC <=25% 178 18.7% 2,785 20.2% 387 23.7% 2,576 19.6%

Limitations: Data presented in this report is based on Medicaid claims history and has several inherent limitations.  Diagnostic accuracy: Diagnoses based on claims history may not be accurate and patients without a recent medical claim for bipolar disorder would be excluded from the analysis. In addition, because many patients have other co-occurring mental health conditions such as depression, the diagnostic accuracy of ICD-10 codes based on claims data is unclear. ICD-10 codes classify bipolar disorder according to current symptoms (manic, hypomanic, depressed, or mixed episodes) making it difficult to determine differences between patients with bipolar type I and II disorder.  Provider specialty: Information on provider specialty may be inaccurate, out-of-date, or incomplete for some providers. Prescribers with multiple specialties or designations may not be identified.  Proportion of days covered: Use of proportion of days covered attempts to estimate the frequency which a patient takes a prescription, but accuracy of this method has not been validated and patients may not always be categorized appropriately. The current data does not describe the intended duration of treatment. Therapy may be intended as long-term maintenance treatment or it may be prescribed as short-term treatment during a manic episode.  Medical claims for non-pharmacological services: Due to delays in submission of medical claims and billing mechanisms for non-pharmacological therapies, the frequency of patient visits for psychotherapy or counseling is difficult to evaluate. Often billing for medical visits is significantly delayed and claims data may not accurately capture all visits. For patients enrolled in a CCO, non-pharmacological treatments, hospitalizations, and emergency department visits are paid for by the patients CCO while medication therapy for the member is paid by FFS.  Unidentified patient populations: Because patients with bipolar disorder were identified based on paid claims for a bipolar medication (Table A2), it is unclear what proportion of bipolar patients may be prescribed antidepressant monotherapy. Fifty-six percent of identified patients had a recent diagnosis of comorbid unipolar depression, and it is unclear which diagnosis (unipolar or bipolar depression) may be most accurate.

References: Author: Servid October 2020 38 1. Bipolar Disorder. In: Dynamed [internet database]. Ipswich, MA: EBSCO Publishing. Updated December 4, 2018. Accessed June 17, 2019. 2. National Institute for Health and Care Excellence. Bipolar Disorder: assessment and management. Published 24 September 2014. Updated April 2018. Available at: www.nice.org.uk/guidance/cg185. 3. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. 4. Acute Bipolar Depression Algorithm. Pharmacy and Therapeutics - Mental Health Clinical Advisory Group. Updated December 2019. Accessed February 14, 2020. Available at https://apps.state.or.us/Forms/Served/le7549i.pdf. 5. Acute Bipolar Mania Algorithm. Pharmacy and Therapeutics - Mental Health Clinical Advisory Group. Updated December 2019. Accessed February 14, 2020. Available at https://apps.state.or.us/Forms/Served/le7549j.pdf.

Author: Servid October 2020 39 Appendix 1: Clinical Safety Edits Low Dose Quetiapine

Goal(s):  To promote and ensure use of quetiapine that is supported by the medical literature.  To discourage off-label use for insomnia.  Promote the use of non-pharmacologic alternatives for chronic insomnia.

Initiative:  Low dose quetiapine (Seroquel® and Seroquel XR®)

Length of Authorization:  Up to 12 months (criteria-specific)

Requires PA:  Quetiapine (HSN = 14015) doses <50 mg/day  Auto PA approvals for : o Patients with a claim for a second generation antipsychotic in the last 6 months o Patients with prior claims evidence of schizophrenia or bipolar disorder o Prescriptions identified as being written by a mental health provider

Covered Alternatives:  Preferred alternatives listed at www.orpdl.org/drugs/  Zolpidem is available for short-term use (15 doses/30 days) without PA.

Table 1. Adult (age ≥18 years) FDA-approved Indications for Quetiapine Bipolar Disorder F3010; F302; F3160-F3164; F3177- 3178; F319 Major Depressive F314-315; F322-323; F329; F332-333; Adjunctive therapy with Disorder F339 antidepressants for Major Depressive Disorder Schizophrenia F205; F209; F2081; F2089 Bipolar Mania F3010; F339; F3110-F3113; F312 Bipolar Depression F3130

Table 2. Pediatric FDA-approved indications

Author: Servid October 2020 40 Schizophrenia Adolescents (13-17 years) Bipolar Mania Children and Adolescents Monotherapy (10 to 17 years)

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code. Do not proceed and deny if diagnosis is not listed in Table 1 or Table 2 above (medical appropriateness)

2. Is the prescription for quetiapine less than or equal to 50 Yes: Go to #3 No: Trouble-shoot claim mg/day? (verify days’ supply is accurate) processing with the pharmacy.

3. Is planned duration of therapy longer than 90 days? Yes: Go to #4 No: Approve for titration up to maintenance dose (60 days).

4. Is reason for dose <50 mg/day due to any of the following: Yes: Approve for up to 12 No: Pass to RPh. Deny for  low dose needed due to debilitation from a medical months medical appropriateness. condition or age;  unable to tolerate higher doses; Note: may approve up to 6  stable on current dose; or months to allow taper.  impaired drug clearance?  any diagnosis in table 1 or 2 above?

P&T/DUR Review: 3/19 (DM); 9/18; 11/17; 9/15; 9/10; 5/10 Implementation: 1/1/18; 10/15; 1/1/11

Appendix 2: Coding information

Table A1. ICD-10 Codes for medical conditions ICD10 ICD-10 Description Category F310x Bipolar disorder, current episode hypomanic Bipolar Disorder F311x Bipolar disorder, current episode manic without psychotic features Bipolar Disorder F312x Bipolar disorder, current episode manic severe with psychotic features Bipolar Disorder F313x Bipolar disorder, current episode depressed, mild or moderate severity Bipolar Disorder F314x Bipolar disorder, current episode depressed, severe, without psychotic features Bipolar Disorder F315x Bipolar disorder, current episode depressed, severe, with psychotic features Bipolar Disorder

Author: Servid October 2020 41 F316x Bipolar disorder, current episode mixed Bipolar Disorder F317x Bipolar disorder, currently in remission Bipolar Disorder F318x Other bipolar disorders (including bipolar II disorder) Bipolar Disorder F319x Bipolar disorder, unspecified Bipolar Disorder F30xx Manic episode Single Maniac Episode F32xx Major depressive disorder, single episode MDD F33xx Major depressive disorder, recurrent MDD F34xx Persistent mood [affective] disorders Other mood disorders F39xx Unspecified mood [affective] disorder Other mood disorders F10xxx Alcohol related disorders Alcohol abuse or dependence F11xxx Opioid related disorders Opioid abuse or dependence F12xxx Cannabis related disorders Cannabis abuse or dependence F14xxx- Cocaine related disorders Stimulant abuse or dependence F15xxx Other stimulant related disorders Stimulant abuse or dependence F19xxx Other psychoactive substance related disorders Stimulant abuse or dependence F32xxx Major depressive disorder, single episode MDD F33xxx Major depressive disorder, recurrent MDD F41xxx Other anxiety disorders Panic or anxiety disorder F40xxx Phobic anxiety disorders Panic or anxiety disorder F43xxx Reaction to severe stress, and adjustment disorders PTSD or adjustment disorders F34xxx Persistent mood [affective] disorders Other mood disorders F84xxx Pervasive developmental disorders Developmental disorders F90xxx Attention-deficit hyperactivity disorders ADHD Z590 Homelessness Housing and Economic Circumstances Z591 Inadequate housing Housing and Economic Circumstances Z598 Other problems related to housing and economic circumstances Housing and Economic Circumstances Z599 Problem related to housing and economic circumstances, unspecified Housing and Economic Circumstances Z595 Extreme Poverty Housing and Economic Circumstances

Table A2. Bipolar Drug Codes PDL Class HSN Generic Carve Out Antipsychotics, 2nd Gen 004834 clozapine Y Antipsychotics, 2nd Gen 008721 risperidone Y Antipsychotics, 2nd Gen 011814 olanzapine Y Antipsychotics, 2nd Gen 014015 quetiapine fumarate Y Antipsychotics, 2nd Gen 021974 ziprasidone HCl Y Antipsychotics, 2nd Gen 034343 paliperidone Y Antipsychotics, 2nd Gen 036576 asenapine maleate Y Antipsychotics, 2nd Gen 037321 lurasidone HCl Y Antipsychotics, 2nd Gen 024551 aripiprazole Y Antipsychotics, 2nd Gen 042283 brexpiprazole Y Author: Servid October 2020 42 Antipsychotics, 2nd Gen 042552 cariprazine HCl Y Antipsychotics, 2nd Gen 043373 pimavanserin tartrate Y Mood stabilizers 001669 lithium carbonate Y Mood stabilizers 001670 lithium citrate Y Mood stabilizers 001882 valproic acid (as sodium salt) Y Mood stabilizers 001883 valproic acid Y Mood stabilizers 001884 divalproex sodium Y Mood stabilizers 007378 lamotrigine Y Other Bipolar Medications 001893 carbamazepine Y and N Other Bipolar Medications 001621 chlorpromazine Y Other Bipolar Medications 025800 olanzapine/fluoxetine Y Antipsychotics, Parenteral 024551 aripiprazole Y Antipsychotics, Parenteral 008721 risperidone Y Antipsychotics, Parenteral 001621 chlorpromazine HCl Y

Table A3. Other mental health drug therapy PDL Class HSN Generic Carve Out Antidepressants 001643 amitriptyline HCl Y Antidepressants 001648 amoxapine Y Antidepressants 036156 bupropion HBr Y Antidepressants 001653 bupropion HCl Y Antidepressants 010321 citalopram hydrobromide Y Antidepressants 004744 clomipramine HCl Y Antidepressants 001645 desipramine HCl Y Antidepressants 040202 desvenlafaxine Y Antidepressants 040692 desvenlafaxine fumarate Y Antidepressants 035420 desvenlafaxine succinate Y Antidepressants 001650 doxepin HCl Y Antidepressants 026521 duloxetine HCl Y Antidepressants 024022 escitalopram oxalate Y Antidepressants 001655 fluoxetine HCl Y Antidepressants 006338 fluvoxamine maleate Y Antidepressants 001641 imipramine HCl Y Antidepressants 001642 imipramine pamoate Y Antidepressants 001638 isocarboxazid Y Antidepressants 040632 levomilnacipran HCl Y Antidepressants 001651 maprotiline HCl Y Antidepressants 011505 mirtazapine Y Antidepressants 009612 nefazodone HCl Y Antidepressants 001644 nortriptyline HCl Y Antidepressants 025800 olanzapine/fluoxetine HCl Y Author: Servid October 2020 43 Antidepressants 007344 paroxetine HCl Y Antidepressants 025796 paroxetine mesylate Y Antidepressants 001639 phenelzine sulfate Y Antidepressants 001646 protriptyline HCl Y Antidepressants 033510 selegiline Y Antidepressants 006324 sertraline HCl Y Antidepressants 001640 tranylcypromine sulfate Y Antidepressants 001652 trazodone HCl Y Antidepressants 001649 trimipramine maleate Y Antidepressants 008847 venlafaxine HCl Y Antidepressants 037597 vilazodone HCl Y Antidepressants 040637 vortioxetine hydrobromide Y Antipsychotics, Parenteral 042595 aripiprazole lauroxil Y Antipsychotics, Parenteral 045050 aripiprazole lauroxil,submicr. Y Antipsychotics, Parenteral 001624 fluphenazine decanoate Y Antipsychotics, Parenteral 001626 fluphenazine HCl Y Antipsychotics, Parenteral 001660 haloperidol decanoate Y Antipsychotics, Parenteral 001661 haloperidol lactate Y Antipsychotics, Parenteral 011814 olanzapine Y Antipsychotics, Parenteral 036716 olanzapine pamoate Y Antipsychotics, Parenteral 036479 paliperidone palmitate Y Antipsychotics, Parenteral 025509 risperidone microspheres Y Antipsychotics, Parenteral 001630 trifluoperazine HCl Y Antipsychotics, Parenteral 023379 ziprasidone mesylate Y Benzodiazepines 001617 alprazolam Y Benzodiazepines 001656 amitriptyline/chlordiazepoxide Y Benzodiazepines 001611 chlordiazepoxide Y Benzodiazepines 001610 chlordiazepoxide HCl Y Benzodiazepines 002037 chlordiazepoxide/clidinium Br N Benzodiazepines 001894 clonazepam N Benzodiazepines 001612 clorazepate dipotassium Y Benzodiazepines 001615 diazepam Y Benzodiazepines 004846 lorazepam Y Benzodiazepines 001616 oxazepam Y Other Stimulants 034868 armodafinil Y Other Stimulants 010865 modafinil Y ADHD Drugs 043652 amphetamine N ADHD Drugs 002064 amphetamine sulfate N ADHD Drugs 024703 atomoxetine HCl Y ADHD Drugs 000113 clonidine HCl Y ADHD Drugs 022987 dexmethylphenidate HCl N Author: Servid October 2020 44 ADHD Drugs 002065 dextroamphetamine sulfate N ADHD Drugs 013449 dextroamphetamine/amphetamine N ADHD Drugs 000120 guanfacine HCl Y ADHD Drugs 034486 lisdexamfetamine dimesylate N ADHD Drugs 002067 methamphetamine HCl N ADHD Drugs 033556 methylphenidate N ADHD Drugs 001682 methylphenidate HCl N ADHD Drugs 043652 amphetamine N Antipsychotics, 1st Gen 001626 fluphenazine HCl Y Antipsychotics, 1st Gen 001662 haloperidol Y Antipsychotics, 1st Gen 001661 haloperidol lactate Y Antipsychotics, 1st Gen 039886 loxapine Y Antipsychotics, 1st Gen 001664 loxapine succinate Y Antipsychotics, 1st Gen 001627 perphenazine Y Antipsychotics, 1st Gen 001637 pimozide Y Antipsychotics, 1st Gen 001631 thioridazine HCl Y Antipsychotics, 1st Gen 001668 thiothixene Y Antipsychotics, 1st Gen 001667 thiothixene HCl Y Antipsychotics, 1st Gen 001630 trifluoperazine HCl Y

Table A4. Non-pharmacological services Code Short Name Long Name Category Development Of Cognitive Skills To Improve Attention, Memory, Or Problem Solving, 97532 Cognitive Skills Development Each 15 Minutes Counseling or Other Therapy Development Of Cognitive Skills To Improve Attention, Memory, Problem Solving, 97770 Development Of Cognitive, Skills To Impr Includes Compensatory Counseling or Other Therapy 99510 Home Visit Sing/M/Fam Couns Home Visit For Individual, Family, Or Marriage Counseling Counseling or Other Therapy Behavior Treatment Social Skills Group Administered By Physician Or Other Qualified 0372T Social Skills Training Group Health Care Prof Counseling or Other Therapy Patient Counseled Regarding Psychosocial And Pharmacologic Treatment Options For 4306F Pt Tlk Psych & Rx Opd Addic Opioid Addiction (S Counseling or Other Therapy Patient Counseled Regarding Psychosocial And Pharmacologic Treatment Options For 4320F Pt Talk Psychsoc&Rx Oh Dpnd Alcohol Dependence Counseling or Other Therapy BA013 Mhddsd - Med (Children): Family Therapy Mhddsd - Med (Children): Family Therapy Counseling or Other Therapy BA024 Mhddsd - Med (Children): Individual Psyc Mhddsd - Med (Children): Individual Psychosocial Skills Development Counseling or Other Therapy BA113 Mhddsd - Med(Adult): Family Therapy Mhddsd - Med(Adult): Family Therapy Counseling or Other Therapy BA152 Mhddsd - Med (Jobs): Individual Therapy Mhddsd - Med (Jobs): Individual Therapy Counseling or Other Therapy BA154 Mhddsd - Med (Jobs): Family Therapy Mhddsd - Med (Jobs): Family Therapy Counseling or Other Therapy BA155 Mhddsd-Med (Jobs): Physician Individual Mhddsd - Med (Jobs): Physician Individual Therapy Counseling or Other Therapy

Author: Servid October 2020 45 BA156 Mhddsd - Med (Jobs): Group Therapy Mhddsd - Med (Jobs): Group Therapy Counseling or Other Therapy BA312 Oadap: Individual/Family Therapy Oadap: Individual/Family Therapy Counseling or Other Therapy BA321 Oadap: Multi-Family Group Therapy Oadap: Multi-Family Group Therapy Counseling or Other Therapy BA383 Oadap - Methadone: Individual/Family The Oadap - Methadone: Individual/Family Therapy Counseling or Other Therapy BA388 Oadap - Methadone: Multi-Family Group Th Oadap - Methadone: Multi-Family Group Therapy Counseling or Other Therapy BA392 Oadap - Residential: Individual/Family T Oadap - Residential: Individual/Family Therapy Counseling or Other Therapy BA397 Oadap - Residential: Multi-Family Group Oadap - Residential: Multi-Family Group Therapy Counseling or Other Therapy BA413 Mhddsd - Med (Adult) Extended Care: Fami Mhddsd - Med (Adult) Extended Care: Family Therapy Counseling or Other Therapy CDA02 Oadap: Family Therapy, For Morrison Cent Oadap: Family Therapy, For Morrison Center Clients Only Counseling or Other Therapy Social Work And Psychological Services, Directly Relating To And/Or Furthering The G0409 Corf Related Serv 15 Mins Ea Patient'S Rehabil Counseling or Other Therapy G0443 Brief Alcohol Misuse Counsel Brief Face-To-Face Behavioral Counseling For Alcohol Misuse, 15 Minutes Counseling or Other Therapy High Intensity Behavioral Counseling To Prevent Sexually Transmitted Infection; Face-To- G0445 High Inten Beh Couns Std 30m Face, Indivi Counseling or Other Therapy G0447 Behavior Counsel Obesity 15m Face-To-Face Behavioral Counseling For Obesity, 15 Minutes Counseling or Other Therapy G0473 Group Behave Couns 2-10 Face-To-Face Behavioral Counseling For Obesity, Group (2-10), 30 Minutes Counseling or Other Therapy H0004 Alcohol And/Or Drug Services Behavioral Health Counseling And Therapy, Per 15 Minutes Counseling or Other Therapy H5010 Therapy, Individual, By Social Worker, P Therapy, Individual, By Social Worker, P Counseling or Other Therapy T1006 Family/Couple Counseling Alcohol And/Or Substance Abuse Services, Family/Couple Counseling Counseling or Other Therapy Behavioral Health Prevention Education Service (Delivery Of Services With Target H0025 Alcohol And/Or Drug Preventi Population To Affec Education H1010 Nonmed Family Planning Ed Non-Medical Family Planning Education, Per Session Education H2027 Psychoed Svc, Per 15 Min Psychoeducational Service, Per 15 Minutes Education BA021 Mhddsd - Med (Children): Group Skills De Mhddsd - Med (Children): Group Skills Development Family or Skills Training BA121 Mhddsd - Med (Adult): Skills Training - Mhddsd - Med (Adult): Skills Training - Group Family or Skills Training BA122 Mhddsd - Med (Adult): Skills Training - Mhddsd - Med (Adult): Skills Training - Individual Family or Skills Training BA153 Mhddsd - Med (Jobs): Skills Training - G Mhddsd - Med (Jobs): Skills Training - Group Family or Skills Training BA421 Mhddsd - Med (Adult) Extended Care: Skil Mhddsd - Med (Adult) Extended Care: Skills Training - Group Family or Skills Training BA422 Mhddsd - Med (Adult) Extended Care: Skil Mhddsd - Med (Adult) Extended Care: Skills Training - Individual Family or Skills Training ECC60 Mhddsd-Encounter Or Ocp Only: Group Pare Mhddsd-Encounter Or Ocp Only: Group Parent Psychosocial Skills Development Family or Skills Training ECC70 Mhddsd-Encounter Or Ocp Only: Individual Mhddsd-Encounter Or Ocp Only: Individual Parent Psychosocial Skills Development Family or Skills Training Training And Educational Services Related To The Care And Treatment Of Patient'S G0177 Opps/Php; Train & Educ Serv Disabling Mental He Family or Skills Training Development Of Cognitive Skills To Improve Attention, Memory, Problem Solving G0515 Cognitive Skills Development (Includes Compensatory Family or Skills Training H2014 Skills Train And Dev, 15 Min Skills Training And Development, Per 15 Minutes Family or Skills Training OR360 Training, Family; Per Session Training, Family; Per Session Family or Skills Training Author: Servid October 2020 46 OR361 Training, Non-Family; Per Session Training, Non-Family; Per Session Family or Skills Training OR400 Independent Living Skills Training And D Independent Living Skills Training And Development Family or Skills Training OR513 Family Training For Child Development, G Family Training For Child Development, Group Family or Skills Training OR514 Family Training And Counseling For Child Family Training And Counseling For Child Development, Individual Family or Skills Training OR515 Family Training And Counseling For Child Family Training And Counseling For Child Development, Social Worker Family or Skills Training OR516 Family Training And Counseling For Child Family Training And Counseling For Child Development, Psychologist Family or Skills Training OR529 Independent Skills Assessment\Training\I Independent Skills Assessment\Training\Instructions, Dd, Home Or Community Family or Skills Training OR570 Behavioral Consultation, Assessment And Behavioral Consultation, Assessment And Training For Dd Family or Skills Training T1012 Alcohol/Substance Abuse Skil Alcohol And/Or Substance Abuse Services, Skills Development Family or Skills Training T1027 Family Training & Counseling Family Training And Counseling For Child Development, Per 15 Minutes Family or Skills Training Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90804 Psytx Office 20-30 Min Office Or Ou Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90805 Psytx Off 20-30 Min W/E&M Office Or Ou Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90806 Psytx Off 45-50 Min Office Or Ou Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90807 Psytx Off 45-50 Min W/E&M Office Or Ou Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90808 Psytx Office 75-80 Min Office Or Ou Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90809 Psytx Off 75-80 W/E&M Office Or Ou Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90810 Intac Psytx Off 20-30 Min Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90811 Intac Psytx 20-30 W/E&M Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90812 Intac Psytx Off 45-50 Min Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90813 Intac Psytx 45-50 Min W/E&M Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90814 Intac Psytx Off 75-80 Min Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90815 Intac Psytx 75-80 W/E&M Interpreter, Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90816 Psytx Hosp 20-30 Min Inpatient Ho Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90817 Psytx Hosp 20-30 Min W/E&M Inpatient Ho Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90818 Psytx Hosp 45-50 Min Inpatient Ho Psychotherapy

Author: Servid October 2020 47 Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90819 Psytx Hosp 45-50 Min W/E&M Inpatient Ho Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90821 Psytx Hosp 75-80 Min Inpatient Ho Psychotherapy Individual Psychotherapy, Insight Oriented, Behavior Modifying And/Or Supportive, In An 90822 Psytx Hosp 75-80 Min W/E&M Inpatient Ho Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90823 Intac Psytx Hosp 20-30 Min Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90824 Intac Psytx Hsp 20-30 W/E&M Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90826 Intac Psytx Hosp 45-50 Min Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90827 Intac Psytx Hsp 45-50 W/E&M Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90828 Intac Psytx Hosp 75-80 Min Interpreter, Psychotherapy Individual Psychotherapy, Interactive, Using Play Equipment, Physical Devices, Language 90829 Intac Psytx Hsp 75-80 W/E&M Interpreter, Psychotherapy 90832 Psytx W Pt 30 Minutes Psychotherapy, 30 Minutes Psychotherapy 90833 Psytx W Pt W E/M 30 Min Psychotherapy, 30 Minutes Psychotherapy 90834 Psytx W Pt 45 Minutes Psychotherapy, 45 Minutes Psychotherapy 90836 Psytx W Pt W E/M 45 Min Psychotherapy, 45 Minutes Psychotherapy 90837 Psytx W Pt 60 Minutes Psychotherapy, 60 Minutes Psychotherapy 90838 Psytx W Pt W E/M 60 Min Psychotherapy, 60 Minutes Psychotherapy 90839 Psytx Crisis Initial 60 Min Psychotherapy For Crisis, First 60 Minutes Psychotherapy 90840 Psytx Crisis Ea Addl 30 Min Psychotherapy For Crisis Psychotherapy 90841 Individual Medical Psychotherapy By A Ph Individual Medical Psychotherapy By A Ph Psychotherapy 90843 Individual Medical Psychotherapy By A Ph Individual Medical Psychotherapy By A Ph Psychotherapy 90844 Individual Medical Psychotherapy By A Ph Individual Medical Psychotherapy By A Ph Psychotherapy 90846 Family Psytx W/O Pt 50 Min Family Psychotherapy, 50 Minutes Psychotherapy 90847 Family Psytx W/Pt 50 Min Family Psychotherapy Including Patient, 50 Minutes Psychotherapy 90848 Family Medical Psychotherapy (Conjoint Family Medical Psychotherapy (Conjoint Psychotherapy) With Continuing Medical Dia Psychotherapy 90849 Multiple Family Group Psytx Multiple-Family Group Psychotherapy Psychotherapy 90853 Group Psychotherapy Group Psychotherapy Psychotherapy 90857 Intac Group Psytx Interactive Group Psychotherapy Psychotherapy Individual Psychophysiological Therapy Incorporating Biofeedback Training With 90875 Psychophysiological Therapy Psychotherapy, 30 Min Psychotherapy Individual Psychophysiological Therapy Incorporating Biofeedback Training With 90876 Psychophysiological Therapy Psychotherapy, 45 Min Psychotherapy Author: Servid October 2020 48 4060F Psych Svcs Provided Psychotherapy Services Provided (Mdd, Mdd Adol) Psychotherapy G0072 Individual Psychotherapy, Insight Orient Individual Psychotherapy, Insight Orient Psychotherapy G0073 Individual Psychotherapy, Insight Orient Individual Psychotherapy, Insight Orient Psychotherapy G0074 Individual Psychotherapy, Insight Orient Individual Psychotherapy, Insight Orient Psychotherapy G0075 Individual Psychotherapy, Insight Orient Individual Psychotherapy, Insight Orient Psychotherapy G0088 Individual Psychotherapy, Insight Orient Individual Psychotherapy, Insight Orient Psychotherapy G0089 Individual Psychotherapy, Interactive, I Individual Psychotherapy, Interactive, I Psychotherapy G0090 Individual Psychotherapy, Interactive, I Individual Psychotherapy, Interactive, I Psychotherapy G0091 Individual Psychotherapy, Interactive, I Individual Psychotherapy, Interactive, I Psychotherapy G0092 Individual Psychotherapy, Interactive, I Individual Psychotherapy, Interactive, I Psychotherapy G0093 Individual Psychotherapy, Interactive, I Individual Psychotherapy, Interactive, I Psychotherapy G0094 Individual Psychotherapy, Interactive, I Individual Psychotherapy, Interactive, I Psychotherapy Group Psychotherapy Other Than Of A Multiple-Family Group, In A Partial Hospitalization G0410 Grp Psych Partial Hosp 45-50 Setting, App Psychotherapy G0411 Inter Active Grp Psych Parti Interactive Group Psychotherapy, In A Partial Hospitalization Setting, 45 To 50 Minute Psychotherapy H2017 Psysoc Rehab Svc, Per 15 Min Psychosocial Rehabilitation Services, Per 15 Minutes Psychotherapy H2018 Psysoc Rehab Svc, Per Diem Psychosocial Rehabilitation Services, Per Diem Psychotherapy H5020 Psychotherapy, Group (Maximum 8 Persons Psychotherapy, Group (Maximum 8 Persons Psychotherapy H5025 Psychotherapy, Group (Maximum 8 Persons Psychotherapy, Group (Maximum 8 Persons Psychotherapy

Author: Servid October 2020 49 Appendix 3. RetroDUR Proposal

Inclusion Criteria

 Patients currently enrolled in FFS AND  Patients with a at least 3 medical visits associated with bipolar disorder (F31x) in the past year AND  Patients with at least 3 psychiatric hospitalizations or ED visits in the past 6 months AND  Meeting at least one of the following criteria: o No paid claims in the last 60 days for bipolar therapy (including mood stabilizers or antipsychotics, 2nd generation) OR o Paid claims in the last 60 days an antidepressant AND without paid claims for bipolar therapy in the last 60 days OR o Paid claims in the last 60 days for aripiprazole AND with recent diagnosis of bipolar II disorder or bipolar depression OR o Paid claims for ≥3 unique bipolar therapies (based on HSN) in the last 60 days from more than one prescriber o Paid claims for ≥4 unique bipolar therapies (based on HSN) in the last 60 days from any single provider o Paid claims for bipolar medications with PDC <30% in the past 4 months

Exclusion Criteria

 Patients previously reviewed with this initiative in the last 6 months (once the program is implemented)  Patients with other primary insurance (Medicare Part D or TPL)  Patients who are deceased

RetroDUR Reporting Profile Review: High-risk patients – bipolar disorder

 Proiles reviewed  Providers notified  Change in bipolar drug therapy in the following 90 days o New bipolar therapy prescribed o Drug discontinued

Author: Servid October 2020 50 Prescriber alert: High Risk Patient On Bipolar Therapy

Date: MM/DD/YYYY To: Provider name NPI: NPI Address: Mailing address City: City State: State ZIP: ZIP Phone number: ###-###-#### Fax number: ###-###-#### Total pages: # Regarding patient: Name, Medicaid ID, DOB

Dear Physician/Allied Health Prescriber:

The Oregon Health Authority (OHA) reviews fee-for-service prescription medications dispensed and prescribed to Oregon Health Plan (OHP) members. Based on OHA’s review of your patient’s current profile, there is an opportunity for optimization of their bipolar therapy to prevent adverse outcomes, as described below:

What should you do? OHA offers the following recommendations to help ensure your patient’s medication regimen is safe and appropriate:  

Please consider these clinical recommendations then coordinate with co-prescribers and your patient as clinically appropriate. Thank you for continuing to serve OHP patients.

For additional recommendations on bipolar disorder, including medication algorithms, Mental Health Clinical Advisory Group recommendations are available at: https://www.oregon.gov/oha/HSD/OHP/Pages/PT-MHCAG.aspx

Confidentiality Notice: The information contained in this request is confidential and legally privileged. It is intended only for use of the recipient(s) named. If you are not the intended recipient, you are hereby notified that the disclosure, copying, distribution, or taking of any action in regards to the contents of this fax document- except its direct delivery to the intended recipient – is strictly prohibited. If you have received this request in error, please notify the sender immediately and destroy all copies of this request along with its contents and delete from your system, if applicable.

Author: Servid October 2020 51 Examples of Concern/Rationale/Recommendations (select which are appropriate based on profile review):

(A) Concern: Patient with 3 or more bipolar medications from more than one provider  Rationale: Use of 3 concurrent bipolar medications is not consistent with current evidence-based guidelines.  Recommendation: Consider reassessment of current regimen to decrease pill burden and avoid duplication of therapy. Ask for a copy of your patient’s recent prescription claim history by initialing this line and faxing this page to 503-947-2596 (Salem). Prescriber initials: ______

(B) Concern: Low adherence to currently bipolar regimen  Rationale: Many reasons can contribute to adherence including medication efficacy, adverse effects from treatment, lack of motivation or knowledge about treatment, or lack of social support. Estimates of adherence are based on paid claims for the patient and may not accurately categorize patients paying cash or patients with other insurance. Ask for a copy of your patient’s recent prescription claim history by initialing this line and faxing this page to 503-947-2596 (Salem). Prescriber initials: ______ Recommendation: Discuss medication adherence with your patient to identify potential concerns with therapy. For lack of efficacy or significant adverse events, consider modifying therapy. Consider engagement with psychosocial therapy to build skills to improve medication adherence.

(C) Concern: No claims billed for recent psychosocial treatment  Rationale: Current guidelines recommend psychosocial treatment in conjunction with medication management to improve patient outcomes including quality of life and recurrent hospitalization.  Recommendation: Optimize of multi-modal therapies to address patient concerns and decrease their risk of readmission or hospitalization.

(D) Concern: Lack of prescribed therapy for bipolar disorder in a patient with recent emergency department visits or hospitalization for psychiatric illnesses  Rationale: Current guidelines recommended medication in combination with psychosocial therapy for bipolar disorder in order to improve outcomes and prevent readmission  Recommendation: Consider use of evidence based recommendations for bipolar depression or mania. First-line medication options for bipolar depression include lamotrigine, lithium, or quetiapine. Lithium or quetiapine are recommended as first-line treatments for acute mania.

(E) Concern: Use of antidepressant monotherapy in a patient with bipolar depression  Rationale: Use of antidepressant monotherapy in patients with bipolar depression may trigger manic or mixed episodes.  Recommendation: Avoid use of antidepressant monotherapy. Consider combination treatment with another bipolar treatment medication.

(F) Concern: Use of aripiprazole for acute bipolar depression  Rationale: Current Mental Health Clinical Advisory Group algorithms recommend against use of aripiprazole for acute bipolar depression due to evidence of ineffectiveness. As this patient has had multiple recent medical visits associated with mental health diagnoses, consider therapy with a different agent if appropriate.  Recommendation: Reassess therapy efficacy and consider an alternative treatment option to optimize treatment if needed. Quetiapine is an alternative treatment option for patients with acute bipolar depression.

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-2596

Drug Class Update with New Drug Evaluation: Parkinson’s Disease Drugs

Date of Review: October 2020 Date of Last Review: March 2018 Dates of Literature Search: 01/01/2018 - 08/24/2020 Generic Name: istradefylline Brand Name (Manufacturer): NOURIANZ (Kyowa) opicapone OGENTYS (Neurocrine) apomorphine sublingual KYNMOBI (Sunovion) Dossier Received: yes

Current Status of PDL Class: See Appendix 1.

Purpose for Class Update: Review the evidence for new drugs recently approved as adjunctive treatment to levodopa therapy in adults with Parkinson’s disease. Review updated evidence for the drug class in a broader context to validate current Oregon Health Plan (OHP) Fee-for-Service (FFS) Preferred Drug List (PDL) and current clinical Prior Authorization (PA) criteria.

Research Questions: 1. Is there new comparative evidence that drugs indicated for treatment of Parkinson's disease (PD) differ in efficacy or effectiveness at improving symptoms, quality of life or in stabilizing disease progression in adults with PD? 2. Is there new comparative evidence that drugs indicated for treatment of PD differ in serious adverse events or tolerability when used to treat adults with PD? 3. Are there specific subpopulations based on demographic characteristics (e.g., age, gender, race, disease severity or longevity, disease subtype, or concomitant therapies) for which one anti-PD drug is better tolerated or more effective than other available drugs used to manage PD?

Conclusions:  Three new high-quality systematic reviews of drugs indicated for treatment of PD and one new drug approval for adjunctive treatment of PD were identified since the last drug class review. No new high-quality clinical practice guidelines, safety alerts or new drug formulations in this drug class were found.  One systematic review provided low quality evidence that monoamine oxidase B inhibitors (MAOBIs) are effective compared to placebo, both when given as monotherapy and in combination with levodopa therapy.1 No statistically significant differences in relative effectiveness between rasagiline, safinamide and selegiline were found based on achievement of 20% score reduction in the total Unified Parkinson’s Disease Rating Scale (UPDRS) score (relative risk [RR]

Author: Andrew Gibler, PharmD 58

1.560 (95% CI, 1.409 to 1.734), RR 1.449 (95% CI, 0.873 to 2.413) and RR 1.532 (95% CI, 1.337 to 1.757), respectively).1 Rasagiline, safinamide and selegiline were also effective compared to placebo when these drugs were used as adjunctive therapy with levodopa therapy (RR 1.573 (95% CI, 1.369 to 1.803), RR 1.178 (95% CI, 1.031 to 1.350) and RR 2.307 (95% CI, 1.802 to 2.936), respectively).1 No increased risk for serious adverse events with a MAOBI compared to placebo or placebo plus levodopa therapy were found.1  The incidences of adverse effects between immediate-release (IR) and extended-release (ER) formulations of pramipexole, a dopamine agonist, were systematically reviewed and found to be similar.2  One multi-centered randomized controlled trial (RCT) provided moderate quality evidence that delaying initiation of levodopa therapy in patients with newly diagnosed PD by 40 weeks does not impact long-term functioning based on change in the total UPDRS score at 80 weeks (mean difference 1.0 (95% CI, -1.5 to 3.5; p=0.44).3 Istradefylline:  Istradefylline was studied as adjunctive treatment to levodopa therapy in patients with advanced PD in 8 RCTs. Five RCTs4-8 found istradefylline decreased daily “off” time in patients and 3 RCTs did not, including an active-controlled study that found benefit with entacapone but not istradefylline.9-11 The FDA approved istradefylline based on the positive findings of 4 of the 8 RCTs.4,6-8  The primary efficacy endpoint in these RCTs was the change from baseline in daily awake percentage of “off” time, or the change from baseline in total daily “off” time based on 24-hour “on/off” diaries completed by patients, over 12 weeks. These studies provide low quality evidence of benefit for istradefylline over placebo in reduction of “off” time by about 0.7 to 0.9 hours per day, which correlated to a relative reduction of about 15% from “off” time experienced at baseline.12  Of the 4 trials the FDA considered for approval, 2 trials found a 2-point benefit with the 40 mg dose in the UPDRS part 3 “on” state7,8 and one trial found a 1.7-point benefit in the UPDRS part 2 “off” state with the 40 mg dose.8 Other UPDRS sections did not improve with istradefylline, including Part 1; Part 2 “on” and Part 4. Total UPDRS scores also did not differ between istradefylline and placebo.4 None of the clinical trials found clinically meaningful differences between istradefylline and placebo in improvement of UPDRS scores over 12 weeks of treatment.  The most frequent adverse effects observed in clinical trials 5% or greater frequency than placebo were dyskinesia, dizziness, constipation, nausea, hallucinations and insomnia.12 Overall, the frequency of serious adverse events was low and similar across all treatment groups. Opicapone:  The efficacy and safety of opicapone was established in two identical double-blind, randomized, placebo-controlled trials in patients with idiopathic PD and motor fluctuations already treated with levodopa therapy. The primary efficacy endpoint for both studies was the total reduction in daily “off” time assessed using 24-hour patient diaries in which patients recorded their status at 30-minute intervals for the 3 consecutive days before clinic visit 7 (week 14-15).13,14 The studies provide low quality evidence that opicapone 50 mg daily reduced “off” time by 54-61 minutes per day versus placebo (study 301: mean difference [MD] = -60.8 min [95% CI, -97.2 to -24.4]; and study 302: MD = -54.3 min [95% CI, -96.2 to -12.4]).13,14 None of the key secondary endpoints, which included change in total UPDRS, change in the Parkinson’s Disease Sleep Scale (PDSS), change in Non-motor Symptoms Scale (NMSS), and the Parkinson’s Disease Questionnaire (PDQ-39) questionnaire, were found to differ between opicapone and placebo. Dyskinesia was the most common adverse event reported with opicapone, and the most common adverse event leading to early study discontinuation.13,14 Apormorphine, sublingual (SL):  The efficacy and safety of apomorphine SL was established in a single randomized, placebo-controlled trial.15 The study included an open-label apomorphine SL titration phase and a 12•week double-blind, placebo-controlled maintenance phase.15 In the titration phase, all patients were titrated to a tolerable dose of apomorphine SL (maximum dose 35 mg) that achieved a full “on” response. Patients who met criteria were randomized to apomorphine SL or placebo in

Author: Gibler Date October 2020 59

the maintenance phase. The primary endpoint for the study was the mean change from pre-dose to 30 minutes post-dose in the MDS-UPDRS Part 3 (motor examination).15 The key secondary endpoint was the percentage of patients with a patient-rated full “on” response within 30 minutes at the week 12.15  The study provides low quality evidence that apomorphine SL provided greater reduction in the MDS-UPDRS part 3 score at week 12 than placebo (-11.1; 95% CI, -14.0 to -8.2 vs. -3.5; 95% CI, -6.1 to -0.9, respectively) by a least squares mean difference of -7.6 (95% CI, -11.5 to -3.7).15 The response rate for a full “on” response within 30 minutes at the week 12 visit was also greater in patients treated with apomorphine SL than in those treated with placebo (35% vs. 16%, respectively; OR 2.81; 95% CI, 1.04 to 7.64).15 Treatment-emergent adverse events led to early study discontinuation in 28% of patients treated with apomorphine SL and in 9% of those treated with placebo.15 Oropharyngeal adverse events occurred in 31% of patients treated with apomorphine SL and were the most common type of adverse event that led to study discontinuation in the double-blind maintenance phase of the trial (17%).15 Nausea was the most commone adverse event associated with opicapone and an antiemetic is recommended prior to initiation; however, 5-HT3 agents must be avoided.15,16

Recommendations:  Designate istradefylline, opicapone and apomorphine SL as a non-preferred drug on the OHP Practitioner-Managed Prescription Drug Plan (PMPDP).  Update clinical PA criteria to ensure safe and appropriate use of istradefylline, opicapone and apomorphine SL as outlined in Appendix 6.  Review comparative drug costs in the executive session.

Summary of Prior Reviews and Current Policy  The current OHP FFS PDL includes first-line treatment options for PD, including several formulations of levodopa/carbidopa, and adjunctive therapy such as dopamine agonists (pramipexole), MAOBI (selegiline), catechol-O-methyltransferase inhibitors (COMTI) (entacapone, tolcapone), and anticholinergic agents (benztropine, trihexyphenidyl).  Clinical PA criteria limits these agents to funded conditions under the OHP and requires current use of levodopa/carbidopa in patients prescribed safinamide.  Current guidance from the National Institute for Health and Care Excellence (NICE) supports the current PDL and clinical PA criteria.17  From the previous drug class update18:  No new safety alerts or comparative evidence of anti-PD drugs were identified.  Extended-release amantadine (Gocovri™) was approved by the FDA for the treatment of dyskinesia in patients with PD receiving levodopa-based therapy based on low quality evidence from 2 placebo-controlled studies.  Low quality of evidence demonstrated that safinamide, when used as an adjunct to levodopa therapy, may improve quality of life, increase total daily “on” time, and decrease “off” time in patients in later stages of PD relative to placebo.

Background: Parkinson’s disease is an incurable, progressive neurodegenerative disorder caused by the death of dopamine-secreting neurons in the sunbstantia nigra. The resulting dopamine deficiency within the basal ganglia slowly leads to a movement disorder characterized by “parkinsonian” motor symptoms, including bradykinesia, rigidity and resting tremor.19 However, non-specific non-motor symptoms such as olfactory dysfunction, constipation, sleep disorders, and depression may precede motor symptoms by several years.19 As PD advances, patients develop motor fluctuations (alterations between response to anti-PD drug therapy and reemergance of symptoms as the benefit of drug therapy wears off) and non-motor complications (e.g., autonomic, psychiatric and cognitive impairment).

Author: Gibler Date October 2020 60

Parkinson’s disease is the most common neurodegenerative disorder after Alzheimer’s disease.19 Parkinson’s disease was earlier thought to be caused primarily by environmental factors, but research continues to reveal that PD develops from a complicated interplay of genetic and environmental factors.19 Age is the greatest risk factor for the development of PD; other established risk factors include gender (male-to-female ratio of 1.5:1) and ethnicity (highest in people of Hispanic descent, followed by non-Hispanic Whites, Asians and Blacks).19 The typical age of onset is around 60 years, but prevalence and incidence increase almost exponentially with age and peak after 80 years of age.19,20 The prevalence of PD is about 1 million people in North America, or about 1% of the population older than 60 years.20

The mainstay of PD management is symptomatic treatment with drugs that increase dopamine concentrations or directly stimulate dopamine receptors. However, PD will ultimately cause progressive disability despite treatments that may be initially effective. As PD advances, nondopaminergic regions of the brain become involved and this results in treatment-resistant motor and nonmotor symptoms.20 There are no established disease-modifying or neuroprotective therapies for PD; therefore, treatment does not need to begin at time of diagnosis but, rather, when patients experience functional impairment or social embarrassment from their symptoms.20 The primary goal of treatment is to improve function and quality of life for as many years as possible.

The most effective treatment for the disease is oral levodopa (dopamine’s lipophilic precursor) in combination with a dopa decarboxylase inhibitor (e.g., carbidopa) to reduce the peripheral degradation of levodopa. Multiple large trials have shown levodopa provides the greatest symptomatic benefit for PD and is associated with less freezing, somnolence, edema, hallucinations, and risk of impulse disorders than dopamine agonists.20 However, long-term treatment with levodopa and a dopa decarboxylase inhibitor (hereafter referred to as levodopa therapy) is complicated by the development of motor fluctuations and dyskinesia. Motor fluctuations are characterized by a cycle in which patients have a long period of drug responsiveness (“on” periods) followed by a return of parkinsonian symptoms (“off” episode) before the benefit from the next subsequent dose takes effect. These motor fluctuations are largely due to the short half-life of levodopa. Off episodes can manifest as “parkinsonian” motor symptoms. Dopamine agonists, however, are associated with less dopaminergic complications like dyskinesia, which can be a major factor when treatment is initiated in younger patients with PD who are at higher risk for dyskinesia.20 Other adjunctive therapies include MAOBIs and COMTIs. Evidence supporting amantadine for treatment of PD is insufficient; however, the drug is believed to be effective when used in clinical practice.20

Three new anti-PD agents were recently approved by the FDA to manage “off” episodes. Istradefylline was approved by the FDA in August 2019 for adjunctive treatment to levodopa therapy in patients with advanced PD experiencing “off” episodes.12 Istradefylline is a new molecular entity, and the first adenosine A2A receptor antagonist approved for the treatment of motor fluctuations in advanced PD. Opicapone was approved by the FDA in April 2020 for adjunctive treatment to levodopa therapy in patients with PD experiencing “off” episodes.21,22 Opicapone is a COMTI similar to entacapone and tolcapone. Entacapone is the most commonly used COMTI for the management of “off” episodes, but it needs to be given concomitantly with each levodopa dose; tolcapone is limited by hepatotoxicity and continuous monitoring of liver function.23 Until recently, two treatment options are available for on-demand, “rescue” management of “off” episodes: subcutaneous apomorphine, a non-ergoline dopamine agonist, and an inhaled dry powder formulation of levodopa. However, an apomorphine sublingual film formulation was approved by the FDA in May 2020 to address the practical limitations with the SC apomorphine.15,16

When motor fluctuations are present in advanced PD, strategies to reduce “off” time include increasing the dose of dopaminergic medication, adding another dopaminergic medication (e.g., dopamine agonist), dividing the levodopa dose into smaller but more frequent doses, or adding a COMTI or MAOBI to inhibit the breakdown of levodopa and dopamine and prolong their effect.20 However, few trials have compared these different strategies. As PD progresses, patients on levodopa therapy often add one of these classes of drug; and as PD advances further, patients may eventually take drugs from 2 or 3 of these classes, in addition to levodopa.12 The overall benefit of these adjunctive treatments relative to placebo in decreasing total “off” time ranges from about 0.5 to 2 hours.12 None of Author: Gibler Date October 2020 61 these adjunctive drugs have been shown to be superior to others for treating “off” time.12 In practice, it is important to regularly re-evaluate the ongoing efficacy and adverse effects of these adjunctive drugs so treatment can be tailored to the patient’s needs.

In an evaluation of paid and denied claims from 7/1/19 to 9/30/19, there were approximately 370 OHP FFS patients prescribed therapies within this drug class. About 64% of prescribed therapy was for preferred agents (primarily benztropine and pramipexole). Of note, only 25 patients (7%) had claims for levodopa therapy. Amantadine and ropinirole were the most commonly prescribed non-preferred products. Of the patients prescribed a non-preferred drug, 47% had a subsequent PA request approved and 5% of patients switched to a preferred drug. Of the patients with no subsequent paid PD therapy, 37% were enrolled in a coordinated care organization, lost eligibility or had other insurance which may have paid for their medication. Only 5% of patients had a PA denied and 5% of patients had no PA requested by the prescribing provider.

The PD-specific instruments commonly used in clinical trials to evaluate disease progression and treatment efficacy include the Hoehn and Yahr (HY) staging system, the UPDRS: Parts I-IV, and the Parkinson’s Disease Questionnaire (PDQ-39).

Hoehn and Yahr staging was originally designed to be a descriptive staging scale that provided a general estimate of clinical function in PD, combining functional deficits (disability) and objective signs (impairment). The 5-point (1 to 5) HY scale is based on the 2-fold concept that the severity of overall parkinsonian dysfunction relates to bilateral motor involvement and compromised balance and gait. Increasing parkinsonian motor impairment is scaled from unilateral (Stage 1) to bilateral disease without balance difficulties (Stage 2), to the presence of postural instability (Stage 3), loss of physical independence (Stage 4), and being wheelchair‐ or bed‐dependent (Stage 5).24

The UPDRS scale is a rating tool used to gauge the course of PD in patients.25 The UPDRS continues to be used in research to estimate treatment effects for PD. The UPDRS scale consists of the following 4 sections: 1) non-motor experiences of daily living (evaluation of mentation, behavior and mood); 2) motor experiences of daily living (e.g., speech, swallowing, handwriting, falling, walking, etc.); 3) motor examination (by clinician); and 4) motor complications.25 Each item in each section is ranked on a 5-point scale (0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe) and higher scores indicate more severe PD; the total cumulative UPDRS score will range from 0 (no disability) to 199 (total disability). The UPDRS cut-off points between mild/moderate and moderate/severe levels for each section are estimated to be: Part 1: 10/11 and 21/22; Part 2: 12/13 and 29/30; Part 3: 32/33 and 58/59; and Part 4: 4/5 and 12/13.26 The minimally important clinical difference (MCID) thresholds for components of the UPDRS have been estimated based on clinical trials.27,28 The MCID for improvement in Part 2 of the UPDRS is about -2 points, and the MCID for Part 3 is about -6 points in both early and advanced PD patients.27 An updated UPDRS by the Movement Disorders Society (MDS) in 2008 provided clarity to some ambiguities of the original scale with slight modifications.25 The MCID thresholds for Part 3 MDS-UPDRS motor examination score have also been examined, and are estimated to be -3.25 points for observing minimal, but clinically relevant improvement and 4.63 points for observing minimal, but clinically relevant worsening.28

The PDQ-39 is a PD-specific quality of life questionnaire.29,30 The instrument has been tested for reliability and validity and is now widely used in clinical trials and practice.30 The PDQ-39 assesses how often people with PD experience difficulties across 8 dimensions of health: mobility, activities of daily living, emotional well- being, stigma, social support, cognition, communication and body discomfort.29,30 Dimension scores are coded on a scale of 0 (perfect health as assessed by the measure) to 100 (worst health as assessed by the measure).30 The MCID thresholds for PDQ-39 total index (100-point scale) are estimated to be -4.72 and +4.22 for detecting minimal clinically important improvement and worsening, respectively.31

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Non-motor symptoms in PD are common and can significantly reduce quality of life. The Non-motor Symptoms Scale (NMSS) addresses non-motor symptoms, and consists of 30 questions, covering 9 dimensions (cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany), whereby each item is scored based on a multiple of severity (from 0 to 3) and frequency scores (from 1 to 4).32 The NMSS is rated by the healthcare provider and obtained through interview. The NMSS total score is calculated by adding all domain scores (0-360), and lower scores mean less disability.32 An MCID has not been recognized for the NMSS.

The Parkinson's disease Sleep Scale (PDSS) is a specific scale for the assessment of sleep disturbances in subjects with PD.33 The PDSS is a visual analogue scale addressing 15 commonly reported symptoms associated with sleep disturbance.33 Items of the PDSS address the following: overall quality of night’s sleep (item 1); sleep onset and maintenance insomnia (items 2 and 3); nocturnal restlessness (items 4 and 5); nocturnal psychosis (items 6 and 7); nocturia (items 8 and 9); nocturnal motor symptoms (items 10–13); sleep refreshment (item 14); and daytime dozing (item 15).33 The PDSS total score is a sum score of all 15 questions and ranges from 0 to 150, with lower scores meaning more disability.33 An MCID has not been recognized for the PDSS.

Other non-specific, health-related quality-of-life instruments that may be used in PD clinical trials include Clinical Global Impression rating scales, Patient Global Impression – Improvement Scale (PGI-I), and the Medical Outcomes Study 36-Item Short Form (SF-36).34 The Clinical Global Impression – Improvement scale (CGI-I) is a 7-point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to baseline at the beginning of the intervention.35 The Clinical Global Impression – Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis.35 The PGI-I is a 7-point scale that allows the patient to rate how much their illness has improved or worsened relative to a baseline state at the beginning of the intervention.36 The SF-36 is a general indicator of function and well-being and includes primarily non-psychiatric health status questions.37 The SF-36 is a commonly used, reliable and broad-based instrument for a wide variety of medical conditions.34,37 The MCID thresholds of these instruments in PD patients have not been formally investigated.

Methods: A Medline literature search for new systematic reviews and randomized controlled trials (RCTs) assessing clinically relevant outcomes to active controls, or placebo if needed, was conducted. The Medline search strategy used for this review is available in Appendix 3, which includes dates, search terms and limits used. The OHSU Drug Effectiveness Review Project, Agency for Healthcare Research and Quality (AHRQ), National Institute for Health and Clinical Excellence (NICE), Department of Veterans Affairs, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were manually searched for high quality and relevant systematic reviews. When necessary, systematic reviews are critically appraised for quality using the AMSTAR tool and clinical practice guidelines using the AGREE tool. The FDA website was searched for new drug approvals, indications, and pertinent safety alerts.

The primary focus of the evidence is on high quality systematic reviews and evidence-based guidelines. Randomized controlled trials will be emphasized if evidence is lacking or insufficient from those preferred sources.

Systematic Reviews: Systematic reviews were excluded for poor quality, wrong study design of included trials (e.g., observational), comparator (e.g., no control or placebo- controlled), or outcome studied (e.g., non-clinical).

A systematic review was conducted to identify published RCTs that assessed the efficacy and safety of MAOBIs in patients with PD.1 Eligible publications included double-blinded RCTs that enrolled patients 18 years and older and compared selegiline, rasagiline or safinamide to each other or to placebo, as monotherapy or Author: Gibler Date October 2020 63 in combination with levodopa therapy.1 A total of 27 RCTs met inclusion criteria. The investigators were interested in response to MAOBI therapy, defined as the number of patient with at least 20% reduction from baseline to end of study in the UPDRS score or an improvement (minimally improved, much improved or very much improved) on the CGI-I scale.1 Total UPDRS score was used if provided; otherwise, parts II and III or only part III were evaluated if only these scores were provided.1 The relative effect of each MAOBI versus the comparator was then compared using a combination of direct and indirect network meta-analyses based on the comparator with levodopa therapy.1 Overall, there were 4072 patients given a MAOBI, 1489 given placebo, and 1457 given placebo and levodopa therapy. The trials lasted between 6 weeks and 6.5 years, but most lasted up to 24 weeks.1

Rasagiline, safinamide and selegiline monotherapy all achieved 20% reduction in UPDRS scores relative to placebo (RR 1.560 (95% CI, 1.409 to 1.734), RR 1.449 (95% CI, 0.873 to 2.413) and RR 1.532 (95% CI, 1.337 to 1.757), respectively).1 In addition, rasagiline, safinamide, and selegiline given as adjunctive treatment with levodopa therapy all achieved 20% reduction in UPDRS scores relative placebo and levodopa therapy (RR 1.573 (95% CI, 1.369 to 1.803), RR 1.178 (95% CI, 1.031 to 1.350) and RR 2.307 (95% CI, 1.802 to 2.936), respectively).1 No increased risk for serious adverse events with a MAOBI compared to placebo or joint placebo and levodopa therapy were found.1

The investigators concluded all of the MAOBIs were effective compared to placebo, both when given as monotherapy and in combination with levodopa therapy.1 When given as monotherapy, no significant difference in relative effectiveness between selegiline, rasagiline or safinamide was found.1 When combination therapy with MAOBIs and levodopa therapy were analyzed, all 3 MAOBIs were effective compared to placebo, but selegiline with levodopa therapy was found to be the most effective combination based on direct and indirect meta-analysis.1 Most of the included trials used change in UPDRS scores as an efficacy endpoint.1 However, the investigators remained uncertain of their definition of clinical response and concluded a 20% score reduction in an UPDRS score, which may amount to only a few points in many patients, may not impact an individual’s quality of life.1

Another systematic review studied the impact of dopaminergic anti-PD drugs on cognitive functioning in mild-to-moderate, non-demented PD patients with compromised or intact cognition.38 Eligible studies included RCTs or non-randomized studies (e.g., pre-post study) with a control group or within-group comparisons, with or without placebo.38 Parkinson’s disease severity had to be mild to moderate, defined by HY stages 3 or less and a PD duration of 10 years or less at baseline.38 Results had to be reported on at least one validated cognitive measure before and after the intervention.38 Exclusion criteria included cohort and case-control studies; case reports and animal model studies; trials including patients presenting with major psychiatric or neurologic disorder besides PD; and PD with dementia per the DSM criteria or an Mini-Mental State Examination (MMSE) score less than 26, as recommended by the Movement Disorder Society.38 Fourteen studies met inclusion criteria. These studies evaluated levodopa therapy, pramipexole, selegiline and rasagiline. No studies were found that evaluated the effects of ropinirole or COMTIs on cognition.38

Overall methodological quality of the studies was low due to small sample sizes, the lack of blinding for patients and data assessors, the absence of power calculations or the lack of concealment of patient allocation.38 Levodopa therapy showed both statistically significant deleterious and beneficial results on some cognitive outcome measures, most notably in executive functions and episodic memory.38 Pramipexole was associated with worsening of episodic memory and impulse control.38 Results on selegiline indicated a deterioration of global cognition over time and of concept formation.38 Rasagiline had some benefits on working memory and verbal fluency.38 Overall, the investigators found possible association between dopaminergic anti-PD drugs and cognitive changes in patients with mild-to-moderate PD without dementia.38 However, they concluded that the inconsistency between studies and their low quality call into question the validity of any association.38 To better understand whether an association between cognitive function and dopaminergic anti-PD therapy exists, studies of significantly higher methodological quality are required.

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The incidences of adverse effects between IR and ER formulations of pramipexole, a dopamine agonist, was systematically reviewed.2 Eligible studies were double-blinded RCTs that evaluated both IR and ER pramipexole in PD patients and evaluated nausea, dizziness, somnolence and dyskinesia.2 Out of 81 citations identified, only 3 studies met inclusion criteria. Quality of the 3 studies were assessed based on random sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. All 3 trials met quality standards except for concern with performance bias in one trial and attrition bias in another trial. Based on results from 3 trials, there was no significant difference between IR and ER formulations for somnolence [relative risk (RR) = 1.16 (95% CI, 0.95 to 1.43; p=0.14)], nausea [RR = 0.96 (95% CI, 0.72 to 1.28; p=0.80)], or dizziness [RR = 1.11 (95% CI, 0.80 to 1.54; p=0.54)].2 Only 2 trials reported the incidence of dyskinesia, and no significant difference between IR and ER formulations was found [RR = 0.87 (95% CI, 0.47 to 1.60; p=0.66)].2

New Guidelines: No clinical practice guidelines within this drug class were identified since the last class update.

New Formulations or Indications: No new formulations or indications within this drug class were identified since the last class update.

New FDA Safety Alerts: No new safety alerts within this drug class were published by the FDA since the last class update.

Randomized Controlled Trials: A total of 132 citations were manually reviewed from the initial literature search. Studies were excluded because of wrong study design (e.g., observational), comparator (e.g., no control or placebo-controlled), or outcome studied (e.g., non-clinical). The remaining 3 trials are summarized in Table 1. Full abstracts are included in Appendix 2.

Table 1. Description of Randomized Comparative Clinical Trials. Study Comparison Population Primary Outcome Results Lee, et al.39 1. PD-ICD cohort PD diagnosis; age 40-80 y; stable doses of Mean  mMIDI score (0-12  mMIDI = -5.27; p<0.001 vs. baseline in dopaminergic drugs including dopamine weeks) in the PD-ICD cohort PD-ICD cohort MC, OL 2. PDTC cohort agonists >6 months; plus: - PD-ICD: ICD diagnosis developed after anti- (other cohorts served as Conclusion: Switching from a dopamine 3. PDNC cohort PD drug treatment (PD-ICD cohort); or controls and were not agonist to levodopa/carbidopa SR may - PDTC: no ICD diagnosis and mMIDI score compared) alleviate ICD behaviors in patients with PD. =0

PDNC: new PD diagnosis; age 40-80 y; never treated for PD

Dopamine agonists substituted w/ equivalent dose of levodopa/carbidopa SR Author: Gibler Date October 2020 65

tablets and adjusted during 4-week titration period. Verschuur, 1. Levodopa/carbidopa PD diagnosis in past 2 y; insufficient Mean  total UPDRS score 1. Early-start Group (n=207): et al.3 100/25 mg PO TID x80 disability to warrant treatment w/ anti-PD (0 to 80 weeks) 28.0  11.2 (baseline) weeks (early start drug; age 30 y; life expectancy >2 y 27.0  14.8 (week 80) MC, DB, PC, group) Difference: -1.0  13.1 RCT 2. Delayed-start Group (n=210): 2. Placebo PO TID x40 29.0  11.8 (baseline) weeks, then 27.0  14.3 (week 80) levodopa/carbidopa Difference: -2.0 13.0 100/25 mg PO TID x40 weeks (delayed start Between Group Difference: 1.0 group) (95% CI, -1.5 to 3.5; p=0.44) Abbreviations: CI = confidence interval; DB = double blind; HR = Hoehn and Yahr; MC = multi-center; mMIDI = modified Minnesota Impulsive Disorders Interview; OL = open label; PC = placebo-controlled; PD = Parkinson’s disease; PD-ICD = Parkinson’s disease with Impulse Control Disorder; PDNC = Parkinson’s disease drug-naïve control; PDTC = Parkinson’s disease treatment control; PO = orally; RCT = randomized controlled trial; SR = sustained release; TID = three times daily; UPDRS = unified Parkinson’s disease rating scale; y = years;  = standard deviation.

NEW DRUG EVALUATION:

See Appendix 4 for Highlights of Prescribing Information from the manufacturer, including Boxed Warnings and Risk Evaluation Mitigation Strategies (if applicable), indications, dosage and administration, formulations, contraindications, warnings and precautions, adverse reactions, drug interactions and use in specific populations.

Clinical Efficacy: The drug sponsor for istradefylline originally submitted a new drug application to the FDA in 2007 but it was not approved out of concern for lack of efficacy.12 In 4 of the 5 original earlier studies, the primary endpoint was change in “off” time from baseline to 12 weeks (the 5th trial evaluated the primary endpoint at 16 weeks). The drug sponsor had originally submitted 3 RCTs which showed istradefylline, when used as an adjunctive treatment in patients with advanced PD, decreased the percent of daily “off” time in patients.4-6 However, 2 other adequately sized, well-controlled trials did not demonstrate decrease in “off” time, including an active-controlled study that found benefit with entacapone but not istradefylline.9,10 In addition, secondary endpoints commonly used to assess symptoms in PD drug trials (e.g., UPDRS, “on” time) or global measures of functioning (e.g., CGI, SF-36) did not find statistically significant benefit with istradefylline versus placebo. The FDA had concern that a lack of consistent benefit in the primary endpoint across multiple studies might suggest either that the effect seen on “off” time was inconsistent or clinically trivial, or that the drug’s adverse effects were sufficiently distressing to cause patients’ overall judgements to be of no overall benefit.12 The FDA response indicated that approval would be supported if the drug sponsor was able to demonstrate additional evidence in an adequately designed trial of a decrease in “off” time with istradefylline in patients with advanced PD who were “explicitly maximally and optimally treated with all appropriate available treatments”.12

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Since the original new drug application, the drug sponsor conducted 3 additional RCTs that increase confidence that the gain in “off” time with istradefylline is not obtained at the expense of other benefits like quality of life or functioning.7,8,11 In total, 8 similarly designed RCTs of istradefylline contributed to the body of evidence reviewed by the FDA for approval as adjunctive treatment to levodopa therapy in patients with PD experiencing “off” episodes.4-11 All but one 16-week study has a 12-week duration. The data from these clinical trials are summarized and evaluated below in Table 5.

Approval of istradefylline was based on 4 of the clinical trials conducted that found positive benefit.4,6-8 Similar to the other studies, these trials were randomized, multi-center, double-blind, 12-week, placebo-controlled studies. Two trials were conducted in Japan.7,8 These studies enrolled patients with a mean duration of PD of about 9 years with HY scale of 2 to 4 who experienced at least 2 hours of “off” time per day (mean time was 6 hours per day).12 All patients were already treated with levodopa for at least one year(dose range 416 to 785 mg/day).12 Patients continued levodopa therapy with other concomitant PD medications, provided the medication doses were stable for at least 4 weeks before screening and throughout the study period. Concomitant PD medications included dopamine agonists (85%), COMTIs (38%), MAOBIs (40%), amantadine (33%), and anticholinergics (13%).12

The primary efficacy endpoint in all of the trials was the change from baseline in daily awake percentage of “off” time, or the change from baseline in total daily “off” time based on 24-hour “on/off” diaries completed by patients. These diaries consisted of 30-minute time periods for 24 hours. Each 30-minute period was classified into the following 5 categories of the patient’s condition: Asleep, “off” state, “on” state without dyskinesia, “on” state with nontroublesome dyskinesia, and “on” state with troublesome dyskinesia.

Enrolled patients reported to the clinic to complete 4 consecutive 30-minute periods (and more if necessary) during which the patient had to experience both “on/off” periods. To ensure all enrolled patients were adequately trained, there had to be at least an 80% concordance between the patient’s and clinician’s ratings of the patient’s motor state prior to randomization. Outcome assessments included the review of 2 valid patient diaries completed on any 2 consecutive days during the week prior to the baseline visit and each subsequent visit at weeks 2, 4, 8, and 12. A “valid” patient diary was defined as a diary in which there were no more than 4 incorrect entries (i.e., missing or duplicate entries).

The benefit over placebo in “off” time reduction was 0.7 to 0.9 hour per day, which correlated to a relative reduction of about 15% from “off” time experienced at baseline.12 Based on evidence submitted to the FDA, there was also an improvement in “on” time without troublesome dyskinesia in patients treated with istradefylline, which supports the benefit found in the primary endpoint of reduction in “off” time.12 Relative to placebo, the increase in “on” time without troublesome dyskinesia with istradefylline ranged between 0.7 to 1 hour for the 40 mg daily dose, and between 0.6 and 0.8 hour for the 20 mg daily dose.12 In addition, the FDA emphasized that any clinically meaningful effects on “off” time should be accompanied with an increase in “on” time without troublesome dyskinesia, which would then translate into an improvement on non-specific global or quality of life measures rated by patients. Of the 4 trials the FDA considered for approval, 2 trials found a 2-point benefit with the 40 mg dose in the UPDRS part III “on” state7,8 and one trial found a 1.7-point benefit in the UPDRS part II “off” state with the 40 mg dose.8 Other UPDRS sections did not improve with istradefylline, including Part I; Part II “on” and Part IV. Total UPDRS scores also did not differ between istradefylline and placebo.4 None of the clinical trials found clinically meaningful differences between istradefylline and placebo in improvement of UPDRS scores over 12 weeks of treatment. One trial found improvement in CGI-I, which observed 20.8% and 28.7% felt “much improved” or “very much improved”, relative to only 10.7% of patients treated with placebo.8 Other trials did not find a statistically significant difference in CGI- I, CGI-S, PGI-I, PDQ-39, and SF-36 scores between istradefylline and placebo.6,7

Risks of bias for each trial are outlined in Table 5. In summary, risk of selection and performance bias is unclear as methodology of randomization and practices to keep group allocation concealed and patients, providers, investigators, and data analysts blinded to the treatment were not described. Symptoms were Author: Gibler Date October 2020 67 documented retrospectively in a patient diary and submitted to investigators. While practical for the patient, this may introduce some detection bias depending on the accuracy of the patient’s diary entry. A modified intention-to-treat principle was applied, meaning only patients successfully enrolled, randomized and had taken at least one dose of treatment were included in the data analysis. However, because attrition was low prior to administration of first treatment dose, it is doubtful bias could be introduced. Reporting bias was a concern overall. Two studies have not been published and results were not submitted to ClinicalTrials.gov.10,11 In addition, key secondary endpoints were often presented differently than described in the methods, or were not described at all.5-7,9 Kyowa Pharmaceuticals provided study funding for all clinical trials.

Overall, there is general applicability of these studies to patients with PD covered under the OHP. Patients had PD with HY scale 2 to 4 and were already optimized on levodopa therapy and 1-2 other PD drugs like a dopamine agonist. Mean ages ranged from 63-66 years of age. Two positive studies considered by the FDA were conducted in Japan, but subgroup analyses conducted by the FDA did not consider lack of efficacy to be an issue in patients specifically from North America. A clear dose response was not observed between the 20 mg and 40 mg doses; however, doses less than 20 mg or more than 40 mg are not recommended based on the studies conducted that evaluated these doses.5,9

As is common with short-term Phase 3 clinical trials, there are gaps in evidence with the efficacy of long-term use of istradefylline. Clinical trials were limited to 12 weeks and designed to assess initial efficacy of istradefylline. However, an open-label, 52-week continuation study appears to show that the improvement in “off” time is largely sustained.40 Comparative trials with other adjunctive PD therapies are also lacking, the exception being a comparison of istradefylline or entacapone versus placebo, which demonstrated statistically superior efficacy of entacapone versus placebo but not with istradefylline.12 The 0.7 to 0.9 improvement in “off” time observed with istradefylline is within the 0.5 to 2.0 hour range seen with other PD drugs in clinical trials.12 Based on the demographics of the patients studied, levodopa therapy should be optimized along with at least one additional adjunctive PD drug before a trial of istradefylline is initiated.

Clinical Safety: The most frequent adverse effects observed in clinical trials (5% or more frequent than placebo) were dyskinesia, dizziness, constipation, nausea, hallucinations and insomnia.12 Table 2 summarizes adverse events with an incidence of at least 2% and higher than placebo in patients treated with istradefylline. The drug sponsor describes the effect of istradefylline as being non-dopaminergic; however, the adverse event profile suggests istradefylline increases dopaminergic activity in the brain.12 Dyskinesia, hallucinations and dizziness are adverse effects frequently reported in patients treated with medications that increase the effects of dopamine in the central nervous system. Evidence also suggests that istradefylline, like other PD drugs, may increase risk for impulse control disorders.12 In these clinical studies, rates of impulse control disorders were 0.8% with istradefylline 20 mg and 0.6% with istradefylline 40 mg.12 Impulse control disorders were not observed in any patients treated with placebo.12

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Table 2. Adverse Events with an Incidence of at Least 2% in Patients Treated with Istradefylline, and Higher than Placebo.12 Adverse Event PBO (n=426) IST 20 mg (n=356) IST 40 mg (n=378) % % % Nervous System Dyskinesia 8 15 17 Dizziness 4 3 6 Gastrointestinal Constipation 3 5 6 Nausea 5 4 6 Diarrhea 1 1 2 Psychiatric Hallucinations 3 2 6 Insomnia 4 1 6 Nutritional Decreased Appetite 1 1 3 Laboratory Data Blood Alkaline Phosphatase 1 1 2 Blood Glucose 0 1 2 Blood Urea 0 1 2 Respiratory Upper Respiratory Tract Infections 0 1 2 Skin Rash 1 1 2 Abbreviations: IST = istradefylline; PBO = placebo

None of the reported deaths during participation in clinical trials were clearly related to istradefylline. Overall, the frequency of serious adverse events was low and similar across all treatment groups (istradefylline 20 mg, 3.9%; istradefylline 40 mg, 4.8%; placebo 3.1%). There were no clinically meaningful changes in vital signs, ECG parameters (e.g., QT interval), hematology, electrolytes or chemistry values in patient enrolled in these trials.

About 90% of patients completed the studies. The percentage of patients who discontinued a study prematurely because of an adverse event was similar between placebo, istradefylline 20 mg and istradefylline 40 mg. The most common adverse events leading to early study discontinuation were nausea/vomiting, (0.4%) and psychosis/delusions/hallucinations (0.4%). Table 3 summarizes the pooled attrition across all studies and these specific study arms.

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Table 3. Pooled Attrition Rates Across all Studies.12 Reason for Early Study PBO (n=1010) IST 20 mg (n=869) IST 40 mg (n=869) Discontinuation % % % Adverse Event 5.4 5.5 7.5 Completed Study 89.8 90.4 89.4 Death 0.5 0 0.3 Lack of Efficacy 0.2 0.2 0.3 Non-compliance with Study Drug 0.2 0 0.3 Other 0.3 0.2 0.2 Physician Decision 0.3 0.3 0 Protocol Deviation 0.6 0.9 0.1 Screen Failure 0.1 0.1 0.1 Withdrawal by Subject 2.8 2.2 1.9 Abbreviations: IST = istradefylline; PBO = placebo

As is common with short-term Phase 3 clinical trials, there are gaps in evidence with the safety of long-term use of istradefylline. Clinical trials were limited to 12 weeks and designed to assess initial efficacy of istradefylline, not the safety of the drug. An open-label, 52-week continuation study reported higher frequencies of the most commonly observed treatment-emergent adverse effects (TEAE) than the 12-week clinical trials.40 The most commonly reported TEAEs were nasopharyngitis (25.0%) and dyskinesia (25.0%), followed by visual hallucinations (11.0%), contusion (9.0%), and weight decrease (8.0%).40 Comparative trials with other adjunctive PD therapies are also lacking, so harms cannot be directly compared between istradefylline and other commonly used adjunctive PD drugs. However, early adverse event rates appear to be similar to those observed in short-term clinical trials with other PD drugs. The FDA did not request any further post-marketing requirements.

Look-alike / Sound-alike Error Risk Potential: none reported.

Table 4. Pharmacology and Pharmacokinetic Properties.41 Parameter Selective adenosine A2A receptor antagonist. These receptors are on the medium spiny neurons of the striatopallidal pathway, which results in an increase in the striatal GABAergic inhibition and decreased release of -aminobutyric acid. These changes decrease excessive Mechanism of Action activation of the striatopallidal output and potential alleviation of motor symptoms of Parkinson’s disease.

Oral Bioavailability Median Tmax about 4 hours under fasting conditions Distribution and The plasma protein binding is about 98% Protein Binding Vd/F = 557 L Elimination Total clearance = 4.6 L/h; about 48% in feces and about 39% in urine

Half-Life Cmax = 2-5 h; t1/2 = 83 h (at steady-state) Author: Gibler Date October 2020 70

Metabolism Primarily hepatic through CYP3A4 and CYP1A1 pathway; modest CYP3A4 inhibitor Abbreviations: Cmax = maximum concentration; h = hours; L = liters; t1/2 = half-life; Tmax = time to reach the maximum concentration; Vd/F = apparent volume of distribution

In patients with moderate hepatic impairment (Child-Pugh B), the steady-state exposure (AUC0-24) of istradefylline is predicted to be 3.3-fold higher relative to healthy patients, based on the estimated mean terminal half-life.41 No clinically relevant changes in istradefylline exposure were observed in patients with severe renal impairment (creatinine clearance [CrCL] 15-29 mL/min) or mild hepatic impairment.41 Istradefylline has not been studied in patients with end-stage renal disease (ESRD) (CrCL < 15 mL/min), ESRD patients requiring hemodialysis, or severe hepatic impairment (Child-Pugh C).41

Comparative Endpoints: Clinically Meaningful Endpoints: Primary Study Endpoint: 1) Motor symptoms (e.g., bradykinesia, rigidity, resting tremor) 1) Change in % “off” time per day at week 12 from baseline 2) Non-motor symptoms (e.g., autonomic, psychiatric and cognitive impairment) 3) Function (disability and impairment) 4) Health-related quality of life (e.g., PDQ-39) 5) Serious adverse events

Author: Gibler Date October 2020 71

Table 5. Comparative Evidence Table for Istradefylline. Ref./ Drug Regimens/ Patient Population N Efficacy Endpoints ARR/NNT Safety Outcomes ARR/NNH Risk of Bias/ Study Duration Applicability Design 1. LeWitt, et 1. istradefylline 40 Demographics: ITT: Primary Endpoint: TEAE: NA Risk of Bias (low/high/unclear): al.4 mg/d -Mean age: 63 y 1. 129  % OFF state during daily 1. 89.1% Selection Bias: (unclear) Method of -Male: 60% 2. 66 awake time (0-12 weeks) 2. 86.4% randomization and concealment of allocation DB, PC, RCT, 2. placebo -White: 95% [total hr per day denoted as not described; demographics similar between MC -Mean L-dopa dose: PP: OFF divided by total hr TESAE: groups. 2:1 ~570 mg/d 1. 114 awake] 1. 7.8% Performance Bias: (unclear) states study was 12 weeks -Dopa agonist: 86% 2. 58 2. 1.5% “double blind” but no other details provided. -Daily OFF state: 1. -10.8% 16.6% Detection Bias: (high) Patients underwent 6002-US-005 ~38%; or 7.2 h/d Attrition: (95% CI, -13.46 to -7.52%) Dyskinesia: diary training to record PD states (ON, OFF, -Daily ON state w/o 1. 15 2. -4.0% 15.7% 1. 30.2% ASLEEP). Patients recorded status over each troublesome (11.6%) (95% CI, -7.73 to 0.31%) 2. 15.2% 30-min period during a 24-hour day. 80% dyskinesia: 57.6%; 2. 8 concordance with investigator’s simultaneous or 9.5 h/d (12.1%) LSMD: -6.8% (95% CI, -11.6 Accidents from Falls: ratings during a 5-hr observation trial was to -1.9%; p=0.007) NA 1. 3.1% needed to verify symptom interpretation and Key Inclusion 2. 9.1% diary training. Patients recorded symptoms in Criteria: Secondary Endpoints: diary for 2 consecutive days during the 7-d -Idiopathic PD  total hours OFF state Study period preceding each visit. -HY scale 2-4 during daily awake time (0- Discontinuation Attrition Bias: (low) mITT principle applied -L-dopa 12 weeks): from TEAE: using LOCF (subjects who took 1 dose of responsiveness 1 y 1. -1.8 h 2.8h (SD) 1. 7.0% study drug); 88% completed study. -L-dopa 4 doses/d 2. -0.6h 2.7h (SD) 2. 7.6% Reporting Bias: (low) Endpoints provided as (3 doses/d if 2 Difference: p=0.006 (CI NR) NA described in methods but 95% CI not from sustained provided. release  total hours of daily awake Other Bias: (high) Kyowa Pharmaceuticals formulation) time in ON state w/o provided study drug but funding of study not -OFF time 2 h/24 h troublesome dyskinesia: disclosed; extent sponsor was involved in based on home 1. 1.5 h 2.9 h (SD) study data interpretation was not disclosed. diary 2. 0.5 h 2.7 h (SD) -Other PD drugs Difference: p=0.026 (CI NR) NA Applicability: permitted w/o dose Patient: All patients took L-dopa; 86% took at

changes  UPDRS evaluations, total least one additional PD drug, most on a

of part I-IV (0-12 weeks): dopaminergic agonist.

Key Exclusion 1. -2.0 (SD 8.42) Intervention: FDA-approved dose studied.

Criteria: 2. -1.5 (SD 9.97) Study medication compliance “nearly NS NR Difference: p=0.598 (CI NR) complete”. Comparator: Placebo appropriate to establish efficacy of istradefylline.

Author: Gibler Date October 2020 72

Outcomes: 1.4 hr difference in OFF state between istradefylline and placebo may be clinically significant to PD patients. Setting: 23 clinic sites in US and Canada. 2. Stacy, et 1. Istradefylline 20 Demographics: ITT: Primary Endpoint: TEAE: NA Risk of Bias (low/high/unclear): al.5 mg/d -Mean age: 64 y 1. 163  % OFF state during daily 1. 60.1% Selection Bias: (unclear) See LeWitt, et al. -Male: 67% 2. 155 awake time (0-12 weeks): 2. 63.2% Performance Bias: (unclear) Administered in a DB, PC, RCT, 2. Istradefylline 60 -Race: NR 3. 77 1. -7.83% (95% CI, -10.05 to - 3. 55.8% “double-dummy” fashion, no other details of MC mg/d -Mean L-dopa dose: 5.60%) blinding provided. NR PP: 2. -7.96% (95% CI, -10.28 to - TESAE: Detection Bias: (high) See LeWitt, et al. 12 weeks 3. Placebo -Dopa agonist: 91% 1. 152 5.65%) 1. 3.7% Attrition Bias: (high) mITT principle applied -Daily OFF state: 2. 126 3. -3.47% (95% CI, -6.68 to - 2. 10.3% using LOCF (subjects who took 1 dose of 6002-US-006 2:2:1 ~35%; or 5.9 h/d 3. 69 0.27) 3. 6.5% study drug); 20% attrition in 60 mg group. -Daily ON state w/o Reporting Bias: (high) Primary endpoint and troublesome Attrition: LSMD 1 vs. 3: -4.35% (95% Dyskinesia: key secondary endpoint provided as dyskinesia: ~44.8%; 1. 11 CI, -8.16 to -0.54%; p=0.026) NA 1. 23.9% described in methods. Missing data for all or 7.5 h/d (7%) LSMD 2 vs. 3: -4.49% (95% 2. 22.6% other secondary efficacy endpoints, including 2. 29 CI, -8.35 to -0.62; p=0.024) NA 3. 14.3% UPDRS and CGI-I. Key Inclusion (19%) Other Bias: (high) Kyowa Pharmaceuticals Criteria: 3. 8 Secondary Endpoints: Nausea: developed the research protocol, provided See LeWitt, et al. (10%)  daily awake hours OFF (0- 1. 20.0% the data set, and conducted the statistical 12 weeks): 2. 10.4% analysis of this clinical trial. Authors were Key Exclusion 1. -1.24 h (95% CI, -1.62 to - 3. 6.5% major shareholders, employees or paid Criteria: 0.86 h) consultants for Kyowa Pharmaceuticals. NR 2. -1.37 h (95% CI, -1.77 to - Dizziness: 0.97 h) 1. 11.0% Applicability: 3. -0.60 h (95% CI, -1.15 to - 2. 11.0% Patient: All patients took L-dopa; 91% 0.05 h) 3. 6.5% received at least one additional dopaminergic agent. Overall treatment effect: Hallucinations: Intervention: 60 mg/d not approved by FDA; p=0.65 (mean differences 1. 5.2% 95% of subjects in each group 90% and 95% CI NR) NS 2. 4.9% compliant with study drug. 3. 1.3% Comparator: placebo appropriate to establish  daily awake hours ON w/o efficacy of istradefylline. troublesome dyskinesia: Outcomes: 0.64 hr difference in OFF state Individual group data NR. between istradefylline and placebo may not 1 vs. 3: 0.71 h; p=NS (CI NR) NS be clinically significant to PD patients without 2 vs. 3: 0.60 h; p=NS (CI NR) NS improvement in functioning or quality of life. No dose response observed in efficacy  UPDRS (0-12 weeks): between 20 mg and 60 mg doses. 1 vs. 3: data NR but p=NS NS Setting: 40 clinic sites in North America. 2 vs. 3: data NR but p=NS NS

 CGI-I (0-12 weeks): 1 vs. 3: data NR but p=NS NS 2 vs. 3: data NR but p=NS NS Author: Gibler Date October 2020 73

3. Hauser, et 1. Istradefylline 20 Demographics: ITT: Primary Endpoint: TEAE: NA Risk of Bias (low/high/unclear): al.6 mg/d -Mean Age: 63.5 y 1. 112  % OFF state during daily 1. 79.1% Selection Bias: (unclear) Randomization -Male: 66.5% 2. 113 awake time (0-12 weeks): 2. 75.7% scheduled in blocks of 4 and provided by DB, PC, RCT, 2. Placebo -White: 91.7% Aptuit Clinical Packaging and Logistics; MC -PD Duration: 9.4 y PP: 1. -9.3% Early demographics similar between groups. 1:1 -90% received PD 1. 104 2. -5.0% Discontinuation Performance Bias: (low) Placebo “matched” 12 weeks drugs (in addition to 2. 103 from AE: the 20-mg istradefylline tablet. The subject, L-dopa) LSMD: 4.6% (95% CI, 0.6 to NA 1. 5.2% site personnel, and sponsor were blinded to 6002-US-013 -% OFF state per Attrition: 8.6%; p=0.03) 2. 6.1% the subject’s assigned treatment group. day: 39.8% 1. 12 Detection Bias: (low) Clinical monitors and istradefylline and (11%) Secondary Endpoints: SAE: data management personnel were blinded 38.7% placebo. 2. 12  total hours OFF state 1. 3.5% until after the study was complete. -Mean L-dopa dose: (11%) during daily awake time (0- 2. 4.3% Attrition Bias: (high) Efficacy analysis based 642 mg/d 12 weeks): on mITT (subjects who took 1 dose of study 1. 1.6 h (6.7 h to 5.1 h) Dyskinesia: drug and who provided at least one valid Key Inclusion 2. 0.9 h (6.5 h to 5.7 h) 1. 22.6% postbaseline diary). Unclear how missing data Criteria: LSMD 0.7 h (95% CI, -1.4 to - 2. 12.2% or unusable data (nonvalid diary entry) See LeWitt, et al. 0.1 h; p=0.03) NA imputed. except: Lightheadedness: Reporting Bias: (high) Only primary endpoint -OFF time 3 h/24 h  UPDRS (0-12 weeks): 1. 7.8% disclosed in methods; all other endpoints based on home 2. 3.5% were not defined a priori. diary Part II (activities of daily Other Bias: (unclear) Study sponsored by living), ON state: Kyowa Pharmaceutical, Inc. Key Exclusion 1. -0.3 (SD 3.2) Criteria: 2. -0.9 (SD 3.5); p=0.21 NS Applicability: -Previous Patient: All patients took L-dopa; 90% istradefylline tx Part II (activities of daily received at least one additional dopaminergic -Atypical or living), OFF state: agent. secondary 1. -1.3 (SD 3.8) Intervention: FDA-approved dose studied. Parkinsonism 2. -1.6 (SD 3.7); p=0.38 NS Adherence rate not disclosed. -Prior neurosurgery Comparator: placebo appropriate to establish for PD Part III (motor): efficacy of istradefylline. -MMSE score <26 1. -3.2 (SD 8.7) Outcomes: 0.7 hr difference in OFF state -Antipsychotic use 2. -1.9 (SD 8.7); p=0.41 NS between istradefylline and placebo may not in the last 3 months be clinically significant to PD patients without Part II and III total score: an improvement in functioning or quality of 1. -4.7 (SD 12.1) life observed. 2. -4.3 (SD 11.7); p=0.97 NS Setting: 26 clinic sites in the U.S.

 PDQ-39, SF-36, CGI-S and PGI-I (0-12 weeks): 1. NR for all 2. NR for all, but all p=NS NS Author: Gibler Date October 2020 74

4. Mizuno, 1. Istradefylline 20 Demographics: ITT: Primary Endpoint: TEAE: NA Risk of Bias (low/high/unclear): et al.7 mg/d -Mean age: 65 y 1. 119  total hours OFF state 1. 59.3% Selection Bias: (unclear) Method of -Male: 42% 2. 125 during daily awake time (0- 2. 59.2% randomization and concealment of allocation DB, PC, RCT, 2. Istradefylline 40 -PD Duration: 8 y 3. 119 12 weeks): 3. 58.0% not described; demographics similar between MC mg/d -Mean L-dopa dose: 1. -1.31 h (LSM) groups. 1) 407 mg PP: 2. -1.58 h (LSM) Dyskinesia: Performance Bias: (unclear) Only states the 12 weeks 3. Placebo 2) 415 mg 1. 106 3. -0.66 h (LSM) 1. 8.5% study was “double blind”. 3) 426 mg 2. 112 2. 6.4% Detection Bias: (high) 95% CI not provided for 6002-0608 1:1:1 -Daily OFF time: 3. 109 LSMD 1 vs. 3: -0.65 h (95% 3. 2.5% endpoints; unclear if data analysists blinded. 1) 6.79 h CI, -1.23 to -0.07h; p=0.013) NA Attrition Bias: (high) mITT applied (1 dose 2) 6.55 h Attrition: LSMD 2 vs. 3: -0.92 h (95% Nasopharyngitis: received + 1 set of diaries submitted). 3) 6.43 h 1. 13 CI, -1.49 to -0.35h; p<0.001) NA 1. 5.9% Missing values at week 12 or early -Dopamine agonist: (11%) 2. 8.8% termination were imputed using LOCF. 1) 95.7% 2. 13 Secondary Endpoints: 3. 4.2% Reporting Bias: (high) Several key secondary 2) 91.9% (10%) CGI-I: endpoints related to functioning and ON state 3) 89.0% 3. 10 “Much Improved”: without dyskinesia not disclosed as outlined (8%) 1. 20.9% in methods. Key Inclusion 2. 23.4% Other Bias: (unclear) Study supported by an Criteria: 3. 14.4% unrestricted research grant from Kyowa -Idiopathic PD “Minimally Improved”: Hakko Kirin CO., Ltd., Japan. -HY scale 2-4 1. 56.5% -3 doses of L- 2. 56.5% Applicability: dopa/DCI per day 3. 46.6% Patient: Only Japanese patients studied. All -L-dopa dose 300 Overall CGI-I Improvement: patients took L-dopa; >90% received at least mg/d 1 vs. 3: p=0.074 (CI NR) NS one additional dopaminergic agent. -Stable PD drug 2 vs. 3: p=0.096 (CI NR) NS Intervention: FDA-approved doses studied regimen but no dose-response observed. Adherence -OFF time 2 h/24 h  UPDRS Part I-III total rate not disclosed. based on home score: NR NA Comparator: Placebo appropriate to establish diary efficacy of istradefylline. -Age 20 y  UPDRS part III ON state (0- Outcomes: Difference in efficacy between 20 12 weeks): mg and 40 mg doses not observed; the 0.65 h Key Exclusion 1. -5.7 (LSM) and 0.92 h differences in OFF state between Criteria: 2. -5.7 (LSM) istradefylline doses and placebo may not be -Prior neurosurgery 3. -3.7 (LSM) clinically significant to PD patients without for PD 1 vs. 3: -2.0; p=0.006 (CI NR) NA improvement in quality of life; some function -TMS in past 6 2 vs. 3: -2.0; p=0.006 (CI NR) NA improvement reported, but lack of reporting months of several key secondary endpoints makes -MMSE score <26 or  ON state w/o troublesome interpretation difficult. dementia dyskinesia (0-12 weeks): NR Setting: 47 clinic sites in Japan. 1. 0.57h12 2. 0.65h12 3. NR 1 vs. 3: NR NA Author: Gibler Date October 2020 75

2 vs. 3: “nominal” p<0.0512 NA

5. Mizuno, 1. Istradefylline 20 Demographics: ITT: Primary Endpoint: TEAE: Risk of Bias (low/high/unclear): et al.8 mg/d -Mean age: 66 y 1. 120  total hours OFF state 1. 65.0% Selection Bias: (unclear) Method of -Male: 44% 2. 123 during daily awake time (0- 2. 59.7% randomization and concealment of allocation DB, PC, RCT, 2. Istradefylline 40 -PD Duration: 7.7 y 3. 123 12 weeks): 3. 51.6% not described; demographics similar between MC mg/d -Mean L-dopa dose: 1. -0.99 h (LSM) groups. 1) 431 mg PP: 2. -0.96 h (LSM) SAE: Performance Bias: (unclear) Only states the 12 weeks 3. Placebo 2) 421 mg N=373 3. -0.23 h (LSM) 1. 5.0% study was “double blind”. 3) 425 mg (groups 2. 4.9% Detection Bias: (unclear) 95% CI not provided 6002-009 1:1:1 -Daily OFF time: NR) LSMD 1 vs. 3: -0.76 h (95% 3. 1.6% for endpoints; unclear if data analysts were 1) 6.55 h CI, -1.30 to -0.22 h; p=0.003) NA blinded. Patients completed diaries for 7 2) 5.97 h Attrition: LSMD 2 vs. 3: -0.74 h (95% Dyskinesia: consecutive days before visits in weeks 2, 4, 8 3) 6.31 h 7 CI, -1.27 to -0.20 h; p=0.003) NA NR and 12. -Dopamine agonist: subjects Attrition Bias: (unclear) mITT defined as 1) 85.8% total Secondary Endpoints: patients who received 1 dose and submitted 2) 83.7% (groups  Daily ON state w/o 4 valid diaries for evaluation. Attrition rates in 3) 91.1% NR) troublesome dyskinesia: each group are unclear. Unclear how missing -Daily “on” time 1. 1.09 h data were imputed. without 2. 1.08 h Reporting Bias: (low) Endpoints reported as troublesome 3. 0.26 h outlined in methods but some secondary dyskinesia: endpoints were emphasized more than 1) 1.00 h LSMD 1 vs. 3: 0.83 h (CI NR) others. 2) 1.13 h (p=0.003) NA Other Bias: (unclear) Study supported by an 3) 0.94 h LSMD 2 vs. 3: 0.81 h (CI NR) unrestricted research grant from Kyowa (p=0.004) NA Hakko Kirin CO., Ltd., Japan. Key Inclusion Criteria:  UPDRS Part I-IV total Applicability: See Mizuno7 score: NR NA Patient: Only Japanese patients studied. All patients took L-dopa; >90% received at least Key Exclusion  Part I: p=NS for all NS one additional dopaminergic agent. Criteria:  Part II ON: p=NS for all NS Intervention: FDA-approved doses studied 7 See Mizuno  Part II OFF: but no dose-response observed. Adherence 1 vs. 3 p=NS; NS rate not disclosed. 2 vs. 3 = -1.7 (p=0.009) NA Comparator: Placebo appropriate to establish  Part III ON: efficacy of istradefylline. 1 vs. 3 p=NS; NS Outcomes: Difference in efficacy between 20 2 vs. 3 = -2.0 (p=0.001) NA mg and 40 mg doses not observed; the 0.76 h  Part IV: p=NS for all NS and 0.74 h differences from istradefylline and placebo in OFF state may not be clinically CGI-I: significant to PD patients. Safety outcomes “Much Improved” and “Very not clearly reported. much Improved”: Setting: 44 clinic sites in Japan. 1. 20.8% (p=0.005 vs. 3) NA 2. 28.7% (p<0.01 vs. 3) NA 3. 10.7% Author: Gibler Date October 2020 76

6. Pourcher, 1. Istradefylline 10 Demographics: ITT: Primary Endpoint: TEAE: NA Risk of Bias (low/high/unclear): et al.9 mg/d -Mean age: 63 y 1. 155  % OFF state during daily 1. 82.4% Selection Bias: (unclear) Method of -Male: 67% 2. 149 awake time (0-12 weeks): 2. 83.9% randomization and concealment of allocation DB, PC, RCT, 2. Istradefylline 20 -White: 93% 3. 152 1. -5.7% 3. 84.2% not described; demographics similar between MC mg/d -PD Duration: 8.9 y 4. 154 2. -6.1% 4. 76.2% groups. -Mean % time in 3. -9.1% Performance Bias: (unclear) the study used a 12 weeks 3. Istradefylline 40 OFF state: 40.2% PP: 4. -7.6% (p=0.475 vs 2 and 3) NS Early “matching placebo” and stated the patient, mg/d (6.7 h) 1. 149 Discontinuation site personnel, and the study sponsor were 6002-US-018 -Mean L-dopa dose: 2. 144 Secondary Endpoints: from TEAE: blinded to group assignments. 4. Placebo 663 mg/d 3. 145  total hours OFF state 1. NR Detection Bias: See LeWitt, et al. 4. 146 during daily awake time (0- 2. 10.1% Attrition Bias: (low) mITT defined as patients 1:1:1:1 Key Inclusion 12 weeks): 3. 9.2% who received 1 dose and had 1 valid Criteria: Attrition: 1. -1.0 h 4. 4.2% baseline and 1 valid post-baseline diary -Age 30 y 1. 19 2. -1.1 h assessment; missing data analyzed by LOCF. -UKPDS criteria for (12.4%) 3. -1.5 h Dyskinesia: Reporting Bias: (high) Several secondary PD diagnosis 2. 18 4. -1.3 h (p=0.529 vs 2 and 3) NS 1. 21.6% outcomes not reported except to note study - HY scale 2-4 in OFF (12.1%) 2. 16.8% drug was not statistically different from state 3. 17  total hours per day awake 3. 26.3% placebo. Overall p-values between all doses -Mean 180 min/d (11.2%) in ON state (w/ and w/o 4. 19.2% given without confidence intervals; unclear in OFF time 4. 14 dyskinesia and w/ and w/o how individual groups statistically compare -3 doses/d of L- (9.3%) nontroublesome dyskinesia): Insomnia: vs. placebo based on overall treatment p- dopa for 1 y NR but p=NS for all NS 1. 6.5% values. -Predictable end-of- 2. 7.4% Other Bias: (high) Kyowa Hakko Kirin Pharma, dose wearing-off  UPDRS Part II ON state (0- 3. 10.5% Inc., developed the research protocol, -Stable PD regimen 12 weeks): 4. 7.3% provided the data set, and conducted the for 4 weeks 1. -0.5 (SD 3.7); 2. -0.2 (SD statistical analysis of the trial. Multiple 3.4); 3. -0.7 (SD 3.8); 4. -0.6 Worsened PD: authors received compensation from Kyowa Key Exclusion (SD 3.6); overall p=0.961 NS 1. 11.1% Hakko Kirin Pharma, Inc. Criteria: 2. 6.0% NR  UPDRS Part II OFF state (0- 3. 4.6% Applicability: 12 weeks): 4. 5.3% Patient: All patients took L-dopa; 90% took at 1. -1.0 (SD 4.2); 2. -1.8 (SD least one additional dopaminergic agent. 4.6); 3. -1.4 (SD 4.0); 4. -2.1 Intervention: FDA-approved 20 mg and 40 mg (SD 3.8); overall p=0.085 NS doses studied. Some dose-response observed but difficult to interpret with similar response  UPDRS Part III ON state from placebo. Adherence rate not disclosed. (motor scale) (0-12 weeks): Comparator: Placebo appropriate to establish 1. -0.8 (SD 8.5); 2. -1.0 (SD efficacy of istradefylline. 6.9); 3. -0.8 (SD 8.2); 4. -2.9 Outcomes: Study unable to find statistically (SD 9.9); Overall p=0.042 (CI NA significant differences between study drug NR) doses and placebo. Setting: 59 sites in the U.S. and 15 sites in SF-36 (0-12 weeks): Canada. Data NR but 2 vs. 4, p=0.003 NA and 3 vs. 4, p=0.009 Author: Gibler Date October 2020 77

7. NCT 1. Istradefylline 40 Demographics: N=405 Primary Endpoint: TEAE: Note: 0019939410,4 mg/d NR  % OFF state during daily 1. 64.8% Study completed but unpublished so risk of 2 awake time (0-16 weeks): 2. 66.0% bias and applicability of study unclear. 2. Entacapone 200 Key Inclusion 3. 63.8% DB, PC, RCT, mg w/ each L-dopa Criteria: 1. -5.14% Results not submitted to ClinicalTrials.gov and MC dose -Age 30 y 2. -7.82% SEA: are provided by drug sponsor’s dossier. -UKPDS criteria for 3. -4.53% 1. 3.1% 16 weeks 3. Placebo PD diagnosis 1 vs. 3: p=NS per FDA12 NS 2. 3.3% - HY scale 2-4 in OFF 2 vs. 3: p<0.05 per FDA12 NA 3. 3.9% 6002-EU-007 1:1:1 state -Mean 180 min/d Secondary Endpoints: Early in OFF time  % ON state during daily Discontinuation -3 doses/d of L- awake time (also w/ and from AE: dopa for 1 y w/o dyskinesia and w/ and 1. 4.4% -Predictable end-of- w/o nontroublesome 2. 6.5% dose OFF episodes dyskinesia): 3. 6.6% -Stable PD regimen 1 vs. 3: p=NS NS for 4 weeks 2 vs. 3: NR NR

Key Exclusion  UPDRS Part III score Criteria: (motor subscale): -Dopamine 1 vs. 3: p=NS NS antagonist or 2 vs. 3: NR NR investigational drug w/i 30 d -Psychotic illness -Atypical or secondary parkinsonism -Cancer in past 5 y

Author: Gibler Date October 2020 78

8. NCT 1. Istradefylline 20 Demographics: N=613 Primary Endpoint: TEAE: Note: 0196803111,4 mg/d NR  total hours OFF state 1. 58.7% Study completed but unpublished so risk of 2 during daily awake time (0- 2. 64.7% bias and applicability of study unclear. 2. Istradefylline 40 Key Inclusion 12 weeks): 3. 55.9% DB, PC, RCT, mg/d Criteria: Results not submitted to ClinicalTrials.gov and MC -Age 30 y 1 vs. 3: -0.32 h; p=0.156 NS SEA: are provided by drug sponsor’s dossier. 3. Placebo -UKPDS criteria for 2 vs. 3: -0.27 h; p=0.234 NS 1. 3.0% 12 weeks PD diagnosis 2. 3.9% 1:1:1 - HY scale 2-4 in OFF Secondary Endpoints: 3. 3.4% 6002-014 state  total hours ON state w/o -Mean 180 min/d troublesome dyskinesia Early in OFF time during daily awake time (0- Discontinuation -3 doses/d of L- 12 weeks): from AE: dopa for 1 y 1. 5.0% -Predictable end-of- 1 vs. 3: 0.24 h; p=0.366 NS 2. 10.6% dose OFF episodes 2 vs. 3: 0.00 h; p=0.986 NS 3. 6.4% -Stable PD regimen for 4 weeks

Key Exclusion Criteria: -Apomorphine, dopamine antagonist, direct GI L-dopa infusion, anticholinergic agents, amantadine alone, or investigational drug w/i 30 d -H/o psychotic illness -H/o sleep attacks -Neurosurgery for PD -Previously treated with istradefylline -CYP3A4 inhibitors and inducers Abbreviations: ARR = absolute risk reduction; CGI-I = Clinical Global Impressions – Improvement in illness scale; CGI-S = Clinical Global Impressions – Severity of Illness Scale; CI = confidence interval; d= days; DB = double blind; DCI = decarboxylase inhibitor (e.g., carbidopa); GI = gastrointestinal; H/o = history of; HY = Hoehn & Yale scale; ITT = intention to treat; L-dopa = levodopa; LOCF = last observation carried forward; LSM = least-square mean; LSMD = least-square mean difference; MC = multicentered; mg = milligrams; mITT = modified intention to treat; MMSE = Mini-Mental State Examination; N = number of subjects; NA = not applicable; NNH = number needed to harm; NNT = number needed to treat; NR = not reported; NS = not statistically significant; PC = placebo controlled; PD = Parkinson’s Disease; PDQ-39 = Parkinson’s Disease Questionnaire; PGI-I = Patient Global Impression – Improvement Scale; PP = per protocol; RCT = randomized controlled trial; SD = standard deviation; SF-36 = Medical Outcomes Study 36-Item Short Form; TEAE = treatment-emergent adverse effects; TESAE = treatment-emergent serious adverse effects; TMS = transcranial magnetic stimulation; UKPDS = United Kingdom’s Parkinson’s Disease Society; UPDRS = Unified Parkinson Disease Rating Scale; y = years. Author: Gibler Date October 2020 79

NEW DRUG EVALUATION:

Clinical Efficacy: The efficacy and safety of opicapone 25 mg and 50 mg daily was established in two identical double-blind, randomized, placebo-controlled trials (Studies 301 and 302) in patients with idiopathic PD and motor fluctuations already treated with levodopa therapy.13,14 Key inclusion and exclusion criteria are listed in Table 8. In both studies, patients were eligible if they were between 30 and 83 years of age with a minimum duration of PD of at least 3 years.13,14 Patients had to be in HY stages 1 to 3 during an “on” state and had to have at least 1.5 hours of “off” time per day.13,14 The primary differences in Study 301 were the addition of a 5 mg opicapone arm and an entacapone arm, which served as an active control to assess non-inferiority of opicapone.13 Each study included multiple study centers across several countries, but no sites in North America participated.13,14 Patients were mostly male (~60%), White (100% in Study 301), with an average age of about 64 years and “off” time of about 6.2-6.5 hours per day.13,14 Mean daily levodopa doses were 700 to 800 mg and most patients were also on a dopamine agonist.13,14

The primary efficacy endpoint for both studies was the total reduction in daily “off” time assessed at 14-15 weeks (visit 7), which was assessed using 24-hour patient diaries in which patients recorded their status as “off”, “on” with troublesome dyskinesia, “on” with non-troublesome dyskinesia, “on” without dyskinesia, or “asleep” for every 30-minute interval for the 3 consecutive days before each clinic visit.13,14 Opicapone 50 mg daily reduced “off” time by 54-61 minutes per day versus placebo (study 301: mean difference [MD] = -60.8 min [95% CI, -97.2 to -24.4]; and study 302: MD = -54.3 min [95% CI, -96.2 to - 12.4]).13,14

The benefit associated with a reduction in absolute “off” time found with the opicapone 50 mg dose must be balanced with a potential increase in “on” time without troublesome dyskinesia. The FDA review of the clinical data found that reduction in “off” time was supported by an increase in “on” time without troublesome dyskinesia for the 50 mg dose.22 The 25 mg dose of opicapone did not reach statistical significance versus placebo in either study.13,14 The 50 mg dose was found to be non-inferior to entacapone in study 301 (see Table 8 for details).13

Key pre-specified secondary endpoints included change in total UPDRS; change in the Parkinson’s Disease Sleep Scale (PDSS), a specific scale used to assess sleep disturbances in patients with PD; and a Non-motor Symptoms Scale (NMSS), all assessed at 14-15 weeks.22 Quality of life was also assessed using the PDQ-39 questionnaire.13,14 Neither study found statistically significant differences between doses of opicapone studied and placebo for these key secondary endpoints.13,14

As outlined in Table 8, both studies were limited by their applicability to the Oregon Medicaid population and concern for potentially high risk of detection and reporting bias.

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Clinical Safety: The most common reason for early withdrawal from the trials was adverse events.13,14 Eight percent of patients treated with opicapone 50 mg discontinued because of an adverse event in studies 301 and 302, with 4% withdrawing early in Study 301 and 12% withdrawing early in Study 302.13,14 Among patients treated with opicapone 50 mg, dyskinesia was the most common adverse event leading to early study discontinuation (3%), contrasting with no discontinuations for dyskinesia in the placebo arms.22 Two percent of patients treated with opicapone 50 mg discontinued because of nausea or vomiting, compared with 0.4% of patients on placebo.22 Five percent of patients treated with opicapone 50 mg experienced at least one serious adverse event in both studies, compared to 4% of patients on placebo.22

Dyskinesia and constipation were the most common adverse events observed in both studies (see Table 6).22 A dose-response for dyskinesia, constipation, and elevated blood creatine phosphokinase was found in the opicapone arms.22 In both studies, 2% of patients treated with opicapone 50 mg developed an impulse control disorder versus zero patients in the placebo arms.22 The incidence of sleep attacks and somnolence was not greater in patients treated with opicapone than on placebo.22

Table 6. Adverse Events reported in ≥2% of Patients Treated with Opicapone 50 mg and With a Higher Incidence Than Placebo.22 Adverse Event Opicapone 50 mg/day (n=265) Placebo (n=257) % % Nervous System Disorders Dyskinesia 20 6 Dizziness 3 1 Gastrointestinal Disorders Constipation 6 2 Dry Mouth 3 1 Psychiatric Disorders Hallucination 3 1 Insomnia 3 2 Vascular Disorders Hypertension 3 2 Hypotension/Syncope 5 2 Other Increased Blood Creatinine Phosphokinase 3 2 Decreased Weight 5 2

Few patients had abnormal ECG findings. In the opicapone 50 mg arm, 5.1% had an QTc greater than 480 milliseconds, versus 2.1% on placebo.22

Creatine kinase (CK) was elevated to at least 3-times the upper limit of normal in 5.4 % of patients treated with opicapone 50 mg, compared with 1.7% on placebo.22 Two patients treated with opicapone discontinued the study early because of elevated CK.22

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In both trials, dyskinesia, constipation, urinary tract infection, headache, and dry mouth were more common in females and in patients 65 years of age or older treated with opicapone 50 mg.22 Elevated CK was observed more frequently in Asian patients than in White patients (9% vs. 4%), but the relatively small number of Asian patients studied limits the interpretability of that observation.22

Overall, the safety profile of opicapone is consistent with its mechanism of action, with adverse reactions mostly mediated by increased exposure to levodopa and dopamine. The safety profile is similar to entacapone and tolcapone, but in contrast with tolcapone, with no identified significant hepatic toxicity.22

Look-alike / Sound-alike Error Risk Potential: none reported.

Table 7. Pharmacology and Pharmacokinetic Properties.21,22 Parameter Mechanism of Action Catechol-O-methyltransferase (COMT) inhibition, thereby increasing systemic exposure to levodopa. Not determined.

Repeat daily dosing of opicapone 50 mg with administration of carbidopa/levodopa every 3 or 4 hours increased levodopa Cmax by 43- 44% and AUC by 62-94%.22

The administration of opicapone 50 mg with a high fat meal decreased the opicapone Cmax and AUC by 62% and 31%, respectively, and 22 delayed the median Tmax by 4 hours compared to opicapone administration under fasted conditions. Labeling for opicapone Oral Bioavailability recommends that patients not eat food for at least one hour before and after taking opicapone. Distribution and Opicapone is highly bound to plasma proteins (>99%), which is independent of serum concentration. Protein Binding About 70% of a dose of opicapone is eliminated in the feces (22% unchanged) and 5% in urine (<1% unchanged).

No clinically significant differences in the pharmacokinetics of opicapone were observed in patients with mild to moderate renal impairment. No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. Avoid use of in patients Elimination with ESRD (ClCR <15 mL/min). Half-Life The mean elimination half-life of opicapone is 1 hour. Sulfation is the primary metabolic pathway of opicapone. Other metabolic pathways include glucuronidation, methylation (by COMT), Metabolism reduction, and glutathione conjugation. Abbreviations: AUC = area under the curve; Cmax = maximum concentration; ClCR = creatinine clearance; COMT = catechol O-methyl transferase; ESRD = end stage renal disease; h = hours; L = liters; t1/2 = half-life; Tmax = time to reach the maximum concentration; Vd/F = apparent volume of distribution

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Comparative Endpoints: Clinically Meaningful Endpoints: Primary Study Endpoint: 1) Motor symptoms (e.g., bradykinesia, rigidity, resting tremor) 1) Change in time per day in “off” state 2) Non-motor symptoms (e.g., autonomic, psychiatric and cognitive impairment) 3) Function (disability and impairment) 4) Health-related quality of life (e.g., PDQ-39) 5) Serious adverse events

Table 8. Comparative Evidence Table for Opicapone. Ref./ Drug Regimens/ Patient Population N Efficacy Endpoints ARR/NNT Safety Outcomes ARR/ Risk of Bias/ Study Duration NNH Applicability Design 1. Ferreira, 1. Opicapone PO Demographics: ITT: Primary Endpoint: TEAE: NA Risk of Bias (low/high/unclear): et al. 5 mg QHS -Mean age: 64 y 1. 122  time in OFF state (baseline 1. 52% Selection Bias: (low) randomized by computer- -Male: 59% 2. 119 to 14-15 wks) 2. 55% generation by blocks of 8-10 depending on Study 301 2. Opicapone PO -White: 100% 3. 116 1. -91.3 min (95% CI, -117.5 3. 54% regimen, stratified by center; demographic 25 mg QHS -Mean L-dopa dose: 4. 122 to -64.8 min) 4. 57% characteristics evenly matched. DB, AC, NI, 662 mg/d 5. 121 2. -85.9 (95% CI, -112.8 to - 5. 50% Performance Bias: (low) patients and PC, RCT, MC 3. Opicapone PO -Dopa agonist: 67.5% 59.1 min) investigators blinded to treatment allocation; 50 mg QHS -Daily OFF state: 40%; PP: 3. -116.8 min (95% CI, -144.2 Serious TEAE: masking maintained by use of identical over- 14-15 weeks or 6.5 h/d 1. 110 to -89.4) 1. 3% encapsulation of opicapone and entacapone 4. Entacapone -Daily ON state w/o 2. 105 4. -96.3 min (95% CI, -122.6 2. 1% tablets; placebo matched appearance of 200 mg w/ each troublesome 3. 106 to -70.0) 3. 3% opicapone and entacapone and included L-dopa dose dyskinesia: 6.4%; or 4. 104 5. -56.0 min (95% CI, -82.3 to 4. 5% riboflavin to mimic urinary discoloration caused 0.3 h/d 5. 112 -29.7) 5. 7% by entacapone. Daytime doses of active drugs 5. Placebo PO HY stage during ON given concomitantly w/ L-dopa (ie, 3-8 daily daily state: 2.4 Attrition: MD Vs. Placebo (95% CI): Dyskinesia: doses); additional QHS dose administered at least 1. 9.8% 1. -35.2 min (-71.4 to 0.9) NS 1. 14% 1 h after last daily dose of L-dopa. Opicapone 1:1:1:1:1 Key Inclusion Criteria: 2. 9.2% 2. -29.9 min (-66.3 to 6.5) NS 2. 8% arms took placebo for the daytime doses and -Age 30-83 y 3. 7.8% 3. -60.8 min (-97.2 to -24.4) NA 3. 16% active tx QHS. Entacapone group took active tx -PD 3 y 4. 14.8% 4. -40.3 min (-76.2 to -4.3) NA 4. 8% during the day and placebo at QHS. -HY scale 1-3 during 5. 7.4% 5. 4% Detection Bias: (high) unknown if data assessors ON state 3 vs. 4: MD -26.2 min (95% blinded; endpoints dependent on accuracy/recall -L-dopa use 1 y CI -63.8 to 11.4) meeting NI NA Hallucinations: of patient diaries; tested superiority of each -Stable doses of L- 1. 2% opicapone dose vs. placebo in the mITT analysis dopa and other PD Secondary Endpoints: 2. 8% data set and non-inferiority vs. entacapone in the drug regimens 4 wks 3. 4% PP data set (non-inferiority margin of 30 min). -Awake OFF state 1.5  UPDRS total score (p-value 4. 1% 106 participating centers w/ 600 enrolled patients hr/day, excluding vs. placebo [95% CI NR]) 5. 2% between 2011-2013 might be a source of practice morning akinesia 1. -7.3 (p=0.13) NS variations; low rate of enrollment may suggest 2. -7.0 (p=0.19) NS Study inclusion into the trial was overly selective. Key Exclusion Criteria: 3. -6.1 (p=0.56) NS Discontinuation Attrition Bias: (low) overall attrition <10% in most -Previous use of 4. -6.1 (p=0.56) NS from TEAE: study arms but entacapone arm; however, mITT entacapone 5. -5.4 1. 6% used to analyze efficacy data in patients who took Author: Gibler Date October 2020 83

-UPDRS item 33 2. 7% 1 dose of study drug and had 1 assessment of (disability) score >3  PDSS score (p-value vs. 3. 4% time in OFF state after baseline; compliance w/ (range 0-4) placebo [95% CI NR]) 4. 7% diary entries ranged from 90-100%; LOCF used to -Severe and/or 1. 5.2 (p=0.09) NS 5. 7% impute missing diary data. unpredictable OFF 2. 5.5 (p=0.07) NS Reporting Bias: (high) key pre-specified secondary state 3. 2.9 (p=0.45) NS endpoints registered with the NIH were not -Previous surgery or 4. 2.9 (p=0.45) NS emphasized in publication; alternate secondary deep brain stimulation 5. 1.0 endpoints around ON/OFF times were for PD emphasized; 95% CI not reported for key -h/o NMS or  NMSS score (p-value vs. secondary endpoints. rhabdomyolysis placebo (95% CI NR]) Other Bias: (high) authors employed by drug -Clinically significant 1. -5.6 (p=0.98) NS sponsor and participated in the study design, data CV or psychiatric 2. -4.2 (p=0.45) NS collection, data management, and data analysis. illness 3. -2.0 (p=0.90) NS -Concomitant 4. -4.7 (p=0.63) NS Applicability: tolcapone, 5. -5.7 Patient: Composed of Russians and Europeans apomorphine, without non-White representation; no U.S. neuroleptics,  % time in ON state w/o citizens in study. Patients were mostly older venlafaxine, MAOBI troublesome dyskinesia: males on L-dopa and a dopamine agonist. PD (except selegiline up to 1. 9.1% course for most was mild to moderate, with 10 mg/d PO or 1.25 2. 8.8% bilateral disease without balance difficulties. mg/d buccal and 3. 10.8% Intervention: Dose range study used to determine rasagiline up to 1 4. 9.6% efficacy of opicapone. Findings suggest only the mg/d), antiemetic w/ 5. 5.4% 50 mg dose has efficacy. antidopamine Comparator: Both placebo and active comparator properties MD Vs. Placebo (95% CI): entacapone used to establish efficacy. Opicapone 1. 3.7% (-0.1 to 7.6%) NS 50 mg was non-inferior to entacapone suggesting 2. 3.5% (-0.4 to 7.4%) NS opicapone is another COMTI tx option. 3. 5.4% (1.5 to 9.3%) NA Outcomes: Opicapone evaluated specifically for L- 4. 4.2% (0.4 to 8.1%) NA dopa end-of-dose wearing off; 50 mg dose decreased time in OFF state by 1 hr/day and increased time in ON state without troublesome dyskinesia. However, these changes had no impact on functional status or quality of life. Setting: 106 centers in Europe and Russia. 2. Lees, et 1. Opicapone PO Demographics: ITT: Primary Endpoint: TEAE: NA Risk of Bias (low/high/unclear): al.14 25 mg QHS -Mean age: 63.1 y 1. 129  time in OFF state (baseline 1. 69.6% Selection Bias: (low) patients randomized by -Male: 60.4% 2. 154 to 14-15 wks) 2. 72.0% interactive web response system using blocks Study 302 2. Opicapone PO -White: 67.3% 3. 144 1. -101.7 min (SD 14.9) 3. 64.0% stratified by region. Placebo had fewer males and 50 mg QHS -Mean L-dopa dose: 2. -118.8 min (SD 13.8) more Asian patients compared to active DB, PC, RCT, 700-806 mg/d PP: 3. -64.5 min (SD 14.4) TESAE: treatment arms. MC 3. placebo -Dopa agonist: 69.5% 1. 118 1. 3.2% Performance Bias: (low) opicapone doses and -Daily OFF state: ~38%; 2. 128 MD vs. Placebo (95% CI): 2. 6.0% placebo were identically encapsulated to 14-15 weeks 1:1:1 or 6.2 h/d 3. 130 1. -37.2 min (-80.8 to 6.4) NS 3. 3.7% maintain blinding. -Daily ON state w/o 2. -54.3 min (-96.2 to -12.4) NA Detection Bias: (high) data analyzed by mITT (1 troublesome Attrition: Dyskinesia: dose received and 1 post-baseline assessment); Author: Gibler Date October 2020 84

dyskinesia: ~58%; or 1. 8.5% Secondary Endpoints: 1. 24.0% unknown if data assessors blinded. Endpoints 9.4 h/d 2. 16.9%  UPDRS total score (p-value 2. 24.0% dependent on accuracy/recall of patient diaries; 3. 9.7% vs. placebo [95% CI NR]) 3. 8.1% 71 participating centers w/ 485 enrolled patients Key Inclusion Criteria: 1. -4.4 (p=0.37) NS between 2011-2013 might be concern for practice See Ferreira, et al. 2. -3.5 (p=0.45) NS Falls: variation; low rate of enrollment may suggest 3. -3.5 1. 5.6% inclusion into the trial was overly selective. Key Exclusion Criteria: 2. 4.7% Attrition Bias: (high) 17% attrition in opicapone 50 See Ferreira, et al.  PDSS score (p-value vs. 3. 6.6% mg arm; diary compliance not disclosed; LOCF placebo) method used for missing data. 1. 2.5 (p=0.29) NS Study Reporting Bias: (high) Key pre-specified secondary 2. 2.3 (p=0.23) NS Discontinuation endpoints registered with the NIH were not 3. 5.1 from TEAE: emphasized, rather alternate endpoints around 1. 4.0% ON/OFF times were emphasized; 95% CI not  NMSS score (p-value vs. 2. 12.0% reported for key secondary endpoints. placebo) 3. 7.4% Other Bias: (high) study was funded by the drug 1. -2.0 (p=0.13) NS sponsor; authors received funding or were 2. -4.9 (p=0.88) NS Constipation: employed by drug sponsor. 3. -5.2 1. 9.6% 2. 6.7% Applicability:  time in ON state w/o 3. 1.5% Patient: Patients on stable doses of L-dopa with troublesome dyskinesia: mild to moderate PD without balance difficulties; 1. 84.1 min study did not include any participants from North 2. 85.6 min America; age and gender balanced for PD. 3. 48.1 min Intervention: Opicapone 50 mg demonstrated efficacy at decreasing OFF time vs. placebo with MD vs. Placebo (95% CI): increased risk of adverse events and attrition. The 1. 36.0 min (-5.6 to 77.5) NS 25 mg dose did not demonstrate efficacy. 2. 37.4 min (-2.4 to 77.2) NS Comparator: Placebo was appropriate to establish efficacy in a Phase 3 trial. Outcomes: 50 mg dose decreased time in OFF state by 54 min daily but unclear if ON state without troublesome dyskinesia improved. No impact on functional status or quality of life was observed. Setting: 71 centers in 12 counties (no sites in North America). Abbreviations: AC = active controlled; ARR = absolute risk reduction; CI = confidence interval; COMTI = Catechol-O-methyltransferase inhibitor; d = days; DB = double blind; GI = gastrointestinal; H/o = history of; HY = Hoehn & Yale scale; ITT = intention to treat; L-dopa = levodopa; LOCF = last observation carried forward; MAOBI = monoamine oxidase B inhibitor; MC = multicentered; MD = mean difference; mg = milligrams; mITT = modified intention to treat; N = number of subjects; NA = not applicable; NI = non-inferiority; NMS = neuroleptic malignant syndrome; NMSS = Non-motor Symptoms Scale; NNH = number needed to harm; NNT = number needed to treat; NR = not reported; NS = not statistically significant; PC = placebo controlled; PD = Parkinson’s Disease; PDSS = Parkinson’s Disease Sleep Scale; PO = orally; PP = per protocol; QHS = at bedtime; RCT = randomized controlled trial; SD = standard deviation; TEAE = treatment-emergent adverse effects; TESAE = treatment-emergent serious adverse effects; tx = treatment; UPDRS = Unified Parkinson Disease Rating Scale; y = years.

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NEW DRUG EVALUATION:

Clinical Efficacy: A sublingual (SL) film formulation of apomorphine was developed to address the practical limitations of subcutaneous apomorphine for on-demand, “rescue” treatment of individual “off” episodes. The SL film is designed to be placed under the tongue and deliver apomorphine systemically through absorption from the oral cavity mucosa, thus bypassing extensive first-pass metabolism associated with gastrointestinal administration of the drug.15

The efficacy of apomorphine SL for the acute, intermittent treatment of “off” episodes in patients with PD was established in one randomized, double-blind, placebo-controlled, multi-centered, parallel-group study which included sites from 32 academic neurology centers in the U.S. and one in Canada.15 The effectiveness of apomorphine SC for injection had previously been studied in 3 RCTs for the acute symptomatic treatment of the recurring “off” episodes associated with advanced PD.43

The study enrolled patients with a mean duration of PD of 9 years (range: 2 years to 22 years) who were HY Stage 3 or less in the “on” state.15 The mean number of daily “off” episodes was 4 and the mean duration of “off” episodes was slightly over an hour in both groups.15 The baseline mean MDS-UPDRS part 3 score was 43.15 All patients enrolled were receiving concomitant levodopa at a stable dose (mean 1033 mg/day) for at least 4 weeks before screening.15 The most commonly used concomitant PD medications in addition to levodopa were dopamine agonists (51%), MOABIs (41%), amantadine (21%), and other dopaminergic agents (8%).15

The study included an open-label apomorphine SL titration phase and a 12•week double-blind, placebo-controlled maintenance phase.15 In the open-label titration phase, all patients were titrated at 5 mg increments from 10 mg up to a tolerable dose of apomorphine SL (maximum dose 35 mg) that achieved a full “on” response.15 In the titration phase, 141 patients arrived at the study site in an “off” state having not taken their regular morning dose of carbidopa/levodopa or any other adjunctive PD medications, as well as having taken their last dose of carbidopa/levodopa and any other adjunctive PD medications no later than midnight the night before.15 Patients who tolerated the apomorphine SL dose but did not adequately respond were asked to return to the clinic within 3 days and the dose was increased by 5 mg.15 The titration process was continued up to a maximum dose of 35 mg or until a full “on” response was achieved as determined by the investigator and the patient.15 Patients who achieved a full “on” state with a tolerable dose of apomorphine SL were then randomized in a blinded fashion to apomorphine SL or placebo in a 1:1 ratio.15 Thirty-two patients discontinued the study during the titration phase, including 12 patients who did so because of adverse events.15 In the double-blind maintenance phase, 109 patients were randomly assigned to receive apomorphine SL (n=54) or placebo (n=55).15 The doses of apomorphine SL administered at randomization that resulted in a full “on” response during the titration phase were: 10 mg (18%), 15 mg (27%), 20 mg (21%), 25 mg (19%) 30 mg (8%) and 35 mg (6%).15 Dose administration was permitted up to 5-times per day in the double-blind maintenance phase.15

The primary endpoint of the study was the mean change from pre-dose to 30 minutes post-dose in the MDS-UPDRS Part 3 (motor examination) at the week 12 visit (of note, MDS-UPDRS Part 3 was measured pre-dose, and at 15, 30, 45, 60, and 90 minutes post-dose).15 The key secondary endpoint was the percentage of patients with a patient-rated full “on” response within 30 minutes at the week 12 visit.15 Author: Gibler Date October 2020 86

The change from pre-dose to 30 minutes post-dose in the MDS-UPDRS part 3 score at week 12 was greater in patients who received apomorphine SL (-11.1; 95% CI, -14.0 to -8.2) than in patients treated with placebo (-3.5; 95% CI, -6.1 to -0.9) by a least squares mean difference of -7.6 (95% CI, -11.5 to -3.7; p=0.002), which was statistically significant and met the estimated MCID threshold for part 3 of the MDS-UPDRS (see Background section).15 The investigators found statistically significant differences between the responses in the two arms at all post-dose time measurements (15, 30, 45, 60, 75 and 90 minutes).15

The response rate for a full “on” response within 30 minutes at the week 12 visit was also greater in patients treated with apomorphine SL than in those treated with placebo (35% vs. 16%, respectively; OR 2.81; 95% CI, 1.04 to 7.64; p=0.043).15 Apomorphine SL did not result in statistically significant differences from placebo in improvement in PGI-I at week 12, MDS-UPDRS Part 2 at week 12, or change in PDQ-39 summary index score at week 12.15 More patients treated with apomorphine SL saw improvement in CGI-I scores at week 12 versus patients treated with placebo (41% vs. 20%, respectively; 95% CI not reported; p=0.027); however, it is unclear if the improvement was in CGI-I scores were clinically meaningful.15

The evidence for apomorphine SL is limited to a single trial of 144 patients. The primary endpoint of the study was established to determine the efficacy of apomorphine SL to achieve an “on” response within 30 minutes. The study met the primary endpoint, but some limitations to the trial should be noted. Only patients who were responsive to levodopa and achieved a full “on” response at a tolerable dose during the titration phase were enrolled in the double-blind maintenance phase. Thus, the study was filled with patients who had already responded to apomorphine SL treatment. The treatment effect for “off” episodes were artificially assessed in the clinic in a defined “off” state, although it is worth noting that patients kept diaries that recorded “off” time which were largely congruent with the clinic results for the 2 days prior to the clinic visit. In addition, the high early study discontinuation rate in patients treated with apomorphine SL compared with those treated with placebo might increase risk of attrition bias and affect efficacy outcomes. Lastly, the drug sponsor funded the study and was responsible for data collection, monitoring, and statistical analysis. Details of the study, including risk of bias and applicability, are detailed in Table 11.

Clinical Safety: During the titration phase with apomorphine SL, 58% of patients had at least one TEAE (see Table 9), which led to study discontinuation in 12% of patients.15 During the double-blind maintenance phase, 89% of patients treated with apomorphine SL had at least one TEAE, compared with 45% of patients who received placebo.15 During the double-blind maintenance phase, the TEAEs that resulted in early study discontinuation in the apomorphine SL arm were lip swelling, oral mucosal erythema, oropharyngeal swelling, delusion, disorientation, facial swelling, fall, fatigue, gingival edema, irritable bowel syndrome, lip edema, lip ulceration, mouth edema, nausea, vomiting, oral allergy syndrome, oropharyngeal pain, pharyngeal erythema, rhinorrhea, somnolence, swollen tongue, tongue polyp, and urticaria.15

Treatment-emergent adverse events led to early study discontinuation in 28% of patients treated with apomorphine SL and in 9% of those treated with placebo.15 Oropharyngeal adverse events occurred in 31% of patients treated with apomorphine SL and were the most common type of adverse event that led to study discontinuation in the double-blind maintenance phase of the trial (17%).15 A summary of TEAEs, including oropharyngeal-related TEAEs, is found in Table 9. Adverse events commonly attributed to dopamine-agonists, such as nausea, somnolence and dizziness, were more common in patient treated with apomorphine SL than placebo, but were infrequently associated with study discontinuation.15 Nausea was reported more frequently in the apomorphine SL arm (28%) than the placebo arm (4%) despite provision of antiemetic therapy during the trial (excluding 5HT3 antagonists).15 During the double-blind maintenance phase, orthostatic hypotension, hallucinations, and QT interval prolongation occurred in one patient each who received apomorphine SL.15 However, no patients in the apomorphine SL arm experienced syncope, worsening dyskinesia, or an impulse control disorder.15 No clinically meaningful differences were found in vital signs, electrocardiograms, or laboratory parameters.15 Author: Gibler Date October 2020 87

Table 9. Summary of Adverse Events in Phase 3 Apomorphine SL Trial.15 TEAEs in >5% of Patients in the TEAEs in >5% of Patients in the DB Maintenance Phase TEAEs Related to Oropharyngeal Disorders in ≥2% of Patients in the DB OL Titration Phase Maintenance Phase APO APO PBO APO PBO Any 58% Any 89% 45% Oral Mucosal Erythema 7% 4% Nausea 21% Nausea 28% 4% Dry Mouth 6% - Yawning 12% Somnolence 13% 2% Glossodynia 4% - Dizziness 11% Dizziness 9% - Lip Edema 4% - Somnolence 11% Fatigue 7% - Lip Swelling 4% - Headache 8% Oral Mucosal Erythema 7% 4% Oropharyngeal Swelling 4% - Rhinorrhea 6% Rhinorrhea 7% - Throat irritation 4% - Chills 6% Vomiting 7% - Dry Mouth 6% - Fall 6% 2% Headache 6% - Hyperhidrosis 6% 4% Lacerations 6% - Abbreviations: APO = apomorphine SL; DB = double-blind; OL = open-label; PBO = placebo; TEAE = treatment-emergent adverse event

Look-alike / Sound-alike Error Risk Potential: none reported.

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Table 10. Pharmacology and Pharmacokinetic Properties.16 Parameter

 A non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C receptors.  The precise mechanism of action as a treatment for “off” episodes is unknown, although it is believed to be due to stimulation of Mechanism of Action post-synaptic dopamine D2-type receptors within the caudate-putamen in the brain.

Oral Bioavailability  Tmax 0.5-1 hour Distribution and  Vd/F = 3630 L Protein Binding  Protein binding not reported.

 T1/2 = 1.7 h (range 0.8 to 3 h)  The apparent clearance of apomorphine does not appear to be influenced by age, gender, race, weight, duration of PD, levodopa dose, use of antiemetic, or duration of therapy.  No differences in apomorphine exposure were noted after administration of the SL formulation in patients with mild renal impairment (CLcr of ≥60 mL/min and <90 mL/min) versus patients with normal renal function (CLcr of ≥ 90 mL/min). Studies have not Half-Life been conducted in patients with moderate to severe renal impairment.  The major metabolic pathways for SL apomorphine are sulfation by multiple sulfotransferase (SULT) enzymes; glucuronidation by multiple glycosyltransferase (UGT) enzymes; N-demethylation catalyzed by multiple enzymes, including CYP2B6, CYP2C8, and CYP3A4/5; followed by conjugation.  Metabolism of apomorphine SL results in 3 major inactive metabolites: apomorphine sulfate, apomorphine glucuronide, and Metabolism norapomorphine glucuronide. Abbreviations: Cmax = maximum concentration; h = hours; L = liters; PD = Parkinson’s Disease; SL = sublingual; t1/2 = half-life; Tmax = time to reach the maximum concentration; Vd/F = apparent volume of distribution.

Comparative Endpoints: Clinically Meaningful Endpoints: Primary Study Endpoint: 1) Motor symptoms (e.g., bradykinesia, rigidity, resting tremor) 1) Motor symptoms, as assessed by  MDS-UPDRS part 3 (pre-dose to 2) Non-motor symptoms (e.g., autonomic, psychiatric and cognitive impairment) 30 minutes post-dose) 3) Function (disability and impairment) 4) Health-related quality of life (e.g., PDQ-39) 5) Serious adverse events

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Table 11. Comparative Evidence Table for Apomorphine Sublingual Film. Ref./ Drug Regimens/ Patient Population N Efficacy Endpoints ARR/NNT Safety Outcomes ARR/NNH Risk of Bias/ Study Duration Applicability Design 1. 1. apomorphine SL Demographics: ITT: Primary Endpoint: TEAE (OL titration): Risk of Bias (low/high/unclear): mg/d -Mean age: 62.7 y 1. 54  MDS-UPDRS part 3 from 82/141 (58%) NA Selection Bias: (low) randomized by DB, PC, RCT, -Male: 62% 2. 55 pre-dose to 30 min post- interactive web-response system, was not MC 2. placebo -White: 93% dose (at week 12 visit): TEAE (DB RCT): stratified; block size was 4. Computer- -MDS-UPDRS part 3 PP: 1. 89% 44%/NA generated random allocation use 12 weeks 1:1 (pre-dose): 43.1 1. 34 1. -11.1 2. 45% corresponded with the sequentially -HY ON score 2 or 2. 46 2. -3.5 numbered foil pouches of study medication. 6002-US-005 OL titration period: 2.5: 83% LSMD -7.6 (95% CI, -11.5 to - NA Nausea (OL However, the small number of participants Titration started at -OFF episodes/day: Attrition: 3.7) titration): led to unequal demographic characteristics 10 mg, which could 3.9 1. 37% 29/141 (21%) NA between groups in gender and HY stages. be increased on -Mean L-dopa dose: 2. 16% Secondary Endpoints: Performance Bias: (unclear) all patients and subsequent days in 1033 mg/d % w/ self-rated full ON Nausea (DB RCT): study personnel were masked to treatment 5 mg increments to -Dopa agonist: 56% response within 30 min (at 1. 28% 24%/NA assignments; active and placebo study a max of 35 mg until week 12 visit): 2. 4% medication and packaging identical in size, full ON response Key Inclusion 1. 35% shape, color and appearance. However, achieved within 45 Criteria: 2. 16% Somnolence (OL patients assigned to placebo after OL titration min of -Age ≥18 y OR 2.81 (95% CI, 1.04 to 19%/6 titration): period w/ apomorphine may have unmasked administration w/o -Idiopathic PD 7.64) 16/141 (11%) NA treatment arms. intolerable AE. -Responsive to L- Detection Bias: (high) efficacy assessments dopa w/ DCI but w/ Improved PGI-I (baseline to Somnolence (DB performed at the clinic in patients in a early AM OFF week 12): RCT): practically defined OFF state at week 0, 4, 8, episodes 1. 37% 1. 13% 11%/NA and 12. Assessment included part 3 of the -Stable doses of L- 2. 20% 2. 2% MDS-UPDRS (motor exam) done pre-dose and dopa administered (1 vs. 2, p=0.062, CI NR) NS at 15, 30, 45, 60 and 90 min post-dose. QID or more. Dizziness (OL Patients self-administered study drug at -OFF time ≥2 h/day Improved CGI-I (baseline to titration): home for treatment of up to 5 OFF episodes -HY Stage 3 or less week 12): 16/141 (11%) NA per day. A diary was kept for the 2 days prior in ON state 1. 41% to the clinic visit to determine whether full -MMSE >25 2. 20% Dizziness (DB RCT): ON response was achieved at 30 min post- (1 vs. 2, p=0.027, CI NR) 21%/5 1. 9% 9%/NA dose. Anti-nausea medication was Key Exclusion 2. 0% administered for 3 days before initiation of Criteria:  PDQ-39 (baseline to week titration in OL phase and could be continued -Atypical or 12): OL Titration during DL maintenance phase. Unknown if Secondary PD 1. 0.309 Discontinuation data assessors were blinded to treatment. -Previous 2. -1.671 from TEAE: Attrition Bias: (high) Very high attrition rate neurological MD 1.979 (95% CI, -2.162 to NS 9/141 (9%) NA for apomorphine arm; analysis of endpoints procedure for PD, 6.120) based on mITT (patients who received at least continuous SC DB RCT one post-randomization dose). Missing data apomorphine Discontinuation imputed using LOCF. infusion, or from TEAE: Reporting Bias: (low) endpoints reported as Duodopa/Duopa 1. 28% 19%/NA designed in methodology, but some CI NR. 2. 9% Author: Gibler Date October 2020 90

-Current 5HT3 Other Bias: (high) study funded by drug antagonist*, sponsors Cynapsus Therapeutics and dopamine Sunovion, and who were responsible for data antagonist** or collection, monitoring and statistical analyses. dopamine depleting agent Applicability: -Major psychiatric Patient: 32% of enrolled participants d/c’d OL disorder titration phase limiting DB phase to patients -Drug or alcohol who could achieve full ON response to dependency apomorphine at a tolerable dose. -H/o hallucinations Intervention: patients received the or ICD medication in a defined OFF state (anti-PD -Dementia medication withheld overnight for ~12h); trained staff administered medication and patients were specifically instructed not to swallow for 3 min (apomorphine is rapidly sulfonated in the stomach and not absorbed). Patients were maintained on their standard anti-PD medication regimen. Doses that resulted in full ON response during titration phase were: 10 mg (18%), 15 mg (27%), 20 mg (21%), 25 mg (19%), 30 mg (8%), 35 mg (6%). Comparator: placebo appropriate to establish efficacy of the SL formulation. Outcomes: A full ON response was defined as an ON response similar to that obtained with L-dopa; time to medication effect was 21 min. Setting: 32 academic neurology centers in the U.S. and one in Canada. Abbreviations: AM = morning; ARR = absolute risk reduction; CGI-I = Clinical Global Impressions – Improvement in illness scale; CI = confidence interval; d = days; DB = double blind; DCI = decarboxylase inhibitor (e.g., carbidopa); GI = gastrointestinal; H/o = history of; HY = Hoehn & Yale scale; ICD = impulse control disorder; ITT = intention to treat; L-dopa = levodopa; LOCF = last observation carried forward; LSM = least-square mean; LSMD = least-square mean difference; MC = multicentered; mg = milligrams; MDS-UPDRS = Movement Disorder Society Unified Parkinson’s Disease Rating Scale; mITT = modified intention to treat; MMSE = Mini-Mental State Examination; N = number of subjects; NA = not applicable; NNH = number needed to harm; NNT = number needed to treat; NR = not reported; NS = not statistically significant; OL = open label; OR = odds ratio; PC = placebo controlled; PD = Parkinson’s Disease; PDQ-39 = Parkinson’s Disease Questionnaire; PGI-I = Patient Global Impression – Improvement Scale; PP = per protocol; QID = 4-times daily; RCT = randomized controlled trial; SC = subcutaneous; SD = standard deviation; TEAE = treatment-emergent adverse effects; TESAE = treatment- emergent serious adverse effects; UPDRS = Unified Parkinson Disease Rating Scale; y = years. *ie, ondansetron, granisetron, dolasetron, palonosetron, alosetron **excluding quetiapine or clozapine

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References: 1. Binde CD, Tvete IF, Gasemyr J, Natvig B, Klemp M. A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson's disease. Br J Clin Pharmacol 2018;84:1917-27. 2. Shen Z, Kong D. Meta-analysis of the adverse events associated with extended-release versus standard immediate-release pramipexole in Parkinson disease. Medicine (Baltimore) 2018;97:e11316. 3. Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease. N Engl J Med 2019;380:315-24. 4. LeWitt PA, Guttman M, Tetrud JW, et al. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double- blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 2008;63:295-302. 5. Stacy M, Silver D, Mendis T, et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology 2008;70:2233-40. 6. Hauser RA, Shulman LM, Trugman JM, et al. Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations. Mov Disord 2008;23:2177-85. 7. Mizuno Y, Hasegawa K, Kondo T, Kuno S, Yamamoto M. Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study. Mov Disord 2010;25:1437-43. 8. Mizuno Y, Kondo T. Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson's disease. Mov Disord 2013;28:1138-41. 9. Pourcher E, Fernandez HH, Stacy M, Mori A, Ballerini R, Chaikin P. Istradefylline for Parkinson's disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Relat Disord 2012;18:178-84. 10. ClinicalTrials.gov Identifier NCT 00199394. ClinicalTrials.gov. (Accessed November 26, 2019, at https://clinicaltrials.gov/ct2/show/NCT00199394?term=00199394&draw=2&rank=1.) 11. ClinicalTrials.gov Identifier NCT 01968031. (Accessed November 26, 2019, at https://clinicaltrials.gov/ct2/show/NCT01968031?term=01968031&draw=2&rank=1 ) 12. Application Number 022075Orig1s000 Summary Review. U.S. Food and Drug Administration. (Accessed November 26, 2019, at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022075Orig1s000SumR.pdf.) 13. Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P. Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of- dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol 2016;15:154-65. 14. Lees AJ, Ferreira J, Rascol O, et al. Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol 2017;74:197-206. 15. Olanow CW, Factor SA, Espay AJ, et al. Apomorphine sublingual film for off episodes in Parkinson's disease: a randomised, double-blind, placebo- controlled phase 3 study. Lancet Neurol 2020;19:135-44. 16. KYNMOBI (apomorphine hydrochloride sublingual film) [Prescribing Information]. Marlborough, MA. Sunovion Pharmaceuticals, Inc: May 2020. 17. Parkinson’s disease in adults; NICE guideline NG71. National Institute for Health and Care Excellence, July 2017. (Accessed November 27, 2019, at https://www.nice.org.uk/guidance/ng71.) 18. Parkinson’s Disease Drug Class Update, Drug Use Research & Management. Oregon State University College of Pharmacy. (Accessed November 26, 2019, at https://www.orpdl.org/durm/meetings/meetingdocs/2018_03_22/archives/2018_03_22_AntiParkinsons_ClassUpdate.pdf.) 19. Kalia LV, Lang AE. Parkinson's disease. Lancet 2015;386:896-912. 20. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. Jama 2014;311:1670-83. 21. OGENTYS (opicapone) [Prescribing Information]. San Diego, CA: Neurocrine Biosciences, Inc. April 2020. 22. Application Number: 212489Orig1s000. Summary Review. U.S. Food and Drug Administration, 2020. (Accessed May 27, 2020, at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212489Orig1s000SumR.pdf.) Author: Gibler Date October 2020 92

23. TASMAR (tolcapone) [Prescribing Information]. Bridgewater, NJ: Valeant Pharmaceuticals. May 2013. 24. Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 2004;19:1020-8. 25. Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008;23:2129-70. 26. Martinez-Martin P, Rodriguez-Blazquez C, Mario A, et al. Parkinson's disease severity levels and MDS-Unified Parkinson's Disease Rating Scale. Parkinsonism Relat Disord 2015;21:50-4. 27. Hauser RA, Gordon MF, Mizuno Y, et al. Minimal clinically important difference in Parkinson's disease as assessed in pivotal trials of pramipexole extended release. Parkinsons Dis 2014;2014:467131. 28. Horvath K, Aschermann Z, Acs P, et al. Minimal clinically important difference on the Motor Examination part of MDS-UPDRS. Parkinsonism Relat Disord 2015;21:1421-6. 29. Jenkinson C, Fitzpatrick R, Peto V, Greenhall R, Hyman N. The Parkinson's Disease Questionnaire (PDQ-39): development and validation of a Parkinson's disease summary index score. Age Ageing 1997;26:353-7. 30. Peto V, Jenkinson C, Fitzpatrick R. Determining minimally important differences for the PDQ-39 Parkinson's disease questionnaire. Age Ageing 2001;30:299-302. 31. Horvath K, Aschermann Z, Kovacs M, et al. Changes in Quality of Life in Parkinson's Disease: How Large Must They Be to Be Relevant? Neuroepidemiology 2017;48:1-8. 32. Chaudhuri KR, Martinez-Martin P, Brown RG, et al. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study. Mov Disord 2007;22:1901-11. 33. Chaudhuri KR, Pal S, DiMarco A, et al. The Parkinson's disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson's disease. J Neurol Neurosurg Psychiatry 2002;73:629-35. 34. Barone P, Erro R, Picillo M. Quality of Life and Nonmotor Symptoms in Parkinson's Disease. Int Rev Neurobiol 2017;133:499-516. 35. Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont) 2007;4:28-37. 36. Yalcin I, Bump RC. Validation of two global impression questionnaires for incontinence. Am J Obstet Gynecol 2003;189:98-101. 37. Patel AA, Donegan D, Albert T. The 36-item short form. J Am Acad Orthop Surg 2007;15:126-34. 38. Roy MA, Doiron M, Talon-Croteau J, Dupre N, Simard M. Effects of Antiparkinson Medication on Cognition in Parkinson's Disease: A Systematic Review. Can J Neurol Sci 2018;45:375-404. 39. Lee JY, Jeon B, Koh SB, et al. Behavioural and trait changes in parkinsonian patients with impulse control disorder after switching from dopamine agonist to levodopa therapy: results of REIN-PD trial. J Neurol Neurosurg Psychiatry 2019;90:30-7. 40. Kondo T, Mizuno Y. A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin Neuropharmacol 2015;38:41-6. 41. NOURIANZ (istradefylline) [Prescribing Information]. Bedminster, NJ. Kyowa Kirin, Inc: August 2019. 42. NOURIANZ (istradefylline) [AMCP DOSSIER]. Bedminster, NJ. Kyowa Kirin, Inc: August 2019. 43. APOKYN (apomorphine for inj) [Prescribing Information]. Durham, NC. Mylan Bertek Pharmaceuticals, Inc: April 2004.

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Appendix 1: Current Preferred Drug List

Generic Brand Form Route PDL benztropine mesylate BENZTROPINE MESYLATE TABLET ORAL Y carbidopa/levodopa CARBIDOPA/LEVODOPA TABLET ORAL Y carbidopa/levodopa SINEMET 10-100 TABLET ORAL Y carbidopa/levodopa SINEMET 25-100 TABLET ORAL Y carbidopa/levodopa SINEMET 25-250 TABLET ORAL Y carbidopa/levodopa CARBIDOPA-LEVODOPA ER TABLET ER ORAL Y carbidopa/levodopa SINEMET CR TABLET ER ORAL Y carbidopa/levodopa/entacapone CARBIDOPA-LEVODOPA-ENTACAPONE TABLET ORAL Y carbidopa/levodopa/entacapone STALEVO 100 TABLET ORAL Y carbidopa/levodopa/entacapone STALEVO 125 TABLET ORAL Y carbidopa/levodopa/entacapone STALEVO 150 TABLET ORAL Y carbidopa/levodopa/entacapone STALEVO 200 TABLET ORAL Y carbidopa/levodopa/entacapone STALEVO 50 TABLET ORAL Y carbidopa/levodopa/entacapone STALEVO 75 TABLET ORAL Y entacapone COMTAN TABLET ORAL Y entacapone ENTACAPONE TABLET ORAL Y pramipexole di-HCl MIRAPEX TABLET ORAL Y pramipexole di-HCl PRAMIPEXOLE DIHYDROCHLORIDE TABLET ORAL Y selegiline HCl SELEGILINE HCL CAPSULE ORAL Y trihexyphenidyl HCl TRIHEXYPHENIDYL HCL ELIXIR ORAL Y trihexyphenidyl HCl TRIHEXYPHENIDYL HCL TABLET ORAL Y amantadine HCl GOCOVRI CAP ER 24H ORAL N amantadine HCl AMANTADINE CAPSULE ORAL N amantadine HCl AMANTADINE SOLUTION ORAL N amantadine HCl OSMOLEX ER TAB BP 24H ORAL N amantadine HCl AMANTADINE TABLET ORAL N bromocriptine mesylate BROMOCRIPTINE MESYLATE CAPSULE ORAL N bromocriptine mesylate PARLODEL CAPSULE ORAL N bromocriptine mesylate BROMOCRIPTINE MESYLATE TABLET ORAL N bromocriptine mesylate PARLODEL TABLET ORAL N carbidopa CARBIDOPA TABLET ORAL N carbidopa LODOSYN TABLET ORAL N carbidopa/levodopa RYTARY CAPSULE ER ORAL N carbidopa/levodopa DUOPA INT PMP SP MISCELL N carbidopa/levodopa CARBIDOPA-LEVODOPA TAB RAPDIS ORAL N levodopa INBRIJA CAP W/DEV INHALATION N levodopa INBRIJA CAPSULE INHALATION N Author: Gibler Date October 2020 94

levodopa LARODOPA TABLET ORAL N pramipexole di-HCl MIRAPEX ER TAB ER 24H ORAL N pramipexole di-HCl PRAMIPEXOLE ER TAB ER 24H ORAL N rasagiline mesylate AZILECT TABLET ORAL N rasagiline mesylate RASAGILINE MESYLATE TABLET ORAL N ropinirole HCl REQUIP XL TAB ER 24H ORAL N ropinirole HCl ROPINIROLE ER TAB ER 24H ORAL N ropinirole HCl REQUIP TABLET ORAL N ropinirole HCl ROPINIROLE HCL TABLET ORAL N rotigotine NEUPRO PATCH TD24 TRANSDERM N safinamide mesylate XADAGO TABLET ORAL N selegiline HCl ZELAPAR TAB RAPDIS ORAL N selegiline HCl SELEGILINE HCL TABLET ORAL N tolcapone TASMAR TABLET ORAL N tolcapone TOLCAPONE TABLET ORAL N

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Appendix 2: Abstracts of Comparative Clinical Trials

Lee J-Y, Jeon B, Koh S-B, et al. Behavioural and trait changes in parkinsonian patients with impulse control disorder after switching from dopamine agonist to levodopa therapy: results of REIN-PD trial. J Neurol Neurosurg Psychiatry. 2019; 90:30–37.

Objective: In this multicentre open-label trial, we compared behavioural and neuropsychiatric symptoms in Parkinson’s disease (PD) patients with impulse control disorders (ICD) treated with dopamine agonists before and 12 weeks after substituting dopamine agonists with an equivalent dose of levodopa/carbidopa slow-release formulation. Methods: Baseline characteristics of 50 PD patients with ICD were compared with those of 60 medicated and 40 drug-naïve PD control groups. Neuropsychiatric trait changes in the pD-IcD group were investigated 12 weeks after the intervention. ICD behaviours were assessed via modified Minnesota Impulsive Disorders Interview (mMIDI), whereas parkinsonian severity and neuropsychiatric characters were systematically assessed with the Unified PD Rating Scale (UPDRS) and a predefined neuropsychological assessment battery. Results at baseline, ICD patients showed higher scores in the Neuropsychiatric Inventory and anxiety, anger and obsessive-compulsive traits compared with both PD control groups. In contrast, the three PD groups showed indifference in the impulsivity scales. At 12 weeks post intervention, ICD behaviours significantly improved (p<0.001, Δ modified MIDI score = ‒5.27 ± 5.75) along with the UPDRS II daily activity scores (p=0.02, Δ = ‒2.07 ± 4.53). Behavioural disinhibition tended to improve (p=0.06), although no significant changes were observed in the Neuropsychiatric Inventory and personality trait scores. Dopamine agonist withdrawal syndrome developed in 5.3% of the PD-ICD group. Conclusions: This study provides class IV evidence suggesting that switching from dopamine agonists to levodopa/carbidopa slow-release formulations alleviated ICD behaviours in PD patients leading to improvement in daily activities whereas neuropsychiatric traits associated with ICD persisted after the 12-week therapy.

Trenkwalder C, Kuoppamaki M, Vahterito M, et al. Increased dose of carbidopa with levodopa and entacapone improves “off” time in a randomized trial. Neurology. 2019; 92:1487-1496.

Objective: To investigate whether increased fixed carbidopa doses of 65 or 105 mg (ODM-101/65 and ODM-101/105) in combination with 75, 100, 125, or 150 mg of levodopa and 200 mg of entacapone might improve “off” time in fluctuating Parkinson disease (PD) compared to the standard combination of 4:1 levodopa/carbidopa with the usual 200 mg of entacapone (LCE) during a 4-week treatment period. Methods: This was a randomized, double-blind, double-dummy, active-controlled, crossover, multicenter, phase II, proof-of-concept study in patients with fluctuating PD. Results: One hundred seventeen patients were randomized into the study (mean age 67.0 years; daily “off” time 5.3 hours; mean daily levodopa dose 610 mg). Carryover-adjusted mean changes from baseline “off ” times were during ODM-101/65, −1.53 hours (p = 0.02 vs LCE), during ODM-101/105, −1.57 hours (p = 0.01 vs LCE), and during LCE −0.91 hours. Changes in daily “on” time without dyskinesia were 1.54 hours (p = 0.005 vs LCE), 1.38 hours (p = 0.0214 vs LCE), and 0.69 hours, respectively. Changes in “on” time with troublesome dyskinesia were <0.1 hours and not significantly different between treatments. In patients with high-activity COMT genotypes Val/Met or Val/Val, “off ” time was reduced more with ODM-101/65 and ODM-101/105 than with LCE (p = 0.015 and p = 0.006). No difference between the treatments was seen in safety and tolerability. The most common treatment-related adverse effects were nausea, dizziness, drug- effect decrease, and dyskinesia, which were in most cases mild or moderate in severity. Treatment-related serious adverse events were diarrhea (ODM-101/105 and LCE), and myocardial ischemia and blood creatine kinase increase (LCE). Conclusion: Increasing the dose of carbidopa in combination with levodopa and entacapone should be considered in the treatment of fluctuating PD to improve daily “off ” times. Genotyping patients with PD according to COMT activity may improve individual treatment strategies.

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Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med. 2019; 380:315-324.

Background: Levodopa is the main treatment for symptoms of Parkinson’s disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. Methods: In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson’s disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. Results: A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1 ±11.4 points in the early-start group and 29.3 ±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was −1.0 ±13.1 points and −2.0 ±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], −1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04 ±0.23 in the early-start group and 0.06 ±0.34 in the delayed-start group (difference, −0.02; 95% CI, −0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10 ±0.25 and 0.03 ±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups. Conclusions: Among patients with early Parkinson’s disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect.

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Appendix 3: Medline Search Strategy

1 exp Benztropine/ 696 2 exp Levodopa/ 16281 3 entacapone.mp. 661 4 exp Pramipexole/ 962 5 exp Selegiline/ 2344 6 exp Trihexyphenidyl/ 919 7 exp Amantadine/ 5926 8 exp Bromocriptine/ 6965 9 exp Carbidopa/ 2379 10 rasagiline.mp. 685 11 ropinirole.mp. 943 12 rotigotine.mp. 569 13 safinamide.mp. 182 14 exp Tolcapone/ 332 15 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 34566 16 limit 15 to (english language and humans and yr="2018 -Current" and (clinical study or clinical trial, all or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative study or controlled clinical trial or guideline or meta analysis or multicenter study or practice guideline or pragmatic clinical trial or randomized controlled trial or "systematic review") and "humans only (removes records about animals)") 136

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Appendix 4: Prescribing Information Highlights

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Appendix 5: Key Inclusion Criteria

Population Patients with Parkinson’s disease diagnosis Intervention FDA-approved pharmacological agent Comparator FDA-approved pharmacological agent(s) Outcomes Mortality, morbidity, quality of life, functioning or symptoms Timing Multiple days Setting Outpatient management

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Appendix 6: Prior Authorization Criteria Anti-Parkinson’s Agents Goals:  Promote preferred drugs for Parkinson’s disease.  Restrict use for non-funded conditions (e.g., restless leg syndrome).  To limit utilization of safinamide to FDA-approved indications.

Length of Authorization:  Up to 12 months

Requires PA: Non-preferred drugs

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code

2. Is the diagnosis Parkinson’s disease or another chronic Yes: Go to #5 No: Go to #3 neurological condition?

3. Is the diagnosis Restless Leg Syndrome? Yes: Pass to RPh. Deny; not No: Go to #4 funded by the OHP.

4. RPh only: Funded: Go to #5 Not Funded: Deny; not funded All other indications need to be evaluated to determine if by the OHP. treatment is for a funded condition.

5. Is this a request for continuation of therapy? Yes: Go to Renewal Criteria. No: Go to #6

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Approval Criteria

6. Will the prescriber consider a change to a preferred Yes: Inform prescriber of No: Go to #7 product? covered alternatives in class.

Message:  Preferred products do not require PA.  Preferred products are reviewed for comparative effectiveness and safety by the Pharmacy and Therapeutics (P&T) Committee.

7. Does the patient have a diagnosis of Parkinson’s disease Yes: Go to #8 No: Approve for the shorter of 1 and experiences “off” episodes? year or length of prescription.

8. Is the request for safinamide or istradefylline? Yes: Go to #13Go to #9 No: Approve for the shorter of 1 year or length of prescription.Go to #9

9. Is the request for opicapone?Is the patient currently taking Yes: Approve for the shorter of 1 No: Go to #11No: Pass to RPh. levodopa/carbidopa? year or length of Deny; medical appropriateness. prescription.Yes: Go to #10

10. Is the patient on a non-selective monoamine oxidase Yes: Pass to RPh. Deny; No: Approve for the shorter of 1 (MAO) inhibitor? medical appropriateness. year or length of prescription.

Note: selective MAO-B inhibitors are permitted (moclobemide; rasagiline; safinamide; selegiline)

11. Is the request for apomorphine sublingual film? Yes: Go to #12 No: Go to #13

12. Is the patient on a 5-HT3 antagonist (eg., ondansetron, Yes: Pass to RPh. Deny; No: Approve for the shorter of 1 dolasetron, granisetron, palonosetron, etc.) medical appropriateness. year or length of prescription.

13. Is the patient currently taking levodopa/carbidopa? Yes: Approve for the shorter of 1 No: Pass to RPh. Deny; year or length of prescription. medical appropriateness.

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Renewal Criteria

1. Has the patient’s condition improved as assessed by the Yes: Approve for the shorter of 1 No: Pass to RPh; Deny; medical prescribing physician and physician attests to patient’s year or length of prescription. appropriateness. improvement?

P&T Review: 10/20 (AG); 3/18; 7/16; 9/14; 9/13; 09/10 Implementation: 4/16/18; 8/16, 1/1/14, 1/1/11

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-2596

Drug Class Update: Asthma and COPD Maintenance Medications

Date of Review: October 2020 Date of Last Review: Inhalers (May 2019) Asthma Biologics (July 2018) Oral Agents (Sept 2015) Literature Search: Inhalers 05/01/19 – 07/08/20 Asthma Biologics 04/01/18 – 08/07/20 Oral Agents 10/01/15 -- 07/08/20

Current Status of PDL Class: See Appendix 1.

Purpose for Class Update: Asthma and chronic obstructive pulmonary disease (COPD) maintenance medications are being reviewed to evaluate need to change policy based on evidence published since the last class updates.

Research Questions: 1. What is the comparative evidence of efficacy for asthma and COPD maintenance medications for important outcomes such as symptoms, lung function, hospitalizations and mortality? 2. What is the evidence for harms associated with asthma and COPD maintenance medications? 3. Are there subgroups of patients based on demographics (age, racial groups, gender), comorbidities (drug-disease interactions), or other medications (drug-drug interactions) for which treatments for asthma or COPD differ in efficacy/effectiveness or frequency of adverse events?

Conclusions: ASTHMA  A Cochrane review evaluated the safety of formoterol compared to formoterol combined with an inhaled corticosteroid (ICS) in adult, children and adolescent patients with asthma.1 All-cause mortality occurred in 17 of 18,645 adults who were using formoterol with an ICS compared to 13 patients taking an ICS alone, which equated to 1 patient per 1000 patients for each group over a 26-week time period, based on moderate strength of evidence. No deaths were reported for children or adolescents. Non-fatal severe adverse events were similar between groups for adults, children and adolescents.

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 A 2020 National Institute for Health and Care Excellence (NICE) guidance found low quality evidence of no significant reduction in asthma exacerbations upon increasing ICS doses in children and young people via self-directed management at the onset of an asthma exacerbation compared to keeping the usual maintenance ICS dose as part of a self-directed management plan.2  A 2019 NICE update provided guidance on the use of the biologic treatment, benralizumab, for the treatment of severe eosinophilic asthma. Benralizumab is recommended for adult patients with inadequately controlled asthma despite optimization of maintenance therapy with high-dose corticosteroids and LABAs who also have blood eosinophil counts of 300 cells/µL or more and 4 or more exacerbations needing systemic corticosteroids in the previous 12 months or those who have continuous oral corticosteroid use equivalent to prednisone 5 mg/day over the previous 6 months or blood eosinophil count has been recorded as 400 cells/µL or more with at least 3 exacerbations needing systemic corticosteroids in the past 12 months.  European Respiratory Society and the American Thoracic Society (ERS/ATS) 2019 recommendations for the treatment of severe asthma are consistent with current policy for monoclonal antibodies.

COPD  A Cochrane systematic review provided evidence that phosphodiesterase-4 (PDE4) inhibitors improved lung function and reduction in COPD exacerbations but had no effect on symptoms and quality of life (moderate to high quality of evidence). PDE4 inhibitors modestly improved forced expiratory volume in one second (FEV1) compared to placebo in patients with moderate to very severe COPD by a mean difference (MD) of 70.7 mL, which is lower than the clinically meaningful change of 100 mL.3 St. George’s Respiratory Questionnaire (SGRQ) scores were also more improved with PDE4 inhibitors compared to placebo by a MD of 3.27 points, which is lower than the minimal clinically important difference (MCID) of 4 points.3 Mortality was not different between groups.  An Agency for Healthcare Research and Quality (AHRQ) review of adult patients with COPD found insufficient evidence for the use of ICS (with or without terbutaline or formoterol) on hospitalizations, intubations and mortality.4 There was low quality evidence from one trial that ICS improved FEV1 percent predicted by 10.10% more than placebo which almost meets the threshold for MCID for change.  A 2017 review by NICE provided guidance on the use of roflumilast in adult patients with COPD which is consistent with current policy.5

Recommendations:  Update roflumilast prior authorization (PA) criteria with clinical definition of severe and very severe COPD (Appendix 5).  Clarify age recommendations for use of monoclonal antibodies.  New clinical evidence does not warrant changes to the preferred drug list (PDL).  Evaluate costs in executive session.

Summary of Prior Reviews and Current Policy Asthma and COPD  Maintenance therapies for the treatment of asthma and COPD were last reviewed in 2015. There was no compelling efficacy or safety evidence to justify changes to the PDL.

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 A new PDL class for combination long-acting muscarinic antagonists (LAMA) and long-acting beta-agonists (LABA) products was created.  The PA criteria for maintenance inhalers was reorganized with the following changes: o All non-preferred LABA, ICS, LABA/ICS, and LAMA/LABA inhalers require PA to ensure appropriate step therapy. o Prior authorization was removed for leukotriene inhibitors. Non-preferred leukotriene receptor antagonist (LTRA) currently use the generic non-preferred PDL PA. Asthma Monoclonal Antibodies  A recent review of asthma biologics in 2018 found no clinical evidence to support changes to the PDL. There are 5 monoclonal antibodies for asthma all of which require PA which limits coverage to refractory asthma and attempts to mitigate risk of severe adverse reactions (e.g., anaphylaxis). Mepolizumab, reslizumab, dupilumab and benralizumab are reserved for use in patients with severe asthma with the eosinophilic phenotype. Omalizumab is indicated for allergic asthma and chronic uticaria; however, chronic uticaria is not a funded diagnosis on the Oregon Health Evidence Review Commission (HERC) prioritized list.  Current criteria require that auto-injectable epinephrine be co-prescribed with all asthma biologics due to the risk of delayed anaphylaxis.  There are no preferred monoclonal antibodies for asthma.

Utilization  Adherence to preferred therapies is high for inhaled and oral therapies for asthma and COPD; however, cost for the classes account for a significant expenditure to the OHP. Claims for miscellaneous pulmonary drugs (e.g., asthma biologics, leukotriene antagonists, and PDE4 inhibitors) are few, with the majority of claims being for the preferred product montelukast.

Background: ASTHMA Asthma is a chronic inflammatory condition of the lungs resulting in airway obstruction, bronchial hyperresponsiveness and airway edema. Genetics and environmental factors are thought to contribute to asthma development. Centers for Disease Control and Prevention data from 2018 reports the burden of asthma in Oregon to be over 11%.6 Nationwide total asthma costs were projected to be over $20 billion in 2010.7

Asthma is characterized by symptoms of wheezing, cough, dyspnea and chest tightness. Diagnosis is confirmed by spirometry (FEV1 > 200 mL or ≥ 12% from baseline after short-acting beta agonist [SABA] use), airway obstruction that is at least partially reversible and exclusion of other potential diagnoses. Asthma is characterized as being intermittent or persistent (further divided into mild, moderate or severe).8 The underlying pathophysiology of asthma is multi-factorial and include several phenotypes: eosinophil predominant, neutrophil predominant and allergic asthma. In particular those patients with eosinophil asthma Type 2 (T2)-high, which indicates high levels of T-helper type 2 lymphocytes, respond well to ICS therapy and biologic therapy if asthma remains uncontrolled.9 Patients with eosinophil asthma also have high levels of sputum eosinophils, and while a correlation of blood eosinophil levels to sputum eosinophils is not well defined, guidelines define the threshold as blood eosinophils of ≥150 cells/µL.10 Studies of biologic therapies have evaluated use in patients with eosinophil levels of greater than 150 cells/µL to more than 400 cells/µL.

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Asthma treatment can be divided into two categories, quick-relief medication and long-term control medications. The Expert Panel Report 3 (EPR3) recommends asthma treatment be approached in a stepwise manner based on the severity of asthma symptoms.8 Patients with persistent asthma require long-term control medications to contain the underlying inflammation associated with asthma. ICSs are the preferred maintenance therapy for all patients with persistent asthma. If additional therapy is required to control asthma symptoms, LABAs are recommended in combination with ICS.8 Other maintenance therapy options include leukotriene inhibitors, methylxanthines, cromolyn sodium and nedocromil. SABAs, anticholinergics and systemic corticosteroids are recommended for acute symptom management. Biological asthma treatments are recommended for those patients with severe asthma that is unresponsive to controller-drug therapy.9 Biologic asthma therapy includes an anti-immunoglobulin E (IgE) monoclonal antibody (omalizumab), an interleukin 13 and 4 receptor inhibitor (dupilumab), and 3 different anti-interleukin (IL)-5 antibodies (benralizumab, reslizumab and mepolizumab).

Outcome measures used in asthma trials are FEV1, asthma exacerbations, hospitalization, emergency room visits, and need for oral corticosteroids. Change from baseline in FEV1 is a common surrogate endpoint used since it is highly reproducible. Research in COPD patients 11 suggest that minimally important FEV1 changes range from 100-140 mL. Moderate-quality evidence suggests that targeting interventions for asthma based on sputum eosinophil levels compared to clinical symptoms may reduce the number and severity of asthma attacks in adults; however, additional research is needed.12

COPD COPD is a chronic respiratory disorder characterized by reduced expiratory flow due to irreversible airway inflammation. Airway narrowing, hyperinflation and impaired gas exchange are pathological changes associated with COPD. The most common cause of COPD is airway irritation, usually from cigarette smoking. In rare cases alpha-1 antitrypsin (AAT) deficiency has been implicated in the development of early onset COPD. It is estimated almost 6% of Oregonians were diagnosed with COPD in 2011.13 Forty-one percent of these individuals were on at least one daily treatment for COPD.13

Chronic cough or sputum production and dyspnea are common symptoms of COPD. The diagnosis and management of COPD is based on 1 spirometry (post-bronchodilator ratio of FEV1/FVC <0.70), symptom severity, risk of exacerbations and comorbidities. COPD is classified into four stages based on spirometric measurements of FEV1/FVC: grade 1 (mild), grade 2 (moderate), grade 3 (severe), and grade 4 (very severe). The Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) guidelines recommend therapeutic approaches based on disease burden as well as FEV1, which classifies patients into groups A-D (low to high risk of symptoms and 1 exacerbations). This type of classification system shifts the focus from including just FEV1 measurements, as these are not always indicative of COPD status.

Common treatment options for patients with COPD are bronchodilators (SABAs, SAMAs, LABAs and LAMAs), corticosteroids and methylxanthines. Bronchodilators (short and long-acting) have demonstrated improvements in FEV1 and symptom improvement. Long-acting

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bronchodilators (LAMAs and LABAs) improve lung function, dyspnea, health status and reduce exacerbation rates.9 Inhaled corticosteroids/LABAs have been shown to improve health status, reduce exacerbations and improve lung function compared to monotherapy. Conclusive evidence of benefit has not been demonstrated with ICS alone in patients with COPD. Phosphodiesterase-4 inhibitors have a role in COPD management by minimizing airway narrowing and damage due to inflammation. Phosphodiesterase-4 inhibitors are used as add-on therapy for patients with COPD who have persistent symptoms or exacerbations despite optimal treatment with other COPD therapies. There is a lack of conclusive benefit of improved survival rates with any of the inhaled respiratory medications used in the management of COPD and no medications have shown a preventative effect in the decline of lung function.9

Goals of therapy for COPD management are to improve symptoms and reduce frequency of exacerbations. Important outcomes to access the effectiveness of therapies include: lung function, quality of life (QoL), dyspnea, exacerbation rate and/or severity, mortality and adverse events. FEV1 is the most common surrogate outcome used in studies to determine therapy effectiveness. The MCID in FEV1 values for COPD changes 1 have not been clearly defined but Cochrane reviews recommend a change of 100 mL. Other sources suggest a change in percent predicted FEV1 of 10.38% or more is considered a MCID.14 The SGRQ is used to determine the effects of COPD on quality of life with scores ranging from 0-100, higher scores indicate more limitations. The MCID for the SGRQ is a change of 4 units.3

New Systematic Reviews:

ASTHMA

Cochrane – Inhaled Steroids With and Without Regular Formoterol for Asthma: Serious Adverse Events A recent Cochrane review analyzed safety data associated with the use of ICS compared to ICS and formoterol in adults and children with asthma.1 The review is in response to safety concerns with an increased mortality risk with LABAs and if this risk is attenuated with the addition

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of an ICS. Thirty-nine studies were identified in a search through February 2019. This is an update from a previous review published in 2012. ICS therapies included in the review were: beclomethasone (200 to 800 mcg), budesonide (200 to 1600 mcg), fluticasone (200 to 250 mcg), and mometasone (200 to 800 mcg).1 Formoterol was studied at doses of 12 to 48 mcg. Most of the combination beta-2 agonist and ICS regimens were provided in a fixed dose combination inhaler. Studies in adults were a weighted mean duration of 26 weeks and those in children and adolescents were 12.5 weeks. Most domains had a low risk of bias with the exception of detection bias due to lack of independent assessment.

Asthma related deaths were low in all populations studied. There were no children or adolescents (n=4035) that died from asthma. However, 3 adult patients (n=12,777) who were taking an ICS and formoterol died of asthma.  All-cause mortality occurred in 17 of 18,645 adults who were using formoterol with an ICS compared to 13 patients taking an ICS alone (Odds ratio [OR] 1.25; 95% confidence interval [CI], 0.61 to 2.56) or one death for every 1000 adults who were treated for 26 weeks which was the same for both groups (moderate strength of evidence).1  All-cause, non-fatal serious adverse events (life-threatening, hospitalization or prolonging of existing hospitalization, causing persistent or significant disability, or congenital abnormality or defect) were the same in both groups, 2.1% (OR 1.00; 0.87 to 1.16) (high strength of evidence).1  Asthma-related, non-fatal serious adverse events at 26 weeks occurred in 6 of 1000 patients for those treated with an ICS compared to 5 per 1000 patients treated with ICS/formoterol (OR 0.86; 95% CI, 0.64 to 1.14) (moderate strength of evidence).1  All-cause non-fatal serious adverse events occurred in 8 per 1000 children and adults taking ICS alone compared to 11 per 1000 taking formoterol with an ICS (OR 1.33; 95% CI, 0.71 to 2.49) with follow-up of 12.5 weeks (moderate strength of evidence).1

In conclusion, there was no conclusive evidence suggesting an increase safety risk with the use of combination formoterol and ICS compared to ICS alone; however, the potential for an increased risk with formoterol cannot be ruled out due to the low incidence of deaths.1

COPD

Cochrane – Phosphodiesterase-4 inhibitors for Chronic Obstructive Pulmonary Disease A Cochrane review analyzed the data on treating COPD with PDE4 inhibitors (roflumilast, cilomilast [not available in the US] and tetomilast [not available in the US].3 Literature was searched through March 2020, which identified 42 randomized clinical trials for inclusion; 28 roflumilast trials (500 µg was evaluated in all trials with the exception of one roflumilast 250 µg trial), 14 cilomilast trials and 1 trial for tetomilast. Trial duration was 6 weeks to 1 year.3 Mean participant age was 64 years and patients had moderate to very severe COPD. Important endpoints were changes in lung function (FEV1) and QoL. Allocation bias was present in half of the roflumilast trials, but otherwise risk of bias was generally low for performance, detection, attrition and reporting bias.

Improvements in lung function as measured by FEV1 were higher with PDE4 inhibitors compared to placebo, MD of 49.33 mL (95% CI, 44.17 to 54.49 mL) compared to placebo, with a mean follow up of 40 weeks (moderate quality of evidence).3 FEV changes were a mean difference of

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86.98 mL higher for PDE4 inhibitors compared placebo (95% CI, 74.65 to 99.31), based on high quality of evidence of trials lasting a weighted mean of 45 weeks. There is moderate quality of evidence that PDE4 inhibitors were more effective at improving SGRQ scores but only by 3.27 units which is less than the MCID.3 There were more patients with 1 or more exacerbations in those treated with placebo compared to PDE4 inhibitors, 33 per 100 patients versus 27 per 100 patients (OR 0.78; 95% CI, 0.73 to 0.84) based on high quality evidence.3

Gastrointestinal adverse reactions (e.g., diarrhea) were more common in patients treated with PDE4 inhibitors compared to placebo (OR 3.10; 95% CI, 2.74 to 3.50) based on high quality of evidence. Roflumilast 500 µg increased risk of psychiatric adverse events compared to placebo by an additional 4 patients per 100 treated, 7 per 100 patients versus 3 per 100 patients (moderate quality of evidence).3 No difference in morality was demonstrated between PDE4 inhibitors and placebo based on moderate quality of evidence (OR 0.98; 95% CI, 0.77 to 1.24).

AHRQ – Pharmacological and Nonpharmacological Therapies in Adult Patients with Exacerbation of COPD AHRQ conducted a systematic review of therapies to manage adult patients with COPD experiencing an exacerbation.4 Evidence was searched through January 2020. There were 98 randomized trials, totaling 13,401 patients meeting criteria for inclusion.4 Effectiveness of interventions were measured by health outcomes including mortality, exacerbation resolution, hospital readmission, repeat exacerbations and need for intubation. Studies on the use of maintenance medications for an acute exacerbation of COPD looked at surrogate outcomes (changes in FEV1). Overall, there was insufficient evidence on hospitalizations, intubations and mortality.

Four studies evaluated the effects of ICS in patients with mild, moderate and severe COPD. Patients (n=106) with moderate to severe COPD taking inhaled budesonide demonstrated higher FEV1 percent predicted (FEV1PP) increases compared to placebo (weighted mean difference [WMD] 10.10%; 95% CI, 4.23 to 15.97%).4 No difference was found between ICS and placebo in dyspnea, 30-day hospital admission, and need for intubation. Combination budesonide and terbutaline increased FEV1PP compared to placebo in 40 patients (WMD 8.30%; 95% CI, 2.92 to 13.68%).4 There were no significant differences in adverse events between active treatment and placebo in all studies. Combination ICS and 4 LABA (budesonide and formoterol) compared to placebo had no significant effect on FEV1 in 30 patients with mild COPD.

Evidence is insufficient to support the use of inhaled corticosteroids in acute exacerbations of COPD for outcomes of mortality, dyspnea, need for intubation and hospital admission.

After review, 4 systematic reviews were excluded due to poor quality, wrong study design of included trials (e.g., observational), comparator (e.g., no control or placebo-controlled), or outcome studied (e.g., non-clinical).15–19

New Guidelines: High Quality Guidelines:

NICE – Asthma Diagnosis, Monitoring and Chronic Management

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A February 2020 update was done by NICE to determine if increasing ICS treatment in children and young people (ages less than 18years) via self-management is an effective way to manage asthma at the onset of an exacerbation.2 Children and young people who use ICS preventative therapy and have a personalized action plan were included in the evidence review. Adults who use ICS therapy and have action plans to manage exacerbation were also included due to a paucity of evidence in children and young people. Five studies were identified for inclusion. The primary outcome of interest was the number of subsequent asthma exacerbations.

The quality of evidence was low with only one study in children and young people. The number of adolescents included in the adult studies was too small to extrapolate evidence to children and young people. NICE recommends that the ICS dose not be increased according to a self- directed action plan in children and young people at the onset of an exacerbation due to the lack of high quality evidence.2

NICE – Benralizumab for Treating Severe Eosinophilic Asthma A 2019 NICE update provided guidance on the use of the biologic treatment, benralizumab, for the treatment of severe eosinophilic asthma.20 NICE recommends the use of benralizumab for patients meeting the following criteria: - Adult patients with inadequately controlled asthma despite optimization of maintenance therapy with high-dose corticosteroids and LABAs20 AND - Blood eosinophil counts of 300 cells/µL or more and 4 or more exacerbations needing systemic corticosteroids in the previous 12 months or continuous oral corticosteroid use equivalent to prednisone 5 mg/day over the previous 6 months20 OR - Blood eosinophil count has been recorded as 400 cells/µL or more with at least 3 exacerbations needing systemic corticosteroids in the past 12 months20 NICE recommends that patients meeting the criteria for benralizumab use be referred to a specialist for management. NICE recommends that benralizumab therapy be reevaluated every 12 months to ensure that there has been a reduction in the number of severe exacerbations needing systemic corticosteroids or clinically significant reduction in continuous oral corticosteroid without exacerbations of symptoms. 20

The evidence supporting the recommendations for benralizumab come from 2 randomized-controlled trials. Pooled results from 2 trials demonstrated a reduction in the annual rate of exacerbations by 43% with benralizumab compared to placebo (relative risk [RR] 0.57; 95% CI, 0.47 to 0.69; p<0.0001).20 Efficacy was greatest in patients with blood eosinophil counts greater than 300 cells/µL or in those with 3 or more exacerbations. Trial data found a reduction in the median final oral corticosteroid dose by 75% with benralizumab compared to a placebo reduction of 25%. There is insufficient head-to-head evidence to compare the efficacy of benralizumab to either reslizumab or mepolizumab.

NICE - Roflumilast for Treating Chronic Obstructive Pulmonary Disease A 2017 NICE guidance outlined treatment recommendations for the use of roflumilast for patients with COPD.5 Recommendations for the use of roflumilast are based on evidence used for roflumilast approval in 2011.

NICE Recommendations for Roflumilast use in Patients with COPD:

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- Adult patients having severe COPD with bronchitis - COPD has been classified as severe based on FEV1 of less than 50% of predicted normal after bronchodilator use And - Patient has had 2 or more exacerbations in the previous 12 months despite triple inhaled therapy with LAMA/LABA/ICS - Treatment is initiated by a specialist in respiratory medicine Roflumilast is generally well tolerated. Most common reasons for discontinuations were weight loss and gastrointestinal side effects.

European Respiratory Society and the American Thoracic Society (ERS/ATS) – Management of Severe Asthma A 2019 guidance on the management of severe asthma was authored by the ERS/ATS. Guideline methodology was generally of high quality based on the AGREE evaluation tool; however, most authors reported conflicts of interest.21 A literature search was conducted through September 2018. Twelve trials were included which evaluated the use of monoclonal anti-interleukin (IL)-5 antibodies (mepolizumab, reslizumab and benralizumab) in adults and children with severe asthma.

All monoclonal anti-IL-5 antibody products reduce exacerbations and hospitalizations in patients with severe eosinophilic asthma. Mepolizumab and benralizumab reduced the oral corticosteroid dose in corticosteroid-dependent asthma. For the outcomes of asthma control, QoL and FEV1, there was only modest benefit which did not meet MCID.

Table 1. ERS/ATS Management of Severe Asthma Recommendations21 Recommendation 1. Anti-IL-5 should be offered to patients as add-on therapy for adult patients with severe uncontrolled asthma with an eosinophilic phenotype and for those patients with severe oral corticosteroid dependent asthma (low quality of evidence) 2. A blood eosinophil count of > 150 µL-1 can be used as a marker for anti-IL-5 initiation in adult patients with severe asthma and prior asthma exacerbations (low quality of evidence) 3. In adults and adolescents with severe asthma considering omalizumab the following should be considered: - Blood eosinophil count of > 260 µL-1 to identify adolescents (>12 years) and adults with severe allergic asthma who would likely to benefit from therapy (low quality of evidence) - FENO cut off of > 19.5 ppb to identify adolescents and adults with severe allergic asthma who would likely benefit from anti-IgE treatment (low quality of evidence) 4. For children, adolescents and adults with severe asthma uncontrolled with therapies outlined below in GINA step 4-5 or NAEPP guidelines as step 5 therapies, tiotropium is recommended (moderate quality of evidence) Abbreviations: FENO- exhaled nitric oxide fraction; GINA – Global Initiative for Asthma; IL – interleukin; ppb = parts per billion; NAEPP – National Asthma Education and Prevention Program

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Additional Guidelines for Clinical Context:

GINA – Global Strategy for Asthma Management and Prevention GINA updates their recommendations on an annual basis to guide diagnosis and management of asthma in adults and adolescents.9 Guidelines are based on a systematic search of the literature and publications are reviewed for acceptance by at least two committee members that are without conflicts of interest. Evidence is graded based on criteria developed by the National Heart Lung and Blood Institute which ranks the level of evidence from A to D, with A level evidence defined as: well-designed randomized controlled trials, meta-analyses or post-hoc or observational data.9 There is no risk of bias assessment used as inclusion criteria for publications used for guideline development. Other limitations to the guideline include the absence of the following: target users, objective of the guidelines, specifics on evidence selection, diversity in representation from professional groups, patient and public input, external review by experts in the field, and discussion on resource implications/barriers of recommendations.9 Therefore, guideline recommendations for pharmaceutical management will be provided for clinical context but not relied upon for decisions regarding the PDL.

Recommendations provided by GINA are based on asthma symptom severity ranging from steps 1 to step 5 as outlined below.9 Medication recommendations based on corresponding steps are displayed in Table 2. A major update to the guidelines is the recommendation that adults and adolescents with asthma should no longer be treated with a SABA alone (Tables 2 and 3).9 Daily or as-needed (ICS-formoterol) controller treatment should contain an ICS and replace SABA monotherapy. For step 1 and 2, as-needed low dose ICS-formoterol is recommended as the preferred reliever therapy. As-needed low dose ICS-formoterol for patients prescribed maintenance and reliever therapy is recommended for steps 3-5 (if patients prescribed budesonide-formoterol or beclometasone dipropionate (BDP)-formoterol for maintenance and reliever therapy).9 As-needed SABA is an alternative option for all asthma steps. Patients with difficult to treat asthma (uncontrolled step 4 or step 5 asthma despite optimal therapy) should add treatment such as tiotropium, LTRA, and low dose macrolides and biologic agents for severe allergic or severe Type 2 asthma.

Asthma Severity Directing Therapy Mild Asthma Step 1 – Symptoms less than twice a month Step 2 – Symptoms twice a month or more, but less than daily Moderate Asthma Step 3 – Symptoms most days or waking with asthma once a week or more Severe Asthma Step 4 – Symptoms most days or waking with asthma once a week or more or low lung function Step 5 – Severely uncontrolled asthma

Table 2. 2020 GINA Recommendations for Initial Controller Medications in Adults and Adolescents with Asthma*9 STEP Treatment Recommendation Level of Evidence STEP 1 - As-needed low dose ICS-formoterol or B - Low dose ICS whenever a SABA is taken B

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STEP 2 - Daily low dose ICS or A - As-needed low dose ICS-formoterol A STEP 3 - Lose dose ICS-LABA or A - Medium dose ICS or B - Low dose ICS + LTRA A STEP 4 - Medium dose ICS-LABA or D - High dose ICS, add on tiotropium or add-on LTRA A STEP 5 - High dose ICS-LABA A - Refer for phenotypic assessment +/- add-on Not reported therapy (tiotropium, anti-IgE, anti-IL5/5R, anti- IL4R) or Not reported - Add low dose OCS but consider side effects Key: * Preferred controller option listed first Abbreviations: ICS – inhaled corticosteroid; LABA – long-acting beta agonist; LTRA – leukotriene receptor antagonist; OCS – oral corticosteroid; SABA – short-acting beta agonist

Table 3. 2020 GINA Recommendations for Initial Controller Medications in Children 6-11 with Asthma*9 STEP Treatment Recommendation Level of Evidence STEP 1 - As-needed SABA Not reported - Low dose ICS when SABA taken or - Daily low dose ICS STEP 2 - Daily low dose ICS or A - Daily LTRA or low dose ICS when SABA is taken B STEP 3 - Lose dose ICS-LABA or medium dose ICS or A - Low dose ICS + LTRA STEP 4 - Medium dose ICS-LABA and Not reported - Referral to expert or - High dose ICS-LABA or add on tiotropium or add on Not reported LTRA STEP 5 - Refer for phenotypic assessment +/- add-on Not reported therapy (e.g. anti-IgE) or - Add-on anti-IL5 or add-on low dose OCS, but consider side effects

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Key: * Preferred controller option listed first Abbreviations: ICS – inhaled corticosteroid; LABA – long-acting beta agonist; LTRA – leukotriene receptor antagonist; OCS – oral corticosteroid; SABA – short-acting beta agonist

GOLD – Global Initiative for Chronic Obstructive Lung Disease A 2020 guidance on the management of COPD was published by GOLD.22 Methodology is the same as for the GINA guidelines (above) with the associated limitations as well. Bronchodilators and anti-inflammatory therapies are the cornerstone of COPD management. Recommendations are similar for the 2019 and 2020 COPD classification (Table 4) and initial management of COPD (Figure 1). A refined ABCD assessment tool was published in the 2020 guidance that recommends a three step process for COPD classification. The first step is a spirometrically confirmed diagnosis of COPD as indicated by a post-bronchodilator FEV1/FVC <0.7. Assessment of airflow limitation should follow as described in Table 4. Lastly, assessment of symptoms/risk of exacerbations should be based off of Figure 1 to determine the group that the patient would best fit (A, B, C, or D) which also will guide therapy selection. Group classification also requires the administration of modified Medical Research Council dyspnea questionnaire (mMRC) or COPD assessment test (CATm) to determine dyspnea symptoms. There is no high quality evidence to support the initial treatment selection for COPD; however, lower quality evidence suggests initiation of ICS/LABA is more effective than treatments with LAMA in patients with previous exacerbations and high levels of blood eosinophils (>300 cells/µL).22

Table 4. Classification of COPD Based on GOLD Guidelines*20 Classification Severity Post-Bronchodilator FEV1 (% predicted) GOLD 1 Mild ≥ 80 GOLD 2 Moderate 50 -79 GOLD 3 Severe 30-49 GOLD 4 Very severe < 30 * For patients with a FEV1/FVC < 0.70

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Figure 1. Initial Pharmacological Management of COPD22 ≥ 2 moderate exacerbations or ≥ 1 leading Group C Group D to a hospitalization LAMA LAMA or LAMA + LABA* or ICS + LABA** * Consider if highly symptomatic (e.g., CAT > 20) ** Consider if EOS ≥ 300 0 or 1 moderate exacerbations Group A Group B (not leading to hospital admission) A Bronchodilator A Long Acting Bronchodilator (short or long-acting) (LABA or LAMA)

mMRC 0-1 CAT <10 mMRC ≥ 2 CAT ≥ 10

Abbreviations: EOS = blood eosinophil count in cells per microliter; mMRC = modified Medical Research Council dyspnea questionnaire; CAT = COPD assessment test Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2020 Report. Available at: 14. Accessed July 15, 2020.

Pharmacotherapy management of dyspnea and exacerbations should be directed by a review of the symptoms, assessment of current therapy (technique and adherence) and adjustment of therapy with escalation or de-escalation. Patients with persistent dyspnea on long acting bronchodilator monotherapy should be considered for dual therapy with a second long-acting bronchodilator.22 Patients on ICS/LABA therapy can be considered for triple therapy with the addition of a LAMA. For patients who experience exacerbations on long acting bronchodilator therapy, transitioning to a LABA/LAMA or LABA/ICS is recommended.22 Patients with a history of asthma and/or a peripheral blood level of 300 or more eosinophils per microliters are more likely to respond to LABA/ICS.22 Patients with exacerbations on LABA/LAMA should be treated with roflumilast or azithromycin if blood eosinophils are less than 100 cells per microliter, or triple therapy with LABA/LAMA/ICS if blood eosinophil levels are 100 cells per microliter or greater. Patients on triple therapy who continue to have exacerbations can be considered for roflumilast, macrolide therapy or discontinuation of ICS (due to risk of pneumonia or based on lack of efficacy).22

After review, one guideline was excluded due to poor quality.23

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New Formulations and Indications:

Mepolizumab (NUCALA) – Mepolizumab was approved for use in pediatric patients, ages 6 years and older, for the treatment of severe asthma with an eosinophilic phenotype.24 The efficacy of mepolizumab was extrapolated from data in adults in addition to pharmacokinetic data to support approval.

Budesonide/glycopyrrolate/formoterol (BREZTRI AEROSPHERE) – Budesonide 160 mcg/glycopyrrolate 9 mcg/formoterol fumarate 4.8 mcg (BGF) triple drug inhalation therapy (ICS/anticholinergic/LABA), indicated for maintenance therapy in patients with COPD, was approved in late July 2020.25 BGF was studied in two phase 3, multicenter, parallel-group trials in patients with moderate to severe COPD, which are described in Table 6.26,27 BGF was found to reduce COPD exacerbations and improve FEV1 outcomes compared to budesonide/formoterol fumarate and glycopyrrolate/formoterol fumarate; however, differences were small with unknown clinical significance.

Most common adverse reaction are upper respiratory tract infection, pneumonia, back pain, oral candidiasis, influenza, muscle spasm, urinary tract infection, cough, sinusitis, and diarrhea.25

New FDA Safety Alerts:

Table 5. Description of New FDA Safety Alerts Generic Name Brand Name Month / Year Location of Change (Boxed Addition or Change and Mitigation Principles (if applicable) of Change Warning, Warnings, CI) Montelukast28 Singulair April 2020 Boxed Warning Serious neuropsychiatric events have been reported. Monitor for neuropsychiatric symptoms in patients taking montelukast and discontinue if symptoms occur. Only use montelukast in patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies. Roflumilast29 Daliresp August 2017 Warnings and Precautions Psychiatric events including suicidality have been reported. Patients should be aware of worsening insomnia, anxiety, depression, suicidal thoughts or other mood changes.

Randomized Controlled Trials: A total of 130 citations were manually reviewed from the initial literature search. After further review, 124 citations were excluded because of wrong study design (eg, observational), comparator (eg, no control or placebo-controlled), or outcome studied (eg, non-clinical). The remaining three publications are summarized in the table below. Full abstracts are included in Appendix 2.

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Table 6. Description of Randomized Comparative Clinical Trials. Study Comparison Population Primary Outcome Results Interpretation Rabe, et al26 1) Budesonide 320 µg/ Glycopyrrolate Patients with The annual rate 1) 1.08 Triple therapy with 18 µg/ Formoterol fumarate 9.6 µg moderate to (estimated mean 2) 1.07 budesonide/glycopyrrolate/ (ETHOS) inhaled twice daily very severe number per patient 3) 1.42 formoterol (low [160 µg Vs. COPD and at per year) of moderate 4) 1.24 budesonide dose] and high 52-week, phase 2) Budesonide 160 µg/ Glycopyrrolate least one or severe COPD [320 µg budesonide dose]) was 3, DB, MC, PG, 18 µg/ Formoterol fumarate 9.6 µg exacerbation in exacerbations 1 vs. 3 more effective than RCT inhaled twice daily the last year RR 0.76 (95% CI, glycopyrrolate/formoterol and Vs. 0.69 to 0.83) budesonide/formoterol for 3) Glycopyrrolate 18 µg/ Formoterol (n=8509) P<0.001 reducing the rate of COPD fumarate 9.6 µg exacerbations. The absolute inhaled twice daily 1 vs. 4 reduction in exacerbations was Vs. RR 0.87 (95% CI, less than 1 exacerbation per 4) Budesonide 320 µg/ Formoterol 0.79 to 0.95) patient per year. fumarate 9.6 µg P = 0.003 inhaled twice daily 2 vs. 3 RR 0.75 (95% CI, 0.69 to 0.83) P<0.001

2 vs. 4 RR 0.86 (95% CI, 0.79 to 0.95) P=0.002 Ferguson, et 1) Budesonide 320 µg/ Glycopyrrolate Patients with FEV1 area under the FEV1 AUC0-4mL There was no difference al27 18 µg/ Formoterol fumarate 9.6 µg moderate to curve from 0-4 hours 1) 305 mL between triple therapy inhaled twice daily severe COPD (AUC0-4) for 1) versus 2) 288 mL (budesonide/glycopyrrolate/fo (KRONOS) Vs. without a 3) and 1) versus 4) and 3) 201 mL rmoterol fumarate) and 2) Glycopyrrolate 18 µg/ Formoterol requirement for analysis of change 4) 214 mL glycopyrrolate/formoterol 24-week, phase fumarate 9.6 µg a history of from baseline in fumarate in changes in FEV1 3, DB, MC, PG, inhaled twice daily exacerbations morning pre-dose 1 vs. 2 AUC0-4mL . Triple therapy was RCT Vs. trough FEV1 for 1) LSM 16 mL (95% more effective in increasing 3) Budesonide 320 µg/ Formoterol versus 2) and non- CI, -6 to 38) FEV1 AUC0-4mL compared to fumarate 9.6 µg (n = 3047) inferiority analysis of P=0.1448 budesonide/formoterol inhaled twice daily 3) versus 4) (non- fumarate. inferiority analysis of -

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4) Budesonide 400 µg/ Formoterol 50 mL from lower 1 vs. 3 Increases in baseline morning fumarate 12 µg bound of 95% CI) LSM 104 mL (95% pre-dose trough FEV1 were inhaled twice daily (open-label) CI, 77 to 131) larger for P<0.0001 budesonide/glycopyrrolate/for moterol fumarate compared to 1 vs. 4 glycopyrrolate/formoterol 91 (95% CI, 64 to fumarate and 117) budesonide/formoterol P<0.0001 fumarate.

Change from Differences between groups in baseline in lung function for both groups is morning pre-dose small and unlikely to be trough FEV1 clinically significant. 1) 147 mL 2) 125 mL 3) 73 mL 4) 88 mL

1 vs. 2 22 mL (95% CI, 4 to 39) P=0.0139

1 vs. 3 (prespecified secondary endpoint) 74 mL (95% CI, 52 to 95) P<0.0001

1 vs. 4 59 mL (95% CI, 38 to 80) P<0.0001

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Criner, et al14 Benralizumab 30 mg given every 8 Patients with Annualized COPD Benralizumab 30 Benralizumab was not found to weeks* moderate to exacerbation rate mg: 1.19 reduce annualized rate of (GALATHEA) very severe ratio at week 56 in Benralizumab COPD exacerbations more than Benralizumab 100 mg given every 8 COPD with patients with blood 100mg: 1.03 placebo Phase 3, DB, weeks* frequent eosinophil counts of Placebo: 1.24 PC, RCT exacerbations 220 per cubic Vs. despite millimeter or greater Benralizumab 30 56 weeks receiving (same as microliter) mg vs. placebo: Placebo given every 8 weeks* guideline-based RR 0.96 (95% CI inhaled 0.80 to 1.15) treatment P=0.65 Benralizumab 100 (n=1120) mg vs. placebo: RR 0.83 (95% CI, 0.69 to 1.00) P=0.05

Criner, et al14 Benralizumab 10 mg given every 8 Patients with Annualized COPD Benralizumab 10 Benralizumab was not found to weeks* moderate to exacerbation rate mg: 0.99 reduce annualized rate of (TERRANOVA) very severe ratio at week 56 in Benralizumab 30 COPD exacerbations more than Benralizumab 30 mg given every 8 COPD with patients with blood mg: 1.21 placebo Phase 3, DB, weeks* frequent eosinophil counts of Benralizumab PC, RCT exacerbations 220 per cubic 100mg: 1.09 Benralizumab 100 mg given every 8 despite millimeter or greater Placebo: 1.17 weeks* receiving (same as microliter) 56 weeks guideline-based Benralizumab 10 Vs. inhaled mg vs. placebo: treatment RR 0.85 (95% CI, Placebo given every 8 weeks* 0.71 to 1.01) (n=1545) P=0.6 Benralizumab 30 mg vs. placebo: RR 1.04 (95% CI, 0.88 to 1.23) P=0.066 Benralizumab 100 mg vs. placebo:

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RR 0.93 (95% CI, 0.78 to 1.10) P=0.40

30 Virchow, et al 1) Beclometasone dipropionate 100 µg Adults with Pre-dose expiratory Pre-dose FEV1 The addition of a long-acting /formoterol 6 µg /glycopyrronium 10 uncontrolled volume in 1 second change from muscarinic antagonist to (TRIMARAN) µg, 2 inhalations twice daily asthma, a (FEV1) at week 26 and baseline existing ICS and LABA therapy history of one rate of moderate and 1) 185 mL improves lung function and PG, DB, Phase Vs. or more severe exacerbations 2) 127 mL exacerbations (difference in 3, RCT exacerbations over 52 weeks MD 57 mL (95% FEV1 less than MCID of 100 mL) 2) Beclometasone 100 µg in the previous CI, 15 to 99) dipropionate/formoterol 6µg, 2 year and P=0.0080 inhalations twice daily previously treated with ICS Annualized rate of and LABA moderate to severe (n=1155) exacerbations 1) 1.83 2) 2.16 RR 0.85 (95% CI, 0.73 to 0.99) P=0.033

30 Virchow, et al 1) Beclometasone dipropionate 200 µg Adults with Pre-dose expiratory Pre-dose FEV1 The addition of a long-acting /formoterol 6 µg /glycopyrronium 10 uncontrolled volume in 1 second change from muscarinic antagonist to (TRIGGER) µg, 2 inhalations twice daily asthma, a (FEV1) at week 26 and baseline existing ICS and LABA therapy history of one rate of moderate and 1) 229 mL improves lung function. There PG, DB, Phase Vs. or more severe exacerbations 2) 157 mL was no difference in lung exacerbation in over 52 weeks 3) 274 mL function or exacerbations upon 2) Beclometasone dipropionate 200 µg the previous comparison of glycopyrronium /formoterol 6 µg, 2 inhalations twice year and 1 vs. 2 and tiotropium. daily previously MD 73 mL (95% treated with ICS CI, 26 to 120 mL) Vs. and LABA P= 0.0025

3) Beclometasone dipropionate 200 µg (n=1437) 1 vs. 3 /formoterol 6 µg, 2 inhalations twice MD -45 mL (95% CI, -103 to 13 mL)

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daily + tiotropium 2.5 µg, 2 inhalations P= 0.13 once daily (open-label)

Annualized rate of moderate to severe exacerbations 1) 1.73 2) 1.96 3) 1.61

1 vs. 2 RR 0.88 (95% CI, 0.75 to 1.03) P= 0.11

1 vs. 3 RR 1.07 (95% CI, 0.88 to 1.30) P= 0.50 Key: * Given every 4 weeks for the first 3 doses Abbreviations: COPD – chronic obstructive pulmonary disease; DB – double-blind; FEV1 – forced expiratory volume in 1 second; ICS – inhaled corticosteroids; LABA – long-acting Beta 2 agonist; LSM – least squares mean; MCID – minimal clinically important difference; MD – mean difference; PC – placebo-controlled; PG – parallel group; RCT – randomized controlled trial; RR – rate ratio

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References: 1. Janjua S, Schmidt S, Ferrer M, Cates CJ. Inhaled Steroids With And Without Regular Formoterol For Asthma: Serious Adverse Events. Cochrane Database of Systematic Reviews. 2019;(9). doi:10.1002/14651858.CD006924.pub4. 2. National Institute for Health and Care Excellence. Asthma: Diagnosis, Monitoring And Chronic Asthma Management. NICE Guideline. February 2020. Available at: www.nice.uk.org. Accessed July 22, 2020. 3. Janjua S, Fortescue R, Poole P. Phosphodiesterase‐4 Inhibitors For Chronic Obstructive Pulmonary Disease. Cochrane Database of Systematic Reviews. 2020;(5). doi:10.1002/14651858.CD002309.pub6. 4. Dobler CC, Morrow AS, Farah MH, et al. Pharmacologic and Nonpharmacologic Therapies in Adult Patients With Exacerbation of COPD: A Systematic Review. Agency for Healthcare Research and Quality (AHRQ). 2019. doi:10.23970/AHRQEPCCER221. 5. National Institute for Health and Care Excellence. Roflumilast For Treating Chronic Obstructive Pulmonary Disease. Technology Appraisal Guidance. July 2017. Available at: www.nice.uk.org. Accessed July 25, 2020. 6. Centers for Disease Control and Prevention. Most Recent Ashtma Data. May 2018. Available at: https://www.cdc.gov/asthma/most_recent_data.htm. Accessed February 23, 2019. 7. The Oregon Asthma Program 2013. The Burden of Asthma in Oregon; 2013. Available at: http://public.health.oregon.gov/DiseasesConditions/ChronicDisease/Asthma/Documents/burden/OR_Asthma_2013.pdf. Accessed July 27, 2020. 8. US Department of Health and Human Services, National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma; 2007. US Department of Health and Human Services, National Heart, Lung and Blood Institute. Published 2007. Accessed May 23, 2012. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. 9. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2020 Update. Available at: https://ginasthma.org/wp-content/uploads/2020/06/GINA-2020-report_20_06_04-1-wms.pdf. Accessed July 7, 2020. 10. Wenzel S. Treatment Of Severe Asthma In Adolescents And Adults. UpToDate. June 2020. Accessed July 21, 2020. 11. Cazzola M, Macknee W, Martinez F, et al. Outcomes For COPD Pharmacological Trials: From Lung Function To Biomarkers. Eur Respir J. 2008; 31:416-469. 12. Petsky HL, Li A, Chang AB. Tailored Interventions Based On Sputum Eosinophils Versus Clinical Symptoms For Asthma In Children And Adults. Cochrane Database of Systematic Reviews. 2017;(8). doi:10.1002/14651858.CD005603.pub3. 13. Center for Disease Control. Chronic Obstructive Pulmonary Disease. COPD Among Adults In Oregon. Available at:https://www.cdc.gov/copd/maps/docs/pdf/OR_COPDFactSheet.pdf. Accessed March 10, 2019. 14. Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the Prevention of COPD Exacerbations. N Engl J Med. 2019;381(11):1023-1034. doi:10.1056/NEJMoa1905248 15. Tian B, Zhang G, Lou J, Zhou H, Cui W. Efficacy And Safety Of Benralizumab For Eosinophilic Asthma: A Systematic Review And Meta- Analysis Of Randomized Controlled Trials. Journal of Asthma. 2018;55(9):956-965. doi:10.1080/02770903.2017.1379534. 16. He L-L, Zhang L, Jiang L, Xu F, Fei D-S. Efficacy And Safety Of Anti-Interleukin-5 Therapy In Patients With Asthma: A Pairwise And Bayesian Network Meta-Analysis. International Immunopharmacology. 2018;64:223-231. doi:10.1016/j.intimp.2018.08.031.

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17. Siddiqui MK, Shukla P, Jenkins M, et al. Systematic Review And Network Meta-Analysis Of The Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler In Comparison With Other Long-Acting Muscarinic Antagonist/Long-Acting Beta2- Agonist Fixed-Dose Combinations In COPD. Therapeutic Advances in Respiratory Disease. 2019;1:1753466619894502. doi:10.1177/1753466619894502. 18. Wu J, Ye Y, Li C, Zhou W, Chang R. Correlation of Inhaled Long-Acting Bronchodilators With Adverse Cardiovascular Outcomes in Patients With Stable COPD: A Bayesian Network Meta-Analysis of Randomized Controlled Trials. Journal of Cardiovascular Pharmacology. 2019;74(3):255- 265. doi:10.1097/FJC.0000000000000705 19. Yang M, Zhang Y, Chen H, Lin J, Zeng J, Xu Z. Inhaled Corticosteroids And Risk Of Upper Respiratory Tract Infection In Patients With Asthma: A Meta-Analysis. Infection. 2019;47(3):377-385. doi:10.1007/s15010-018-1229-y. 20. National Institute for Health and Care Excellence. Benralizumab for Treating Severe Eosimophilic Asthma. Technology Appraisal Guidance. March 2019. Available at www.nice.org.uk/guidance/ta565. Accessed July 27, 2020. 21. Holguin F, Cardet JC, Chung KF, et al. Management Of Severe Asthma: A European Respiratory Society/American Thoracic Society Guideline. Eur Respir J. 2020;55(1):1900588. doi:10.1183/13993003.00588-2019. 22. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2020 Report. Available at: https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2- 03Dec19_WMV.pdf. Accessed July 7, 2020. 23. Bourbeau J, Bhutani M, Hernandez P, et al. Canadian Thoracic Society Clinical Practice Guideline On Pharmacotherapy In Patients With COPD – 2019 Update Of Evidence. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2019;3(4):210-232. doi:10.1080/24745332.2019.1668652. 24. Nucala (mepolizumab) [product information]. Philadelphia, PA: GlaxoSmithKline LLC, June 2019. 25. Breztri (budesonide/glycopyrrolate/formoterol fumarate) [product information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP, 2020. 26. Rabe KF, Martinez FJ, Ferguson GT, et al. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD. New England Journal of Medicine. Published online June 24, 2020. doi:10.1056/NEJMoa1916046. 27. Ferguson GT, Rabe KF, Martinez FJ, et al. Triple Therapy With Budesonide/Glycopyrrolate/Formoterol Fumarate With Co-Suspension Delivery Technology Versus Dual Therapies In Chronic Obstructive Pulmonary Disease (KRONOS): A Double-Blind, Parallel-Group, Multicentre, Phase 3 Randomised Controlled Trial. Lancet Respir Med. 2018;6(10):747-758. doi:10.1016/S2213-2600(18)30327-8 28. Singulair (montelukast) [product information]. Whitehouse Station, NJ: Merck and Co, Inc., April 2020. 29. Daliresp (roflumilast) [product information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP, August 2017. 30. Virchow JC, Kuna P, Paggiaro P, et al. Single Inhaler Extrafine Triple Therapy In Uncontrolled Asthma (TRIMARAN and TRIGGER): Two Double-Blind, Parallel-Group, Randomised, Controlled Phase 3 Trials. Lancet. 2019;394(10210):1737-1749. doi:10.1016/S0140-6736(19)32215-9.

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Appendix 1: Current Preferred Drug List LABA/LAMA Combination, Inhalers Generic Brand Form PDL aclidinium brom/formoterol fum DUAKLIR PRESSAIR AER POW BA N fluticasone/umeclidin/vilanter TRELEGY ELLIPTA BLST W/DEV N glycopyrrolate/formoterol fum BEVESPI AEROSPHERE HFA AER AD N indacaterol/glycopyrrolate UTIBRON NEOHALER CAP W/DEV N tiotropium Br/olodaterol HCl STIOLTO RESPIMAT MIST INHAL N umeclidinium brm/vilanterol tr ANORO ELLIPTA BLST W/DEV N budesonide/glycopyrrol/form fum BREZTRI AEROSPHERE MIST INHAL N

Beta-agonists, Inhaled Long-acting Generic Brand Form PDL salmeterol xinafoate SEREVENT DISKUS BLST W/DEV Y arformoterol tartrate BROVANA VIAL-NEB N formoterol fumarate PERFOROMIST VIAL-NEB N indacaterol maleate ARCAPTA NEOHALER CAP W/DEV N olodaterol HCl STRIVERDI RESPIMAT MIST INHAL N

Anticholinergics, Inhaled Generic Brand Form PDL aclidinium bromide TUDORZA PRESSAIR AER POW BA Y ipratropium bromide ATROVENT HFA HFA AER AD Y ipratropium bromide IPRATROPIUM BROMIDE SOLUTION Y ipratropium/albuterol sulfate IPRATROPIUM-ALBUTEROL AMPUL-NEB Y tiotropium bromide SPIRIVA CAP W/DEV Y glycopyrrol/nebulizer/accessor LONHALA MAGNAIR STARTER VIAL-NEB N glycopyrrolate SEEBRI NEOHALER CAP W/DEV N glycopyrrolate/neb.accessories LONHALA MAGNAIR REFILL VIAL-NEB N ipratropium/albuterol sulfate COMBIVENT RESPIMAT MIST INHAL N revefenacin YUPELRI VIAL-NEB N tiotropium bromide SPIRIVA RESPIMAT MIST INHAL N umeclidinium bromide INCRUSE ELLIPTA BLST W/DEV N

Corticosteroids, Inhaled Generic Brand Form PDL

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budesonide PULMICORT FLEXHALER AER POW BA Y fluticasone propionate FLOVENT DISKUS BLST W/DEV Y fluticasone propionate FLOVENT HFA AER W/ADAP Y mometasone furoate ASMANEX AER POW BA Y beclomethasone dipropionate QVAR REDIHALER HFA AEROBA N budesonide BUDESONIDE AMPUL-NEB N budesonide PULMICORT AMPUL-NEB N ciclesonide ALVESCO HFA AER AD N fluticasone furoate ARNUITY ELLIPTA BLST W/DEV N mometasone furoate ASMANEX HFA HFA AER AD N mometasone furoate ASMANEX HFA HFA AER AD

Corticosteroid/LABA Combination, Inhalers Generic Brand Form PDL BUDESONIDE-FORMOTEROL budesonide/formoterol fumarate FUMARATE HFA AER AD Y budesonide/formoterol fumarate SYMBICORT HFA AER AD Y fluticasone propion/salmeterol ADVAIR DISKUS BLST W/DEV Y fluticasone propion/salmeterol ADVAIR HFA HFA AER AD Y fluticasone propion/salmeterol FLUTICASONE-SALMETEROL BLST W/DEV Y fluticasone propion/salmeterol WIXELA INHUB BLST W/DEV Y mometasone/formoterol DULERA HFA AER AD Y fluticasone propion/salmeterol AIRDUO RESPICLICK AER POW BA N fluticasone propion/salmeterol FLUTICASONE-SALMETEROL AER POW BA N fluticasone/vilanterol BREO ELLIPTA BLST W/DEV N

Miscellaneous Pulmonary Agents Generic Brand Route Form PDL montelukast sodium MONTELUKAST SODIUM PO TAB CHEW Y montelukast sodium MONTELUKAST SODIUM PO TABLET Y montelukast sodium SINGULAIR PO TAB CHEW Y montelukast sodium SINGULAIR PO TABLET Y benralizumab FASENRA SQ SYRINGE N benralizumab FASENRA PEN SQ AUTO INJCT N mepolizumab NUCALA SQ AUTO INJCT N mepolizumab NUCALA SQ SYRINGE N

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mepolizumab NUCALA SQ VIAL N montelukast sodium MONTELUKAST SODIUM PO GRAN PACK N montelukast sodium SINGULAIR PO GRAN PACK N omalizumab XOLAIR SQ SYRINGE N omalizumab XOLAIR SQ VIAL N reslizumab CINQAIR IV VIAL N roflumilast DALIRESP PO TABLET N zafirlukast ACCOLATE PO TABLET N zafirlukast ZAFIRLUKAST PO TABLET N zileuton ZILEUTON ER PO TBMP 12HR N zileuton ZYFLO PO TABLET N

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Appendix 2: Abstracts of Comparative Clinical Trials

Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD Klaus F. Rabe , Fernando J Martinez , Gary T Ferguson , Chen Wang , Dave Singh , Jadwiga A Wedzicha , Roopa Trivedi , Earl St Rose , Shaila Ballal , Julie McLaren , Patrick Darken , Magnus Aurivillius , Colin Reisner , Paul Dorinsky , ETHOS Investigators

Background: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking.

Methods: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only.

Results: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group.

Conclusions: Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).

Benralizumab for the Prevention of COPD Exacerbations Gerard J Criner , Bartolome R Celli , Christopher E Brightling , Alvar Agusti , Alberto Papi , Dave Singh , Don D Sin , Claus F Vogelmeier , Frank C Sciurba , Mona Bafadhel , Vibeke Backer , Motokazu Kato , Alejandra Ramírez-Venegas , Yu-Feng Wei , Leif Bjermer , Vivian H Shih , Maria

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Jison , Sean O'Quinn , Natalya Makulova , Paul Newbold , Mitchell Goldman , Ubaldo J Martin , GALATHEA Study Investigators; TERRANOVA Study Investigators

Background: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.

Methods: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed.

Results: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.

Conclusions: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials Johann Christian Virchow , Piotr Kuna , Pierluigi Paggiaro , Alberto Papi , Dave Singh , Sandrine Corre , Florence Zuccaro , Andrea Vele , Maxim Kots , George Georges , Stefano Petruzzelli , Giorgio Walter Canonica

Author: Sentena October 2020 131

Background: To date, no studies have assessed the efficacy of single-inhaler triple therapy in asthma. Here we report on two studies that compared the single-inhaler extrafine combination of beclometasone dipropionate (BDP; inhaled corticosteroid), formoterol fumarate (FF; long- acting β2 agonist), and glycopyrronium (G; long-acting muscarinic antagonist) with the combination of BDP with FF.

Methods: Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]) recruited patients from 171 sites across 16 countries (TRIMARAN), and from 221 sites across 17 countries (TRIGGER). The sites were a mixture of secondary and tertiary care centres and specialised investigation units. Eligible patients were adults (aged 18-75 years) with uncontrolled asthma, a history of one or more exacerbations in the previous year, and previously treated with inhaled corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus a long-acting β2 agonist. Enrolled patients were initially treated with BDP/FF (TRIMARAN: 100 μg BDP and 6 μg FF; TRIGGER: 200 μg BDP and 6 μg FF) for 2 weeks, then randomly assigned to treatment using an interactive response technology system with a balanced block randomisation scheme stratified by country. Patients, investigators, site staff, and sponsor staff were masked to BDP/FF/G and BDP/FF assignment. In TRIMARAN, patients were randomly assigned (1:1) to 52 weeks of BDP/FF/G (100 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (100 μg BDP and 6 μg FF), two inhalations twice daily. In TRIGGER, patients were randomly assigned (2:2:1) to 52 weeks of BDP/FF/G (200 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (200 BDP and 6 μg FF), both two inhalations twice daily, or open-label BDP/FF (200 μg BDP and 6 μg FF) two inhalations twice daily plus tiotropium 2·5 μg two inhalations once daily. Coprimary endpoints for both trials (BDP/FF/G vs BDP/FF) were pre-dose forced expiratory volume in 1 s (FEV1) at week 26 and rate of moderate and severe exacerbations over 52 weeks. Safety was assessed in all patients who received at least one dose of study treatment. These trials were registered with ClinicalTrials.gov, NCT02676076 (TRIMARAN), NCT02676089 (TRIGGER).

Findings: Between Feb 17, 2016, and May 17, 2018, 1155 patients in TRIMARAN were given BDP/FF/G (n=579) or BDP/FF (n=576). Between April 6, 2016, and May 28, 2018, 1437 patients in TRIGGER were given BDP/FF/G (n=573), BDP/FF (n=576), or BDP/FF plus tiotropium (n=288). Compared with the BDP/FF group, week 26 predose FEV1 improved in the BDP/FF/G group by 57 mL (95% CI 15-99; p=0·0080) in TRIMARAN and by 73 mL (26-120; p=0·0025) in TRIGGER, with reductions in the rate of moderate and severe exacerbations of 15% (rate ratio 0·85, 95% CI 0·73- 0·99; p=0·033) in TRIMARAN and 12% (0·88, 0·75-1·03; p=0·11) in TRIGGER. Four patients had treatment-related serious adverse events, one in TRIMARAN in the BDP/FF/G group and three in TRIGGER-one in the BDP/FF/G and two in the BDP/FF group. Three patients in the BDP/FF/G group in TRIMARAN and two patients in TRIGGER-one in the BDP/FF/G group and one in the BDP/FF group-had adverse events leading to death. None of the deaths were considered as related to treatment.

Interpretation: In uncontrolled asthma, addition of a long-acting muscarinic antagonist to inhaled corticosteroid plus long-acting β2-agonist therapy improves lung function and reduces exacerbations.

Author: Sentena October 2020 132

Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial Gary T Ferguson 1, Klaus F Rabe, Fernando J Martinez, Leonardo M Fabbri, Chen Wang, Masakazu Ichinose, Eric Bourne, Shaila Ballal, Patrick Darken, Kiernan DeAngelis, Magnus Aurivillius, Paul Dorinsky, Colin Reisner

Abstract Background: Inhaled corticosteroids have been used in patients with chronic obstructive pulmonary disease (COPD), but the potential benefits of their use in triple therapy are not well known. We aimed to compare the efficacy of a triple therapy with corresponding dual therapies in symptomatic patients with moderate to very severe COPD, without a requirement for a history of exacerbations.

Methods: In this double-blind, parallel-group, multicentre phase 3 randomised controlled trial, we recruited patients from hospitals and care centres in Canada, China, Japan, and the USA. Eligible patients were 40-80 years of age, were current or former smokers (with a smoking history of ≥10 pack-years), had an established clinical history of COPD, and were symptomatic for COPD, despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening. We randomly assigned patients (2:2:1:1) using an interactive web response system to receive budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler 320/18/9·6 μg (BGF MDI), glycopyrrolate/ formoterol fumarate metered-dose inhaler 18/9·6 μg (GFF MDI), budesonide/formoterol fumarate metered-dose inhaler 320/9·6 μg (BFF MDI), or open- label budesonide/formoterol fumarate dry-powder inhaler 400/12 μg (BUD/ FORM DPI). Primary endpoints for the Europe/Canada statistical analysis approach were FEV1 area under the curve from 0-4 h (AUC0-4) for BGF MDI versus BFF MDI and BGF MDI versus BUD/FORM DPI over 24 weeks; and change from baseline in morning pre-dose trough FEV1 for BGF MDI versus GFF MDI and non-inferiority of BFF MDI versus BUD/FORM DPI (margin of -50 mL from lower bound of 95% CI) over 24 weeks. Comparisons with BUD/FORM DPI were made for the Europe/Canada statistical analysis approach only. This study is registered with ClinicalTrials.gov, number NCT02497001.

Findings: Between Aug 20, 2015, and Jan 5, 2018, 3047 patients were screened from 215 sites, and 1902 were randomly assigned to receive BGF MDI (n=640), GFF MDI (n=627), BFF MDI (n=316), or BUD/FORM DPI (n=319). Over 24 weeks, BGF MDI significantly improved FEV1 AUC0-4 versus BFF MDI (least squares mean difference 104 mL, 95% CI 77 to 131; p<0·0001) and BUD/FORM DPI (91 mL, 64 to 117; p<0·0001). BGF MDI also significantly improved pre-dose trough FEV1 versus GFF MDI (22 mL, 4 to 39; p=0·0139) and was non-inferior to BUD/FORM DPI (-10 mL, -36 to 16; p=0·4390). At week 24, patients in the BGF MDI group had a significantly improved FEV1 AUC0-4 compared with patients receiving BFF MDI (116 mL, 95% CI 80 to 152; p<0·0001); there was a non-significant improvement in the change from baseline in morning pre-dose trough FEV1 at week 24 versus GFF MDI (13 mL, -9 to 36 mL; p=0·2375). The most common treatment-emergent adverse events were nasopharyngitis (n=49 [8%] in the BGF MDI group; n=41 [7%] in the GFF MDI group; n=26 [8%] in the BFF MDI group; and n=30 [9%] in the BUD/FORM DPI group) and upper respiratory tract infection (n=65 [10%]; n=38 [6%]; n=18 [6%]; and n=22 [7%]). Pneumonia incidence was low (<2%) and similar across treatments. There were two treatment-related deaths, both in the GFF MDI group.

Author: Sentena October 2020 133

Interpretation: BGF MDI was efficacious, well tolerated, and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history.

Author: Sentena October 2020 134

Appedix 3: Medline Search Strategy

Author: Sentena October 2020 135

Appendix 4: Key Inclusion Criteria

Population Adults and children with asthma and adults with chronic obstructive pulmonary disease (COPD) Intervention Oral, inhaled and biological maintenance treatments for asthma and/or COPD Comparator Placebo or active therapies Outcomes Mortality, exacerbations, hospitalizations Timing As needed Setting Outpatient

Author: Sentena October 2020 136

Appendix 5: Prior Authorization Criteria

Inhaled Corticosteroids (ICS)

Goals:  To optimize the safe and effective use of ICS therapy in patients with asthma and COPD.  Step-therapy required prior to coverage for non-preferred ICS products: o Asthma: inhaled short-acting beta-agonist. o COPD: short-acting and long-acting bronchodilators (inhaled anticholinergics and beta-agonists). Preferred short-acting and long-acting bronchodilators do NOT require prior authorization. See preferred drug list options at http://www.orpdl.org/drugs/.

Length of Authorization:  Up to 12 months

Requires PA:  Non-preferred ICS products

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 Code

Author: Sentena October 2020 137

Approval Criteria

2. Will the prescriber consider a change to a preferred Yes: Inform prescriber of No: Go to #3 product? covered alternatives in class.

Message: Preferred products are reviewed for comparative effectiveness and safety by the Oregon Pharmacy and Therapeutics (P&T) Committee.

3. Is the request for treatment of asthma or reactive Yes: Go to #7 No: Go to #4 airway disease?

4. Is the request for treatment of COPD, mucopurulent Yes: Go to #5 No: Pass to RPh. Deny; chronic bronchitis and/or emphysema? medical appropriateness.

Need a supporting diagnosis. If prescriber believes diagnosis is appropriate, inform prescriber of the appeals process for Medical Director Review. Chronic bronchitis is unfunded.

5. Does the patient have an active prescription for an Yes: Go to #6 No: Pass to RPh. Deny; on-demand short-acting bronchodilator medical appropriateness. (anticholinergic or beta-agonist)?

Author: Sentena October 2020 138

Approval Criteria

6. Does the patient have an active prescription for an Yes: Approve for up to 12 No: Pass to RPh. Deny; inhaled long-acting bronchodilator (anticholinergic or months medical appropriateness. beta-agonist)?

7. Does the patient have an active prescription for an Yes: Approve for up to 12 No: Pass to RPh. Deny; on-demand short-acting beta-agonist (SABA) or an months medical appropriateness alternative rescue medication for acute asthma exacerbations?

P&T/DUR Review: 10/20 (KS), 5/19 (KS), 1/18; 9/16; 9/15 Implementation: 3/1/18; 10/13/16; 10/9/15

Long-acting Beta-agonists (LABA)

Goals:  To optimize the safe and effective use of LABA therapy in patients with asthma and COPD.  Step-therapy required prior to coverage of non-preferred LABA products: o Asthma: inhaled corticosteroid and short-acting beta-agonist. o COPD: inhaled short-acting bronchodilator.

Length of Authorization:  Up to 12 months

Requires PA:  Non-preferred LABA products

Covered Alternatives:

Author: Sentena October 2020 139

 Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 Code

2. Will the prescriber consider a change to a preferred Yes: Inform prescriber No: Go to #3 product? of covered alternatives in class Message:  Preferred products are reviewed for comparative effectiveness and safety by the Oregon Pharmacy and Therapeutics (P&T) Committee.

3. Does the patient have a diagnosis of asthma or Yes: Go to #6 No: Go to #4 reactive airway disease?

4. Does the patient have a diagnosis of COPD, Yes: Go to #5 No: Pass to RPh. Deny; medical mucopurulent chronic bronchitis and/or emphysema? appropriateness.

Need a supporting diagnosis. If prescriber believes diagnosis is appropriate, inform prescriber of the appeals process for Medical Director Review. Chronic bronchitis is unfunded

5. Does the patient have an active prescription for an Yes: Approve for up to No: Pass to RPh. Deny; medical on-demand short-acting bronchodilator 12 months appropriateness. (anticholinergic or beta-agonist)?

Author: Sentena October 2020 140

Approval Criteria

6. Does the patient have an active prescription for an Yes: Go to #7 No: Pass to RPh. Deny; medical on-demand short-acting beta-agonist (SABA) or an appropriateness alternative rescue medication for acute asthma exacerbations?

7. Does the patient have an active prescription for an Yes: Approve for up to No: Pass to RPh. Deny; medical inhaled corticosteroid (ICS) or an alternative asthma 12 months appropriateness controller medication?

P&T/DUR Review: 10/20 (KS), 5/19 (KS); 1/18; 9/16; 9/15); 5/12; 9/09; 5/09 Implementation: 3/1/18; 10/9/15; 8/12; 1/10

Long-acting Beta-agonist/Corticosteroid Combination (LABA/ICS)

Goals:  To optimize the safe and effective use of LABA/ICS therapy in patients with asthma and COPD.  Step-therapy required prior to coverage: o Asthma: short-acting beta-agonist and inhaled corticosteroid or moderate to severe persistent asthma. o COPD: short-acting bronchodilator and previous trial of a long-acting bronchodilator (inhaled anticholinergic or beta-agonist). Preferred LABA/ICS products do NOT require prior authorization.

Length of Authorization:  Up to 12 months

Requires PA:  Non-preferred LABA/ICS products

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Author: Sentena October 2020 141

Approval Criteria

1. What diagnosis is being treated? Record ICD10 Code

2. Will the provider consider a change to a preferred Yes: Inform provider of No: Go to #3 product? covered alternatives in class

Message:  Preferred products are reviewed for comparative effectiveness and safety by the Oregon Pharmacy and Therapeutics (P&T) Committee.

3. Does the patient have a diagnosis of asthma or Yes: Go to #7 No: Go to #4 reactive airway disease?

4. Does the patient have a diagnosis of COPD, Yes: Go to #5 No: Pass to RPh. Deny; mucopurulent chronic bronchitis and/or emphysema? medical appropriateness.

Need a supporting diagnosis. If prescriber believes diagnosis is appropriate, inform prescriber of the appeals process for Medical Director Review. Chronic bronchitis is unfunded.

5. Does the patient have an active prescription for an Yes: Go to #6 No: Pass to RPh. Deny; on-demand short-acting bronchodilator medical appropriateness. (anticholinergic or beta-agonist)?

Author: Sentena October 2020 142

Approval Criteria

6. Is there a documented trial of an inhaled long-acting Yes: Approve for up to 12 No: Pass to RPh. Deny; bronchodilator (anticholinergic or beta-agonist)? months. Stop coverage of all medical appropriateness. other LABA and ICS inhalers.

7. Does the patient have an active prescription for an Yes: Go to #8 No: Pass to RPh. Deny; on-demand short-acting beta-agonist (SABA) or an medical appropriateness alternative rescue medication for acute asthma exacerbations?

8. Is there a documented trial of an inhaled Yes: Approve for up to 12 No: Pass to RPh. Deny; corticosteroid (ICS) or does the patient have months. Stop coverage of all medical appropriateness moderate or severe persistent asthma? other ICS and LABA inhalers.

P&T/DUR Review: 10/20 (KS), 5/19 (KS); 1/18; 9/16; 11/15; 9/15; 11/14; 11/13; 5/12; 9/09; 2/06 Implementation: 3/1/18; 10/13/16; 1/1/16; 1/15; 1/14; 9/12; 1/10

Long-acting Muscarinic Antagonist/Long-acting Beta-agonist (LAMA/LABA) and LAMA/LABA/Inhaled Corticosteroid (LAMA/LABA/ICS) Combinations

Goals:  To optimize the safe and effective use of LAMA/LABA/ICS therapy in patients with COPD.  Step-therapy required prior to coverage: o COPD: short-acting bronchodilator and previous trial of a long-acting bronchodilator (inhaled anticholinergic or beta-agonist). Preferred LAMA and LABA products do NOT require prior authorization.

Length of Authorization:  Up to 12 months

Author: Sentena October 2020 143

Requires PA:  All LAMA/LABA and LAMA/LABA/ICS products

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 Code

2. Will the prescriber consider a change to a preferred Yes: Inform prescriber of No: Go to #3 product? preferred LAMA and LABA products in each class Message:  Preferred products are reviewed for comparative effectiveness and safety by the Oregon Pharmacy and Therapeutics (P&T) Committee.

3. Does the patient have a diagnosis of asthma or Yes: Pass to RPh. Deny; No: Go to #4 reactive airway disease without COPD? medical appropriateness.

Need a supporting diagnosis. If prescriber believes diagnosis is appropriate, inform prescriber of the appeals process for Medical Director Review.

Author: Sentena October 2020 144

Approval Criteria

4. Does the patient have a diagnosis of COPD, Yes: Go to #5 No: Pass to RPh. Deny; mucopurulent chronic bronchitis and/or emphysema? medical appropriateness.

Need a supporting diagnosis. If prescriber believes diagnosis is appropriate, inform prescriber of the appeals process for Medical Director Review. Chronic bronchitis is unfunded.

5. Does the patient have an active prescription for an Yes: Go to #6 No: Pass to RPh. Deny; on-demand short-acting bronchodilator medical appropriateness. (anticholinergic or beta-agonist)?

6. Is the request for a LAMA/LABA combination Yes: Go to #7 No: Go to #8 product?

7. Is there a documented trial of a LAMA or LABA, or Yes: Approve for up to 12 No: Pass to RPh. Deny; alternatively a trial of a fixed dose combination short- months. Stop coverage of all medical appropriateness. acting anticholinergic with beta-agonist other LAMA and LABA (SAMA/SABA) (i.e., ipratropium/albuterol), or ≥ 2 inhalers or scheduled moderate exacerbations or ≥ 1 leading to a SAMA/SABA inhalers (PRN hospitalization? SABA or SAMA permitted).

8. Is the request for a 3 drug ICS/LABA/LAMA Yes: Approve for up to 12 No: Pass to RPh. Deny; combination product and is there a documented trial months. Stop coverage of all medical appropriateness. of a LAMA and LABA, or ICS and LABA or ICS and other LAMA, LABA and ICS LAMA? inhalers.

Author: Sentena October 2020 145

P&T Review: 10/20 (KS), 5/19 (KS); 1/18; 9/16; 11/15; 9/15; 11/14; 11/13; 5/12; 9/09; 2/06 Implementation: 3/1/18; 10/13/16; 1/1/16; 1/15; 1/14; 9/12; 1/10

Roflumilast Goals:  Decrease the number of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and with a history of exacerbations.

Length of Authorization:  Up to 12 months

Covered Alternatives:  Preferred alternatives listed at http://www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code

2. Is the diagnosis an OHP-funded diagnosis? Yes: Go to #3 No: Pass to RPh. Deny; not covered by the OHP

3. Does the patient have documented severe or very Yes: Go to #4 No: Pass to RPh. Deny for severe COPD (e.g., FEV1 of < 50% predicted)? medical appropriateness

4. Does the patient have a diagnosis of chronic Yes: Go to #5 No: Pass to RPh. Deny for bronchitis (ICD10 J410-J42; J440-J449)? medical appropriateness

Author: Sentena October 2020 146

Approval Criteria

5. Does the patient have documented prior COPD Yes: Go to #6 No: Pass to RPh. Deny for exacerbations? medical appropriateness

6. Does the patient have an active prescription for a Yes: Approve for up to 12 No: Pass to RPh. Deny; long-acting bronchodilator (long-acting months recommend trial of preferred anticholinergic agent or long-acting beta-agonist) and long-acting bronchodilator inhaled corticosteroid (ICS)? and ICS

P&T/DUR Review: 10/20 (KS), 9/15 (KS); 5/13; 2/12 Implementation: 10/15; 1/14; 5/12

Monoclonal Antibodies for Severe Asthma Goal(s): Restrict use of monoclonal antibodies to patients with severe asthma requiring chronic systemic corticosteroid use or with history of asthma exacerbations in the past year that required an Emergency Department visit or hospitalization. Restrict use for conditions not funded by the OHP (e.g., chronic urticaria).

Length of Authorization:  Up to 12 months

Requires PA: Omalizumab Mepolizumab Reslizumab Benralizumab This PA does not apply to dupilumab, which is subject to separate clinical PA criteria.

Author: Sentena October 2020 147

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Table 1. Maximum Adult Doses for Inhaled Corticosteroids. High Dose Corticosteroids: Maximum Dose Qvar (beclomethasone) 320 mcg BID Pulmicort Flexhaler (budesonide) 720 mcg BID Alvesco (ciclesonide) 320 mcg BID Aerospan (flunisolide) 320 mcg BID Arnuity Ellipta (fluticasone furoate) 200 mcg daily Flovent HFA (fluticasone propionate) 880 mcg BID Flovent Diskus (fluticasone propionate) 1000 mcg BID Asmanex Twisthaler (mometasone) 440 mcg BID Asmanex HFA (mometasone) 400 mcg BID High Dose Corticosteroid / Long-acting Beta-agonists Maximum Dose Symbicort (budesonide/formoterol) 320/9 mcg BID Advair Diskus (fluticasone/salmeterol) 500/50 mcg BID Advair HFA (fluticasone/salmeterol) 460/42 mcg BID Wixela Inhub (fluticasone/salmeterol) 500/50 mcg BID Airduo RespiClick (fluticasone/salmeterol) 464/28 mcg BID Breo Ellipta (fluticasone/vilanterol) 200/25 mcg daily Dulera (mometasone/formoterol) 400/10 mcg BID

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Is the request for continuation of therapy Yes: Go to Renewal Criteria No: Go to #3 previously approved by the FFS program?

3. Is the request for omalizumab, mepolizumab, Yes: Go to #5 No: Go to #4 reslizumab, or benralizumab?

Author: Sentena October 2020 148

Approval Criteria

4. Is the request for a newly approved monoclonal Yes: Go to #9 No: Go to #5 antibody for severe asthma and does the indication match the FDA-approved indication?

5. Is the claim for reslizumab in a patient under 18 Yes: Pass to RPh. Deny; No: Go to #6 years of age? medical appropriateness.

6. Is the claim for mepolizumab in a patient under 6 Yes: Pass to RPh. Deny; No: Go to #7 years of age or benralizumab in a patient under medical appropriateness 12 years of age?

7. Is the claim for omalizuamb in a patient under 6 Yes: Pass to RPh. Deny; No: Go to #8 years of age? medical appropriateness

8. Is the claim for mepolizumab in an adult patient Yes: Approve 300 mg (3 x No: Go to #9 diagnosed with eosinophilic granulomatosis with 100mg syringes) every 4 polyangiitis (EGPA) for at least 6 months that is weeks x 1 year refractory to at least 4 weeks of oral corticosteroid therapy (equivalent to oral prednisone or prednisolone 7.5 to 50 mg per day)?

9. Does the patient have a concurrent prescription Yes: Go to #10 No: Pass to RPh. Deny; for EpiPen® or equivalent so they are prepared to medical appropriateness. manage delayed anaphylaxis if it occurs after monoclonal antibody therapy?

Author: Sentena October 2020 149

Approval Criteria

10. Is the diagnosis an OHP-funded diagnosis? Yes: Go to #11 No: Pass to RPh. Deny; not Note: chronic urticaria is not an OHP-funded funded by the OHP. condition

11. Is the prescriber a pulmonologist or an allergist Yes: Go to #12 No: Pass to RPh. Deny; who specializes in management of severe medical appropriateness. asthma?

12. Has the patient required at least 1 hospitalization Yes: Go to #13 No: Pass to RPh. Deny; or ≥ 2 ED visits in the past 12 months while medical appropriateness. receiving a maximally-dosed inhaled Document number of hospitalizations or ED visits corticosteroid (Table 1) AND 2 additional in past 12 months: controller drugs (i.e., long-acting inhaled beta- ______. This is the agonist, montelukast, zafirlukast, theophylline)? baseline value to compare to in renewal criteria.

13. Has the patient been adherent to current asthma Yes: Go to #14 No: Pass to RPh. Deny; therapy in the past 12 months? medical appropriateness.

14. Is the patient currently receiving another Yes: Pass to RPh. Deny; No: Go to #15 monoclonal antibody for asthma (e.g., medical appropriateness. omalizumab, mepolizumab, benralizumab or reslizumab)?

Author: Sentena October 2020 150

Approval Criteria

15. If the claim is for omalizumab, can the prescriber Yes: Approve once every 2-4 No: Go to #16 provide documentation of allergic IgE-mediated weeks for up to 12 months. asthma diagnosis, confirmed by a positive skin Document test and test or in vitro reactivity to perennial allergen? result:______

16. If the claim is for mepolizumab, benralizumab or Yes: Approve once every 4 No: Pass to RPh. Deny; reslizumab, can the prescriber provide to 8 weeks for up to 12 medical appropriateness. documentation of severe eosinophilic asthma, months.

confirmed by blood eosinophil count ≥300 Note: Initial benralizumab cells/μL in the past 12 months? dose is 30 mg every 4 weeks x 3 doses followed by 30 mg every 8 weeks

Document eosinophil count (date):______

Renewal Criteria

1. Is the request to renew mepolizumab for EGPA? Yes: Go to #2 No: Go to #3

2. Have the patient’s symptoms improved with Yes: Approve for 12 months No: Pass to RPh. Deny; mepolizumab therapy? medical appropriateness.

Author: Sentena October 2020 151

Renewal Criteria

3. Is the patient currently taking an inhaled Yes: Go to #4 No: Pass to RPh. Deny; corticosteroid and 2 additional controller drugs medical appropriateness. (i.e., long-acting inhaled beta-agonist, montelukast, zafirlukast, theophylline)?

4. Has the number of ED visits or hospitalizations in Yes: Approve for up to 12 No: Pass to RPh. Deny; the last 12 months been reduced from baseline, months. medical appropriateness. or has the patient reduced their systemic corticosteroid dose by ≥50% compared to baseline?

P&T Review: 10/20 (KS),7/19 (DM); 7/18; 7/16 Implementation: 8/19/19, 8/15/18, 8/16

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-2596

Drug Class Update with New Drug Evaluation: Antiepileptics

Date of Review: October 2020 Date of Last Review: June 2020 Dates of Literature Search: 02/11/2020 – 7/30/2020 Generic Name: Fenfluramine Brand Name (Manufacturer): Fintepla® (Zogenix Inc.) Dossier Received: Yes

Current Status of PDL Class: See Appendix 1.

Purpose for Class Update: To define place in therapy for a new antiepileptic drug (AED) fenfluramine, recently approved by the Food and Drug Administration (FDA) for the treatment of seizures associated with Dravet Syndrome (DS) in patients 2 years of age and older. In addition, new comparative evidence for antiepileptic agents used in management of seizures will be reviewed.

Research Questions: 1. Is there new comparative evidence that AEDs differ in efficacy or harms for management of seizures? 2. What is the effectiveness of fenfluramine in reducing seizures in people with DS? 3. What are the comparative harms of fenfluramine in people with DS? 4. Are there certain sub-populations (based on age, gender, ethnicity, comorbidities, disease duration or severity) in which fenfluramine may be beneficial or cause more harm?

Conclusions:  No new publications were identified to provide comparative evidence on the efficacy or harms of AEDs in the management of seizures.  Two phase 3 clinical trials (Study 1 and Study 2) contribute to the safety and efficacy data of fenfluramine in managing seizures associated with DS.1,2  Study 1 was a multi-center, randomized, double-blind study that compared two doses of fenfluramine (0.2 and 0.7 mg/kg/day) with placebo in children with DS (n=119) aged 2-18 years over 14 weeks.1 Patients receiving stiripentol were excluded from this study because pharmacokinetic data were not yet available to evaluate dosage modifications for an expected fenfluramine-stiripentol drug interaction.1 Moderate-quality evidence shows that patients receiving adjunctive fenfluramine 0.7 mg/kg/day experienced a 62.3% (95% CI 47.7 to 72.8) reduction in mean monthly convulsive seizure frequency (MCSF) compared to participants receiving adjunctive placebo (p<0.0001).1 Significant reduction in MCSF was also observed with the fenfluramine 0.2mg/kg/day dose compared to placebo (MCSF difference of 32.4%; 95% CI 6.2 to 51.3; p=0.021).1

Author: Deanna Moretz, PharmD, BCPS 153

 Study 2 was similar to Study 1, but used a different dosing regimen because adjunctive stiripentol therapy was permitted in this trial.2 Fenfluramine 0.4 mg/kg/day was compared with placebo in DS children (n=87) aged 2-18 years over 15 weeks.2 The 0.4 mg/kg/day dose was used to account for the interaction between fenfluramine and stiripentol and was designed to approximate the fenfluramine 0.7 mg/kg/day dose used in Study 1.2 Low-quality evidence shows patients receiving adjunctive fenfluramine 0.4 mg/kg/day experienced a 54.0% (95% CI 35.6 to 67.2) greater reduction in mean MCSF compared to those receiving adjunctive placebo (p<0.001).2 Low-quality evidence demonstrates significantly more patients in the fenfluramine group than the placebo group experienced 50% or greater reduction in mean MCSF (54% vs. 5%; p<0.001) and a statistically significant duration of longer seizure-free intervals (median [range], 22.0 [3.0-105.0] days vs. 13.0 [1.0-40.0] days; p=0.004).2  The most common adverse events reported during fenfluramine treatment at doses of 0.2 mg/kg/day, 0.7 mg/kg/day and 0.4mg/kg/day were decreased appetite (23-49%), diarrhea (15-31%), somnolence (23-26%), fatigue (15-30%), pyrexia (5-21%), and decreased weight (5-13%).3  Fenfluramine is only available through a Risk Evaluation and Mitigation Strategy (REMS) program due to boxed warnings of possible valvular heart disease and pulmonary arterial hypertension occurring with fenfluramine administration.3 Cardiac monitoring with an echocardiogram is required before, during, and after treatment with fenfluramine.3 No cases of pulmonary arterial hypertension or valvular heart disease were observed among DS patients who were exposed to fenfluramine in the 2 short-term clinical trials, but trials were not designed or powered to detect these serious adverse events.1,2  Comparative effectiveness of fenfluramine with other AEDs approved for DS has not been evaluated. There is insufficient evidence regarding the long-term safety and efficacy of fenfluramine in DS patients.  In July 2020, the Food and Drug Administration (FDA) approved cannabidiol oral solution for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients 1 year of age and older.4 Cannabidiol dosing in TSC patients can be titrated up to 25 mg/kg/day, which differs from the maximum dose of 20 mg/kg/day approved for patients with DS and Lennox-Gastaut Syndrome (LGS).4 Cannabidiol is now approved to treat seizures associated with DS, LGS, and TSC for patients 1 year of age and older.4 The previous age range for DS and LGS was 2 years of age and older.

Recommendations:  Designate fenfluramine as non-preferred with implementation of prior authorization (PA) criteria to ensure medically appropriate utilization on the Oregon Health Plan (OHP) Practitioner-Managed Prescription Drug Plan (PMDP).  Revise PA criteria for cannabidiol to reflect expanded indication and appropriate dosing for TSC in patients 1 year of age and older.  Rename AED class name from “oral and rectal” to “non-injectable” to account for nasal formulations.  Review costs in executive session.

Summary of Prior Reviews and Current Policy The AED class of drugs was recently reviewed at the June 2020 Pharmacy and Therapeutics (P&T) Committee meeting. A new AED, cenobamate, approved for treatment of focal seizures was reviewed at this meeting. The P&T Committee designated cenobamate as a non-preferred drug on the OHP PMPDP with PA criteria to ensure medically appropriate utilization. The preferred and non-preferred oral and rectal AEDs included on the Oregon Medicaid FFS (Fee-For-Service) Preferred Drug List (PDL) are listed in Appendix 1. Lamotrigine is classified as a voluntary medication due to its utilization in mental health treatment. The utilization of cannabidiol, clobazam, pregabalin, stiripentol, and topiramate is guided by prior authorization (PA) criteria to ensure they are prescribed for indications supported by the medical literature. The PA criteria for specific AEDs are presented in Appendix 5.

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Medicaid Fee-for-Service Utilization A review of pharmacy AED claims provided an overview of Medicaid Fee for Service (FFS) utilization in the second quarter of 2020. Ninety-eight percent of the claims were for preferred or voluntary agents in the AED class. The most frequently requested preferred agent was lamotrigine with over 60% of claims, followed by divalproex (23%) and gabapentin (4%). The most requested non-preferred AED was pregabalin followed by clobazam.

Background: Severe myoclonic epilepsy infancy (SMEI), also known as Dravet syndrome, is a rare genetic epilepsy syndrome characterized by refractory seizures beginning before the age of 1 year with poor neurodevelopmental outcomes and a high mortality rate.5 It accounts for less than 5% of epilepsy cases presenting in the first year of life, and is estimated to affect 1 in 40,000 live births in the US.6 Dravet syndrome affects males and females in equal proportions.7 Mutations in the voltage-gated sodium channel alpha-1 (SCN1A) gene are identified in 70 to 80% of patients with DS.5 The most common presenting symptom is a hemiclonic or generalized seizure, often precipitated by fever, in an otherwise healthy infant between five and eight months of age. 5 Early seizures tend to be prolonged, recurrent, and may evolve into status epilepticus. Neurodevelopmental decline typically begins shortly after seizure onset. Between one and five years of age, patients with DS have refractory epilepsy characterized by multiple types of seizures, both febrile and afebrile, including convulsive seizures, myoclonic seizures, atypical absence seizures, and focal seizures.5 Reduction in seizure frequency of 50% or more is generally accepted as demonstrating efficacy for FDA approval of new AEDs.

Drug resistance is a well-recognized feature of seizures in DS, and antiepileptic therapies have overall limited efficacy.8 Pharmacologic therapy remains the mainstay of treatment.5 Ketogenic diet and neuromodulation are viable options in selected patients.5 The goals of treatment are to reduce both the length and number of seizures, prevent status epilepticus, limit adverse effects of antiepileptics to promote better neurocognitive development, and improve quality of life.5 The most commonly used drugs in patients with DS include valproate, clobazam, topiramate, levetiracetam, and zonisamide.5 In 2018, stiripentol and cannabidiol received FDA approval for use as adjunctive therapy in DS.4,9 National Institute for Health and Care Excellence (NICE) 2012 guidance on management of epilepsy recommends valproate and topiramate as first-line agents for treatment of DS.10 The NICE guidance recommends clobazam and stiripentol as second- line medications to manage DS.10 Certain AEDs can worsen seizures in patients with DS; these include phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, lamotrigine, vigabatrin, rufinamide, and tiagabine.5 These medications should avoided when managing seizure associated with DS.

Methods: A Medline literature search for new systematic reviews and randomized controlled trials (RCTs) assessing clinically relevant outcomes to active controls, or placebo if needed, was conducted. The Medline search strategy used for this review is available in Appendix 2, which includes dates, search terms and limits used. The OHSU Drug Effectiveness Review Project, Agency for Healthcare Research and Quality (AHRQ), National Institute for Health and Clinical Excellence (NICE), Department of Veterans Affairs, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were manually searched for high quality and relevant systematic reviews. When necessary, systematic reviews are critically appraised for quality using the AMSTAR tool and clinical practice guidelines using the AGREE tool. The FDA website was searched for new drug approvals, indications, and pertinent safety alerts.

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Systematic Reviews: After review, 4 systematic reviews were excluded due to poor quality (e.g., indirect network-meta analyses),11,12 wrong study design of included trials (e.g., observational), comparator (e.g., no control or placebo-controlled),13 or outcome studied (e.g., non-clinical).14

New Guidelines: No new guidelines were identified for this review.

New Indications and Formulations: 1. Cannabidiol Oral Solution: Expanded Indication In July 2020, the FDA approved cannabidiol oral solution (Epidiolex®) for the treatment of seizures associated with TSC in patients one year of age and older.4 Tuberous sclerosis complex is a rare genetic disease that causes benign tumors to grow in the brain and other parts of the body, such as the eyes, heart, kidneys, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms, including seizures, developmental delay, and behavioral problems.

The efficacy of cannabidiol in managing with seizures associated with TSC was conducted in 224 patients aged 1 to 65 years in a double blind RCT conducted over 16 weeks.4 The study compared cannabidiol 25 mg/kg/day and 50mg/kg/day with placebo.4 Most patients were taking 1-2 concomitant AEDs during the trial.4 The most commonly used concomitant AEDs (greater than 25%) were valproate (45%), vigabatrin (33%), levetiracetam (29%), and clobazam (27%).4 The baseline median TSC-associated seizure frequency was 57 per 28 days for the combined groups.4 The primary efficacy measure was the change in seizure frequency of TSC-associated seizures over the 16-week treatment period compared with baseline.4 The percentage change from baseline (reduction) in the frequency of TSC-associated seizures was significantly greater for patients treated with cannabidiol 25 mg/kg/day than for placebo (-43 vs.-20; p<0.01).4 The most common adverse reactions that occurred in cannabidiol 25 mg/kg/day-treated patients with TSC (incidence at least 10% at the recommended dosage and greater than placebo) were diarrhea; transaminase elevations; decreased appetite; somnolence; pyrexia; and vomiting.4 The efficacy and safety results for patients treated with cannabidiol 50mg/kg/day were not reported. The maximum recommended daily dose of cannabidiol for seizures associated with TSC is 25 mg/kg/day.4

Previously, cannabidiol was approved for the treatment of seizures associated with LGS and DS aged 2 years and older. With the expanded indication for seizures associated with TSC, the minimum age of approved cannabidiol treatment was lowered to 1 year of age for all 3 seizures types by the FDA.4 The maximum recommended daily dose of cannabidiol to manage seizures associated with LGS and DS is 20mg/kg/day. 4

2. Midazolam: New Formulation In May 2019, the FDA approved a new midazolam nasal spray (Nayzilam®). This product is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity in patients with epilepsy 12 years and older.15 The dose of midazolam nasal spray is 5 mg administered into one nostril.15 If the patient does not respond to the initial dose, 1 additional spray into the opposite nostril may be administered after 10 minutes.15 Nayzilam® is supplied in boxes of 2 single-use nasal spray units each contained within an individual blister pack.15

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New FDA Safety Alerts: Table 1. Description of New FDA Safety Alerts16 Generic Brand Name Month / Year Location of Change Addition or Change and Mitigation Principles (if applicable) Name of Change (Boxed Warning, Warnings, CI) Zonisamide ZONEGRAN 4/2020 Warnings and Acute Myopia and Secondary Angle Closure Glaucoma: Precautions Acute myopia and secondary angle closure glaucoma have been reported in patients receiving zonisamide. Elevated intraocular pressure can lead to serious sequelae, including permanent vision loss, if left untreated.

Symptoms in reported cases have included acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with ciliochoroidal effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within one month after initiating therapy.

In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with zonisamide has been reported both in pediatric patients and in adults. The primary treatment to reverse symptoms is discontinuation of zonisamide as rapidly as possible, according to the judgment of the treating physician.

Other therapeutic measures, in conjunction with discontinuation of zonisamide, may be helpful. Myopia and secondary angle closure glaucoma usually resolve or improve after discontinuation of zonisamide

Hyperammonemia and Encephalopathy: Hyperammonemia and encephalopathy have been reported with the post marketing use of zonisamide. Zonisamide treatment inhibits carbonic anhydrase activity, which may cause metabolic acidosis that is associated with an increased risk for developing hyperammonemia. Hyperammonemia resulting from zonisamide can also be asymptomatic.

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The risks of hyperammonemia and various manifestations of encephalopathy may be increased in patients treated with zonisamide and concomitantly taking other medications that can cause hyperammonemia, including valproic acid or topiramate.

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy and this risk may be increased by zonisamide use.

Measure serum ammonia concentration if signs or symptoms (e.g., unexplained change in mental status, vomiting, or lethargy) of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued. Hyperammonemia from zonisamide may resolve or decrease in severity with a decrease of the daily dose.

Gabapentin NEURONTIN, 4/20 Warnings and Respiratory Depression (Newly added subsection) HORIZANT Precautions There is evidence from case reports, human studies, and animal studies associating gabapentin and pregabalin with serious, life-threatening, or fatal respiratory Pregabalin LYRICA 4/20 depression when co-administered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co- prescribe gabapentin or pregabalin with another CNS depressant, particularly an opioid, or to prescribe gabapentin or pregabalin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating therapy at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including gabapentin or pregabalin).

Topiramate TOPAMAX 6/20 Warnings and Serious Skin Reactions (Newly added subsection) Precautions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. Topiramate should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.

Randomized Controlled Trials: A total of 19 citations were manually reviewed from the initial literature search. After further review, all citations were excluded because of wrong study design (e.g., observational), comparator (e.g., no control or placebo-controlled), or outcome studied (e.g., non-clinical). Author: Moretz Date: October 2020 158

NEW DRUG EVALUATION: Fenfluramine (Fintepla)

See Appendix 3 for Highlights of Prescribing Information from the manufacturer, including Boxed Warnings and Risk Evaluation Mitigation Strategies (if applicable), indications, dosage and administration, formulations, contraindications, warnings and precautions, adverse reactions, drug interactions and use in specific populations.

Clinical Efficacy: Fenfluramine, an amphetamine derivative, was initially approved by the FDA in 1973 as an appetite suppressant in adults. It was removed from the United States (U.S.) market in 1997 due to reports of cardiac valve abnormalities and pulmonary arterial hypertension associated with fenfluramine administration at doses of 60 to 120mg per day, with or without phenteramine.17 Fenfluramine (Fintepla) oral solution, recently received FDA-approval for the treatment of seizures associated with DS in patients 2 years of age and older.3 It is a categorized as a Schedule IV controlled substance due to risk of drug abuse and dependence.3 The initial dose is 0.1 mg/kg twice daily, and can be increased to 0.35 mg/kg twice daily based on efficacy and tolerability for patients not concurrently taking stiripentol.3 Patients taking concomitant stiripentol plus clobazam should not take more than 0.2 mg/kg of fenfluramine twice daily.3 Fenfluramine is only available through a REMS program due to boxed warnings of possible valvular heart disease and pulmonary arterial hypertension occurring with fenfluramine therapy. Prior to starting treatment, patients must undergo an echocardiogram to evaluate for valvular heart disease. 3 Echocardiograms should be repeated every 6 months, and once 3 to 6 months post-treatment with fenfluramine.3

Two, phase 3 clinical trials (Study 1 and Study 2) contribute to the efficacy data for DS which are described and evaluated below in Table 3. The primary efficacy endpoint in the studies was reduction in seizure frequency as measured by change in MCSF from baseline. Study 1 was a multi-center, randomized, double-blind study that compared two doses of fenfluramine (0.2 and 0.7 mg/kg/day) with placebo in DS children (n=119) aged 2-18 years.1 One hundred seventy three patients were screened for eligibility, of whom 54 patients were ineligible.1 The two most common reasons for exclusion were the presence of predefined exclusionary cardiovascular or cardiopulmonary findings, primarily trace mitral or trace aortic valve regurgitation during screening echocardiogram exam and failure to meet other entry requirements.1 After a 6-week period to establish baseline seizure frequency, study participants received fenfluramine or placebo as adjunctive therapy along with their current AED regimen (excluding stiripentol) over a 14-week study period.1 During the 2-week titration period, patients receiving fenfluramine 0.7 mg/kg/day were first initiated with 0.2 mg/kg/day for 4 days, and then 0.4 mg/kg/day for 4 days before reaching their final dose.1 All patients were maintained on their final dose for an additional 12 weeks.1 Patients receiving stiripentol were excluded from this study because pharmacokinetic data were not yet available to evaluate dosage modifications needed to compensate for an expected fenfluramine-stiripentol drug interaction.1 Enrolled patients with Dravet syndrome were experiencing seizures not completely controlled by their current regimen (mean, 40.3 seizures per 28 days) with stable doses of antiepileptic drugs (valproate, n=71 (60%); clobazam, n=70 (59%); topiramate, n=30 (25%); levetiracetam, n=26 (22%).1 During treatment, the median reduction in seizure frequency was 74.9% in the fenfluramine 0·7 mg/kg group (from median 20.7 seizures per 28 days to 4.7 seizures per 28 days), 42.3% in the fenfluramine 0.2 mg/kg group (from median 17.5 seizures per 28 days to 12.6 per 28 days), and 19.2% in the placebo group (from median 27.3 per 28 days to 22·0 per 28 days).1 Those receiving adjunctive fenfluramine 0.7 mg/kg/day experienced a 62.3% (95% CI 47.7 to 72.8%) reduction in mean MCSF compared to participants receiving adjunctive placebo (p<0.0001).1 Significant reduction in MCSF was also observed with the fenfluramine 0.2mg/kg/day dose compared to placebo (difference 32.4%; 95% CI 6.2 to 51.3%; p=0.021).1

Study 2 was similar to Study 1, but used a different dosing regimen because adjunctive stiripentol therapy was permitted in this trial. A total of 115 patients were screened for eligibility, and 87 patients were randomized to treatment.2 Most patients who failed screening did not meet the randomization criteria (26 of 28 Author: Moretz Date: October 2020 159 patients [93%]), including meeting baseline seizure frequency, echocardiogram requirements, and compliance with daily seizure diary; additionally, 1 patient elected to withdraw during screening, and 1 withdrew because of use of a prohibited medication.2 Of those randomized, 3 in the placebo group and 7 in the fenfluramine group withdrew early due to: adverse event (n=2), protocol deviation (n=1), lack of efficacy (n=1), worsening of seizures (n=1), physician decision (n=1), and patient decision (n=1).2 Fenfluramine 0.4 mg/kg/day was compared with placebo in DS children (n=87) aged 2-18 years.2 Participants received fenfluramine as adjunctive therapy along with their current AED regimen over a 15-week study period. Most patients were receiving either 3 concomitant AEDs (placebo group, 26 of 44 [59%]; fenfluramine group, 19 of 43 [44%]) or 4 concomitant AEDs (placebo group, 16 of 44 [36%]; fenfluramine group, 16 of 43 [37%]). 2 Besides the protocol-specified stiripentol, the most frequent AEDs were clobazam (n=82), levetiracetam (n=13), topiramate (n=21), and valproate (n=77).2 The dose titration period in Study 1 was 2 weeks, while Study 2 used a 3-week dose titration period. Both studies used a 12-week maintenance period to evaluate safety and efficacy of fenfluramine. The 0.4 mg/kg/day dose was used to account for the interaction between fenfluramine and stiripentol and was designed to approximate the fenfluramine 0.7 mg/kg/day dose used in Study 1.2 Those receiving adjunctive fenfluramine 0.4 mg/kg/day experienced a 54.0% (95% CI 35.6 to 67.2) greater reduction in mean MCSF compared to those receiving adjunctive placebo (p<0.001).2 Significantly more patients in the fenfluramine group than the placebo group experienced 50% or greater reduction in mean MCSF (fenfluramine group, 54% vs. placebo group, 5%; p<0.001) and significantly longer seizure-free intervals (median [range], 22.0 [3.0-105.0] days vs. 13.0 [1.0-40.0] days; p=0.004).2

Study Limitations: Due to the adverse effect profile of fenfluramine (loss of appetite, somnolence, fatigue), it is possible that unblinding may have occurred in patients receiving the active drug in both RCTs. Unblinding may have impacted caregiver reporting of seizure frequency. Both studies were relatively short and there is insufficient evidence regarding the long-term efficacy and safety of fenfluramine. Comparative effectiveness of fenfluramine with other AEDs approved for DS in head-to-head trials has not been evaluated.

Clinical Safety: The most common adverse events during fenfluramine treatment were decreased appetite, diarrhea, somnolence, fatigue, pyrexia, and decreased weight.3 Adverse reactions that occurred in 10% or more of patients treated with fenfluramine in the 2 placebo-controlled trials are presented in Table 1. No cases of pulmonary arterial hypertension or valvular heart disease were observed among DS patients who were exposed to fenfluramine at doses less than 0.7 mg/kg/day in the 2 short-term clinical trials.1,2 However, based on prior data, fenfluramine does have a boxed warning regarding the risk of valvular heart disease and pulmonary arterial hypertension.3 Cardiac monitoring with an echocardiogram is required before, during, and after treatment with fenfluramine.3 If valvular heart disease or pulmonary arterial hypertension is observed on an echocardiogram, the prescriber must consider the benefits versus the risks of initiating or continuing treatment with fenfluramine.3

Table 1. Adverse Reactions in 10% or More of Patients Treated with Fenfluramine and Placebo Over 14 to 15 Weeks3 Fenfluramine Groups Adverse Reaction 0.2 mg/kg/day 0.7 mg/kg/day 0.4 mg/kg/day Placebo (n=39) (n=40) (n=43) (n=84) Decreased appetite 23% 38% 49% 8% Somnolence, sedation, lethargy 26% 25% 23% 11% Abnormal echocardiogram 18% 23% 9% 6% Diarrhea 31% 15% 23% 6% Constipation 3% 10% 7% 0%

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Fatigue, malaise, asthenia 15% 10% 30% 5% Ataxia, balance disorder, gait 10% 10% 7% 1% disturbance Increased blood pressure 13% 8% 0% 5% Drooling 13% 8% 2% 0% Pyrexia 15% 5% 21% 14% Upper respiratory infection 21% 5% 7% 10% Vomiting 10% 5% 5% 8% Decreased weight 13% 5% 7% 1% Fall 10% 0% 0% 4%

Drug Interactions Fenfluramine should not be concomitantly used with, or within 14 days of the administration of monoamine oxidase (MAO) inhibitors because of an increased risk of serotonin syndrome.3 Concomitant administration of fenfluramine and other drugs that increase serotonin (e.g., selective serotonin-norepinephrine reuptake inhibitors [SNRIs], selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs,] bupropion, triptans, etc.), over-the-counter medications (e.g., dextromethorphan), or herbal supplements (e.g., St. John’s Wort) may increase the risk of serotonin syndrome.3 Fenfluramine dose adjustment is required for patients taking stiripentol plus clobazam.3 Co-administration of fenfluramine with stiripentol plus clobazam, with or without valproate, increases fenfluramine plasma concentrations and decreases its active metabolite, norfenfluramine, because of the inhibition of the metabolism of fenfluramine.3 If fenfluramine is co-administered with stiripentol plus clobazam, the maximum daily dosage of fenfluramine is 0.2 mg/kg twice daily (maximum total daily dosage of 17 mg).3 Fenfluramine co-administration with rifampin or a strong CYP1A2 and CYP2B6 inducer will decrease fenfluramine plasma concentrations.3 An increase in fenfluramine dosage should be considered when co-administered with rifampin or a strong CYP1A2 and CYP2B6 inducer; however, the maximum daily dosage should not be exceeded.3 Cyproheptadine and potent 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C serotonin receptor antagonists may decrease the efficacy of fenfluramine.3 Patients should be monitored with co-administration of these medications.3

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.3 Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.3 Safety of fenfluramine administration longer than 15 weeks is currently being evaluated in an open-label extension trial of patients enrolled in Study 1 and Study 2.

Look-alike / Sound-alike Error Risk Potential: No other medications have been identified

Comparative Endpoints: Clinically Meaningful Endpoints: Primary Study Endpoint: 1) Reduction in seizure frequency (all types) 1) Change in mean monthly frequency of convulsive seizures 2) Decreased time between seizures compared to baseline 3) Improved quality of life 4) Serious adverse events

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5) Study withdrawal due to an adverse event

Table 2. Pharmacology and Pharmacokinetic Properties.3 Parameter Serotonin modulation by interaction with serotonin transporter proteins which increases extracellular serotonin levels and agonist Mechanism of Action activity at 5HT- receptors Oral Bioavailability 68-74% Distribution and Volume of distribution: 11.9 L/kg; 50% bound to human plasma proteins Protein Binding Elimination 90% is excreted in the urine as parent drug and metabolites, less than 5% is found in feces Half-Life 20 hours, age (2 to 50 years) does not affect pharmacokinetics 75% metabolized to active metabolite, norfenfluramine, primarily by CYP1A, CYP2B6, and CYP2D6. Norfenfluramine is metabolized to Metabolism inactive metabolites. Abbreviations: kg=kilogram; L=liters

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Table 3. Comparative Evidence Table. Ref./ Drug Regimens/ Patient Population N Efficacy Endpoints ARR/N Safety Outcomes ARR/ Risk of Bias/ Study Duration NT NNH Applicability Design 1. Lagae L, et 1. Fenfluramine Demographics: ITT: Primary Endpoint: Reduction in AEs: NA for Risk of Bias (low/high/unclear): al.1 0.2 mg/kg/day -Mean age: 9 yrs Total=119 mean monthly convulsive 1. 37 (95%) all Selection Bias: Low. Assigned 1:1:1 via IWRS -Male gender: 54% 1. 39 seizure frequency compared to 2. 38 (95%) stratified across ages (<6 yrs vs. 6 yrs) to Study 1 2. Fenfluramine -Caucasian: 82% 2. 40 placebo from baseline: 3. 26 (65%) ensure balance of 25% across treatments. 0.7 mg/kg/day -Mean baseline 3. 40 1 vs. 3: difference = -32.4% 32%/4 Baseline characteristics balanced across DB, PC, MC, convulsive seizure (95% CI -6.2 to -52.3) SAEs: treatment groups. RCT 3. Placebo frequency per PP: p=0.021 1. 4 (10%) Performance Bias: High. Matched placebo month: 40 Total=110 2 vs. 3 difference = -62.3% 62%/2 2. 5 (13%) used (identical in appearance and taste). Side 14 weeks Current AED -Mean number of 1. 39 (95% CI -47.7 to -72.8) 3. 4 (10%) effects of fenfluramine may have contributed regimen concomitant AEDs: 2. 34 p<0.0001 to unblinding. continued, 2.4 (range 0-5) 3. 37 Decreased Detection Bias: Unclear. Fenfluramine and stiripentol Secondary Endpoints: Appetite: placebo were identical in appearance and excluded Key Inclusion Criteria: Attrition: 1. Median reduction in total 1. 8 (20%) taste. Seizures were documented by parents -DS patients with 1.0 (0%) seizure frequency per 28 days 2. 15 (38%) or caregivers in an electronic diary. uncontrolled seizures 2.6 (15%) 1. 42.3% (17.5 to 12.6 seizures) 3. 2 (5%) Attrition Bias: High. Higher percentage of despite AED therapy 3.3 (8%) Range = -100 to 197.6 study withdrawals in fenfluramine aged 2-18 yrs 2. 74.9% (20.7 to 4.7 seizures) Fatigue: 0.7mg/kg/day arm due to adverse events. Range = -100 to 196.4 1. 4 (10%) Modified ITT analysis used to analyze all Key Exclusion 3. 19.2% (27.3 to 22.0 seizures) 2. 4 (10%) patients who received 1 dose of medication Criteria: Range = -76.1 to 51.8 3. 1 (2%) with 1 week of seizure diary data. Missing -Any mitral or aortic data were not imputed. valve regurgitation 1 vs. 3 p=0.2035, 95% CI NR Reporting Bias: Low. Protocol available at -History of 2 vs. 3 p<0.0001, 95% CI NR Lancet website. Outcomes reported as pulmonary prespecified. hypertension 2.. Patients with 50% reduction Other Bias: High. Funded by Zogenix. -Concurrent in seizure frequency Manufacturer provided trial oversight, serotonergic agents, 1. 15 (38%) preparation of drugs and placebo, data monoamine oxidase 2. 27 (68%) monitoring and statistical analysis. Author inhibitors or 3. 5 (12%) conflict of interest statements reported in cannabidiol products 1 vs.3: 26%/4 depth. 21 days before OR 4.8; 95% CI 1.5 to 15.0 screening p=0.009 Applicability: 2 vs. 3: 56%/2 Patient: Studied in children and young adults, OR = 15; 95% CI 4.5 to 50.0 cannot extrapolate results to adults >19 yo or p<0.0001 in patients taking stiripentol. Study population did not display extensive diversity 3. Longest seizure-free interval (82% Caucasian). in days (mean) Intervention: Dosing based on 1. 26 (SD 31.7) pharmacokinetic analysis. 2. 32.9 (SD 27.5) Comparator: Placebo designed to be 3. 10.6 (SD 6.0) administered in same volume as study drug.

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p-value and 95% CI NR Placebo appropriate comparator as subjects continued with current AED regimen. 4. Longest seizure-free interval Outcomes: Change in convulsive seizure in days (median [range]) frequency is an appropriate outcome to 1. 15 (3 to 106) assess efficacy. 2. 25 (2 to 97) Setting: 55 sites 3. 9.5 (2 to 23) United States n=19 1 vs. 3: Canada n=2 Median difference: 4.5 Western Europe n=27 95% CI 0 to 9; P=0.035 Japan n=4 2 vs. 3: Australia n=3 Median difference: 15.5 95% CI 6 to 25; P=0.0001 2. Nabbout 1. Fenfluramine Demographics: ITT: Primary Endpoint: Reduction in AEs: Risk of Bias (low/high/unclear): R, et al.2 0.4 mg/kg/day Mean age: 9.1 yrs (SD Total =87 monthly mean convulsive 1. 42 (98%) Selection Bias: Low. Randomized 1:1 via IWRS 4.8 yrs) 1. 43 seizure frequency compared 2. 42 (96%) stratified across ages (<6 yrs vs. 6 yrs) to Study 2 2. Placebo Male gender: 57% 2. 44 to placebo from baseline: ensure balance of 40% across treatments. Caucasian: 52% 1 vs. 2 SAE Mean baseline seizure frequency and number DB, PC, In addition to Mean baseline Difference: 54% 1. 6 (14%) of AEDs were balanced across groups. MC,RCT current AED convulsive seizure PP: 95% CI 35.6 to 67.2 2. 7 (16%) Performance Bias: High. Use of matched regimen, frequency per Total=77 P<0.001 54%/2 placebo. Side effects of active drug could lead 15 weeks stiripentol month: 25 (range 21 1. 36 Discontinuations to unblinding. required to 28) 2. 41 Secondary Endpoints: due to AE: Detection Bias: Unclear. Placebo matched to -Mean number of Patients with 50% reduction in 1. 3 (7%) fenfluramine solutions. Caregivers recorded AEDs: 3 (range 2-5) seizure frequency from 2. 0 (0%) doses, rescue medication, and the number Attrition: baseline and type of seizures in handheld electronic Key Inclusion Criteria: 1. 7 (16%) 1. 23 (54%) Decreased diaries. -DS patients with 2. 3 (7%) 2. 2 (5%) 49%/3 Appetite: Attrition Bias: High. Higher percentage of uncontrolled seizures 1. 19 (44%) study withdrawals in fenfluramine arm due to ( 6 seizures during OR 26.0 2. 5 (11%) protocol deviation, lack of efficacy, physician the 6-week baseline) 95% CI 5.5 to 123.2 or patient decision, and AEs (n=1-2 for each). despite stiripentol- P<0.001 Fatigue: Modified ITT analysis used to analyze all inclusive AED therapy 1. 11 (26%) patients who received 1 dose of medication aged 2-18 yrs 2. Longest seizure-free interval 2. 2 (5%) with 1 week of seizure diary data. Missing in days (median range) NA data were not imputed. Key Exclusion 1. 22 (3 to 105) Reporting Bias: Unclear. All prespecified Criteria: 2. 13 (1 to 40) outcomes reported. Protocol available on -Any mitral or aortic line. valve regurgitation 1 vs. 2 Other Bias: High. Funded by Zogenix, also -Diagnosis of Median difference: 9 responsible for design and conduct of the pulmonary 95% CI NR study. Several authors report research hypertension, history p=0.004 support from Zogenix or are employees of the of cardiovascular or manufacturer. cerebrovascular 3. Longest seizure-free interval disease in days (mean) Applicability:

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-Concurrent 1. 29.7 (SD 27.3) Patient: All patients were taking stiripentol, serotonergic agents, 2. 13.4 (SD 7.5) an AED with proven efficacy in DS. Baseline monoamine oxidase seizure control slightly better than Study 1. inhibitors or Mean Difference =19.9 Cannot apply results to patients older than 19 cannabidiol products p value NR yrs. 21 days before Intervention: Active drug dosing adjusted to screening account for drug interaction with concomitantly administered AEDs. Comparator: Placebo appropriate comparator as subjects continued with current AED regimen. Outcomes: Reduction in seizure frequency is an appropriate endpoint. Not all data was reported for primary outcome and secondary outcome of 50% reduction in seizure frequency may be imprecise due to wide CI. Setting: Large number of sites for small population (n=87), potential for inter-site variability with respect to study administration. 32 sites in Canada (n=2) France (n=10) Germany (n=3) Netherlands (n=2) Spain (n=3) United Kingdom (n=5) United States (n=7)

Abbreviations : AED=anti-epileptic drug; AE=adverse event; AED = antiepileptic drug; ARR = absolute risk reduction; CI = confidence interval; DB = double blind; DS = Dravet Syndrome; ITT = intention to treat; IWRS = interactive web response system; MC = multi-center; N = number of subjects; NA = not applicable; NNH = number needed to harm; NR = not reported; NNT = number needed to treat; OR = odds ratio; PC = placebo-controlled: PP = per protocol: RCT = randomized clinical trial; SAE = serious adverse event; SD= standard deviation; yrs = years

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References:

1. Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double- blind, placebo-controlled trial. Lancet (London, England). 2019;394(10216):2243-2254. 2. Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2019;77(3):300-308. 3. Fintepla (fenfluramine) oral solution Prescrbiing Information. Emeryville, CA; Zogenix, Inc. 6/2020. 4. Epidolex (cannabidiol) Oral Solution Prescribing Information. Carlsbad, CA; Greenwich Biosciences, Inc. July 2020. 5. Dravet C, Oguni H. Chapter 65 - Dravet syndrome (severe myoclonic epilepsy in infancy). In: Dulac O, Lassonde M, Sarnat HB, eds. Handbook of Clinical Neurology. Vol 111. Elsevier; 2013:627-633. 6. Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet Syndrome in a US Population. Pediatrics. 2015;136(5):e1310-1315. 7. Skluzacek JV, Watts KP, Parsy O, Wical B, Camfield P. Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia. 2011;52 Suppl 2:95-101. 8. Knupp KG, Wirrell EC. Treatment Strategies for Dravet Syndrome. CNS Drugs. 2018;32(4):335-350. 9. Diacomit (stiripentol) Prescribing Information. Bauvias, France; Biocodex. August 2018. 10. National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and management. nice.org.uk/guidance/cg137. Accessed August 3, 2020. 11. Locher C, Kossowsky J, Koechlin H, et al. Efficacy, Safety, and Acceptability of Pharmacologic Treatments for Pediatric Migraine Prophylaxis: A Systematic Review and Network Meta-analysis. JAMA Pediatr. 2020;174(4):341-349. 12. Lattanzi S, Trinka E, Del Giovane C, Nardone R, Silvestrini M, Brigo F. Antiepileptic drug monotherapy for epilepsy in the elderly: A systematic review and network meta-analysis. Epilepsia. 2019;60(11):2245-2254. 13. Kapustin D, Bhatia A, McParland A, et al. Evaluating the impact of gabapentinoids on sleep health in patients with chronic neuropathic pain: a systematic review and meta-analysis. Pain. 2020;161(3):476-490. 14. Shan D, Zou L, Liu X, Shen Y, Cai Y, Zhang J. Efficacy and safety of gabapentin and pregabalin in patients with vasomotor symptoms: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;222(6):564-579.e512. 15. Nayzilam (midazolam) Nasal Spray. Smyrna, GA; UCB, Inc. May 2019. 16. Food and Drug Administration. Drug Safety Labeling Changes (SLC). https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/. Accessed August 1. 17. Centers for Disease Control. MMWR Weekly November 14, 1997. https://www.cdc.gov/mmwr/preview/mmwrhtml/00049815.htm. Accessed August 3, 2020.

Author: Moretz Date: October 2020 166

Appendix 1: Current Preferred Drug List

Generic Brand Route Form PDL carbamazepine CARBAMAZEPINE ORAL ORAL SUSP Y carbamazepine TEGRETOL ORAL ORAL SUSP Y carbamazepine CARBAMAZEPINE ORAL TAB CHEW Y carbamazepine CARBAMAZEPINE ER ORAL TAB ER 12H Y carbamazepine TEGRETOL XR ORAL TAB ER 12H Y carbamazepine CARBAMAZEPINE ORAL TABLET Y carbamazepine EPITOL ORAL TABLET Y carbamazepine TEGRETOL ORAL TABLET Y diazepam DIASTAT RECTAL KIT Y diazepam DIASTAT ACUDIAL RECTAL KIT Y diazepam DIAZEPAM RECTAL KIT Y divalproex sodium DEPAKOTE SPRINKLE ORAL CAP DR SPR Y divalproex sodium DIVALPROEX SODIUM ORAL CAP DR SPR Y divalproex sodium DEPAKOTE ER ORAL TAB ER 24H Y divalproex sodium DIVALPROEX SODIUM ER ORAL TAB ER 24H Y divalproex sodium DEPAKOTE ORAL TABLET DR Y divalproex sodium DIVALPROEX SODIUM ORAL TABLET DR Y ethosuximide ETHOSUXIMIDE ORAL CAPSULE Y ethosuximide ZARONTIN ORAL CAPSULE Y ethosuximide ETHOSUXIMIDE ORAL SOLUTION Y ethosuximide ZARONTIN ORAL SOLUTION Y ethotoin PEGANONE ORAL TABLET Y gabapentin GABAPENTIN ORAL CAPSULE Y gabapentin NEURONTIN ORAL CAPSULE Y gabapentin GABAPENTIN ORAL TABLET Y gabapentin NEURONTIN ORAL TABLET Y lacosamide VIMPAT ORAL TABLET Y lamotrigine LAMICTAL ORAL TABLET Y lamotrigine LAMOTRIGINE ORAL TABLET Y lamotrigine SUBVENITE ORAL TABLET Y levetiracetam KEPPRA ORAL SOLUTION Y levetiracetam LEVETIRACETAM ORAL SOLUTION Y levetiracetam KEPPRA ORAL TABLET Y levetiracetam LEVETIRACETAM ORAL TABLET Y levetiracetam ROWEEPRA ORAL TABLET Y

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methsuximide CELONTIN ORAL CAPSULE Y oxcarbazepine OXCARBAZEPINE ORAL ORAL SUSP Y oxcarbazepine TRILEPTAL ORAL ORAL SUSP Y oxcarbazepine OXCARBAZEPINE ORAL TABLET Y oxcarbazepine TRILEPTAL ORAL TABLET Y phenobarbital PHENOBARBITAL ORAL ELIXIR Y phenobarbital PHENOBARBITAL ORAL TABLET Y phenytoin DILANTIN-125 ORAL ORAL SUSP Y phenytoin PHENYTOIN ORAL ORAL SUSP Y phenytoin DILANTIN ORAL TAB CHEW Y phenytoin PHENYTOIN ORAL TAB CHEW Y phenytoin sodium extended DILANTIN ORAL CAPSULE Y phenytoin sodium extended PHENYTEK ORAL CAPSULE Y phenytoin sodium extended PHENYTOIN SODIUM ORAL CAPSULE Y EXTENDED primidone MYSOLINE ORAL TABLET Y primidone PRIMIDONE ORAL TABLET Y rufinamide BANZEL ORAL TABLET Y tiagabine HCl GABITRIL ORAL TABLET Y tiagabine HCl TIAGABINE HCL ORAL TABLET Y topiramate TOPAMAX ORAL TABLET Y topiramate TOPIRAMATE ORAL TABLET Y valproic acid VALPROIC ACID ORAL CAPSULE Y valproic acid (as sodium salt) VALPROIC ACID ORAL SOLUTION Y zonisamide ZONISAMIDE ORAL CAPSULE Y lamotrigine LAMICTAL (BLUE) ORAL TAB DS PK V lamotrigine LAMICTAL (GREEN) ORAL TAB DS PK V lamotrigine LAMICTAL (ORANGE) ORAL TAB DS PK V lamotrigine LAMOTRIGINE (BLUE) ORAL TAB DS PK V lamotrigine LAMOTRIGINE (GREEN) ORAL TAB DS PK V lamotrigine LAMOTRIGINE (ORANGE) ORAL TAB DS PK V lamotrigine SUBVENITE (BLUE) ORAL TAB DS PK V lamotrigine SUBVENITE (GREEN) ORAL TAB DS PK V lamotrigine SUBVENITE (ORANGE) ORAL TAB DS PK V lamotrigine LAMICTAL XR ORAL TAB ER 24 V lamotrigine LAMOTRIGINE ER ORAL TAB ER 24 V lamotrigine LAMICTAL ODT ORAL TAB RAPDIS V lamotrigine LAMOTRIGINE ODT ORAL TAB RAPDIS V

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lamotrigine LAMICTAL ORAL TB CHW DSP V lamotrigine LAMOTRIGINE ORAL TB CHW DSP V lamotrigine LAMICTAL XR (BLUE) ORAL TB ER DSPK V lamotrigine LAMICTAL XR (GREEN) ORAL TB ER DSPK V lamotrigine LAMICTAL XR (ORANGE) ORAL TB ER DSPK V lamotrigine LAMICTAL ODT (BLUE) ORAL TB RD DSPK V lamotrigine LAMICTAL ODT (GREEN) ORAL TB RD DSPK V lamotrigine LAMICTAL ODT (ORANGE) ORAL TB RD DSPK V lamotrigine LAMOTRIGINE ODT (BLUE) ORAL TB RD DSPK V lamotrigine LAMOTRIGINE ODT (GREEN) ORAL TB RD DSPK V lamotrigine LAMOTRIGINE ODT (ORANGE) ORAL TB RD DSPK V brivaracetam BRIVIACT ORAL SOLUTION N brivaracetam BRIVIACT ORAL TABLET N cannabidiol (CBD) EPIDIOLEX ORAL SOLUTION N carbamazepine CARBAMAZEPINE ER ORAL CPMP 12HR N carbamazepine CARBATROL ORAL CPMP 12HR N cenobamate XCOPRI ORAL TAB DS PK N cenobamate XCOPRI ORAL TABLET N clobazam SYMPAZAN ORAL FILM N clobazam CLOBAZAM ORAL ORAL SUSP N clobazam ONFI ORAL ORAL SUSP N clobazam CLOBAZAM ORAL TABLET N clobazam ONFI ORAL TABLET N diazepam VALTOCO NASAL SPRAY N eslicarbazepine acetate APTIOM ORAL TABLET N felbamate FELBAMATE ORAL ORAL SUSP N felbamate FELBATOL ORAL ORAL SUSP N felbamate FELBAMATE ORAL TABLET N felbamate FELBATOL ORAL TABLET N fenfluramine HCl FINTEPLA ORAL SOLUTION N gabapentin GABAPENTIN ORAL SOLUTION N gabapentin NEURONTIN ORAL SOLUTION N gabapentin GRALISE ORAL TAB ER 24H N gabapentin enacarbil HORIZANT ORAL TABLET ER N lacosamide VIMPAT ORAL SOLUTION N lacosamide VIMPAT ORAL TAB DS PK N levetiracetam KEPPRA XR ORAL TAB ER 24H N levetiracetam LEVETIRACETAM ER ORAL TAB ER 24H N

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levetiracetam SPRITAM ORAL TAB SUSP N midazolam NAYZILAM NASAL SPRAY N oxcarbazepine OXTELLAR XR ORAL TAB ER 24H N perampanel FYCOMPA ORAL ORAL SUSP N perampanel FYCOMPA ORAL TABLET N pregabalin LYRICA ORAL CAPSULE N pregabalin PREGABALIN ORAL CAPSULE N pregabalin LYRICA ORAL SOLUTION N pregabalin PREGABALIN ORAL SOLUTION N rufinamide BANZEL ORAL ORAL SUSP N stiripentol DIACOMIT ORAL CAPSULE N stiripentol DIACOMIT ORAL POWD PACK N topiramate TROKENDI XR ORAL CAP ER 24H N topiramate QUDEXY XR ORAL CAP SPR 24 N topiramate TOPIRAMATE ER ORAL CAP SPR 24 N topiramate TOPAMAX ORAL CAP SPRINK N topiramate TOPIRAMATE ORAL CAP SPRINK N vigabatrin SABRIL ORAL POWD PACK N vigabatrin VIGABATRIN ORAL POWD PACK N vigabatrin VIGADRONE ORAL POWD PACK N vigabatrin SABRIL ORAL TABLET N vigabatrin VIGABATRIN ORAL TABLET N carbamazepine EQUETRO ORAL CPMP 12HR phenobarbital PHENOBARBITAL ORAL ELIXIR

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Appendix 2: Medline Search Strategy

Ovid MEDLINE(R) without Revisions 1996 to July Week 3 2020, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations July 31, 2020 1 Carbamazepine 6302 2 Diazepam/ 4818 3 divalproex.mp. or Valproic Acid/ 8922 4 Ethosuximide/ 298 5 ethotoin.mp. 2 6 lacosamide.mp. 840 7 lamotrigine.mp. 5211 8 levetiracetam.mp. 3853 9 methsuximide.mp. 20 10 oxcarbazepine.mp. 1840 11 Phenobarbital/ 3185 12 Phenytoin/ 3480 14 Primidone/ 167 14 rufinamide.mp. 259 15 tiagabine.mp. 879 16 topiramate.mp. 4787 17 Valproic Acid/ 8633 18 zonisamide.mp. 1253 19 brivaracetam.mp. 254 20 clobazam.mp. 655 21 esclicarbazepine.mp. 2 22 felbamate.mp. 518 23 perampanel.mp. 475 24 Pregabalin/ 1925 25 Vigabatrin/ 1066 26 Gabapentin 3533 27 midazolam spray.mp 13 28 stiripentol.mp 209 29 Cannabidiol/ 1257 30 cenobamate.mp 16 31 Fenfluramine 1152 32 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31: 44645 33 Epilepsy/ 42396 34 32 and 33 6136

34 limit 29 to (english language and humans and yr="2018 -Current" and (clinical study or clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative study or controlled clinical trial or guideline or meta -analysis or multicenter study or practice guideline or pragmatic clinical trial or randomized controlled trial or systematic reviews)) 19

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Appendix 3: Prescribing Information Highlights

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Appendix 4: Key Inclusion Criteria

Population People with seizures Intervention Anti-epileptic therapy Comparator Placebo Outcomes Reduction in mean convulsive seizure frequency per month Timing 12 week maintenance period Setting United States, Canada, Western Europe, Japan, and Australia

Appendix 5: Prior Authorization Criteria Cannabidiol

Goal(s):  To ensure appropriate drug use and restrict to indications supported by medical literature.

Length of Authorization:  Up to 12 months

Requires PA:  Cannabidiol

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org

 Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

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Approval Criteria

2. Is the request for renewal of therapy previously approved Yes: Go to Renewal Criteria No: Go to #3 by the FFS system?

3. Is this an FDA approved indication? (Lennox-Gastaut Yes: Go to #4 No: Pass to RPh. Deny; syndrome or Dravet syndrome in patients 2 years of age medical appropriateness and older

4. Is the patient uncontrolled on current baseline therapy with Yes: Go to #5 No: Pass to RPh. Deny; at least one other antiepileptic medication AND is medical appropriateness cannabidiol intended to be prescribed as adjuvant Document current seizure antiepileptic therapy? frequency______

5. Is the prescribed dose greater than 250 mg/kg/day? Yes: Pass to RPh. Deny; No: Go to # 6 medical appropriateness

6. Are baseline liver function tests (LFTs) on file (serum Yes: Approve for 12 months No: Pass to RPh. Deny; medical transaminases and total bilirubin levels)? appropriateness Document results here: AND Date of lab work______AST______If LFTs are not within normal limits has the cannabidiol ALT______dose been adjusted per guidance for moderate to severe Total Bilirubin______hepatic impairment in Table 1?

LFTs should be obtained at 1 month, 3 months, and 6 months after starting treatment with cannabidiol and periodically thereafter as clinically indicated, after cannabidiol dose changes, or addition of other medications that are known to impact the liver.

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Renewal Criteria

1. Are recent LFT’s documented in patient records? Yes: Go to # 2 No: Pass to RPh. Deny; medical appropriateness AND Document results here: If LFTs are not within normal limits has the cannabidiol dose been adjusted per guidance for moderate to severe Date of lab work______hepatic impairment in Table 1? AST______

ALT______

Total Bilirubin______

2. Has seizure frequency decreased since beginning therapy? Yes: Go to #3 No: Pass to RPh. Deny for lack of treatment response. Document baseline and current seizure frequency______

3. Is the prescribed dose greater than 25mg/kg/day? Yes: Pass to RPh. Deny; No: Go to # 4 medical appropriateness

4. Is cannabidiol intended to be prescribed as adjuvant Yes: Approve for 12 months No: Pass to RPh. Deny; antiepileptic therapy? medical appropriateness

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Table 1: Dose Adjustments of Cannabidiol in Patients with Hepatic Impairment1 Hepatic Impairment Starting Dosage Maintenance Dosage Range in Patients Maintenance Dosage in Patients with with Lennox-Gastaut Syndrome (LGS) Tuberous Sclerosis Complex (TSC) or Dravet Syndrome (DS)

Mild 2.5 mg/kg twice daily 5 to 10 mg/kg twice daily 12.5 mg/kg twice daily (5 mg/kg/day) (10 to 20 mg/kg/day) (25 mg/kg/day) Moderate 1.25 mg/kg twice daily 2.5 to 5 mg/kg twice daily 6.25 mg/kg twice daily (2.5 mg/kg/day) (5 to 10 mg/kg/day) (12.5 mg/kg/day) Severe 0.5 mg/kg twice daily 1 to 2 mg/kg twice daily 2.5 mg/kg twice daily (1 mg/kg/day) (2 to 4 mg/kg/day) (5 mg/kg/day)

1. Epidolex (cannabidiol) Oral Solution Prescribing Information. Carlsbad, CA; Greenw ich Biosciences, Inc. July 2020.

P&T/DUR Review: 10/20 (DM); 6/2020 (DM); 3/19; 1/19 (DM) Implementation: 5/1/19; 3/1/19

Clobazam

Goal(s): To ensure appropriate drug use and restrict to indications supported by medical literature and funded by Oregon Health Plan.

Length of Authorization:  12 months

Requires PA: Clobazam

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

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Approval Criteria

1. What diagnosis is being treated? Record ICD10 code

2. Is the request for renewal of therapy previously approved Yes: Go to Renewal Criteria No: Go to #3 by the FFS system?

3. Does the patient have a diagnosis of Lennox-Gastaut Yes: Go to #3 No: Go to # 5 syndrome and is the patient 2 years of age or older?

4. Is the patient uncontrolled on current baseline therapy with Yes: Approve for 12 months No: Pass to RPh. Deny; at least one other antiepileptic medication? medical appropriateness

5. Does the patient have a diagnosis of Dravet Syndrome and Yes: Approve for 12 months No: Pass to RPh. Deny; is the patient 2 years of age or older? medical appropriateness.

Renewal Criteria

1. Has seizure frequency decreased since beginning Yes: Approve for 12 months No: Pass to RPh. Deny for lack therapy? of treatment response.

Limitations of Use:  Clobazam is not FDA-approved for epilepsy syndromes other than Lennox-Gastaut.  National Institute for Health and Care Excellence (NICE) guidance recommends clobazam as a second line agent for management of Dravet Syndrome.1

1. National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and management. nice.org.uk/guidance/cg137. Accessed July 30, 2018

P&T Review: 10/20 (DM); 6/2020 (DM); 1/19 (DM); 3/18; 7/16; 3/15; 5/12 Implementation: 3/1/19; 8/16, 8/12

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Pregabalin Goal(s):  Provide coverage only for funded diagnoses that are supported by the medical literature.

Length of Authorization:  90 days to lifetime (criteria-specific)

Requires PA:  Pregabalin and pregabalin extended release

Covered Alternatives  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. Is this a request for renewal of a previously approved prior Yes: Go to Renewal No: Go to # 2 authorization for pregabalin? Criteria

2. What diagnosis is being treated? Record ICD10 code

3. Is the request for pregabalin immediate release? Yes: Go to #4 No: Go to #5

4. Does the patient have a diagnosis of epilepsy? Yes: Approve for No: Go to #5 lifetime

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Approval Criteria

5. Is the diagnosis an OHP-funded diagnosis with evidence Yes: Go to #6 No: Pass to RPh. Deny; not funded supporting its use in that condition (see Table 1 below for by the OHP. examples)?

6. Has the patient tried and failed gabapentin therapy for 90 days Yes: Approve for 90 No: Pass to RPh. Deny and or have contradictions or intolerance to gabapentin? days recommend trial of gabapentin for 90 days

Renewal Criteria

1. Does the patient have documented improvement from Yes: Approve for up No: Pass to RPh. Deny for medical pregabalin? to 12 months appropriateness

Table 1. OHP Funded Diagnosis and Evidence Supports Drug Use in Specific Indication

Condition Pregabalin Pregabalin Extended- Release Funded Diabetic Neuropathy X X Postherpetic X X Neuropathy Painful X Polyneuropathy Spinal Cord Injury X Pain Chemotherapy Induced Neuropathy X

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Non-funded Fibromyalgia X

P&T Review: 10/20 (DM); 1/19 (DM); 7/18; 3/18; 3/17 Implementation: 10/1/18; 8/15/18; 4/1/17

Stiripentol

Goal(s):  To ensure appropriate drug use and restrict to indications supported by medical literature and funded by Oregon Health Plan.

Length of Authorization:  Up to 12 months Requires PA:  Stiripentol capsules and powder for oral suspension

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Is the request for renewal of therapy previously approved Yes: Go to Renewal Criteria No: Go to #3 by the FFS system?

3. Is the request for the FDA approved indication of Dravet Yes: Go to #3 No: Pass to RPh. Deny; syndrome in patients 2 years of age and older taking medical appropriateness clobazam?

Author: Moretz Date: October 2020 180

Approval Criteria

4. Is baseline white blood cell (WBC) and platelet counts on Yes: Approve for 12 months No: Pass to RPh. Deny; file within the past 3 months? medical appropriateness Document results here: Note: Labs should be assessed every six months while Date of lab work______receiving stiripentol therapy. WBC______Platelets______

Renewal Criteria

1. Are recent WBC and platelet counts documented in Yes: Go to # 2 No: Pass to RPh. Deny; patient records? medical appropriateness Document results here: Note: Labs should be assessed every six months while Date of lab work______receiving stiripentol therapy. WBC______Platelets______

2. Has seizure frequency decreased since beginning Yes: Approve for 12 months No: Pass to RPh. Deny for therapy? lack of treatment response.

P&T/DUR Review: 10/20 (DM); 6/2020 (DM); 1/19 (DM) Implementation: 3/1/2019

Author: Moretz Date: October 2020 181

Topiramate Goal(s):  Approve topiramate only for funded diagnoses which are supported by the medical literature (e.g. epilepsy and migraine prophylaxis).

Length of Authorization:  90 days to lifetime

Requires PA:  Non-preferred topiramate products

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code

2. Does the patient have diagnosis of epilepsy? Yes: Approve for lifetime (until 12- No: Go to #3 31-2036)

3. Does the patient have a diagnosis of migraine? Yes: Approve for 90 days with No: Go to #4 subsequent approvals dependent on documented positive response for lifetime.

4. Does the patient have a diagnosis of bipolar affective Yes: Go to #5 No: Go to #6 disorder or schizoaffective disorder?

Author: Moretz Date: October 2020 182

Approval Criteria

5. Has the patient tried or are they contraindicated to at least Yes: Approve for 90 days with No: Pass to RPh; Deny; two of the following drugs? subsequent approvals dependent medical appropriateness.  Lithium on documented positive response Recommend trial of 2 covered  Valproate and derivatives for lifetime approval. alternatives.  Lamotrigine  Carbamazepine  Atypical antipsychotic

Document drugs tried or contraindications.

6. Is the patient using the medication for weight loss? Yes: Pass to RPh. Deny; not No: Pass to RPh. Go to #7 (Obesity ICD10 E669; E6601)? funded by the OHP

7. All other indications need to be evaluated for Use is off-label: Deny; medical appropriateness. Other treatments appropriateness: should be tried as appropriate.  Neuropathic pain Use is unfunded: Deny; not funded by the OHP.  Post-Traumatic Stress Disorder (PTSD) If clinically warranted: Deny; medical appropriateness. Use clinical  Substance abuse judgment to approve for 1 month to allow time for appeal. MESSAGE: “Although the request has been denied for long-term use because it is considered medically inappropriate, it has also been APPROVED for one month to allow time for appeal.”

P&T Review: 10/20 (DM); 6/2020 (DM); 5/19 (KS); 1/19 (DM); 7/18; 3/18; 3/17; 7/16; 3/15; 2/12; 9/07; 11/07 Implementation: 4/18/15; 5/12, 1/12

Author: Moretz Date: October 2020 183

Fenfluramine

Goal(s):  To ensure appropriate drug use and restrict to indications supported by medical literature.

Length of Authorization:  Up to 12 months Requires PA:  Fenfluramine

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Is the request for renewal of therapy previously approved Yes: Go to Renewal Criteria No: Go to #3 by the FFS system?

3. Is the request for the FDA approved indication of Yes: Go to #4 No: Pass to RPh. Deny; seizures associated with Dravet syndrome in patients 2 medical appropriateness years of age and older?

Author: Moretz Date: October 2020 184

Approval Criteria

4. Does the patient have uncontrolled seizures on current Yes: Go to #5 No: Pass to RPh. Deny; baseline therapy with at least one other antiepileptic medical appropriateness medication AND is fenfluramine intended to be prescribed Document seizure as adjuvant antiepileptic therapy? frequency______

5. Is the prescribed dose greater than 0.7 mg/kg/day or 26 Yes: Pass to RPh. Deny; No: Go to # 6 mg/day OR 0.2 mg/kg/day or 17 mg/day in patients medical appropriateness taking stiripentol plus clobazam?

6. Is baseline echocardiogram on file that was performed Yes: Approve for 12 months No: Pass to RPh. Deny; medical within past 6 months? appropriateness Document results here: Date of echocardiogram_____ Results______

Renewal Criteria

1. Has an echocardiogram been obtained within the past 6 Yes: Go to # 2 No: Pass to RPh. Deny; months? medical appropriateness

Document results here:

Date of echocardiogram____

Author: Moretz Date: October 2020 185

Renewal Criteria

2. Has seizure frequency decreased since beginning therapy? Yes: Go to #3 No: Pass to RPh. Deny for lack of treatment response. Document baseline and current seizure frequency______

3. Is the prescribed dose greater than 0.7mg/kg/day or 26 Yes: Pass to RPh. Deny; No: Go to # 4 mg/day or greater than 0.2 mg/kg/day or 17 mg/day in patients medical appropriateness taking stiripentol plus clobazam?

4. Is fenfluramine prescribed as adjuvant therapy and is patient Yes: Approve for 12 months No: Pass to RPh. Deny; adherent to all prescribed seizure medications? medical appropriateness

P&T Review: 10/2020 (DM) Implementation: TBD

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-2596

Drug Class Update: Proton Pump Inhibitors and Histamine-2 Receptor Antagonists

Date of Review: October 2020 Date of Last Review: May 2017 Dates of Literature Search: 05/01/2017 - 05/05/2020

Current Status of PDL Class: See Appendix 1.

Purpose for Class Update: The purpose of this update is to evaluate new evidence for proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). Prior authorization (PA) criteria for PPIs will be reviewed to determine the need to clarify risk factors and appropriate treatment durations.

Research Questions: 1. What is the comparative effectiveness of PPIs in the treatment of peptic ulcer disease (PUD), gastrointestinal esophageal reflux disease (GERD), Zollinger- Ellison syndrome, Helicobacter pylori (H. pylori) eradication and non-steroidal anti-inflammatory drugs (NSAID)-induced ulcers? 2. What is the comparative effective evidence of H2RAs in the treatment of GERD? 3. What is the comparative safety of PPIs in the treatment of PUD, GERD, Zollinger-Ellison Syndrome, H. pylori eradication and NSAID-induced ulcers? 4. What is the comparative safety of H2RAs in the treatment of GERD? 5. What is the evidence is for the risk of gastrointestinal (GI) bleeding for aspirin, NSAIDs or anticoagulants? 6. What is the evidence for the optimal treatment duration with a PPI or H2RA? 7. Are there subpopulations in which a PPI or H2RA may be more effective or cause more harm?

Conclusions:  One high quality guideline, two high quality systematic reviews and meta-analyses, one safety warning and one new product was identified for this drug class update.  A high quality guideline from the National Institute for Health and Care Excellence (NICE) on the management of GERD supports current policy, including treatment durations on PPI and H2RA therapies.1  In a Cochrane review of patients with functional dyspepsia, PPIs improved global symptoms of dyspepsia more than placebo (629 per 1000 patients versus 714 per 1000 patients; RR 0.88; 95% CI, 0.82 to 0.94/NNT 11 up to 8 weeks of therapy) (moderate quality evidence).2 No difference in global symptoms of dyspepsia was demonstrated with the combination of PPIs and prokinetics (cisapride, mosapride [not available in the United States (US)]), itopride [not available in the US]) compared to prokinetics alone based on moderate evidence (RR 0.85; 95% CI, 0.68 to 1.08).2

Author: Kathy Sentena, PharmD 187

 The Food and Drug Administration has recommended that all formulations of ranitidine (ZANTAC) be removed from the market due to contaminates of N- Nitrosodimethylamine (NDMA), a carcinogen, in ranitidine products.3  A new H. pylori triple therapy, TALICIA (omeprazole, amoxicillin and rifabutin), was approved in 2019.4 Approval was based on one placebo-controlled trial and one active treatment trial comparing TALICIA to omeprazole and amoxicillin. There is low strength of evidence from 2 trials that TALICIA has higher eradication rates versus comparators.  There is insufficient evidence to differentiate the need for PPI therapy to reduce the risk of GI bleeds between non-selective NSAIDs, aspirin and anticoagulants.  There was insufficient evidence in subgroups or Medicaid-specific populations.

Recommendations:  After clinical review no changes to the preferred drug list (PDL) are warranted.  Modify PPI PA criteria to clarify durations of therapy.  Review costs in the executive session.

Summary of Prior Reviews and Current Policy:  Previous reviews have demonstrated no clinically significant differences in efficacy or safety between the PPIs. There is insufficient evidence of efficacy and safety differences between H2RAs.  Coverage duration of PPI therapy for GERD is limited to 8 weeks based upon the Health Evidence Review Commission (HERC) funding of the Oregon Health Plan (OHP) prioritized list due to long-term safety concerns. PA criteria for H-pylori therapy is 2 weeks and other funded conditions for up to 1 year (Appendix 4).

Background: There are many indications which necessitate the use of PPIs or H2RAs including PUD, GERD, Zollinger-Ellison syndrome, H. pylori eradication and NSAID-induced ulcers.5 GERD is one of the most common GI conditions affecting one-third of adults.6 Treatment recommendations for GERD depend upon the frequency and severity of symptoms. Eight weeks of low-dose H2RAs is recommended as initial treatment with escalation to a PPI for patients with severe symptoms or failure of twice-daily H2RAs.7

PPIs are the standard of care for the treatment of PUD, most often caused by the presence of H. pylori or NSAIDs.8 Eradication of H. pylori is associated with higher healing rates of duodenal and gastric ulcers and should be treated if present.8 First-line therapy for treatment of H. pylori should consider resistance patterns, prior exposure to antibiotics and patient allergies. First-line treatment options include triple therapy with clarithromycin, amoxicillin and a PPI or clarithromycin, metronidazole and a PPI. In most patients with a H. pylori diagnosis, a 14-day treatment of a PPI is sufficient, without maintenance therapy. Additional considerations in PUD management are the use of NSAIDs, recurrence and size of ulcer. Recommended treatment durations are presented in Table 1. Patients with persistent ulcers (presence of ulcers on repeat endoscopy, giant peptic ulcer [> 2 cm] and > 50 years or other comorbidities are present, history of frequent recurrent peptic ulcers [>2 documented per year], condition requiring long-term NSAID or aspirin use) and patients presenting with idiopathic ulcers (H. pylori negative, NSAID negative ulcer) may require maintenance PPI therapy. Patients with complicated ulcers (e.g., bleeding, perforation, penetration, or gastric outlet obstruction) may need treatment for up to 12 weeks.8 Unless other risk factors are present, long-term prevention of a recurrent bleeding ulcer with additional antisecretory therapy is not recommended.9 In patients with NSAID-induced ulcers, NSAID discontinuation is recommended. If an NSAID must be

Author: Sentena October 2020 188 used, then a cyclooxygenase-2 (COX-2)-selective NSAID, at the lowest effective dose, with a PPI is recommended. If a patient has low-dose aspirin-induced ulcer and they must continue therapy, then long-term concomitant PPI should also be given, regardless of aspirin dose.10

Table 1. Recommended Treatment Duration of PPI Therapy Based on Diagnosis8,1 Diagnosis Duration of Therapy Peptic Ulcer Disease (PUD) 4-8 weeks† Duodenal Ulcer 4 weeks Gastric Ulcer 8 weeks H. pylori infection 14 days Gastrointestinal Reflux Disease (GERD) 8 weeks* Abbreviation: NSAID – non-steroidal anti-inflammatory drug Key: * Coverage of PPI therapy for GERD is limited to 8 weeks for Fee-for-Service OHP patients. † Some patients with complicated peptic ulcer disease (ulcers with bleeding, perforation, penetration, or gastric outlet obstruction) may require up to 12 weeks of therapy.

Important treatment outcomes in the management of patients requiring treatment with PPIs and H2RAs are: healing of ulcers, reduction in symptoms of dyspepsia, eradication of H. pylori and quality of life.

Utilization for this class is not a substantial contributor to the overall prescription expenditures for the Oregon Health Authority (OHA). Preferred PPIs account for 90% of utilization in the Fee-for-Service (FFS) OHP population. Ninety-four percent of H2RAs are for preferred therapies. OHP policy only covers treatment of GERD up to 8 weeks.

New Systematic Reviews:

Cochrane: Proton Pump Inhibitors for Functional Dyspepsia A 2018 Cochrane review evaluated the evidence for PPI use in people with functional dyspepsia (FD) with a focus on symptom management and quality of life.2 Functional dyspepsia was defined as persistent or recurrent epigastric pain in patients with normal upper GI findings and symptom duration for at least a month, Rome II or III criteria (diagnosis of FD based on symptoms) or American Gastrological Association criteria for dyspepsia (dyspepsia not correlating with another Author: Sentena October 2020 189 diagnosis). Comparisons were between PPIs, H2RAs or prokinetics. Twenty-seven trials (only 3 trials were in the United States [US] and 5 trials were in multiple countries including the US) in patients at least 16 years of age were identified through a literature search up to May of 2017. Groups of low-dose and standard dosing of PPIs were combined since evidence suggests similar efficacy. Studies lasted from 2-8 weeks. The primary outcomes were global symptoms of dyspepsia or epigastric pain/discomfort.

Trials included in the analysis were found to be at low risk for selection, detection, reporting and publication bias. Global symptoms of dyspepsia (reporting no or minimal symptoms) were reduced with the administration of PPIs compared to placebo based on moderate-quality evidence (629 per 1000 patients versus 714 per 1000 patients, respectively; RR 0.88; 95% CI, 0.82 to 0.94/NNT 11 with up to 8 weeks of therapy).2 There was no evidence of difference in quality of life between PPIs and placebo based on Psychological General Well-Being Index and SF-36 combined (standard mean difference [SMD] 0.01 (95% CI, 0.09 to 0.11). A small benefit, that was not statistically significant, in reduction of global symptoms of dyspepsia was reported for PPI therapy over H2RAs based on low quality of evidence (650 per 1000 patients versus 739 per 1000 patients, respectively; RR 0.88; 95% CI, 0.74 to 1.04).2 A marginal benefit in reduction of global symptoms of dyspepsia with PPI therapy over prokinetics may exist, but evidence was of low quality (RR 0.89; 95% CI, 0.81 to 0.99/NNT 16 with treatment 2 to 4 weeks). No reduction in global symptoms of dyspepsia was found when PPIs and prokinetics were combined compared to prokinetics alone for the treatment of FD, based on moderate quality evidence (377 per 1000 patients versus 444 per 1000 patients, respectively; RR 0.85; 95% CI, 0.68 to 1.08).2 H. pylori status did not change results of studied outcomes. Adverse reactions between PPIs and placebo were not statistically significantly different based on moderate quality evidence (RR 0.99; 95% CI, 0.73 to 1.33).2 No statistically significant differences between PPIs and H2RAs for adverse events were found, based on moderate quality evidence (137 per 1000 patients vs. 144 per 1000 patients, respectively). No differences between adverse events were reported between prokinetics and PPIs based on moderate quality evidence, 113 per 1000 patients compared to 123 per 1000 patients, respectively (RR 1.09; 95% CI, 0.79 to 1.49).2 Adverse events were decreased in patients receiving combination PPI and prokinetics compared to prokinetics alone, based on moderate quality evidence (132 per 1000 patients versus 220 per 1000 patients, respectively; RR 0.60; 95% CI, 0.39 to 0.93).

Cochrane: Pharmacological Interventions for Prevention and Treatment of Upper Gastrointestinal Bleeding in Newborn Infants A Cochrane review evaluated pharmacological interventions studied in preterm and term neonates for the prevention of upper GI bleeding.11 The following treatments were included: PPIs, H2RAs, antacids, sucralfate or bismuth salts. Eleven trials were included in the systematic review, which included studies published up to July of 2018. None of the identified studies were of high quality and none had a low risk of bias.11

Four trials evaluated H2RAs for the prevention of GI bleeding in infants in the neonatal intensive care unit. Incidence of GI bleeding was 110 per 1000 patients in those treated with an H2RA compared to 305 per 1000 patients treated in the control group (no treatment) based on moderate quality evidence (RR 0.36; 95% CI, 0.22 to 0.58).11 No difference in mortality was found between the groups.

The treatment of infants with an upper GI bleed was studied in 7 trials using either an H2RA or PPI. There was only low or very low quality of evidence available for analysis, and therefore, no strong conclusions could be drawn.

After review, 15 systematic reviews were excluded due to poor quality (e.g, indirect network-meta analyses or failure to meet AMSTAR criteria), wrong study design of included trials (e.g., observational), comparator (e.g., no control or placebo-controlled), or outcome studied (e.g., non-clinical).12–25

Author: Sentena October 2020 190

New Guidelines:

NICE – 2019 Surveillance of Gastro-Esophageal Reflux Disease and Dyspepsia in Adults: Investigation and Management National Institute for Health and Care Excellence (NICE) updated previous guidance on the management of GERD and dyspepsia in adult patients.1 Pharmacotherapies included in the review were PPIs and H2RAs. There was limited new evidence to update long-term safety of PPIs and regimens for H. pylori. Evidence was not pooled due to limited number of studies. A majority of recommendations from the 2014 guideline remained unchanged (Table 2). For the treatment of GERD, PPI therapy of up to 8 weeks is recommended. Recommendations for the treatment of esophagitis are full-dose PPI therapy for 8 weeks. Severe esophagitis may require treatment of a standard dose PPI as maintenance therapy if symptoms persist. Peptic ulcer disease treatment ranges from 2-8 weeks based on underlying cause.1

Table 2. NICE Recommendations for GERD and Dyspepsia1 Indication Recommendation GERD Full-dose PPI for 4-8 weeks Treat recurrence of symptoms with PPI at lowest dose possible to control symptoms Severe Esophagitis Full-dose PPI for 8 weeks Persistent Severe Esophagitis Full dose PPI as maintenance therapy Peptic Ulcer Disease PPI or H2RA therapy for 8 weeks and treat H. pylori if present (stop NSAID if applicable) PPI or H2RA therapy for H. pylori negative patients for 4 to 8 weeks Dilation of a Esophageal Stricture Long-term full-dose PPI therapy Functional Dyspepsia Low-dose PPI or H2RA for 4 weeks If symptoms continue or recur, recommend PPI or H2RA at lowest possible dose (avoid long-term therapy) H. pylori PPI, amoxicillin and clarithromycin or metronidazole for 7 days For penicillin allergic, recommend a PPI, clarithromycin and metronidazole for 7 days For penicillin allergic, with previous clarithromycin exposure, recommend PPI, bismuth, metronidazole and tetracycline for 7 days H. pylori after failure of first-line PPI, amoxicillin, clarithromycin or metronidazole (whichever has not been used previously) for 7 days treatment PPI, amoxicillin and tetracycline if patient has had previous clarithromycin and metronidazole exposure for 7 days For penicillin allergic, recommend PPI, metronidazole and levofloxacin (if not previously used) for 7 days For penicillin allergic, with previous fluoroquinolone use offer a PPI, bismuth, metronidazole, and tetracycline Children and Young People with PPI or H2RA for 4 weeks persistent heartburn, retrosternal or epigastric pain Infants PPI or H2RA for 4 weeks for overt regurgitation and at least 1 of the following: unexplained feeding difficulties (for example, refusing feeds, gagging or choking), distressed behavior and faltering growth

Author: Sentena October 2020 191

Abbreviations: GERD – gastrointestinal reflux disease; H2RA - histamine-2 receptor antagonist; PPI – proton pump inhibitor

There was new high quality evidence supporting the efficacy of PPIs and H2RAs from 2 new systematic reviews and meta-analyses. A review which pooled results from PPIs, H2RAs and prostaglandins (termed “gastroprotectant” drugs) demonstrated prevention and healing of ulcers and upper GI bleeding.1 There was no significant reduction in mortality (OR 0.85; 95% CI, 0.69 to 1.04; p=0.11).1 Symptom recurrence after initial treatment should be treated with a PPI or H2RA at the lowest possible dose.

An update to the guidance on the treatment of H. pylori was made to consider levofloxacin as the fluoroquinolone of choice, but reserve fluoroquinolone use for when other antibacterial treatments cannot be used:1 - First-line option in patients allergic to penicillin and previous exposure to both clarithromycin and metronidazole - Second-line option in patients with previous exposure to both clarithromycin and metronidazole - Second-line treatment in patients who are allergic to penicillin and have not had a previous exposure to a fluoroquinolone

After further review, 4 guidelines were excluded due to poor quality..26–29,30

New Formulations or Indications: TALICIA (omeprazole, amoxicillin and rifabutin): The 3-drug delayed release capsule combination product was approved in 2019 and indicated for the treatment of H. pylori infection in adults.4 Each capsule contains 12.5 mg of rifabutin, 10 mg omeprazole and amoxicillin 250 mg. TALICIA is given as 4 capsules every 8 hours with food for 14 days. Approval was based on two trials. The first trial was a randomized, double-blind trial comparing TALICIA to a total daily dose combination of amoxicillin 3000 mg and omeprazole 120 mg in patients testing positive for H. pylori. Eradication rates were 83.8% in patients treated with TALICIA and 57.7% in the control group (amoxicillin and omeprazole) (P<0.0001).4 A second double-blind, randomized, placebo-controlled trial reported eradication rates of 76.6% with TALICIA compared to 2.4% treated with placebo.4

New FDA Safety Alerts:

Table 3. Description of new FDA Safety Alerts Generic Name Brand Name Month / Year Location of Change (Boxed Warning, Addition or Change and Mitigation Principles of Change Warnings, CI) (if applicable) Ranitidine3 ZANTAC April 2020 Contaminates of N-Nitrosodimethylamine Removal of all ranitidine products from the (NDMA), a carcinogen, in ranitidine market products

Randomized Controlled Trials: A total of 66 citations were manually reviewed from the initial literature search. After further review, all citations were excluded because of wrong study design (eg, observational), comparator (eg, no control or placebo-controlled), or outcome studied (eg, non-clinical).

Author: Sentena October 2020 192

References: 1. National Institute for Health and Care Excellence. 2019 Surveillance of Gastro-oesophageal Reflux Disease and Dyspepsia in Adults: Investigation and Management (NICE Guideline CG184). February 13, 2019. Available at: www.nice.org.uk. Accessed May 5, 2020.

2. Pinto-Sanchez MI, Yuan Y, Bercik P, Moayyedi P. Proton Pump Inhibitors For Functional Dyspepsia. Cochrane Database of Systematic Reviews 2017. Issue 11. Art. No.: CD011194. doi:10.1002/14651858.CD011194.pub2.

3. Food and Drug Administration. FDA Requests Removal of All Raniditine Products (Zantac) from the Market. FDA News Release. Availabe at: https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market. Accessed May 5, 2020.

4. Talicia (R) (omeprazole, amoxicillin and rifabutin) prescribing information. RedHill Biopharma Inc., Raleigh, NC. 2019.

5. Wolfe M, Feldman M, Grover S. Proton Pump Inhibitors: Overview of Use and Adverse Effects in the Treatment of Acid Related Disorders. UpToDate. Accessed May 5, 2020.

6. Canadian Agency for Drugs and Technologies Health. Proton Pump Inhibitors for Gastrointestinal Conditions: A Review of Clinical Effectiveness and Cost- Effectiveness. Rapid Response Report. June 2015. Available at: www.cadth.ca. Accessed May 5, 2020.

7. Kahrilas P, Talley N, Grover S. Medical Management of Gastroesophageal Reflux Disease in Adults. UpToDate. Accessed May 5, 2020.

8. Vakil N, Feldman M, Grover S. Peptic Ulcer Disease: Treatment and Secondary Prevention. UpToDate. Accessed May 5, 2020.

9. Laine L, Jensen DM. Management of Patients With Ulcer Bleeding: American Journal of Gastroenterology. 2012;107(3):345-360. doi:10.1038/ajg.2011.480

10. Lanas A, Wu P, Medin J, Mills E. Low Doses of Acetylsalicylic Acid Increase Risk of Gastrointestinal Bleeding in a Meta-Analysis. Clinical Gastroenterol and Hepatol 2011;9:762-768.

11. Green. Pharmacological Interventions For Prevention And Treatment Of Upper Gastrointestinal Bleeding In Newborn Infants. Cochrane Database of Systematic Reviews 2019. Issue 7. Art. No.: CD011785. doi: 10.1002/14651858.CD011785.pub2.

12. Ko SW, Kim Y-J, Chung WC, Lee SJ. Bismuth Supplements As The First-Line Regimen For Helicobacter Pylori Eradication Therapy: Systemic Review And Meta-Analysis. Helicobacter. 2019;24(2):e12565. doi:10.1111/hel.12565

13. Marin AC, Nyssen OP, McNicholl AG, Gisbert JP. Efficacy and Safety of Quinolone-Containing Rescue Therapies After the Failure of Non-Bismuth Quadruple Treatments for Helicobacter pylori Eradication: Systematic Review and Meta-Analysis. [Review]. Drugs. 2017;77(7):765-776. doi:10.1007/s40265-017- 0730-4 Author: Sentena October 2020 193

14. Willems RPJ, van Dijk K, Ket JCF, Vandenbroucke-Grauls CMJE. Evaluation of the Association Between Gastric Acid Suppression and Risk of Intestinal Colonization With Multidrug-Resistant Microorganisms: A Systematic Review and Meta-analysis. JAMA Intern Med. Published online February 24, 2020. doi:10.1001/jamainternmed.2020.0009.

15. Lopo I, Libanio D, Pita I, Dinis-Ribeiro M, Pimentel-Nunes P. Helicobacter Pylori Antibiotic Resistance In Portugal: Systematic Review And Meta-Analysis. [Review]. Helicobacter. 2018;23(4):e12493. doi:10.1111/hel.12493.

16. Yang X, Wang J, Han S, et al. High Dose Dual Therapy Versus Bismuth Quadruple Therapy For Helicobacter Pylori Eradication Treatment: A Systematic Review And Meta-Analysis. Medicine. 2019;98(7):14396.

17. Sgourakis G, Chatzidakis G, Poulou A, et al. High-Dose Vs. Low-Dose Proton Pump Inhibitors Post-Endoscopic Hemostasis In Patients With Bleeding Peptic Ulcer. A Meta-Analysis And Meta-Regression Analysis. Journal of Gastroenterology. 2018;29(1):22-31. doi:10.5152/tjg.2018.17143.

18. Bundhun PK, Teeluck AR, Bhurtu A, Huang W-Q. Is The Concomitant Use Of Clopidogrel And Proton Pump Inhibitors Still Associated With Increased Adverse Cardiovascular Outcomes Following Coronary Angioplasty: A Systematic Review And Meta-Analysis Of Recently Published Studies (2012 - 2016). [Review]. BMC Cardiovascular Disorders. 2017;17(1):3. doi:10.1186/s12872-016-0453-6.

19. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Long-Term Kidney Outcomes Among Users Of Proton Pump Inhibitors Without Intervening Acute Kidney Injury. Kidney International. 2017;91(6):1482-1494. doi:10.1016/j.kint.2016.12.021.

20. Cheung KS, Chan EW, Wong AYS, Chen L, Wong ICK, Leung WK. Long-Term Proton Pump Inhibitors And Risk Of Gastric Cancer Development After Treatment For Helicobacter Pylori: A Population-Based Study. Gut. 2018;67(1):28-35. doi:10.1136/gutjnl-2017-314605

21. Taipale H, Tolppanen A-M, Tiihonen M, et al. No Association Between Proton Pump Inhibitor Use and Risk of Alzheimer’s Disease. Am J Gastroenterol. 2017 Dec;112(12):1802-1808. doi: 10.1038/ajg.2017.196. Epub 2017 Jul 11.

22. Khan MA, Yuan Y, Iqbal U, et al. No Association Linking Short-Term Proton Pump Inhibitor Use to Dementia: Systematic Review and Meta-analysis of Observational Studies. Am J Gastroenterol. Published online January 2, 2020. doi:10.14309/ajg.0000000000000500.

23. Wang Y, Zhao R, Wang B, et al. Sequential Versus Concomitant Therapy For Treatment Of Helicobacter Pylori Infection: An Updated Systematic Review And Meta-Analysis. [Review]. Journal of Clinical Pharmacology. 2018;74(1):1-13. doi:10.1007/s00228-017-2347-7.

24. Chan FKL, Kyaw M, Tanigawa T, et al. Similar Efficacy of Proton-Pump Inhibitors vs H2-Receptor Antagonists in Reducing Risk of Upper Gastrointestinal Bleeding or Ulcers in High-Risk Users of Low-Dose Aspirin. Gastroenterology. 2017;152(1):105-110.e1. doi:10.1053/j.gastro.2016.09.006.

25. Yeo YH, Hsu C-C, Lee C-C, et al. Systematic review and network meta-analysis: Comparative Effectiveness Of Therapies For Second-Line Helicobacter Pylori Eradication. Journal of Gastroenterology. 2019;34(1):59-67. doi:10.1111/jgh.14462.

Author: Sentena October 2020 194

26. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment Of Helicobacter Pylori Infection. Am J Gastroenterol. 2017;112(2):212- 239. doi:10.1038/ajg.2016.563

27. Oakland K, Chadwick G, East J et al. Diagnosis and Management of Acute Lower Gastrointestinal Bleeding: Guidelines from the British Society of Gastroenterology. Gut 2019; 68:776-789.

28. Jones NL, Koletzko S, Goodman K, et al. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). Journal of Pediatric Gastroenterology. 2017;64(6):991-1003. doi:10.1097/MPG.0000000000001594

29. Barkun AN, Almadi M, Kuipers EJ, et al. Management of Nonvariceal Upper Gastrointestinal Bleeding: Guideline Recommendations From the International Consensus Group. Ann Intern Med. Published online October 22, 2019. doi:10.7326/M19-1795

30. Randel A. H. pylori Infection: ACG Updates Treatment Recommendations. American Family Physician. 2018;97(2):135-137.

Author: Sentena October 2020 195

Appendix 1: Current Preferred Drug List

Histamine-2 Receptor Antagonists Generic Brand Form PDL famotidine ACID CONTROLLER TABLET Y famotidine ACID REDUCER TABLET Y famotidine FAMOTIDINE TABLET Y famotidine HEARTBURN RELIEF TABLET Y famotidine PEPCID TABLET Y ranitidine HCl RANITIDINE HCL SYRUP Y ranitidine HCl ZANTAC SYRUP Y ranitidine HCl ACID CONTROL TABLET Y ranitidine HCl ACID REDUCER TABLET Y ranitidine HCl HEARTBURN RELIEF 150 TABLET Y ranitidine HCl RANITIDINE TABLET Y ranitidine HCl RANITIDINE HCL TABLET Y ranitidine HCl ZANTAC TABLET Y cimetidine ACID REDUCER TABLET N cimetidine CIMETIDINE TABLET N cimetidine HEARTBURN RELIEF TABLET N cimetidine TAGAMET TABLET N cimetidine HCl CIMETIDINE SOLUTION N cimetidine HCl CIMETIDINE HCL SOLUTION N famotidine FAMOTIDINE ORAL SUSP N famotidine PEPCID RPD TAB RAPDIS N famotidine/Ca carb/mag hydrox ACID REDUCER COMPLETE TAB CHEW N famotidine/Ca carb/mag hydrox COMPLETE TAB CHEW N famotidine/Ca carb/mag hydrox DUAL ACTION COMPLETE TAB CHEW N nizatidine NIZATIDINE CAPSULE N nizatidine NIZATIDINE SOLUTION N ranitidine HCl RANITIDINE HCL CAPSULE N

Proton Pump Inhibitors Generic Brand Form PDL omeprazole OMEPRAZOLE CAPSULE DR Y pantoprazole sodium PANTOPRAZOLE SODIUM TABLET DR Y pantoprazole sodium PROTONIX TABLET DR Y dexlansoprazole DEXILANT CAP DR BP N esomeprazole mag/glycerin ESOMEP-EZS KIT CAP SP N esomeprazole magnesium ESOMEPRAZOLE MAGNESIUM CAPSULE DR N Author: Sentena October 2020 196

esomeprazole magnesium HEARTBURN TREATMENT CAPSULE DR N esomeprazole magnesium NEXIUM CAPSULE DR N esomeprazole magnesium NEXIUM 24HR CAPSULE DR N esomeprazole magnesium ESOMEPRAZOLE MAGNESIUM SUSPDR PKT N esomeprazole magnesium NEXIUM SUSPDR PKT N esomeprazole strontium ESOMEPRAZOLE STRONTIUM CAPSULE DR N lansoprazole HEARTBURN TREATMENT 24 HOUR CAPSULE DR N lansoprazole LANSOPRAZOLE CAPSULE DR N lansoprazole PREVACID CAPSULE DR N lansoprazole PREVACID 24HR CAPSULE DR N lansoprazole LANSOPRAZOLE TAB RAP DR N lansoprazole PREVACID TAB RAP DR N omeprazole OMEPRAZOLE TAB RAP DR N omeprazole OMEPRAZOLE TABLET DR N omeprazole magnesium ACID REDUCER CAPSULE DR N omeprazole magnesium OMEPRAZOLE MAGNESIUM CAPSULE DR N omeprazole magnesium PRILOSEC SUSPDR PKT N omeprazole/sodium bicarbonate OMEPRAZOLE-SODIUM BICARBONATE CAPSULE N omeprazole/sodium bicarbonate ZEGERID CAPSULE N omeprazole/sodium bicarbonate OMEPRAZOLE-SODIUM BICARBONATE PACKET N omeprazole/sodium bicarbonate ZEGERID PACKET N pantoprazole sodium PROTONIX GRANPKT DR N rabeprazole sodium ACIPHEX SPRINKLE CAP DR SPR N rabeprazole sodium ACIPHEX TABLET DR N rabeprazole sodium RABEPRAZOLE SODIUM TABLET DR N

Antacids, H. Pylori Generic Brand Form PDL omeprazole/amoxicill/rifabutin TALICIA CAP IR DR N bismuth/metronid/tetracycline PYLERA CAPSULE N lansoprazole/amoxiciln/clarith LANSOPRAZOL-AMOXICIL-CLARITHRO COMBO. PKG N omeprazole/clarith/amoxicillin OMECLAMOX-PAK COMBO. PKG N

Author: Sentena October 2020 197

Appendix 2: Medline Search Strategy

Database(s): Ovid MEDLINE(R) ALL 1946 to April 17, 2020 Search Strategy:

# Searches Results

1 omeprazole.mp. or Omeprazole/ 11353

2 pantoprazole.mp. or Pantoprazole/ 2034

3 dexlansoprazole.mp. or Dexlansoprazole/ 132

4 esomeprazole.mp. or Esomeprazole/ 1654

5 lansoprazole.mp. or Lansoprazole/ 2917

6 rabeprazole.mp. or Rabeprazole/ 1361

7 bismuth.mp. or Bismuth/ 12213

8 famotidine.mp. or Famotidine/ 2243

9 ranitidine.mp. or Ranitidine/ 7110

10 cimetidine.mp. or Cimetidine/ 12587

11 nizantidine.mp. 1

12 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 43450

13 limit 12 to (english language and humans) 22376

14 limit 13 to yr="2017 -Current" 1310

15 limit 14 to (clinical trial, phase iii or meta analysis or practice guideline or "systematic review") 66 Appendix 3: Key Inclusion Criteria

Population Patients with an indication for gastric acid suppression Intervention Proton pump inhibitor and histamine receptor antagonist therapy Comparator Placebo or active treatment regimen Outcomes Dyspepsia, ulcer healing rates, erosive esophagitis healing rates, quality of life Timing Symptom onset Setting Outpatient Author: Sentena October 2020 198

Appendix 4: Prior Authorization Criteria

Proton Pump Inhibitors (PPIs)

Goals:  Promote PDL options  Restrict PPI use to patients with OHP-funded conditions

Requires PA:  Preferred PPIs beyond 68 days’ duration  Non-preferred PPIs

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/  Individual components for treatment of H. pylori that are preferred products

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Is the request for a preferred PPI? Yes: Go to #5 No: Go to #3

3. Is the treating diagnosis an OHP-funded condition (see Table)? Yes: Go to #4 No: Pass to RPh; deny, not funded by OHP.

4. Will the prescriber consider changing to a preferred PPI Yes: Inform prescriber of No: Go to #5 product? covered alternatives.

Message: Preferred products are reviewed for comparative effectiveness and safety by the Pharmacy and Therapeutics (P&T) Committee.

Author: Sentena October 2020 199

5. Has the patient already received 68 days of PPI therapy for Yes: Go to #8 No: Go to #6 either of the following diagnoses:  Esophagitis or gastro-esophageal reflux disease with or without esophagitis (K20.0-K21.9); or  Current H. pylori infection?

6. Does the patient have recurrent, symptomatic erosive Yes: Approve for 1 year No: Go to #7 esophagitis that has resulted in previous emergency department visits or hospitalization?

7. Does the patient have a history of gastrointestinal ulcer or bleed Yes: Approve for 1 year No: Go to #8 and have one or more of the following risk factors?  Age 65 years or older  Requires at least 3 months of continuous daily: i. Anticoagulant; ii. Aspirin (all doses) or non-selective NSAID; or iii. Oral corticosteroid

8. Are the indication, daily dose and duration of therapy consistent Yes: Approve for No: Pass to RPh. Deny; medical with criteria outlined in the Table? recommended duration. appropriateness or not funded by OHP Message: OHP-funded conditions are listed in the Table. Message: Patient may only receive 8 weeks of continuous PPI therapy. RPh may approve a quantity limit of 30 doses (not to exceed the GERD dose in the Table) over 90 days if time is needed to taper off PPI. Note: No specific PPI taper regimen has proven to be superior. H2RAs may be helpful during the taper. Preferred H2RAs are available without PA.

Author: Sentena October 2020 200

Author: Sentena October 2020 201

Table. Dosing and Duration of PPI Therapy for OHP Funded Conditions. Funded OHP Conditions* Maximum Duration Maximum Daily Dose

GERD: 8 weeks* Dexlansoprazole 30 mg Esophageal reflux (K219) Dexlansoprazole Solu Tab 30 mg Esophagitis (K200-K210) *Treatment beyond 8 weeks is not Esomeprazole 20 mg funded by OHP. Lansoprazole 15 mg Omeprazole 20 mg Pantoprazole 40 mg Rabeprazole 20 mg

H. pylori Infection (B9681) 2 weeks

Duodenal Ulcer (K260-K269) 4 weeks

Gastric Ulcer (K250-K259) 8 weeks

Peptic ulcer site unspecified (K270-K279) 12 weeks Dexlansoprazole 60 mg Dexlansoprazole 30 mg† Esomeprazole 40 mg Achalasia and cardiospasm (K220) 1 year Lansoprazole 60 mg Barrett’s esophagus (K22.70; K22.71x) Omeprazole 40 mg Dyskinesia of esophagus (K224) Pantoprazole 80 mg Esophageal hemorrhage (K228) Rabeprazole 40 mg Gastritis and duodenitis (K2900-K2901; K5281) Gastroesophageal laceration-hemorrhage syndrome (K226) Gastrojejunal ulcer (K280-K289) Malignant mast cell tumors (C962) Multiple endocrine neoplasia [MEN] type I (E3121) Neoplasm of uncertain behavior of other and unspecified endocrine glands (D440; D442; D449) Perforation of Esophagus (K223) Stricture & Stenosis of Esophagus (K222) Zollinger-Ellison (E164) *A current list of funded conditions is available at: https://www.oregon.gov/oha/HPA/DSI-HERC/Pages/Prioritized-List.aspx

† Dexlansoprazole SoluTab 30 mg (given as 2 SoluTabs at once) are not recommended for healing of erosive esophagitis.

P&T / DUR Review: 10/20 (KS), 5/17(KS); 1/16; 5/15; 3/15; 1/13; 2/12; 9/10; 3/10; 12/09; 5/09; 5/02; 2/02; 9/01, 9/98 Author: Sentena October 2020 202

Implementation: 6/8/16; 2/16; 10/15; 7/15; 4/15; 5/13; 5/12; 1/11; 4/10; 1/10; 9/06, 7/06, 10/04, 3/04

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-2596

Drug Class Literature Scan: Atopic Dermatitis and Topical Antipsoriatics

Date of Review: October 2020 Date of Last Review: July 2019 Literature Search: 04/17/2019 – 5/20/2020

Current Status of PDL Class: See Appendix 1.

Conclusions:  Since the last atopic dermatitis (AD) and topical antipsoriatic class update, 1 high-quality systematic review1 and 1 high-quality guideline update have been published.2  A 2020 Cochrane review evaluated the safety and efficacy of biologics for chronic rhinosinusitis in adults. 1 Most of the patients were enrolled in trials that evaluated dupilumab, the only biologic Food and Drug Administration (FDA)-approved for management of chronic rhinosinusitis with nasal polyps.3 The primary outcomes were health‐related quality of life (HRQL) and serious adverse events. 1 Health-related quality of life was measured with the Sino‐Nasal Outcome Test-22 (SNOT-22; score range 0 to 110; minimal clinically important difference [MCID] 8.9 points). At 24 weeks, the SNOT-22 score was 19.61 points lower in participants receiving dupilumab (95% confidence interval [CI] -22.54 to -16.69).1 The sample sizes were insufficient and the length of follow‐ up too short (16 to 52 weeks) to adequately assess the risks of serious side effects.1  The Canadian Agency for Drugs and Technologies in Health (CADTH) published updated recommendations for the use of dupilumab in atopic dermatitis April 2020.2 The following recommendations are included in the guideline. Dupilumab should be initiated if the following criteria are met: o Patient is 12 years and older with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.2 o Patients must have had an adequate trial or be ineligible for each of the following therapies: phototherapy (where available), methotrexate, and cyclosporine.2 o The physician must provide the Eczema Area and Severity Index (EASI) and Physician Global Assessment (PGA) score at the time of the initial request.2 o For continued renewal, the physician must provide proof of beneficial clinical effect, defined as 75% or greater improvement from baseline in EASI score (EASI-75) six months after treatment initiation.2  In March 2020, the FDA expanded the indication for crisaborole in children aged 3 months and older for management of mild-to-moderate AD.4  In May 2020, the FDA expanded the indication for dupilumab in children aged 6 years and older for management of moderate-to-severe AD.3

Author: Deanna Moretz, PharmD, BCPS

204

Recommendations:  Revise Prior Authorization (PA) criteria for AD and topical antipsoriatics to reflect expanded indication for crisaborole in children aged 3 months and older with moderate AD.  Revise PA criteria for dupilumab to reflect expanded indication for management of moderate-to-severe AD not well controlled by topical prescription medications in children older than 6 years of age.  Review costs in executive session.

Summary of Prior Reviews and Current Policy According to the Health Evidence Review Commission (HERC), moderate-to-severe AD and moderate-to-severe psoriasis are funded conditions.5 Mild AD and mild psoriasis continue to be an unfunded conditions.5 The HERC Guideline Note 21 provides guidance for coverage and management of inflammatory skin diseases. 5 At the May 2018 meeting, the Pharmacy and Therapeutics (P and T) committee approved revising the PA criteria for topical antipsoriatic drugs to include agents used to manage AD. In addition, the committee approved a recommendation to make dupilumab a non-preferred medication on the Practitioner-Managed Prescription Drug Plan (PMPDP) with PA criteria. After reviewing comparative costs in executive session, tacrolimus 0.03% ointment, tacrolimus 0.1% ointment, and pimecrolimus 1% cream were designated as preferred agents and crisaborole was maintained as a non-preferred agent.

At the July 2019 P and T meeting, a new PA document was approved for dupilumab utilization in moderate-to-severe AD, chronic rhinosinusitis with nasal polyps, and moderate-to-severe asthma. Utilization of AD medications and topical antipsoriatics is very low (3 patients in the first quarter of 2020) in the fee-for-service (FFS) population. Claims were processed for 2 drugs: dupilumab injection and tacrolimus ointment in the first quarter of 2020. The PDL status for topical antipsoriatics and AD medications is presented in Appendix 1. The PA criteria for dupilumab and topical agents used to manage psoriasis and AD are included in Appendix 4.

Methods: A Medline literature search for new systematic reviews and randomized controlled trials (RCTs) assessing clinically relevant outcomes to active controls, or placebo if needed, was conducted. The Medline search strategy used for this literature scan is available in Appendix 3, which includes dates, search terms and limits used. The OHSU Drug Effectiveness Review Project, Agency for Healthcare Research and Quality (AHRQ), National Institute for Health and Clinical Excellence (NICE), Department of Veterans Affairs, and CADTH resources were manually searched for high quality and relevant systematic reviews. When necessary, systematic reviews are critically appraised for quality using the AMSTAR tool and clinical practice guidelines using the AGREE tool. The FDA website was searched for new drug approvals, indications, and pertinent safety alerts.

New Systematic Reviews: Cochrane: Biologics for Chronic Rhinosinusitis A 2020 Cochrane review evaluated the safety and efficacy of biologics for chronic rhinosinusitis in adults.1 Literature was searched through September 2019 with a focus on identifying RCTs with at least three months follow-up comparing biologics against placebo/no treatment in patients with chronic rhinosinusitis. 1 Eight RCTs met inclusion criteria. Of 986 adult participants, 984 had severe chronic rhinosinusitis with nasal polyps; 43% to 100% of participants also had asthma.1

Author: Moretz October 2020 205

Three biologics, with different targets, were evaluated: dupilumab, mepolizumab and omalizumab. Only dupilumab is FDA-approved for management of chronic rhinosinusitis. Overall the risk of bias was low or unclear for most domains in the included trials.1 All the studies were sponsored or supported by industry.

Three studies (784 participants) evaluated dupilumab versus placebo/no treatment.1 Health-related quality of life was measured with the SNOT-22 (score 0 to 110; MCID 8.9 points).1 At 24 weeks, the SNOT-22 score was 19.61 points lower (better) in participants receiving dupilumab (MD -19.61, 95% CI -22.54 to -16.69; 3 studies; 784 participants; high-quality evidence).1 Symptom severity measured on a 0- to 10-point visual analogue scale (VAS) was 3.00 lower in those receiving dupilumab (95% CI -3.47 to -2.53; 3 studies; moderate-quality evidence).1 The sample sizes were insufficient and the length of follow‐up too short (16 to 52 weeks) to adequately assess the risks of serious side effects.1

After review, 6 systematic reviews were excluded due to poor quality, wrong study design of included trials (e.g., observational), comparator (e.g., no control or placebo-controlled), or outcome studied (e.g., non-clinical).6-11

New Guidelines: High Quality Guidelines: Canadian Agency for Drugs and Technologies in Health In April 2020, CADTH published updated recommendations for the use of dupilumab in atopic dermatitis.2 Dupilumab should be initiated if the following criteria are met:  Patient is 12 years and older with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.2  Patients must have had an adequate trial or be ineligible for each of the following therapies: phototherapy (where available), methotrexate, and cyclosporine.2  The physician must provide the EASI and PGA score at the time of the initial request.2  The maximum duration of authorization is 6 months.2  The patient must be under the care of a dermatologist.2  Dupilumab is not to be used in combination with phototherapy or immunosuppressant drugs, such as methotrexate or cyclosporine.2 Renewal Criteria:  The physician must provide proof of beneficial clinical effect, defined as 75% or greater improvement from baseline in EASI score (EASI-75) six months after treatment initiation.2

Additional Guidelines for Clinical Context: Joint American Academy of Dermatology–National Psoriasis Foundation Guidelines of care for the management and treatment of psoriasis in pediatric patients younger than 18 years old were published by the American Academy of Dermatology (AAD) in conjunction with the National Psoriasis Foundation (NPF) in 2020.12 This guideline addresses the management of psoriasis and its extracutaneous manifestations in children and adolescents, with attention to topical and systemic treatment options, phototherapy, and comorbidities, including psychosocial wellness and quality of life (QOL).12 Evidence was obtained by using a search of the PubMed and MEDLINE databases from January 2011 through December 31, 2017, for clinical questions addressed in the previous version of this guideline published in 2008. 12 A multidisciplinary workgroup (WG) of recognized psoriasis experts consisting of dermatologists, a rheumatologist, a cardiologist, and representatives from a patient advocacy organization were

Author: Moretz October 2020 206 convened to identify important clinical questions with regard to pediatric psoriasis. 12Significant efforts were taken to minimize the potential for conflicts of interest to influence guideline content. Funding of guideline production by medical or pharmaceutical entities was prohibited, full disclosure was obtained and evaluated for all guideline contributors throughout the guideline development process, and recusal was used to manage identified relationships.12

The only recommendation that addressed the use of medications in the topical atopic dermatitis/psoriasis class was the use of tacrolimus 0.1% ointment for off- label use as monotherapy for pediatric psoriasis of the face and genital region. 12 (Strength of Recommendation: C - Recommendation based on consensus, opinion, case studies, or disease-oriented evidence.)12

National Institute for Health and Care Excellence : A recommendation for crisaborole for treating mild to moderate atopic dermatitis in people aged 2 years and older is under development. No publication date has been announced.

After review, 2 guidelines were excluded due to poor quality.13,14

New Formulations/Indications Crisaborole In March 2020, crisaborole (Eucrisa) received expanded FDA approval for use in pediatric patients 3 months of age and older with mild-to-moderate atopic dermatitis.4 Previously, crisaborole was indicated for mild-to-moderate atopic dermatitis in patients 2 years and older. Use of crisaborole in pediatric patients aged 2 years and older is supported by data from two 28-day adequate, vehicle-controlled safety and efficacy trials which included 1,313 pediatric subjects ages 2 years to 17 years of whom 874 received crisaborole.4 Additionally, use of crisaborole in pediatric patients ages 3 months to less than 2 years was supported by data from a 28-day open-label, safety and pharmacokinetics (PK) trial in 137 subjects.4 No new safety signals were identified in subjects 3 months to less than 2 years of age.4 The most commonly reported adverse reaction in subjects 2 years and older was application site pain.4

Dupilumab In May 2020, the FDA expanded approval of dupilumab (Dupixent) for use in children aged 6 years and older for treatment of moderate-to-severe AD not well controlled with topical prescription medications.3 Previously, dupilumab was approved for use in children 12 years and older with AD. Safety and efficacy of dupilumab in adolescents with inadequately controlled AD was evaluated in a phase 3, placebo-controlled RCT that recruited 251 patients.15 Patients were randomized (1:1:1) to 16-week treatment with dupilumab 200 mg every 2 weeks (n = 43; baseline weight <60 kg), dupilumab 300 mg (n = 39; baseline weight ≥60 kg) every 2 weeks; dupilumab 300 mg every 4 weeks (n = 84), or placebo (n = 85).15 The primary outcome was the proportion of patients with 75% or more improvement from baseline in EASI-75 and Investigator's Global Assessment (IGA) score of 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16.15

The proportion of patients with EASI-75 improvement from baseline increased in patients treated with dupilumab (every 2 weeks (41.5%) and dupilumab every 4 weeks (38.1%) compared to placebo (8.2%). Absolute differences compared to placebo were 33.2% (95% CI, 21.1%-45.4%) and 29.9% (95% CI, 17.9%-41.8%) for 2 week and 4 week dosing regimens, respectively.15 Efficacy of the 2 week dosing regimen was generally superior to the 4 week dosing regimen.15 Patients in the dupilumab arms had higher percentage values of conjunctivitis (9.8% and 10.8% with 2 and 4 week dosing vs. 4.7% with placebo) and injection site reactions (8.5% and 6.0% with 2 and 4 week dosing vs. 3.5% with placebo), and lower risk of nonherpetic skin infections (9.8% and 9.6% with 2 and 4 week dosing vs. 18.8% with placebo).15

Author: Moretz October 2020 207

New FDA Safety Alerts: No new safety alerts have been published since the last class update.

References: 1. Chong LY, Piromchai P, Sharp S, et al. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2020;2(2):Cd013513. 2. Canadian Agency for Drugs and Technologies in Health (CADTH) Canadian Drug Expert Committee Recommendation. Dupliumab. https://www.cadth.ca/dupilumab-0. April 2020. Accessed June 2, 2020. 3. Dupixent® (dupilumab) Product Information. Tarrytown, NY: Regeneron Pharmaceuticals, Inc. May 2020. 4. Eucrisa (crisaborole) topical ointment Prescribing Information. New York, NY; Pfizer Labs. March 2020. 5. Health Evidence Review Commission. Searchable Prioritized List, Guideline Notes, Multisector Interventions and Services Recommended for Non-Coverage. Accessed May 12, 2020. 6. Hanna S, Zip C, Shear NH. What Is the Risk of Harm Associated With Topical Calcineurin Inhibitors? J Cutan Med Surg. 2019;23(4_suppl):19S-26S. 7. Wernham AGH, Veitch D, Grindlay DJC, Rogers NK, Harman KE. What's new in atopic eczema? An analysis of systematic reviews published in 2017. Part 1: treatment and prevention. Clin Exp Dermatol. 2019;44(8):861-867. 8. Solman L, Lloyd-Lavery A, Grindlay DJC, Rogers NK, Thomas KS, Harman KE. What's new in atopic eczema? An analysis of systematic reviews published in 2016. Part 1: treatment and prevention. Clin Exp Dermatol. 2019;44(4):363-369. 9. Hong CH, Gooderham M, Bissonnette R. Evidence Review of Topical Calcineurin Inhibitors for the Treatment of Adult Atopic Dermatitis. J Cutan Med Surg. 2019;23(4_suppl):5S-10S. 10. Seger EW, Wechter T, Strowd L, Feldman SR. Relative efficacy of systemic treatments for atopic dermatitis. J Am Acad Dermatol. 2019;80(2):411-416.e414. 11. Lee GR, Maarouf M, Hendricks AK, Lee DE, Shi VY. Current and emerging therapies for hand eczema. Dermatologic Therapy. 2019;32(3):e12840. 12. Menter A, Cordoro KM, Davis DMR, et al. Joint American Academy of Dermatology/National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis in pediatric patients. J Am Acad Dermatol. 2020;82(1):161-201. 13. Aoki V, Lorenzini D, Orfali RL, et al. Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology. An Bras Dermatol. 2019;94(2 Suppl 1):67-75. 14. Reda AM, Elgendi A, Ebraheem AI, et al. A practical algorithm for topical treatment of atopic dermatitis in the Middle East emphasizing the importance of sensitive skin areas. Journal of Dermatological Treatment. 2019;30(4):366-373. 15. Simpson EL, Paller AS, Siegfried EC, et al. Efficacy and Safety of Dupilumab in Adolescents With Uncontrolled Moderate to Severe Atopic Dermatitis: A Phase 3 Randomized Clinical Trial. JAMA dermatology. 2019;156(1):44-56.

Author: Moretz October 2020 208

Appendix 1: Current Preferred Drug List Generic Brand Route Form PDL pimecrolimus ELIDEL TOPICAL CREAM (G) Y pimecrolimus PIMECROLIMUS TOPICAL CREAM (G) Y tacrolimus PROTOPIC TOPICAL OINT. (G) Y tacrolimus TACROLIMUS TOPICAL OINT. (G) Y dupilumab DUPIXENT SUB-Q SYRINGE N crisaborole EUCRISA TOPICAL OINT. (G) N

Appendix 2: New Comparative Clinical Trials A total of 15 citations were manually reviewed from the initial literature search. After further review, all citations were excluded because of wrong study design (e.g., observational), comparator (e.g., no control or placebo-controlled), or outcome studied (e.g., non-clinical).

Appendix 3: Medline Search Strategy Ovid MEDLINE(R) without Revisions 1996 to May Week 3 2020, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations 1946 to May 20, 2020

1. Dermatitis, Atopic/ 13907 2. Eczema/ 3811 3. Psoriasis 35149 3. Calcineurin Inhibitors/ 3733 4. Pimecrolimus.mp. 902 5. Tacrolimus/ 13668 6. Crisaborole.mp. 97 7. Dupilumab.mp. 552 8. 1 or 2 or 3 36342 9. 4 or 5 or 6 or 7 or 8 16808 10. 8 and 9 1210 11. limit 10 to (english language and humans and yr="2019 -Current" and (clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative study or controlled clinical trial or meta-analysis or multicenter study or practice guideline or pragmatic clinical trial or randomized controlled trial or "systematic review")) 15

Author: Moretz October 2020 209

Appendix 4: Prior Authorization Criteria

Atopic Dermatitis and Topical Antipsoriatics Goal(s):  Restrict dermatological drugs only for funded OHP diagnoses. Moderate/severe psoriasis and moderate/severe atopic dermatitis treatments are funded on the OHP. Treatments for mild psoriasis, seborrheic dermatitis, keratoderma and other hypertrophic and atrophic conditions of skin are not funded.

Length of Authorization:  From 6 to 12 months

Requires PA:  Non-preferred antipsoriatics  All atopic dermatitis drugs  STC = 92 and HIC = L1A, L5F, L9D, T0A  This PA does not apply to biologics for psoriasis, or dupilumab which are subject to separate clinical PA criteria.

Covered Alternatives:  Preferred alternatives listed at www.orpdl.org/drugs/

Table 1. FDA-approved ages for atopic dermatitis drugs Drug Minimum Age Crisaborole 3 months Pimecrolimus 2 years Tacrolimus 0.3% 2 years Tacrolimus 0.1% 16 years

Approval Criteria

1. What diagnosis is being treated? Record ICD 10 code.

2. Is the diagnosis for seborrheic dermatitis, Yes: Pass to RPh; deny, not funded by No: Go to #3 keratoderma or other hypertrophic and atrophic the OHP. conditions of skin?

Author: Moretz October 2020 210

Approval Criteria

3. Is the request for treatment of severe inflammatory Yes: Go to #4 No: Pass to RPh; deny, not skin disease? funded by the OHP

Severe disease is defined as:1  Having functional impairment (e.g. inability to use hands or feet for activities of daily living, or significant facial involvement preventing normal social interaction) ANDand one or more of the following: 1. At least 10% body surface area involved or with functional impairment 2. Hand, foot or mucous membrane involvement

3.4. Is the diagnosis psoriasis? Yes: Go to #8 No: Go to #5

4.5. Is the diagnosis atopic dermatitis? Yes: Go to #6 No: Go to #10

5.6. Does the patient meet the age requirements per Yes: Go to #7 No: Pass to RPh. Deny; medical the FDA label (Table 1)? appropriateness

6.7. Does the patient have a documented Yes: Document drug and dates trialed, No: Pass to RPh. Deny; medical contraindication, intolerance or failed trials of at least and intolerances (if applicable): appropriateness 2 first line agents indicated for the treatment of 1.______(dates) moderate to severe AD (topical corticosteroids)?* 2.______(dates)

*Note pimecrolimus and crisaborole are FDA Approve for length of treatment; approved to manage mild to moderate AD, while maximum 6 months. tacrolimus is FDA approved to manage moderate to severe AD.

Author: Moretz October 2020 211

Approval Criteria

8. Is the requested product preferred? Yes: Approve for length of treatment; No: Go to #9 maximum 1 year.

9. Will the prescriber consider a change to a preferred Yes: Inform provider of preferred No: Approve for length of product? alternatives. treatment; maximum 1 year.

Message: Preferred products are evidence-based Approve for length of treatment; reviewed for comparative effectiveness & safety by maximum 1 year. the Pharmacy and Therapeutics (P&T) Committee.

10. RPH only: If funded, or clinic provides If not funded: Deny, not funded All other indications need to be evaluated as to whether supporting literature: Approve for 1 by the OHP. they are funded by the OHP.* year.

P&T/DUR Review: 10/20 (DM); 7/19 (DM); 5/19 (DM) 3/18 (DM); 9/17; 7/15; 1/15; 09/10; 9/09; 3/09; 5/07; 2/06 Implementation: TBD, 8/19/19; 4/16/18; 10/15; 8/15; 9/13; 6/12; 9/10; 1/10; 7/09; 6/07; 9/06

*The Health Evidence Review Commission has stipulated via Guideline Note 21 that mild, uncomplicated inflammatory skin conditions including psoriasis, atopic dermatitis, lichen planus, Darier disease, pityriasis rubra pilaris, and discoid lupus are not funded. Uncomplicated is defined as no functional impairment; and/or involving less than 10% of body surface area and no involvement of the hand, foot, or mucous membranes. References: 1. Oregon Health Evidence Review Commission. Coverage Guidance and Reports. http://www.oregon.gov/oha/hpa/csi-herc/pages/index.aspx Accessed June 2, 2020.

Dupilumab Goal(s): Author: Moretz October 2020 212

 Promote use that is consistent with national clinical practice guidelines and medical evidence.

Length of Authorization:  6 months

Requires PA:  Dupilumab (Dupixent) pharmacy and physician administered claims

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Table 1. Maximum Adult Doses for Inhaled Corticosteroids. High Dose Corticosteroids: Maximum Dose Qvar (beclomethasone) 320 mcg BID Pulmicort Flexhaler (budesonide) 720 mcg BID Alvesco (ciclesonide) 320 mcg BID Aerospan (flunisolide) 320 mcg BID Arnuity Ellipta (fluticasone furoate) 200 mcg daily Flovent HFA (fluticasone propionate) 880 mcg BID Flovent Diskus (fluticasone propionate) 1000 mcg BID Asmanex Twisthaler (mometasone) 440 mcg BID Asmanex HFA (mometasone) 400 mcg BID High Dose Corticosteroid / Long-acting Beta-agonists Maximum Dose Symbicort (budesonide/formoterol) 320/9 mcg BID Advair Diskus (fluticasone/salmeterol) 500/50 mcg BID Advair HFA (fluticasone/salmeterol) 460/42 mcg BID Breo Ellipta (fluticasone/vilanterol) 200/25 mcg daily Dulera (mometasone/formoterol) 400/10 mcg BID

Table 2. FDA-approved ages for dupilumab. Condition Minimum Age Asthma 12 years Atopic dermatitis 6 years Chronic rhinosinusitis with nasal polyposis 18 years

Author: Moretz October 2020 213

Approval Criteria

1. What diagnosis is being treated? Record ICD 10 code.

2. Is the diagnosis an OHP funded diagnosis? Yes: Go to #3 No: Pass to RPh. Deny, not funded by the OHP.

3. Is this a request for continuation of therapy? Yes: Go to Renewal Criteria No: Go to #4

4. Is the medication being prescribed by or in consultation with Yes: Go to # 5 No: Pass to RPh. Deny; a dermatologist, otolaryngologist, or allergist who medical appropriateness specializes in management of severe asthma?

5. Is the patient within FDA-approved age limits for the Yes: Go to #6 No: Pass to RPh. Deny; requested indication (Table 2)? medical appropriateness.

6. Is the diagnosis Moderate/Severe Atopic Dermatitis (AD)? Yes: Go to #7 No: Go to #8 Severe disease is defined as:1  Having functional impairment (e.g. inability to use hands or feet for activities of daily living, or significant facial involvement preventing normal social interaction) AND one or more of the following: 1. At least 10% body surface area involved or with functional impairment 2. Hand, foot or mucous membrane involvement

Author: Moretz October 2020 214

Approval Criteria

6.7. Does the patient have a documented contraindication or Yes: Document drug and dates No: Pass to RPh. Deny; failed trial of the following treatments: trialed and intolerances (if medical appropriateness applicable):  Moderate to high potency topical corticosteroid (e.g., 1.______(dates) 2.______(dates) clobetasol, desoximetasone, desonide, mometasone, 3.______(dates) betamethasone, halobetasol, fluticasone, or fluocinonide) AND Approve for length of treatment;  Topical calcineurin inhibitor (tacrolimus, pimecrolimus) maximum 6 months. or topical phosphodiesterase (PDE)-4 inhibitor (crisaborole) AND  Oral immunomodulator therapy (cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, or oral corticosteroids)?

7.8. Is the claim for moderate-to-severe asthma with an Yes: Go to # 9 No: Go to # 12 eosinophilic phenotype or with oral corticosteroid dependent asthma?

8.9. Is the patient currently receiving another monoclonal Yes: Pass to RPh. Deny; medical No: Go to #10 antibody for asthma (e.g., omalizumab, mepolizumab, appropriateness. benralizumab or reslizumab)?

9.10. Has the patient required at least 1 hospitalization or ≥ 2 Yes: Go to #11 No: Pass to RPh. Deny; ED visits in the past 12 months while receiving a maximally- medical appropriateness. dosed inhaled corticosteroid (Table 1) AND 2 additional Document number of hospitalizations or ED visits in past controller drugs (i.e., long-acting inhaled beta-agonist, 12 months: ______. This is the montelukast, zafirlukast, or tiotropiumtheophylline)? baseline value to compare to in renewal criteria.

Author: Moretz October 2020 215

Approval Criteria

10.11. Has the patient been adherent to current asthma Yes: Approve for 6 months No: Pass to RPh. Deny; therapy in the past 12 months? medical appropriateness.

11.12. Does the patient have chronic rhinosinusitis with nasal Yes: Go to # 13 No: Pass to RPh. Deny; polyposis? medical appropriateness.

12.13. Has the patient failed medical therapy with intranasal Yes: Approve for 6 months No: Pass to RPh. Deny; corticosteroids (2 or more courses administered for 12 to 26 medical appropriateness weeks1)?

Renewal Criteria

1. Is the request to renew dupilumab for atopic dermatitis? Yes: Go to #2 No: Go to #3

2. Have the patient’s symptoms improved with dupilumab Yes: Approve for 12 months No: Pass to RPh. Deny; therapy? medical appropriateness.  at least a 50% reduction in the Eczema Area and Severity Index score (EASI 50) from when treatment started OR  at least a 4‑point reduction in the Dermatology Life Quality Index (DLQI) from when treatment started OR  at least a 2 point improvement on the Investigators Global Assessment (IGA) score?

3. Is the request to renew dupilumab for moderate to severe Yes: Go to # 4 No: Go to # 6 asthma?

Author: Moretz October 2020 216

Renewal Criteria

4. Is the patient currently taking an inhaled corticosteroid and Yes: Go to #5 No: Pass to RPh. Deny; 2 additional controller drugs (i.e., long-acting inhaled beta- medical appropriateness. agonist, montelukast, zafirlukast, or tiotropium theophylline)?

5. Has the patient reduced their systemic corticosteroid dose Yes: Approve for up to 12 No: Pass to RPh. Deny; by ≥50% compared to baseline? months. medical appropriateness.

6. Have the patient’s symptoms of chronic rhinosinusitis with Yes: Approve for up to 12 No: Pass to RPh. Deny; polyposis improved? months medical appropriateness.

1. Chong LY, Head K, Hopkins C, Philpott C, Burton MJ, Schilder AG. Different types of intranasal steroids for chronic rhinosinusitis. Cochrane Database Syst Rev. 2016; 4:Cd011993.

P&T/DUR Review: 10/20 (DM), 11/19 (DM); 9/19; 7/19 Implementation: TBD, 1/1/2020; 8/19/19

1. Oregon Health Evidence Review Commission. Coverage Guidance and Reports. http://www.oregon.gov/oha/hpa/csi-herc/pages/index.aspx Accessed June 2, 2020

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-2596

OHSU Drug Effectiveness Review Project Summary Report – Targeted Immune Modulators for Autoimmune Conditions

Date of Review: October 2020 Date of Last Review: February 2020 Literature Search: 1/1/20 – 6/28/20

Current Status of PDL Class: See Appendix 1.

Purpose: New comparative evidence for existing biologics for autoimmune conditions will be reviewed as presented in 3 Drug Effectiveness Review Project (DERP) systematic reviews focused on safety and efficacy of targeted immune modulators (TIMS) to treat ankylosing spondylitis (AS), rheumatoid arthritis (RA), plaque psoriasis (PsO), psoriatic arthritis (PsA), Crohn’s disease (CD), and ulcerative colitis (UC).

Research Questions: 1. What is the comparative effectiveness of TIMs for alleviating symptoms and stabilizing disease in patients with RA, AS, PsO, PsA, CD and UC? 2. What are the comparative harms of TIMs when used to treat RA, AS, PsO, PsA, CD, and UC? 3. Do the included drugs differ in their effectiveness or harms in the following subgroups: age and racial groups, gender, patients with comorbidities, patients taking other commonly prescribed drugs, or in patients with early vs. established disease?

Conclusions: Targeted Immune Modulators for Rheumatoid Arthritis and Ankylosing Spondylitis  Most comparisons for the safety and efficacy of TIMs in RA are limited to single trials. 1 Moderate- or high-quality of evidence (QoE) indicates that baricitinib, sarilumab, and upadacitinib are more effective than adalimumab as first-line treatments for RA.1 In a fair-quality, multi-center, double-blind randomized clinical trial (RCT) comparing adalimimumab with baricitinib (n=1,305), adalimumab was less effective than baricitinib for achieving response American College of Rheumatology (ACR) response (ACR20, 61% vs. 70%; P=0.01) and improvements in functional capacity (Health Assessment Questionnaire- Disability Index [HAQ-DI] of ≥ 0.22, 58% vs. 68%; P<0.01; high QoE at 52 weeks).1 In a fair-quality head-to-head comparison of adalimumab versus sarilumab (n=369), adalimumab was less effective than sarilumab for achieving response (ACR50, 30% vs. 46%; P=0.002) and improvements in functional capacity (HAQ-DI, −0.43 vs. −0.61; p<0.005) at 24 weeks (moderate QoE).1 When adalimumab was compared to upadacitinib in a fair-quality, double-blinded RCT (n=1,629), adalimumab was less effective than upadacitinib for achieving response (ACR50, 29% vs. 45%; P<0.001), remission (28 joint Disease Activity Score [DAS-28] <2.6, 18% vs. 21%; P<0.001), and improvements in functional capacity (HAQ-DI, −0.49 vs. −0.60; P<0.01) at 12 weeks (high QoE for response and remission).1  Moderate QoE shows abatacept is more effective than secukinumab as a second-line treatment for RA.1 In a fair quality, multi-center, double-blind RCT comparing abatacept versus secukinumab (n=551), abatacept was more effective than secukinumab 150 mg or secukinumab 75 mg for achieving response

Author: Deanna Moretz, PharmD, BCPS 218

(ACR50, 28% vs. 17% vs. 12%; P-value NR) and improved functional capacity (HAQ-DI, −0.6 vs. −0.4 vs. −0.3; P-value NR) at 24 weeks (moderate QoE for clinical improvement).1  One head-to-head trial provided evidence for comparative effectiveness of TIMs in AS.1 In this trial, etanercept was less effective for clinical improvement than infliximab at 12 weeks based on the Bath Ankylosing Spondylitis Disease Activity Index [BASDI] (5.9 vs. 4.8; P<0.005; very low QoE).1  Data published in 8 trials show 2 pipeline oral Janus kinase (JAK) inhibitors (filgotinib and peficitinib), have superior efficacy compared to placebo in treating RA.1 In a phase 3 randomized controlled trial (RCT), filgotinib was more effective than placebo at 12 weeks for achieving response to therapy (ACR 20, 66% vs. 31%; p<0.001) and disease remission DAS28-Erythrocyte Sedimentation Rate (ESR), 31% vs. 12%; p<0.001; high QoE for both outcomes).1 Another phase 3 RCT showed that at 12 weeks, peficitinib was more efficacious than placebo for achieving response in patients with moderate-to-severe RA (ACR20, 64% vs. 22%; P<0.001) and remission (DAS28-ESR < 2.6, 35% vs. 8%; p<0.001) at 12 weeks (moderate QoE for both outcomes).1  One fair-quality RCT demonstrated the superior efficacy of filgotinib over placebo for the treatment of AS.1 Participants treated with filgotinib improved based on the Ankylosing Spondylitis Disease Activity Score (ASDAS) compared to placebo (−1.47 vs.−0.57; difference between groups, -0.85; 95% Confidence Interval [CI]-1.17 to -0.53; P<0.001; moderate QoE).1  High- and moderate- QoE has shown no difference in the incidence of overall adverse effects (AEs) and serious adverse effects (SAEs) with TIMs used to manage RA or AS.1 Most observational studies reported no significant differences in mortality, malignancies, cardiovascular events or congestive heart failure between TIMs.1 However, in most studies, infliximab was associated with a higher incidence of serious infections than other TIM agents. 1 Some studies also showed a higher incidence of opportunistic infections, tuberculosis, and varicella zoster infections with infliximab than with other tumor necrosis factor (TNF)-inhibitors.1 Two observational studies reported a higher incidence of gastrointestinal perforations with tocilizumab than with TNF- inhibitors.1  The combination of TNF-inhibitors with a TIM of a different mechanism of action substantially increased the frequency of SAEs. 1 For example, the combination of etanercept with abatacept or anakinra resulted in more SAEs compared to etanercept monotherapy (11% vs. 3%; RR, 5.93; 95% CI, 0.81 to 43.42; moderate QoE).1 Abatacept plus another TIM (adalimumab, anakinra, etanercept, or infliximab) resulted in more SAEs compared to another TIM alone (22% vs. 13%; RR, 1.79; 95% CI, 0.85 to 3.75; low QoE).1 Targeted Immune Modulators for Plaque Psoriasis and Psoriatic Arthritis  The largest body of comparative evidence for PsO with TIM agents is for etanercept and ustekinumab.2 For disease remission outcomes, high QoE shows that etanercept is less effective than ixekizumab, secukinumab, and tildrakizumab.2 Two fair-quality RCTs: UNCOVER-2 (n=1,224) and UNCOVER-3 (n=1,346) compared etanercept to ixekizumab and found etanercept was less effective than ixekizumab for achieving disease remission at 12 weeks (Psoriasis Area and Severity Index [PASI] 75: Absolute Risk Differences [ARDs], 31% to 48% for both RCTs; P-value not reported (NR); high QoE).2 In a fair-quality head to head RCT comparing etanercept to secukinumab (n=1,306), etanercept was less effective than secukinumab for achieving disease remission at 12 weeks (PASI 75: 44% vs. 77% for 300 mg secukinumab; P<0.001 and 44% vs. 67% for 150 mg secukinumab; P<0.001; high QoE). 2 In a fair-quality RCT comparing etanercept versus tildrakizumab (n=934), etanercept was less effective than tildrakizumab for disease remission at 12 weeks (PASI 75: 48% vs. 66% for 200 mg tildrakizumab; P=0.001 and 48% vs. 61% for 100 mg tildrakizumab; P<0.001; high QoE ). 2  High QoE also shows that ustekinumab is less effective than brodalumab and risankizumab; moderate QoE shows it may also be less effective than ixekizumab for disease remission outcomes.2 High QoE shows that adalimumab is less effective than guselkumab and moderate QoE suggests that it is also less effective than risankizumab.2 Moderate QoE suggests that guselkumab is more effective than secukinumab for maintenance therapy. 2  Few differences in harms among TIM agents were observed in patients with PsO, based on moderate-to-low QoE.2  Limited head-to-head comparisons of TIMs for PsA are available to evaluate comparative efficacy and harm.2 Based on low QoE, ixekizumab, tofacitinib, and remtolumab may be more effective than adalimumab with no difference in harms.2

Author: Moretz October 2020 219

Targeted Immune Modulators for Crohn’s Disease and Ulcerative Colitis  Limited evidence exists for the comparative effectiveness of TIM agents for the treatment of CD. 3 The QoE was previously rated as very low for the comparative effectiveness of adalimumab and infliximab (data from 2 RCTs showed no significant differences in QoL or clinical improvement between the 2 drugs), and no new RCTs were identified that evaluated comparative effectiveness of these agents.3  One new RCT evaluated the comparative effectiveness and harms of TIMs for UC. 3 Authors of this study reported greater efficacy and no statistically significant differences in harms for vedolizumab compared to adalimumab.3 At 1 year, more participants randomized to vedolizumab achieved clinical remission compared to participants on adalimumab (31% vs. 23%; absolute risk difference [ARD], 9%; 95% CI 3% to 15%; Number Needed to Treat ([NNT] 12) and endoscopic remission (40% vs. 28%; ARD, 12%; 95% CI 5% to 19%; all results, P<0.05; moderate quality QoE).3  One new cohort study evaluating the comparative harms of adalimumab and infliximab was recently published, but indirectness and imprecision of the data provide very low QoE to compare harms.3 No new cohort studies compared harms between adalimumab and other agents (infliximab, etanercept, certolizumab pegol); thus, the QoE on comparative harms for these agents remains very low.3 Targeted Immune Modulators Summary Conclusions  No studies were identified that evaluated differences in TIM effectiveness and harms in RA, AS, PsO, PsA, CD, or UC based on specific demographic characteristics, such as age, race, gender, comorbidities, or concomitant drugs.1-3  Expanded indications were recently approved by Food and Drug Administration (FDA) for the following medications: o secukinumab for adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation; o canakinumab for treatment of active Still’s disease; o guselkumab to treat adults with active PsA; o ixekizumab for adults with nr-axSpA and objective signs of inflammation; and o ixekizumab for pediatric patients with PsO aged 6 years and older who are candidates for systemic therapy or phototherapy

Recommendations:  After clinical review, no changes to the Preferred Drug List (PDL) are recommended.  Modify PA criteria to reflect updated indications for the TIM agents as noted above.  Evaluate costs in executive session.

Summary of Prior Reviews and Current Policy Targeted Immune Modulators (aka, biologic medications) were last reviewed by the Pharmacy and Therapeutics (P & T) Committee at the February 2020 meeting. At that time, upadacitinib and risankisumab-rzaa were added to the prior authorization (PA) criteria. Adalimumab,etanercept, and secukinumab are preferred medications on the PDL (see Appendix 1 for PDL status of all biologics). All preferred and nonpreferred TIMs require PA to ensure appropriate utilization. Current clinical PA criteria are outlined in Appendix 2.

OHP FFS Utilization: In the second quarter of 2020, there were approximately 152 pharmacy claims for biologic agents in the fee-for-service (FFS) population. Eighty-four percent of the claims were for the preferred agents secukinumab, etanercept and adalimumab. For the non-preferred agents, 4-5% of claims were for certolizumab pegol and ixekizumab, and 1-2% of claims were for tofacitinib, tocilizumab, natalizumab, and vedolizumab. There were no pharmacy claims for brodalumab, canakinumab, guselkumab, ustekinumab, tildrakizumab, sarilumab, risankizumab, or baricitinib. The most frequent utilizaiton for biologic drugs that are physician administered include: infliximab, vedolizumab, abatacept, golimumab, ustekinumab, rituximab and natalizumab. Author: Moretz October 2020 220

Background: Ankylosing Spondylitis and Rheumatoid Arthritis Ankylosing spondylitis is a chronic rheumatic disorder that primarily affects the sacroiliac joints and spine. 4 Diagnosis is based on radiologic confirmation of sacroiliitis and the presence of at least one clinical symptom: low back pain for at least 3 months, limited lumbar spine motion, or decreased chest expansion for age and sex.5 Patients who have chronic pain and other features suggestive of spondyloarthritis (SpA) without radiologic changes are classified as having nr-axSpA.6 Guidelines for management of AS were updated in 2019 by the ACR in conjunction with the Spondylitis Association of America (SAA).7 The Assessments in Ankylosing Spondylitis International Society (ASAS) and European League against Rheumatism (EULAR) recommendations were last updated in 2016.8 Nonsteroidal anti-inflammatory drugs (NSAIDs) and exercise are recommended as first-line therapies to alleviate pain and stiffness.7,8 Tumor necrosis factor inhibitors are recommended for patients with persistent disease activity despite conventional treatment. 7,8 All 5 TNF-inhibitors are proven to provide sustained improvement in disease activity and patient functioning as assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDI) and Functional Index (BASFI) scores.8 Two anti–interleukin monoclonal antibodies, secukinumab and ixekizumab, have also demonstrated efficacy in treating AS.7 However, the ACR/SAA guidance recommends a TNF-inhibitor as the first biologic for use after NSAID therapy over secukinumab or ixekizumab.7 Co-administration of low-dose methotrexate (MTX) with a TNF-inhibitor is not recommended for AS management.7 There is no evidence for the efficacy of systemic glucocorticoids or disease- modifying antirheumatic drugs (DMARDs) in the treatment of AS.8

The BASDI includes 6 different 10-centimeter visual analog scales (VAS) to measure the severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness (both qualitative and quantitative).1 The scale is scored on a scale from 0 to 10, with lower scores indicating less pain and tenderness. 1 The BASFI is a tool used to assess functional ability in AS patients. The score ranges from 0 to 10, with lower scores indicating better function.1 An additional instrument used to measure AS disease activity is the ASDAS. The ASDAS categorizes the disease activity as inactive, low, high, or very high.9 A change of 1.1 or greater in the ASDAS score is considered a significant improvement, while a change of 2.0 or greater is a major improvement.9

The hallmarks of RA are inflammation of the synovial tissues with progressive erosion of bone leading to malalignment of the joint and, in most cases, disability.10 Tumor necrosis factor plays a central role in the pathophysiology of RA.10 The 2015 ACR11 and 2016 EULAR12 recommendations suggest RA treatment begin with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) such as MTX as soon as diagnosis of RA is established. Other csDMARDs recommended to treat RA include sulfasalazine, hydroxychloroquine, and leflunomide.11,12 Biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) are recommended for patients with a suboptimal response or intolerance to csDMARDs.11,12 Biologic DMARDs are proteins that must be administered parentally. Targeted synthetic DMARDs are small chemical molecules that can be given orally. Monotherapy with bDMARDs or tsDMARDs or combination therapy that includes MTX can be initiated as second-line therapy, depending on the patient’s response to previous therapy and any pertinent comorbidities.11,12 Table 1 summarizes the different TIMs FDA-approved for management of RA and AS. FDA-approved biosimilars are available for adalimumab, etanercept, and infliximab.

Author: Moretz October 2020 221

Table 1. FDA-Approved Targeted Immune Modulators for Rheumatoid Arthritis and Ankylosing Spondylitis13,14 Drug - Route of Administration Molecular Target Approved Indication Warnings Biologic DMARDs Adalimumab - SC TNF AS and RA Infections, reactivation of TB, psoriasiform skin changes, exacerbation of (HUMIRA) demyelinating diseases, drug-induced lupus, non-melanoma skin cancer, injection site Certolizumab Pegol - SC or infusion reactions (CIMZIA) Etanercept - SC (ENBREL) Golimumab - IV or SC (SIMPONI and SIMPONI ARIA) Infliximab - IV (REMICADE) Sarilumab - SC IL-6 RA Infections, reactivation of TB, bowel perforation, hypersensitivity reactions, (KEVZARA) neutropenia, injection site reactions, hyperlipidemia Tocilizumab – IV or SC (ACTEMRA) Ixekizumab - SC IL-17 AS Can worsen Crohn’s disease and ulcerative colitis (TALTZ) Secukinumab – IV or SC (COSENTYX) Anakinra - SC IL-1 RA Infections, injection site pain (KINERET) Rituximab - IV B-lymphocyte RA Hypersensitivity reactions, reactivation of hepatitis B, leukocytopenia, PML, tumor (RITUXAN) lysis syndrome, worsening heart failure Abatacept) - IV or SC T-lymphocyte RA Infections, reactivation of TB, leukocytopenia, injection site reactions (ORENCIA) Targeted Synthetic DMARDs Tofacitinib - PO JAK 1,2,3 RA Infections, reactivation of TB, thrombosis, malignancies (XELJANZ) Baricitinib - PO JAK 1,2 (OLUMIANT) Upadacitinib - PO JAK 1 (RINVOQ) Abbreviations: AS=ankylosing spondylitis; CPK=creatine phosphokinase; DMARD=Disease-Modifying Antirheumatic Drug; FDA=Food and Drug Administration; IL=interleukin; IV=intravenous; JAK=Janus Kinase; LFT=liver function test; PML = progressive multifocal leukoencephalopathy; PO=oral; RA=rheumatoid arthritis; SC= subcutaneous; TB=tuberculosis; TNF=tumor necrosis factor

Author: Moretz October 2020 222

Primary endpoints used in RA clinical trials include the ACR response, the HAQ-DI, and the DAS-28. The ACR response score is a composite endpoint with 7 domains used to calculate the proportion of patients achieving a target percentage of improvement from baseline and is a considered a measure of efficacy and overall disease activity.15 Patients are said to meet ACR20 criteria when they have at least 20% reductions in tender joint counts, 20% reduction swollen joint counts and 20% improvement in at least 3 of the 5 remaining domains.15 The additional 5 domains include patient global assessment of arthritis on a visual analog scale (VAS), physician global assessment of arthritis on a VAS, patient assessment of pain on a VAS, patient assessment of physical functioning (e.g., health assessment questionnaire), and acute phase reactant (ESR or c-reactive protein [CRP]). ACR50 and ACR70 criteria are similar, but with improvement of at least 50% and 70% in ACR criteria.15 ACR50 and ACR70 are considered more clinically significant than ACR20.15 The HAQ-DI is a widely used self-reported measure of functional capacity. Scores of 0 to 1 are generally considered to represent mild to moderate disability, 1 to 2 moderate to severe disability, and 2 to 3 severe to very severe disability.16 The minimal clinically important difference (MCID) of an improvement on the HAQ-DI is a change of at least 0.20 from baseline.17 The DAS-28 is another index of disease activity (similar to the ACR response). The DAS is a continuous composite outcome that consists of: the number of painful joints (Ritchie Articular Index, 0-78 joints), 44-joint count for swollen joints, ESR and patient global assessment of disease activity or general health using a VAS.17 A DAS-28 score greater than 5.1 corresponds to high disease activity and less than 3.2 of low disease activity. A DAS-28 score of 2.6 is considered to correspond to remission.18

Plaque Psoriasis and Psoriatic Arthritis Plaque psoriasis is a chronic, immune-mediated inflammatory disorder of the skin, scalp and joints that affects about 2 to 3% of the population. Psoriatic arthritis is a chronic inflammatory arthritis associated with psoriasis that can affect any joint in the body. 19 In all cases, symptoms include pain and stiffness in the affected joint as well as joint-line tenderness, swelling, and sometimes loss of range of motion. Typically, PsO is classified as mild, moderate or severe. Mild disease involves less than 5% of the body surface area and has little to no impact on quality of life or function. Mild PsO is not a funded condition per the Health Evidence Review Commission (HERC) Guideline Note 57.20 Per 2017 National Institute for Health and Care Excellence (NICE) guidance, first-line agents for PsO include: topical medications including corticosteroids, vitamin D analogs (e.g., calcipotriene), retinoids (e.g., tazarotene) or calcineurin inhibitors (e.g., tacrolimus or pimecrolimus).21 Phototherapy is an option for patients with moderate-to-severe PsO who have not responded to topical therapy.21 Systemic non-biologic treatments are recommended for patients with moderate-to-severe PsO unresponsive to topical or phototherapy and include MTX, cyclosporine, or acitretin. 21 Biologics may be added for patients with moderate-to-severe PsO not controlled by other therapies.21 The first line of treatment for PsA is nonsteroidal anti- inflammatory drugs (NSAIDs), although in most cases DMARDs are necessary. The TIMS that are FDA-approved to treat PsO and PsA are presented in Table 2.

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Table 2. FDA-Approved Targeted Immune Modulators for Plaque Psoriasis and Psoriatic Arthritis13,14 Drug – Route of Administration Molecular Target Approved Approved Age Range Warnings Indication(s) for PsO Adalimumab - SC TNF PsA and PsO Adults Infections, reactivation of TB, psoriasiform skin (HUMIRA) changes, exacerbation of demyelinating diseases, Etanercept - SC Patients ≥ 4 years of age drug-induced lupus, non-melanoma skin cancer, (ENBREL) injection site or infusion reactions Infliximab - IV Adults (REMICADE) Certolizumab Pegol - SC Adults (CIMZIA) Golimumab PsA Adults (SIMPONI) Ustekinumab - SC IL-12 and IL-23 PSA and PsO Patients ≥ 12 years of age Infections, malignancies (STELARA) Secukinumab - SC IL-17 PsA and PsO Adults Can worsen Crohn’s disease and ulcerative colitis, (COSYNTEX) infections Ixekizumab - SC Patients ≥ 6 years of age (TALTZ) Brodalumab - SC PsO Adults REMS program for suicide ideation, infections, can (SILIQ) exacerbate Crohn’s disease and ulcerative colitis Guselkumab - SC IL-23 PsA and PsO Adults Upper respiratory infections, tinea infections, and (TREMFYA) herpes simplex infections Tildrakizumab - SC PsO (ILUMYA) Risankizumab-rzaa - SC (SKYRIZI) Apremilast - PO PDE-4 PsA and PsO Adults Worsening depression (OTEZLA) Tofacitinib - PO JAK PsA Adults Infections, reactivation of TB, thrombosis, (XELJANZ) malignancies Abatacept – IV or SC T-lymphocyte PsA Adults Infections, reactivation of TB, leukocytopenia, (ORENCIA) injection site reactions Abbreviations: FDA=Food and Drug Administration; IL=interleukin; IV= intravenous; JAK= Janus Kinase; PASI=Psoriasis Area and Severity Index; PDE=phosphodiesterase; PO=oral; PsA=psoriatic arthritis; PsO=plaque psoriasis; REMS=Risk Evaluation and Mitigation Strategy; SC=subcutaneous; TNF=tumor necrosis factor

Several tools have been developed to evaluate symptom improvement and quality of life in patients with psoriasis. In clinical trials, symptom improvement is often evaluated using the Psoriasis Area and Severity Index (PASI), the static Physician’s Global Assessment scale (sPGA), or the Psoriasis Symptom Inventory (PSI). There is no consensus on the most reliable scale, but the PASI is used most often in clinical trials and is considered the most validated scale.22 The PASI

Author: Moretz October 2020 224 ranges from 0 to 72 points and evaluates body surface area involvement, induration, scaling, and erythema. Because the PASI only evaluates skin involvement on the trunk, head, arms and legs, the PASI has limited sensitivity in patients with mild to moderate disease or limited BSA involvement. 22,23 It does not consider symptoms affecting hands, feet, face or genitals. Because the PASI scale is not linear, small changes in BSA involvement can result in a significant improvement of the overall score without change in other symptoms.22 In addition, though the PASI evaluates symptoms on a range of 0 to 72 points, in clinical practice, patients often do not have scores greater than 40.23 The most commonly reported outcome in clinical trials is improvement of greater than 75% in the PASI score. However, an improvement of 100%, indicating complete disease clearance, is considered more clinically significant.23 The sPGA is another physician- reported symptom severity scale which evaluates symptom severity at a single point in time with higher scores indicating more severe disease (range 0 to 5). Responders to therapy are typically defined as patients with a sPGA score of 0 or 1, corresponding to clear or almost clear skin or patients with an improvement of at least 2 points. In clinical trials of patients with moderate to severe disease, the proportion of patients with a sPGA score of 0 or 1 has a strong correlation with a 75% improvement in PASI.23 Finally, the PSI evaluates patient-reported rather than physician-assessed symptoms. Eight individual symptoms in the prior 24 hours are assessed, including itching, redness, scaling, burning, stinging, cracking, flaking and pain.23 Individual symptoms are rated from 0 to 4 with total scores ranging from 0 to 32 points.23 Patients with total scores of 8 or less with no single item rated greater than 1 are generally considered responders to therapy. An additional tool used to assess QoL is the DLQI. Scores on the DLQI range from 0 to 30; a score of 0 or 1 indicates no effect of psoriasis on QoL.2

Crohn’s Disease and Ulcerative Colitis Crohn’s disease and UC are classified as inflammatory bowel diseases. Crohn’s disease is characterized by inflammation involving the full thickness of the bowel wall at any point from mouth to anus, whereas UC is characterized by mucosal ulceration limited to the colon and rectum.19 Clinical diagnosis of both conditions is most accurately made with colonoscopy.19 The Crohn’s Disease Activity Score (CDAI) is an evaluation of 8 clinical factors, including number of soft stools per day, abdominal pain, general well-being, use of medications for diarrhea, presence of abdominal mass, hematocrit, and percentage deviation from standard weight. A total score of 450 or greater indicates extremely severe disease, a score of 150 or greater indicates active disease, and a score less than 150 indicates minimal disease.24 Practice guidelines for CD recommend taking into account the disease location, severity, complications, and extra intestinal manifestations when choosing a treatment strategy.24,25 Treatment is largely directed at symptom relief rather than cure, and active treatment of acute disease (inducing remission) should be distinguished from preventing relapse (maintaining remission). 24 The National (NICE) guidelines recommend TNF-inhibitors for induction, but only after failure of conventional therapy with corticosteroids, aminosalicylates (i.e., sulfasalazine, mesalamine), azathioprine or mercaptopurine, and should only be used for maintenance if there is clear evidence of active disease.25 The American College of Gastroenterology (ACG) strongly recommends induction with a TNF-inhibitor to maintain remission in patients who have moderate-to-severe CD despite standard therapies.24 Cyclosporine, mycophenolate mofetil, and tacrolimus should not be used to treat CD due to insufficient evidence demonstrating efficacy. 24 The IL-23 inhibitor risankizumab is currently being evaluated in clinical trials for safety and efficacy in CD and UC.16 The JAK inhibitor upadacitinib is also being studied for use in CD and UC.3

The ACG26 and the NICE27 guidelines recommend the use of TIMs for treating moderately to severely active UC in adults whose disease has responded inadequately to, or have intolerance or contraindications to conventional therapy including aminosalicylates, corticosteroids, azathioprine or mercaptopurine. Continuation of these agents is only recommended if there is clear evidence of response.26 Table 3 presents the TIMs that are FDA-approved to treat CD and UC.

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Table 3. FDA-Approved Targeted Immune Modulators for Crohn’s Disease and Ulcerative Colitis13,14 Drug – Route of Administration Molecular Target Approved Warnings Indication(s) Adalimumab - SC TNF CD and UC Infections, Malignancies including Lymphoma (HUMIRA) Infliximab - IV CD and UC (REMICADE) Certolizumab Pegol - SC CD (CIMZIA) Golimumab UC (SIMPONI) Ustekinumab - IV (initial dose) IL-12 and IL-23 CD Infections, malignancies followed by SC (STELARA) Tofacitinib - PO JAK UC Infections, reactivation of TB, thrombosis, (XELJANZ) malignancies Vedolizumab – IV Integrin receptor CD and UC Infections, PML (ENTYVIO) Natalizumab – IV CD Infections, liver injury, PML, thrombocytopenia (TYSABRI) Abbreviations: CD=Crohn’s Disease; FDA=Food and Drug Administration; IL=interleukin; IV=intravenous; JAK= Janus Kinase; PASI=Psoriasis Area and Severity Index; PDE=phosphodiesterase; PML=progressive multifocal encephalopathy; PO=oral; REMS=Risk Evaluation and Mitigation Strategy; SC=subcutaneous; TNF=tumor necrosis factor; UC=Ulcerative Colitis

Methods: The May 2020 drug class summary report on TIMS by DERP at the Center for Evidence Based Policy at the Oregon Health & Science University (OHSU) was used to inform recommendations for this drug class.19 The DERP report summarizes findings from 3 systematic reviews recently completed by DERP. The reviews evaluated the use of TIM agents for: RA and AS;1 PsO and PsA;2 and CD and UC.3

The original report is available to Oregon Pharmacy and Therapeutics Committee members upon request. An executive summary report is publicly available in the agenda packet and on the DURM website.

The searches for standard DERP evidence sources were completed by late August or early September 2019, based on the specific systematic review.19 Randomized controlled trials of at least 12 weeks’ duration, conducted among persons with the clinical conditions of interest were included in the systematic reviews.19 In addition, cohort studies with a sample size of at least 1,000 for the key question about harms. 19 Selected studies had to report health outcomes (e.g., clinical improvement, quality of life or harms).19 Most studies were assessed as fair methodological quality because of extensive manufacturer involvement in study design, execution, and reporting.19 A few studies were evaluated as poor methodological quality for having other relevant biases. 19 Poor-

Author: Moretz October 2020 226 quality trials with very low quality evidence are excluded from the report. Efficacy was evaluated via quality of life assessments, functional capacity, clinical improvement, and disease remission. Harms were assessed through overall AEs, withdrawals due to AEs, SAEs, specific AEs (i.e. serious infectious disease) and mortality. The DERP authors calculated absolute risk differences (ARD), risk ratios (RR), incident rate ratios (IRR), and associated 95% confidence intervals (CI) based on data provided in the study when these values were not reported by the original study authors.19

Of note, the DERP reviews did not include RCTs shorter than 12 weeks in duration, cohort studies with fewer than 1,000 participants, or studies published in languages other than English.19 Only studies published in the peer-reviewed literature were included; data presented in press releases or conference abstracts was not used.19 The current review represents a cumulative synthesis of the evidence; thus, studies included in the prior DERP review on this topic were carried forward into the update if they continued to meet eligibility criteria, but data from these studies were not rechecked against the original sources for accuracy.19 Furthermore, DERP authors did not reevaluate the methodological study quality for the previously included studies, except for RCTs that were previously assessed as good quality.19 The authors reassessed these good-quality RCTs to determine the influence of manufacturer involvement on study design and execution, consistent with current DERP methodology.19 Lastly, the previous report used a modified Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach whereby the lowest quality rating was termed insufficient; the authors converted all previous insufficient quality of evidence ratings to very low for consistency with current GRADE methods.19

1. Targeted Immune Modulators for Rheumatoid Arthritis and Ankylosing Spondylitis Comparative RCTs and cohort studies that evaluated the effectiveness and harms of TIM agents approved for the treatment of moderate-to-severe RA and AS were identified.1 The literature search was conducted through September 2019.1 Twenty-three new studies were identified in addition to 53 studies from the previous DERP review, for a total of 76 eligible studies in this update.1 All RCTs except one, and all cohort studies except 2, evaluated TIM agents in patients with RA.1 One RCT evaluated TIM agents for AS; 2 cohort studies assessed TIMs in a mixed population that included participants with RA and AS.1

Of the 76 eligible studies, 35 were RCTs and 41 were cohort studies.1 Among the 35 RCTs, 6 studies were assessed as poor quality; the others were rated as fair quality.1 Among the 41 cohort studies, 5 studies were of poor methodological quality, 11 studies were of good methodological quality, and the rest were rated as fair quality.1 Outcomes selected for GRADE ratings ranged from very low to high QoE, but most outcomes were rated very low.1 Generally, outcomes were downgraded for study limitations and imprecision (i.e., wide CI because of small sample size).1 For the statistical data analysis, p-values and 95% CI are reported if available.

A. Comparative Effectiveness of Targeted Immune Modulators First-Line Targeted Immune Modulators for Rheumatoid Arthritis The evidence for the comparative effectiveness of TIM agents includes data for 12 comparisons of TIMs as first-line treatments for the treatment of RA.1 Most comparisons are limited to single RCTs.1 Fifteen RCTs provided evidence for 11 different head-to-head TIM comparisons and 2 comparisons of combination treatments with monotherapy when used to treat RA.1 All studies enrolled participants with moderate-to-severe RA despite treatment with DMARDs.1 1 poor- quality, open-label RCT is excluded from this summary.  Abatacept vs. Adalimumab (1 fair-quality, open-label, noninferiority RCT; n=646): No differences were observed between treatment groups in response (ACR 50 45% vs. 57%; P-value not reported [NR), remission (ACR70, 29% vs. 26%; P-value NR), or improvements in functional capacity (HAQ-DI) at 48 weeks (low QoE for response and remission).1

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 Abatacept vs. Infliximab (1 fair-quality, double-blind RCT; n=431): No significant differences were noted between groups in response (ACR50, 40% vs. 37%; P-value NR), remission (ACR70, 21% vs. 24%; P-value NR), or improvements in functional capacity (HAQ-DI) at 24 weeks (low QoE for response and remission).1  Adalimumab vs. Baricitinib (1 fair-quality, multi-center, double-blind RCT; n=1,305): Adalimumab was less effective than baricitinib for achieving response (ACR20, 61% vs. 70%; P=0.01) and improvements in functional capacity (HAQ-DI of ≥ 0.22, 58% vs. 68%; P<0.01; high QoE) at 52 weeks.1 No differences in remission were detected (Simplified Disease Activity Index [SDAI] < 3.3; low QoE).1  Adalimumab vs. Certolizumab Pegol (1 fair-quality RCT; n=915): No differences between groups in response (ACR20, 71% vs. 69%; P=0.47) and remission (ACR70; data NR) at 12 weeks were found (high QoE for response; data NR for remission).1  Adalimumab vs. Etanercept (1 fair-quality, open-label, 24-week RCT [n=64]): After 24 weeks, participants in the adalimumab and the etanercept groups had similar improvements on the HAQ-DI score (0.69 vs. 0.68; P value NR) and the DAS28-ESR (−2.12 vs. −2.84; P value NR).1  Adalimumab vs. Sarilumab (1 fair-quality, double-blinded RCT; n=369): Adalimumab was less effective than sarilumab for achieving response (ACR50, 30% vs. 46%; P=0.002), remission (Clinical Disease Activity Index: 3% vs. 7%; P=0.47), improvements in functional capacity (HAQ-DI, −0.43 vs. −0.61; p<0.005), and quality of life (QoL) (SF-36, 6.09 vs. 8.75; P<0.001) at 24 weeks (moderate QoE for QoL and response; low QoE for remission).1  Adalimumab vs. Tocilizumab (1 fair-quality, double-blind RCT [n=326] and 1 fair-quality, open-label RCT [n=43]): In the larger trial, adalimumab was less effective than tocilizumab for achieving response (ACR50, 28% vs. 47%; P<0.001) and remission (ACR70, 18% vs. 33%; P=0.002) at 24 weeks.1 No differences in QoL (SF-36) at 24 weeks were reported (low QoE for response, remission, and QoL).1 Results of the small, open-label RCT showed no difference in ACR50 between participants treated with adalimumab or tocilizumab.1 In both trials, tocilizumab was used at a higher dose than is FDA- approved (8 mg intravenous (IV) or subcutaneous (SC) once monthly), which makes dosing equivalence to adalimumab 20 to 40mg SC every 2 weeks questionable.1  Adalimumab vs. Tofacitinib (1 fair-quality, double-blinded, noninferiority, 52-week RCT [n=1,146], 1 fair-quality, double-blind, 24-week RCT [n=717] and 1 fair-quality, 12-week, dose-ranging study [n=384]): No difference between groups in response (ACR50, 44% vs. 46% P value NR) was reported in the noninferiority trial (high QoE for response).1 In the RCT with 717 participants, one tofacitinib arm was dosed at 10 mg orally twice daily, a higher dose than is FDA-approved.1 In this trial, similar ACR20 response rates were observed in all 3 treatment groups (adalimumab, 47%; tofacitinib 5 mg, 52%; tofacitinib 10 mg, 53%; P-value NR; high QoE for remission).1 The dose-ranging study reported lower ACR20 response rates after 12 weeks of treatment for participants treated with adalimumab than for those on tofacitinib 5 mg or 10 mg (36% vs. 59% vs. 71%; P-value NR; high QoE for response).1  Adalimumab vs. Upadacitinib (1 fair-quality, double-blinded RCT; n=1,629): Adalimumab was less effective than upadacitinib for achieving response (ACR50, 29% vs. 45%; P<0.001), remission (DAS28<2.6, 18% vs. 21%; P<0.001), and improvements in functional capacity (HAQ-DI, −0.49 vs. −0.60; P<0.01) at 12 weeks (high QoE for response and remission).1  Etanercept vs. Infliximab (1 fair-quality, open-label RCT; n=32): Etanercept was more effective than infliximab for achieving response (ACR20, 74% vs. 60%; P-value NR) and improving functional capacity (HAQ-DI, −32.30 vs. −21.60; P-value NR) at 54 weeks.1 No dose increase was allowed for infliximab (very low QoE for response).1  Etanercept vs. Tocilizumab (1 fair-quality, open-label RCT; n=43): No differences in clinical improvement (DAS-28, -2.84 vs. -2.10; P-value NR) and improvement in functional capacity (HAQ-DI, 0.68 vs. 0.70; P-value NR) were found at 24 weeks (very low QoE).1  Combination Therapies (1 fair-quality RCT; n=244 and 1 fair quality RCT; n=121): The larger study did not detect any benefit for treatment with a combination of etanercept (25 mg/week or 50 mg/week) and anakinra (100 mg/day) compared to monotherapy with etanercept (25 mg twice per week) over 24 weeks.1 The second trial examined a combination of abatacept (2 mg/kg on days 1, 15, and 30 and every 4 weeks thereafter) and etanercept (25

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mg twice weekly) compared to abatacept monotherapy (2 mg/kg).1 The combination was associated with increased SAEs but limited additional efficacy (ACR50, 26% vs. 19%, respectively; P-value NR).1

Second-Line Targeted Immune Modulators for Rheumatoid Arthritis Six RCTs provided evidence for 5 different head-to-head comparisons of TIMs and 1 comparison of TIM combination treatment versus TIM monotherapy as second-line agents (i.e. at least one inadequate response to a TIM) in RA.1 Two poor-quality, open-label RCTs are excluded from this summary.  Abatacept vs. Secukinumab (1 fair-quality, multi-center, double-blind RCT; n=551): Abatacept was more effective than secukinumab 150 mg or secukinumab 75 mg for achieving response (ACR50, 28% vs. 17% vs. 12%; P-value NR) and improved functional capacity (HAQ-DI, −0.6 vs. −0.4 vs. −0.3; P-value NR) at 24 weeks (moderate QoE for clinical improvement).1  TNF-Inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) vs. other TIMs (abatacept, rituximab, tocilizumab) (1 fair-quality, open-label RCT; n=300): Non-TNF-inhibitors were more effective than TNF-inhibitors for achieving response (odds ratio (OR), 2.06; 95% CI, 1.27 to 3.37) and remission (DAS28 < 2.6, 27% vs. 14%; p<0.01) at 52 weeks (low QoE for both assessments).1  Combination therapies (1 fair-quality, double-blind RCT; n=54): Combination treatment (rituximab when given in combination with methotrexate and etanercept or methotrexate and adalimumab) was more effective than TNF-inhibitor maintenance treatment (methotrexate in combination with etanercept or adalimumab) for achieving response (ACR50, 12% vs. 6%; P value NR) and remission (DAS28 < 2.6, 18% vs. 6%; P value NR) at 24 weeks (low QoE for both).1

Pipeline Targeted Immune Modulators for Rheumatoid Arthritis Nine fair-quality RCTs evaluating effectiveness of 3 pipeline (not yet FDA-approved) drugs for the treatment of RA were included in the DERP review.1 These studies provided evidence on filgotinib compared to placebo, peficitinib compared to placebo, peficitinib compared to etanercept, and one combination treatment of certolizumab pegol plus bimekizumab compared to certolizumab pegol monotherapy. 1 Filgotinib and peficitinib are oral Janus kinase (JAK) inhibitors and bimekizumab is an IV interleukin (IL)-17 receptor inhibitor.  Filgotinib vs. Placebo (1 fair-quality, multi-center, phase 3 RCT [n=449]; 2 fair-quality phase 2 RCTs [n=594 and n=283]): Enrolled subjects in all 3 RCTs had moderate-to-severe RA and were naïve to TIM agents (phase 2 trials) or had an inadequate response or intolerance to at least 1 prior TIM agent (phase 3 RCT).1 In the phase 3 RCT, filgotinib was more effective than placebo for achieving response (ACR20, 66% vs. 31%; p<0.001), remission (DAS28- erythrocyte sedimentation rate (ESR), 31% vs. 12%; p<0.001, and improvement of QoL (SF-36: 7.6 vs. 3.6; p<0.001) at 12 weeks (high QoE for all outcomes).1 The 2 phase 2 RCTs reported similar results as the phase 3 RCT for response, remission, and functional capacity.1  Peficitinib vs. Placebo (3 fair-quality phase 2 RCTs [n=379, n=289 and n=281] and 2 fair-quality phase 3 RCTs [RAJ 3; n=509 and RAJ 4; n=519]): All 5 studies were rated as fair-quality because of extensive manufacturer involvement in study design, execution, and reporting. 1 All studies included participants with moderate-to-severe RA for at least 6 months.1 Two studies included participants with inadequate response to, or intolerance of, at least one DMARD agent; in the other 3 studies, participants had an inadequate response to methotrexate.1 Both phase 3 RCTs reported similar results.1 After 12 weeks, more participants in the intervention group achieved an ACR20 response compared to participants in the placebo group (peficitinib 100 mg, 59% and 58%; peficitinib 150 mg, 64% and 75%; placebo, 22% and 31%; P<0.001 for all comparisons with placebo).1 Higher proportions of remission as defined by DAS28-CRP less than 2.6 were achieved with peficitinib than placebo (peficitinib 100 mg, 25% and 31%; peficitinib 150 mg, 35% and 35%; placebo, 8% and 5%; P<0.001 for all comparisons with placebo; high QoE for response and remission).1 Two of the phase 2 studies reported similar results for response, remission, and functional capacity as the phase 3 trials. 1 The third phase 2 study did not identify statistically significant clinical improvements for peficitinib 100 mg and 150 mg compared to placebo.1

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 Peficitinib vs. Etanercept (1 fair-quality RCT; n=509): The double-blinded, multicenter, RAJ 3 trial assessed the efficacy of peficitinib compared to open- label etanercept in participants with RA.1 Participants were randomized to peficitinib 100 mg, peficitinib 150 mg, etanercept 50 mg, or placebo for 52 weeks.1 At 12 weeks, a lower proportion of participants in peficitinib groups achieved an ACR20 response compared to participants in the etanercept group (peficitinib 100 mg, 58%; peficitinib 150 mg, 75%; etanercept 50 mg, 84%; P-value NR; moderate QoE).1  Certolizumab Pegol vs. Certolizumab Pegol + Bimekizumab (1 fair-quality RCT; n=79): At 12 weeks, combination treatment with bimekizumab was more effective than certolizumab pegol monotherapy for achieving response (DAS28-CRP < 3.2, 46% vs. 29%; P value NR) and remission (DAS28-CRP < 2.6, 26% vs. 8%; P-value NR; low QoE for both outcomes).1

Targeted Immune Modulators for Ankylosing Spondylitis One poor-quality, open-label RCT compared etanercept to infliximab in a head-to-head trial, but since the results are based on very low QoE (insufficient evidence) it was excluded from this summary.

Pipeline Targeted Immune Modulators for Ankylosing Spondylitis One placebo-controlled RCT evaluated filgotinib for the treatment of AS.1  Filgotinib vs. Placebo (1 fair-quality RCT; n=116): Participants with active AS and an inadequate response or intolerance to 2 or more NSAIDs were enrolled in this study.1 The study randomized participants to filgotinib 200 mg daily or placebo, with the main outcome being the change from baseline to week 12 in ASDAS.1 Participants treated with filgotinib improved on the ASDAS compared to placebo (−1.47 vs.−0.57; difference between groups, - 0.85; 95% CI -1.17 to -0.53; P < 0.001; moderate QoE).1 More participants reported major improvement (decrease of ASDAS from baseline ≥ 2.0) and clinically significant improvement (decrease of ASDAS from baseline of at least 1.1) in the filgotinib group compared to the placebo group (33% vs. 2%, and 66% vs. 26%; P < 0.001 for both comparisons; moderate QoE).1 Participants in the filgotinib group also had greater improvements on the Ankylosing Spondylitis Quality of Life score than participants treated with placebo (filgotinib 200 mg, –4.76; placebo, –2.24; P=0.004; moderate QoE).1

B. Comparative Harms of Targeted Immune Modulators Targeted Immune Modulators for Rheumatoid Arthritis Twenty-one RCTs provided evidence for comparative harms of TIMs in 18 different head-to-head comparisons and 40 different cohort studies in patients with RA.1 The pharmaceutical industry funded the majority of RCTs that assessed comparative harms of TIM agents.1 Moderate and high QoE indicates no differences in the incidence of overall AEs and SAEs.1 Significant differences in AEs and SAEs for the incidence of some comparisons were rated as very low or low QoE, and should be interpreted with caution.1 However, large observational studies suggest differences in some specific SAEs. 1 In the majority of studies, for example, infliximab was associated with a higher incidence of serious infections than other TIM agents.1 Some studies also indicated a higher incidence of opportunistic infections, tuberculosis, and varicella zoster infections with infliximab than with other TNF-inhibitors.1 Two observational studies reported a higher incidence of gastrointestinal perforations with tocilizumab than with TNF-inhibitors.1 Even in these large observational studies, however, the number of events was generally low and findings need to be interpreted cautiously.1 The majority of observational studies reported no significant differences in mortality, malignancies, and cardiovascular events or congestive heart failure.1 Overall, few differences in harms were observed in head-to-head RCT comparisons of TIM agents.1 Statistically significant differences observed in included studies are highlighted below.1  Abatacept vs. Infliximab (1 fair-quality RCT; n=321): Fewer SAEs with abatacept than infliximab (5% vs. 12%; P-value NR; RR=0.45; 95% CI, 0.20 to 0.99) were found at 24 weeks.1 No differences in overall AE were found (low QoE for SAEs and moderate QoE for overall AEs).1  Adalimumab vs. Baricitinib (1 fair-quality RCT; n=817): Fewer SAEs with adalimumab than baricitinib (4% vs. 8%; RR, 0.50; 95% CI 0.27 to 0.93) were found at 52 weeks.1 No differences in overall AEs were found (low QoE for SAEs and high QoE for overall AEs).1 Author: Moretz October 2020 230

 Combination therapies (4 fair-quality RCTs; n=586): The combination of TNF-inhibitors with a TIM of a different mechanism of action substantially increased the frequency of SAEs.1 For example, the combination of etanercept with abatacept or anakinra resulted in more SAEs compared to etanercept monotherapy (11% vs. 3%; RR, 5.93; 95% CI, 0.81 to 43.42; moderate QoE).1 Abatacept plus another TIM (adalimumab, anakinra, etanercept, or infliximab) resulted in more SAEs compared to another TIM alone (22% vs. 13%; RR, 1.79; 95% CI, 0.85 to 3.75; low QoE).1

Pipeline Targeted Immune Modulators for Rheumatoid Arthritis  Filgotinib vs. Placebo (1 fair-quality, phase 3 RCT [n=449]; 2 fair-quality phase 2 RCTs [n=594 and n=283]): Two RCTs assessed AEs at 24 weeks and 1 RCT assessed AEs at 12 weeks. Findings related to any AE or SAE were consistent across the 3 studies.1 No differences were found between filgotinib and placebo groups in overall AEs or SAEs (moderate QoE for both).1  Peficitinib vs. Placebo (3 fair-quality phase 2 RCTs [n=379, n=28 and n=281]; 2 fair-quality phase 3 RCTs [RAJ 3; n=509 and RAJ 4; n=519]): All 5 RCTs assessed AEs at 12 weeks.1 Findings related to any AE or SAE were consistent across the 5 studies.1 No differences were found between peficitinib and placebo groups in overall AEs or SAEs (moderate QoE for both).1  Peficitinib vs. Etanercept (1 fair-quality, open-label, double-blinded RCT; n=509): No difference in overall AEs and SAEs was reported (low QoE for both).1  Certolizumab Pegol vs. Certolizumab Pegol + Bimekizumab (1 fair-quality RCT; n=79): More participants experienced treatment-emergent AEs in the combination group compared to the certolizumab pegol monotherapy group (79% vs. 59%; P-value NR; low QoE).1

Pipeline Targeted Immune Modulators for Ankylosing Spondylitis  Filgotinib vs. Placebo (1 fair-quality RCT; n=116): No differences in any treatment-emergent AEs were reported between filgotinib and placebo.1 The incidence of treatment-emergent SAEs was higher in filgotinib group compared to placebo (2% vs. 0%; P-value NR; low QoE).1

C. Differences in Effectiveness or Harms in Specific Populations No studies were identified that evaluated differences in TIM effectiveness and harms in specific subgroups based on age and racial groups, gender, patients with comorbidities, patients taking other commonly prescribed drugs, or in patients with early versus established disease.1

D. Conclusions: Most comparisons for the safety and efficacy of TIMs in RA and AS are limited to single trials and the QoE for many outcomes is very low or low.1 Drug manufacturers sponsored nearly all the RCTs, and although the extent to which the manufacturer’s involvement influenced study execution or reporting is not definitively known, findings from a Cochrane systematic review suggest that industry sponsorship is associated with more favorable results than sponsorship by other sources.1 Most observational studies addressing harms were of retrospective design and based on national registries; the quality and completeness of these databases cannot be determined.1

Moderate or high QoE indicates that baricitinib, sarilumab, and upadacitinib are more effective than adalimumab as first-line treatments for RA.1 Based on moderate-quality evidence, abatacept is more effective than secukinumab as a second-line treatment for RA.1 High and moderate quality evidence indicates no differences in the incidence of AEs and SAEs for TIMs.1 Statistically significant differences in the incidence of AEs or SAEs of some comparisons are rated as very low- or low QoE and need to be interpreted with caution.1 Only 1 poor quality head-to-head RCT was identified for AS, which does not allow for conclusions about the comparative effectiveness or safety of etanercept versus infliximab.1 Twenty-four studies of head-to-head comparisons of TIM agents for the treatment of RA and AS are currently in progress; 10 will be completed before 2021.1

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2. Targeted Immune Modulators for Plaque Psoriasis and Psoriatic Arthritis The literature search for the DERP systematic review focused on TIMs for PsO and PsA was conducted from January 1, 2017 through August 20, 2019, with active surveillance of the literature through January 31, 2020.2 The quality of the body of evidence for each drug comparison and indication (PsO or PsA) was evaluated for up to 5 selected outcomes (i.e., disease remission, clinical improvement, quality of life, AEs, and SAEs) using the GRADE approach.2

Twenty new studies were identified and 18 studies from the previous report were carried forward for a total of 38 eligible studies included in this update.2 Thirty studies evaluated TIM agents for PsO, and 8 studies evaluated TIMs for PsA.2 Of the 38 eligible studies, 31 were RCTs and 7 studies were cohort studies.2 Among the 31 RCTs, 3 studies were rated as poor methodological quality and the rest as fair methodological quality.2 Among the 7 cohort studies, 1 study was rated as poor methodological quality and the rest as fair methodological quality.2 Outcomes selected for GRADE ratings ranged from low to high quality of evidence for most efficacy outcomes, and very low to moderate for most harm outcomes2. Generally, outcomes were downgraded for serious or very serious imprecision (i.e., wide confidence interval because of small sample size).2

A. Comparative Effectiveness of Targeted Immune Modulators Targeted Immune Modulators for Plaque Psoriasis Twenty-one RCTs provided direct evidence for 14 head-to-head TIM agent comparisons in patients with moderate-to-severe PsO.2 One RCT was rated as poor- quality because of insufficient blinding and switching treatments.2 The rest of the RCTs were rated as fair-quality, primarily because of industry sponsorship of studies and extensive manufacturer involvement in study design, execution, and reporting, and sponsorship of studies. 2 All studies reported disease remission outcomes as a primary study endpoint; the most commonly reported outcomes were the PASI 90 and PASI 75.2 A score of 0 (no impact) or 1 (very minimal impact) on the PGA or investigator’s global assessment (IGA) measure was also commonly used as either a primary or secondary outcome for disease remission.2 Seventeen RCTs reported QoL; the Dermatology Life Quality Index (DLQI) was the mostly commonly reported QoL outcome.2 One poor-quality RCT comparing etanercept to infliximab is excluded from this summary due to insufficient evidence demonstrating a difference in efficacy between the 2 drugs.  Apremilast vs. Etanercept (1 fair-quality RCT; n=250): No difference in disease remission between apremilast and etanercept (PASI 75, 40% vs. 48%; P=0.26) or QoL was reported (change in DLQI; data and P-value NR; low QoE for remission and QoL) at 16 weeks. The dosage of etanercept used in this RCT (50 mg once per week) is the standard labeled dose in Europe; however, it is less than the FDA-approved dosage in the United States (50 mg twice weekly for 3 months, followed by 50 mg once a week).2  Brodalumab vs. Ustekinumab (2 fair-quality, multi-center RCTs: AMAGINE-2 [n=1,883] and AMAGINE-3 [n=1,881]): Brodalumab was more effective compared to ustekinumab for achieving disease remission at 12 weeks (PASI 100: AMAGINE-2, 44% vs. 22%; P <0.001; AMAGINE-3, 37% vs. 19%; P <0.001; high QoE).2 Those treated with brodalumab had greater response when compared to those receiving ustekinumab (AMAGINE-2: 79% vs. 61%; P <0.001; AMAGINE-3: 80% vs. 57%; P<0.001; high QoE) for achieving a 0 or 1 on the PGA.2  Etanercept vs. Ixekizumab (2 fair-quality RCTs: UNCOVER-2 [n=1,224] and UNCOVER-3 [n=1,346]): Etanercept was less effective than ixekizumab for achieving disease remission at 12 weeks (PASI 75: ARDs, 31% to 48% for both RCTs; P-value NR) and for improving QoL (DLQI 0 or 1: ARDs, 20 to 30 percentage points for both RCTs; P-value NR); high QoE for both remission and QoL.2  Etanercept vs. Secukinumab (1 fair-quality RCT; n=1,306): Etanercept was less effective than secukinumab for achieving disease remission at 12 weeks (PASI 75: 44% vs. 77% for 300 mg secukinumab; P<0.001 and 44% vs. 67% for 150 mg secukinumab; P<0.001; high QoE).2 Etanercept was also less effective at improving QoL (mean change DLQI: -7.9 vs. -10.4 for 300 mg secukinumab; P-value NR and -7.9 vs. -9.7 for 150 mg secukinumab; P-value NR; moderate QoE).2 Etanercept was also less effective at maintaining remission at 52 weeks (PASI 75: 73% vs. 84% for 300 mg secukinumab; and 73% vs. 82%; for 150 mg secukinumab; high QoE).2

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 Etanercept vs. Tildrakizumab (1 fair-quality RCT; n=934): Etanercept was less effective than tildrakizumab for disease remission at 12 weeks (PASI 75: 48% vs. 66% for 200 mg tildrakizumab; P=0.001 and 48% vs. 61% for 100 mg tildrakizumab; P<0.001; high QoE ).2 Etanercept was also less effective than both doses of tildrakizumab for improving QoL at both 12 weeks (PGA 0 or 1: 36% vs. 47% for 200 mg tildrakizumab; p=0.003; moderate QoE) and 28 weeks (PGA 0 or 1: 39% for etanercept vs. 54% for 100 mg tildrakizumab vs. 65% for 200 mg tildrakizumab; P<0.001 for both tildrakizumab doses compared to etanercept; high QoE).2  Etanercept vs. Tofacitinib (not FDA-approved for psoriasis) (1 fair-quality RCT; n=1,106): Etanercept was more effective than 5 mg tofacitinib at achieving disease remission at 12 weeks (PASI 75: 59% vs. 40%; P<0.001) but no differences compared to tofacitinib 10 mg was detected (PASI 75: 59% vs. 64%; P=0.20; moderate QoE).2 Etanercept was more effective than 5 mg tofacitinib for improving QoL (DLQI 0 or 1: 75% vs. 66%, P=0.03; moderate QoE) but no differences compared to 10 mg tofacitinib were found (DLQI 0 or 1: 75% vs. 78%; P=0.31; low QoE).2  Etanercept vs. Ustekinumab (1 fair-quality RCT; n=251): Etanercept was less effective compared to ustekinumab at 12 weeks (PASI 75: 57% vs. 74% for ustekinumab 90 mg; P<0.001, and 57% vs. 68% for ustekinumab 45 mg; P=0.01; low QoE).2  Guselkumab vs. Adalimumab (3 fair-quality RCTs: X-PLORE [n=25]; VOYAGE-1 [n= 663]; and VOYAGE-2 [n=744]): Guselkumab was more effective than adalimumab for disease remission at 16 weeks (PGA 0 or 1: ARD range 16% to 28%; P-value NR; high QoE).2 Guselkumab was also more effective at improving QoL (DLQI 0 or 1: ARD range 13% to 15%; P-value NR; moderate QoE).2  Guselkumab vs. Secukinumab (1 fair-quality RCT; n=251): Guselkumab was more effective than secukinumab for disease remission at 48 weeks (PASI 90: 84% vs. 70%; P<0.001; moderate QoE).2 Guselkumab was noninferior to secukinumab for disease remission at both 12 and 48 weeks (PASI 75: 85% vs. 80%; P<0.001 for non-inferiority; P=0.06 for superiority; moderate QoE).2 A higher PASI 90 response was observed for secukinumab compared to guselkumab (69% vs. 76%), but no statistical testing was performed to control for type I error.2  Ixekizumab vs. Ustekinumab (1 fair-quality RCT; n=302): Ixekizumab was more effective than ustekinumab for disease remission at 12 weeks (PASI 90: 73% vs. 42%; P<0.001; moderate QoE) and at 52 weeks (PASI 90: 77% vs. 59%; P-value NR; moderate QoE).2 Ixekizumab was also more effective for improving QoL at 12 weeks (DLQI 0 or 1: 61% vs. 45%; P=0.01; moderate QoE).2  Risankizumab vs. Adalimumab (1 fair-quality RCT; n= 605) Risankizumab was more effective than adalimumab for disease remission at 16 weeks (PASI 90: 72% vs. 47%; P-value NR; ARD 25%; 95% CI 18 to 32; P<0.001; moderate QoE).2 Risankizumab was also more effective at improving QoL at 16 weeks (DLQI 0 or 1: 66% vs. 49%; P<0.001; moderate QoE).2  Risankizumab vs. Ustekinumab (3 fair-quality RCTs: UltlMMA-1 [n= 506]; UltlMMA-2 [n=393]; and Papp, et al. [n=166]): At 16 weeks, more participants randomized to risankizumab in UltIMMA-1 and UltIMMA-2 had disease remission compared to ustekinumab (PASI 90 75% vs. 42%; P <0.001 in UltIMMA- 1; 75% vs. 48%; P <0.001 in UltIMMA-2; moderate QoE).2 Risankizumab was more effective than ustekinumab for disease remission at 12 to 16 weeks (PASI 90: ARD range 28% to 37%, P-value NR; moderate QoE). Risankizumab was also more effective at improving QoL at 12 to 16 weeks (DLQI 0 or 1: ARD range 19% to 23%; P-value NR; moderate QoE). In the Papp, et al. RCT, risankizumab (data pooled for 90-mg and 180-mg dosages) was more effective than ustekinumab for the PASI 90 response (77% vs. 40%; P <0.001; moderate QoE).2  Secukinumab vs. Ustekinumab (2 RCTs: CLEAR [n=676] and CLARITY [n=1,102]): For the primary study outcome in CLEAR, participants randomized to secukinumab had a higher PASI 90 response (79%) compared to those randomized to ustekinumab (58%; P<0.001; high QoE) at 16 weeks.2 For the primary study outcome in CLARITY, participants randomized to secukinumab had a higher PASI 90 response (67%) compared to those randomized to ustekinumab (48%; P<0.001; high QoE).2 Secukinumab was more effective than ustekinumab for disease remission at 16 weeks (PASI 90: ARDs 21% and 22%; P-value NR; high QoE).2 Secukinumab was also more effective at improving QoL at 16 weeks (DLQI 0 or 1: ARDs 13% and 15%; P-value NR; high QoE).2

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Pipeline Targeted Immune Modulators for Plaque Psoriasis Three pipeline drugs, bimekizumab, BMS-986165, and mirikizumab, have been studied for effectiveness in managing PsO compared to placebo in 4 fair-quality RCTs.2 Bimekizumab is an IL-17 inhibitor administered via SC and IV routes to patients with PsO in clinical trials. BMS-986165 is a novel oral tyrosine kinase 2 inhibitor. Mirikizumab is an IL-23 inhibitor administered via the SC route.  Bimekizumab vs. Placebo (2 fair-quality RCTs; BE-ABLE [n=250] and Glatt, et al. [n=39]): The BE-ABLE trial evaluated various bimekizumab (64 mg, 160 mg, 320 mg, and 480 mg) doses administered SC every 4 weeks and reported outcomes at 12 weeks.2 Glatt et al. administered various bimekizumab doses between 8 mg and 640 mg as a single infusion and reported outcomes over 20 weeks.2 In the BE-ABLE trial, the proportion of participants achieving PASI 90 response varied from 46% to 79% across all bimekizumab doses and was 0% in the placebo group (P<0.001 for all dose comparisons to placebo; moderate QoE for remission).2 The Glatt et al. trial was a first in-human study with AEs designated as the primary study endpoints.2 However, clinical efficacy was evaluated and statistically significant differences between placebo and all doses evaluated were observed at all timepoints for the lesion severity score, and for the higher doses evaluated (160 mg, 480 mg, 640 mg) at nearly all timepoints for percent change from baseline for PASI and PGA.2  BMS-986165 vs. Placebo (1 fair-quality RCT; n=268): One trial evaluated various dosages (3 mg daily, 3 mg every other day, 6 mg twice daily, and 12 mg once daily) of BMS-98165, compared to placebo, over 12 weeks among adults with moderate-to-severe PsO for at least 6 months.2 Except for the lowest dose (3 mg every other day), all doses were more effective than placebo for the primary study endpoint (PASI 75: ARD range 36% to 72%; moderate QoE) and nearly all secondary remission, clinical improvement, and QoL outcomes.2  Mirikizumab vs. Placebo (1 fair-quality RCT, n=205): This phase 2 RCT compared multiple doses of mirikizumab (30 mg, 100 mg, and 300 mg) to placebo among participants with at least moderate PsO for at least 6 months.2 The primary study endpoint was PASI 90 response at 16 weeks.2 For the PASI 90 response, all doses of mirikizumab were superior to placebo (300 mg, 67%; 100 mg, 59%; 30 mg, 29%; 0%, placebo; P< 0.001 for 300 mg and 100 mg vs. placebo; P=0.009 for 30 mg vs. placebo; moderate QoE).2 For QoL, 47% of participants randomized to the 300-mg dosage achieved a 0 or 1 response on the DLQI compared with 49% (100-mg dosage), 35% (30-mg dosage), and 4% (placebo, P<0.001 for all comparisons with placebo; moderate QoE).2

Targeted Immune Modulators for Psoriatic Arthritis Four RCTs evaluated the comparative effectiveness of TIMs in the management of PsA; of these, 1 RCT is new to this update.2 All studies enrolled participants with active PsA; 1 study specifically required active enthesitis (i.e., a common symptom in PsA involving inflammation of the sites where tendon or ligaments attach to bones).2 Two RCTs were rated as poor-quality for various critical methodological flaws and are excluded from this summary. The other 2 RCTs were rated as fair-quality because of industry sponsorship and extensive manufacturer involvement in study design, execution, and reporting. 2 Nearly all studies reported clinical improvement as primary study endpoints; the most commonly reported outcomes were the ACR20 response.2 Only 2 of the RCTs reported QoL outcomes.2  Adalimumab vs. Ixekizumab (1 fair-quality RCT; n=417): Lower rates of clinical improvement was reported at 24 weeks with adalimumab compared to ixekizumab every 2 weeks or every 4 weeks (ACR20: 57% vs. 62% vs. 58%, respectively; low QoE); no statistical significance testing was performed as the primary study aim was to compare ixekizumab to placebo.2 Lower skin disease remission response was also observed with adalimumab compared to ixekizumab every 2 weeks or every 4 weeks (PASI 75: 54% vs. 80% vs. 71%; low QoE).2  Adalimumab vs. Tofacitinib (1 fair-quality RCT; n=422): This trial was designed to evaluate superiority of tofacitinib compared to placebo; it was not designed to show superiority or non-inferiority between the active drug groups and no statistical testing was conducted among active treatment groups.2 Subjects treated with adalimumab had lower rates of clinical improvement at 12 months compared to participants treated with tofacitinib 10 mg, but not compared to participants treated with tofacitinib 5 mg (ACR20: 60% vs. 70% vs. 68%, respectively; low QoE).2 Numerically lower skin disease remission was observed with adalimumab at 12 months compared to tofacitinib 10 mg, but not 5 mg (PASI 75: 56% vs. 67% vs. 56%; low QoE). 2 Higher Author: Moretz October 2020 234

improvement in QoL (SF-36 Physical Health Component Score [PCS]) was reported with adalimumab compared to tofacitinib 10 mg or tofacitinib 5 mg (6.2 vs. 5.7 vs. 5.5, respectively; low QoE).2

Pipeline Targeted Immune Modulators for Psoriatic Arthritis Two RCTs, both new to the DERP update, reported on the efficacy of 2 pipeline TIM agents for PsA: filgotinib and remtolumab.2 Remtolumab is a dual TNF- inhibitor and IL-17 inhibitor administered via the SC route.2  Remtolumab vs. Placebo and Adalimumab (1 fair-quality, phase 2 RCT; n=240): This study was primarily designed to evaluate remtolumab compared to placebo; however, findings for the adalimumab versus remtolumab comparison were also reported.2 With respect to clinical improvement, a higher percentage of participants achieved an ACR50 response with both doses of remtolumab (37% and 53% for the 120 mg and 240 mg dosages, respectively) compared to placebo (13%; P<0.05 and P<0.001 respectively; moderate QoE).2 With respect to remission, the percentage of participants achieving an ACR70 response was higher in both doses of remtolumab (23% for 120 mg dosage, 32% for 240 mg dosage) compared to placebo (4%; P<0.05 for 120 mg dosage and P<0.01 for 240 mg dosage; moderate QoE).2 No difference in clinical improvement (ACR50) with adalimumab at 12 weeks compared to 120 mg remtolumab dose was reported; low QoE).2 A lower proportion of adalimumab-treated patients had disease remission compared to patients who received the 240 mg remtolumab dose (ACR70: ARD, 16.2%; 95% CI, 2.7% to 29.7%), but no difference in disease remission was observed when compared to the 120 mg remtolumab dose (low QoE).2  Filgotinib vs. Placebo (1 fair-quality, phase 2 RCT; n=131): A higher proportion of participants randomized to filgotinib (80%) had an ACR20 response compared to placebo (33%; P<0.001; low QoE) at 16 weeks.2 Filgotinib was also superior to placebo on all secondary remission and clinical improvement outcomes.2

B. Comparative Harms of Targeted Immune Modulators Targeted Immune Modulators for Plaque Psoriasis Overall, few differences in harms were observed in 21 head-to-head RCT comparisons of TIM agents in patients with PsO.2 In the RCT body of evidence, between-agent differences were typically in just one of several harm outcomes reported when differences were present.2 Five cohort studies provided evidence on the comparative harms for various TIMs.2 Two cohort studies were conducted with participants identified based on insurance claims for biologic therapy and diagnosis codes for psoriasis.2 One study was conducted by academic researchers among 107,707 participants who were new users of adalimumab, apremilast, etanercept, infliximab, ustekinumab, and other nonbiological DMARD agents.2 In the second cohort study (n=650), insurance claims were used to identify participants; analyses were restricted to patients on monotherapy.2 This analysis, supported by the manufacturer, found no statistically significant differences in “adverse medical conditions” between adalimumab and the other biological agents that were included in the analysis (etanercept, ustekinumab, and infliximab).2 Two additional cohort studies were conducted with participants identified from the British Association of Dermatologists Biologic Interventions Register (BADBIR), a prospective registry of patients from 157 dermatology centers in the U.K. and Ireland supported by multiple drug manufacturers for pharmacovigilance activities.2 One trial analyzed 7,136 patients with psoriasis recruited within 6 months of initiating or switching to a biologic or conventional systemic therapy.2 The primary goal of this study was to compare the incidence of SAEs among participants in the registry who would meet criteria for typical clinical trials with those participants not meeting trial eligibility criteria. 2 Another study included 3,523 patients and the data were analyzed using the BADBIR to evaluate discontinuations due to AEs.2 The final cohort study was conducted among 10,065 participants with PsO identified from 3 Italian referral centers between 2007 and 2011 and was supported by an unrestricted grant from the manufacturer.2 Findings where a statistically significant difference was observed in AEs, SAEs, or other serious harms are reported below.  Apremilast vs. Adalimumab (1 fair-quality cohort; n=107,707): Lower incidence of serious infection requiring hospitalization for apremilast compared to adalimumab (hazard ratio [HR], 0.31; 95% CI, 0.15 to 0.65; very low QoE).2 Author: Moretz October 2020 235

 Apremilast vs. Etanercept (1 fair-quality RCT; n=250): A lower proportion of overall AEs was observed for apremilast compared to etanercept (53% vs. 71%; RR, 0.75; 95% CI, 0.58 to 0.95; low QoE).2  Etanercept vs. Adalimumab (2 fair-quality cohorts; [n=650 and n=7,136]): Lower incidence of serious infection requiring hospitalization for etanercept (HR, 0.76; 95% CI, 0.61 to 0.94; very low QoE) in 1 study; lower incidence rate of SAEs (incidence rate ratio [IRR], 0.75; 95% CI, 0.66 to 0.86; very low QoE) in other study.2  Etanercept vs. Secukinumab (1 fair-quality RCT; n=1306): In the RCT comparing etanercept to secukinumab over 12 weeks, a higher risk of injection site reactions was observed for etanercept (11%) compared to secukinumab (1%; RR, 14.9; 95% CI, 6.7 to 33.2). 2  Etanercept vs. Tildrakizumab (1 fair-quality RCT; n=1090): Fewer overall AEs for tildrakizumab 200 mg compared with etanercept during weeks 13 to 28 (RR, 0.80; 95% CI, 0.68 to 0.93), but no difference in incidence of AE during weeks 0 to 12 (moderate QoE).2 No difference in incidence of SAEs during both time periods was observed (low QoE).2  Etanercept vs. Ustekinumab (1 fair-quality RCT; n=903 and 1 fair-quality cohort; n=3,523): In the RCT comparing etanercept to ustekinumab, injection site reactions were more frequent with etanercept compared to ustekinumab over 12 weeks (RR, 4.0; 95% CI, 4.0 to 9.8; moderate QoE); however, participants in the etanercept group received more injections than participants receiving ustekinumab. 2 In the cohort study ustekinumab had a statistically significantly higher incidence of SAEs compared to etanercept (IRR, 2.4; 95% CI, 1.8 to 3.1; very low QoE).2  Infliximab vs. Adalimumab (1 fair-quality cohort; n=3,523): A higher incidence of serious infection requiring hospitalization for infliximab was observed compared to adalimumab (HR, 1.9; 95% CI, 1.01 to 3.6; very low QoE).2  Risankizumab vs. Ustekinumab (3 fair quality RCTs UltlMMA-1 [n=506]; UltlMMA-2 [n=393]; Papp, et al. [n=166]): One RCT (Papp, et al.) reported no statistically significant differences in AEs or SAEs between risankizumab and ustekinumab.2 Two RCTs (UltlMMA-1 and UltlMMA-2) reported some differences but not across all time periods evaluated.2 For overall AEs, fewer AEs were observed for risankizumab in the later time period (weeks 17 to 52) of one study (RR, 0.75; 95% CI, 0.11 to 0.77; UltlMMA-2) and fewer SAEs were observed with risankizumab compared to ustekinumab in the early time period (weeks 0 to 16) of the other study (RR, 0.29; 95% CI, 011 to 0.77: UltlMAA-1).2  Ustekinumab vs. Adalimumab (1 fair-quality cohort; n=10,065): No difference in serious infection requiring hospitalization was observed with ustekinumab versus adalimumab (HR, 0.70; 95% CI, 0.49 to 1.0; very low QoE); however, a higher incidence of SAEs for ustekinumab was observed (IRR, 1.2; 95% CI, 1.1 to 1.4, very low QoE).2

Pipeline Targeted Immune Modulators for Plaque Psoriasis Four RCTs reported on the harms versus placebo of 3 pipeline TIM agents.2  Bimekizumab vs. Placebo (2 fair-quality RCTs; BE-ABLE [n=250] and Glatt, et al. [n=39]): In the BE-ABLE trial, an increased risk of AEs was observed with bimekizumab (all dosages pooled) compared to placebo (RR, 1.7; 95% CI, 1.1 to 2.6).2 No differences in SAEs or withdrawals due to AEs were observed. With respect to harms in the Glatt, et al. trial, no differences were observed in AEs compared to placebo (all dosages were pooled).2 Only 1 SAE occurred overall in the bimekizumab group. No withdrawals due to AE were observed in either the bimekizumab or placebo group. 2  BMS-986165 vs. Placebo (1 fair-quality RCT; n=268): AEs were more common at higher doses of BMS-986165 compared to placebo over 12 weeks but no differences in SAEs or withdrawals due to AEs for observed for any doses. Injection site reactions were not reported.  Mirikizumab vs. Placebo (1 fair-quality RCT; n=205): No differences in AEs, SAEs, or injection site reactions were observed with mirikizumab versus placebo.2

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Targeted Immune Modulators for Psoriatic Arthritis Four of 5 RCTs that evaluated efficacy also reported harms associated with TIMs used to treat PsA.2 Few differences in harms were observed in head-to-head comparisons of TIM agents for overall AEs, SAEs, and withdrawals due to AEs.2 One new fair-quality cohort study was identified for the DERP update.2 In this study, insurance claims were used to identify adults with PsA or PsO who initiated therapy with ustekinumab or a TNF-inhibitor between 2009 and 2015.2 No differences were observed for incident atrial fibrillation or major cardiovascular events between the included TIMs.2 The previous review included 1 poor- methodological-quality cohort study which identified patients with various rheumatologic conditions, including PsA, from a Turkish patient registry is excluded from this summary.2

Pipeline Targeted Immune Modulators for Psoriatic Arthritis Two placebo-controlled RCTs reported on the harms of 2 pipeline TIM agents when used to manage PsA.2  Filgotinib Compared to Placebo (1 fair-quality RCT; n=131): For harms, no statistically significant difference was observed for overall AEs (low QoE), SAEs, or withdrawals due to AEs, though findings were imprecise for the latter 2 outcomes (very low QoE).2  Remtolumab vs. Placebo and Adalimumab (1 fair-quality, phase 2 RCT; n=240): No statistically significant differences were observed for either dose for treatment-emergent AEs (low QoE), SAEs, or withdrawals due to AEs, though findings for the latter 2 outcomes were very imprecise (very low QoE).2

C. Differences in Effectiveness or Harms in Specific Populations No studies were identified to evaluate differences in TIM effectiveness and harms in PsO or PsA based on age and racial groups, gender, patients with comorbidities, patients taking other commonly prescribed drugs, or in patients with early, compared to established, disease for this report.2

D. Conclusions: The largest body of comparative evidence is for etanercept and ustekinumab versus other TIM agents in patients with PsO.2 For disease remission outcomes, high-quality evidence suggests that etanercept is less effective than ixekizumab, secukinumab, and tildrakizumab. 2 High-quality evidence also suggests that ustekinumab is less effective than brodalumab and risankizumab and moderate quality evidence suggests it may also be less effective than ixekizumab for disease remission outcomes.2 High-quality evidence suggests that adalimumab is less effective than guselkumab and moderate-quality evidence suggests that it is also less effective than risankizumab2. Finally, moderate-quality evidence suggests that guselkumab is more effective than secukinumab for maintenance therapy.2 Few differences in harms among TIM agents were observed, based on very low- to moderate-quality evidence.2 For PsA, limited head-to-head comparisons were available.2 Based on low-quality evidence, ixekizumab, tofacitinib, and remtolumab may be more effective than adalimumab with no difference in harms.2

Thirty ongoing studies are evaluating the comparative effectiveness or harms of TIM agents.2 Twenty-three of these studies are RCTs and 7 are observational studies.2 Seventeen RCTs are in participants with PsO and 6 are in participants with PsA.2 Two observational studies are in participants with PsO, 3 are in participants with PsA, and 2 studies include participants with either condition.2 Drug manufacturers are funding 27 studies, hospitals are funding 2 studies, and the NIH is funding 1 study.2

3. Targeted Immune Modulators for Crohn’s Disease and Ulcerative Colitis The literature search for the DERP systematic review focused on TIMs for management of CD and UC was conducted from January 1, 2017 through August 2019, with active surveillance of the literature through December 31, 2019. Three new studies were identified and 6 studies were carried forward from the previous

Author: Moretz October 2020 237 report for a total of 9 eligible studies in this update.3 Four studies evaluated TIM agents exclusively among participants with CD, 2 studies evaluated TIM agents exclusively among participants with UC and 3 studies evaluated TIMs among mixed populations that included participants with CD or UC.3

Of the 9 eligible studies, 4 were RCTs and 5 were cohort studies. Among the 4 RCTs, 1 study was rated as poor-quality and the rest were rated as fair-quality.3 Among the 5 cohort studies, 1 was rated as poor-quality and the rest were rated as fair-quality.3 Outcomes selected for GRADE ratings ranged from very low to moderate QoE, with most rated as very low QoE.3 Generally, outcomes were downgraded for indirectness (i.e., applicability) and serious imprecision (i.e., wide confidence interval because of small sample size).3

A. Comparative Effectiveness of Targeted Immune Modulators One fair-quality RCT evaluated comparative effectiveness of adalimumab compared with infliximab in CD; 1 poor-quality study is excluded from this summary. Targeted Immune Modulators for Crohn’s Disease  Adalimumab vs. Infliximab (1 fair-quality, open-label RCT, n=73): No difference between adalimumab and infliximab in changes in quality of life and clinical improvement were reported after 12 months of therapy (low QoE).3

Pipeline Targeted Immune Modulators for Crohn’s Disease One placebo-controlled RCT evaluated the efficacy of an investigational agent, PF-04236921 which is an IL-6 inhibitor administered via the SC route.  PF-04236921 vs. Placebo (1 fair-quality RCT; n=249): Pfizer funded this study, and 5 authors were Pfizer employees who were involved in study design, data collection, data analysis, and data interpretation.3 The study enrolled adults with moderate-to-severe CD who had failed or were intolerant to 1 or more TNF-inhibitors, and compared 3 doses of PF-04236921 (10 mg, 50 mg or 200 mg SC on days 1 and 28) with placebo. The 200-mg dosage was not included in the analysis because this study arm was stopped early due to fatalities seen in patients with lupus who were treated with this dose in a separate trial.3 The primary outcome was the proportion of patients achieving a 70-point or greater reduction in the Crohn’s Disease Activity Index score (CDAI-70). Compared to placebo, the 50-mg dose produced a greater CDAI-70 response at both 8 weeks (49% vs. 31%; P <0.05) and at 12 weeks (47% vs. 29%; P <0 .05; moderate QoE for both time points).3 In contrast, no difference was found with the 10-mg dose at either 8 weeks (35% vs. 31%; P>0.05) or 12 weeks (35% vs. 29%; P >0.05; low QoE for both time points) compared to placebo.3 No differences in QoL were noted between the 50-mg and 10- mg dosages and placebo (low QoE).3

Targeted Immune Modulators for Ulcerative Colitis One head-to-head RCT evaluated comparative efficacy of 2 TIMs approved to treat UC.  Vedolizumab vs. Adalimumab (1 fair-quality RCT; n=769): One RCT compared IV vedolizumab to SC adalimumab for 1 year in patients with moderate- to-severe UC. This study was sponsored by the manufacturer, and was rated as fair quality primarily because of extensive manufacturer involvement in study design and execution.3 Compared to the adalimumab arm , participants who received vedolizumab had a higher incidence of achieving clinical remission (31% vs. 23%; ARD, 9%; 95% CI, 3% to 15%) and endoscopic remission (40% vs. 28%; ARD, 12%; 95% CI, 5% to 19%) at 1 year.3 In addition, larger improvements in QoL at (ARD 9.6%; 95% CI, 2.8% to 16.5%) were observed at 1 year with vedolizumab compared to adalimumab (all results, P<0.05; moderate quality QoE).3 No difference in incidence of corticosteroid-free remission (among those taking steroids at baseline) were observed between the vedolizumab and adalimumab arms (low QoE).3

B. Comparative Harms of Targeted Immune Modulators Author: Moretz October 2020 238

Targeted Immune Modulators for Crohn’s Disease Two cohort studies compared adalimumab with etanercept and infliximab. Both studies were conducted among mixed populations with CD as well as other autoimmune disease for which TIMs are indicated. One study was rated as fair-quality and the other was rated as poor-quality and is excluded from this summary. The fair-quality study (n=8,421) used data from the Health Insurance Review and Assessment Service in South Korea.3 This study reported a statistically significant higher risk of tuberculosis with adalimumab (IRR 3.45; 95% CI, 1.82 to 6.55) or infliximab IRR 6.80; 95% CI, 3.74 to 12.37) compared to etanercept.3 The results of 1 head-to-head RCT and 4 observational, cohort studies evaluating the comparative harms of TIMs when used to manage CD are summarized below.  Adalimumab vs. Infliximab (1 fair-quality, open-label RCT; n=73): No difference in incidence of AEs between adalimumab and infliximab were observed, but results were too imprecise to draw definitive conclusions about SAEs, withdrawals due to AEs, and infection (very low QoE).3  Adalimumab vs. Certolizumab Pegol vs. Infliximab (1 fair-quality cohort; n=3,025): The American College of Gastroenterology sponsored this study, with additional investigator support from the National Institutes of Health.3 This study was conducted using administrative and claims data obtained from OptumLabs, which includes privately insured and Medicare beneficiaries in the United States.3 No difference in the incidence of serious infection was observed between the 3 TIMs agents, however results were imprecise (very low QoE).3  Adalimumab vs. Infliximab vs. Etanercept (2 fair-quality cohorts and 1 poor-quality cohort): One fair-quality cohort study used administrative and registry data from 1,400 patients in Italy that compared infliximab with adalimumab in a population with either CD or UC. 3 Among the population with CD (n=872), a higher incidence of infections with infliximab compared to adalimumab was reported (adjusted hazard ratio [aHR], 1.63; 95% CI, 0.61 to 4.34), but this result was not statistically significant and the estimate was very imprecise (low QoE).3

Pipeline Targeted Immune Modulators for Crohn’s Disease One placebo-controlled RCT evaluated the harms associated with administration of the investigational agent PF-04236921.  PF-04236921 compared to Placebo (1 fair-quality RCT; n=249): PF-0236921 10 mg and 50 mg compared to placebo. No difference in incidence of overall AEs between placebo and the investigational agent was reported (moderate QoE).3 No difference in SAEs, withdrawals due to AEs, or injection site reactions was noted, but results were too imprecise to draw a definitive conclusion (low QoE).3 Common AEs included worsening of CD, abdominal pain, headache, and nasopharyngitis.28 One death occurred in the 50-mg dosage group.3

Targeted Immune Modulators for Ulcerative Colitis One head-to-head RCT and 3 observational, cohort studies evaluated the comparative harms of TIMs when used to manage UC. One poor-quality cohort trial is excluded from this summary.  Vedolizumab vs. Adalimumab (1 fair-quality RCT; n=769): marginally lower incidence of AEs at 1 year was observed for vedolizumab compared to adalimumab (RR 0.91; 95% CI 0.82 to 1.00; moderate QoE).3 No difference in incidence of SAEs, withdrawals due to AEs, or infections at 1 year was observed between vedolizumab and adalimumab, but results were too imprecise to draw a definitive conclusion (low QoE).3  Infliximab vs. Adalimumab (2 fair-quality cohorts): Both observational studies (1 conducted in the U.S (n=1400) and 1 conducted in Italy (n=560) were based on administrative and claims data.3 No differences in risk of serious infection and overall infections were observed when infliximab was compared to adalimumab, but results were too imprecise to draw a definitive conclusion (very low QoE).3  Adalimumab vs. Infliximab vs. Etanercept (1 fair-quality cohort, n=10,021)A higher incidence of tuberculosis was observed with adalimumab (IRR 5.6; 95% CI 3.3 to 9.2) or infliximab (IRR 5.8; 95% CI 3.0 to 8.5 compared to etanercept in participants with UC.3

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C. Differences in Effectiveness or Harms in Specific Populations No studies were identified to evaluate differences in TIM agents for effectiveness and harms in CD or UC based on age and racial groups, gender, patients with comorbidities, patients taking other commonly prescribed drugs, or in patients with early, compared to established, disease.3

D. Conclusions: The evidence for comparative effectiveness and harms of TIM agents in CD is limited to comparisons between adalimumab and certolizumab pegol, etanercept, or infliximab, and nearly all outcomes were rated as low or very low QoE precluding any definitive conclusions.3 For UC, vedolizumab is more effective compared to adalimumab (moderate QoE) with no differences in AEs (moderate to low QoE).3 Other evidence for comparative harms in UC is limited to comparisons between adalimumab and infliximab or etanercept, and all outcomes were rated as very low QoE precluding any definitive conclusions.3 One pipeline drug (PF- 0423691) is more effective at the 50-mg dosage compared to placebo in managing CD (moderate QoE for clinical improvement and remission, low QoE for quality of life) with no difference in incidence of AE (low QoE).3 Thirteen studies of head-to-head comparisons of TIM agents for either CD or UC are currently in progress.3 Seven RCTs are in participants with CD, 5 RCTs are in participants with UC and 1 cohort study is in participants with both conditions. The earliest estimated completion date for any of these studies is March 2021.3

New Formulations and Indications:  Hulio, a sixth biosimilar for Humira (adalimumab), received FDA approval July 2020. This biosimilar is approved for all the indications of Humira including RA, AS, PsA, PsO (age 4 and older), hidradenitis suppurativa (age 12 and older), CD (age 6 and older), UC, uveitis (age 2 and older), and juvenile idiopathic arthritis (age 2 and older). The product will not be available in the U.S. until 2023 due to a patent agreement with AbbVie, the manufacturer of Humira.

 Cosentyx (secukinumab) received an expanded indication for treatment of adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation in June 2020.29 Previously approved indications for secukinumab include PsO, PsA, and AS.

 Taltz (ixekizumab) received an expanded indication for treating nr-axSpA in adults with objectives signs of inflammation in May 2020.30 Previously approved indications include PsO, PsA and AS.

 In March 2020, Taltz (ixekizumab) received an expanded approval for use in pediatric patients with moderate-to-severe PsO aged 6 years and older who are candidates for systemic therapy or phototherapy.30

 The FDA expanded the approved indication for canakinumab (Ilaris) in June 2020 to include treatment of active Still’s disease.31 Canakinumab had previously been approved for systemic juvenile idiopathic arthritis (JIA) in patients aged 2 years and older. According to the FDA, adult onset Still’s disease shares considerable overlap with systemic JIA, which are both characterized by fever, arthritis, rash and elevated inflammation markers.

 Guselkumab (Tremfya) received FDA approval to treat adults with active PsA.32

Author: Moretz October 2020 240

Safety:

Table 4. Description of New FDA Safety Alerts Generic Brand Month / Labeling Addition Description Name Name Year of or Change Change Vedolizumab Entyvio March 2020 Warnings and PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been Precautions reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in a vedolizumab-treated patient with multiple contributory factors has been reported in the post marketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out.

Infusion-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate. These reactions may occur with the first or subsequent infusions of vedolizumab and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur. Infliximab Remicade May 2020 Warnings and The use of infliximab at doses >5 mg/kg is contraindicated in patients with moderate or severe heart Precautions failure. A randomized, double-blind, placebo-controlled study evaluated the use of infliximab (5 mg/kg or 10 mg/kg at Weeks 0, 2, and 6) in patients with moderate or severe heart failure [New York Heart Association (NYHA) Functional Class III/IV]. Compared to patients who received placebo, there was a higher rate of mortality and a higher risk of hospitalization at Week 28 due to heart failure in patients who received the 10 mg/kg infliximab dose, and higher rates of cardiovascular adverse events in patients who received REMICADE doses of 5 mg/kg and 10 mg/kg. There have been post- marketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors (e.g., pre-existing cardiovascular disease), in infliximab-treated patients. Some of these patients have been under 50 years of age. If a decision is made to administer infliximab (≤ 5 mg/kg) to patients with moderate or severe heart failure or to administer infliximab (any approved dose) to patients with mild heart failure, they should be closely monitored during therapy, and infliximab should be discontinued if new or worsening symptoms of heart failure appear.

Author: Moretz October 2020 241

References:

1. Gartlehner G WG, Dobrescu A, et al. Targeted immune modulators: rheumatoid arthritis and ankylosing spondylitis. Portland, OR: Center for Evidence-based Policy, Oregon Health & Science University; 2020. 2. Kahwati L GK, Ali R, Gartlehner G. Targeted Immune Modulators: Plaque Psoriasis and Psoriatic Arthritis. Portland, OR: Center for Evidence-based Policy, Oregon Health & Science University; March 2020. 3. Kahwati L, et al. Targeted Immune Modulators: Crohn’s disease and Ulcerative Colitis. Portland, OR: Center for Evidence-based Policy, Oregon Health & Science University; February 2020. 4. McVeigh CM, Cairns AP. Diagnosis and management of ankylosing spondylitis. Bmj. 2006;333(7568):581-585. 5. Corbett M, Soares M, Jhuti G, et al. Tumour necrosis factor-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation. Health Technol Assess. 2016;20(9):1-334, v-vi. 6. Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2016;68(2):282-298. 7. Ward MM, Deodhar A, Gensler LS, et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis rheumatol. 2019;71(10):1599-1613. 8. van der Heijde D, Ramiro S, Landewé R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978-991. 9. Machado PM, Landewé R, Heijde DV. Ankylosing Spondylitis Disease Activity Score (ASDAS): 2018 update of the nomenclature for disease activity states. Ann Rheum Dis. 2018;77(10):1539-1540. 10. Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. Jama. 2018;320(13):1360-1372. 11. Singh JA, Saag KG, Bridges SL, Jr., et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis rheumatol. 2016;68(1):1-26. 12. Smolen JS, Landewe R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis.76(6):960-977. 13. Lexicomp® Online, Lexi-Drugs, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed July 13, 2020. 14. Micromedex® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. 2020 Available at: https://www- micromedexsolutions-com.liboff.ohsu.edu Accessed July 13, 2020. 15. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis and rheumatism. 1995;38(6):727-735. 16. Pincus T, Swearingen C, Wolfe F. Toward a multidimensional Health Assessment Questionnaire (MDHAQ): assessment of advanced activities of daily living and psychological status in the patient-friendly health assessment questionnaire format. Arthritis and rheumatism. 1999;42(10):2220-2230. 17. Maska L, Anderson J, Michaud K. Measures of functional status and quality of life in rheumatoid arthritis: Health Assessment Questionnaire Disability Index (HAQ), Modified Health Assessment Questionnaire (MHAQ), Multidimensional Health Assessment Questionnaire

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(MDHAQ), Health Assessment Questionnaire II (HAQ-II), Improved Health Assessment Questionnaire (Improved HAQ), and Rheumatoid Arthritis Quality of Life (RAQoL). Arthritis care & research. 2011;63(S11):S4-S13. 18. Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis and rheumatism. 1995;38(1):44-48. 19. Kahwati L WG, Giger K, Gartlehner G. Targeted Immune Modulators: Summary Report. Portland, OR: Center for Evidence-based Policy, Oregon Health & Science University; May 2020. 20. Corrado A, Di Bello V, d'Onofrio F, Maruotti N, Cantatore FP. Anti-TNF-alpha effects on anemia in rheumatoid and psoriatic arthritis. International Journal of Immunopathology & Pharmacology.30(3):302-307. 21. National Institute for Health and Care Excellence. Psoriasis: Assessment and Management. September 1, 2017. https://www.nice.org.uk/guidance/cg153/chapter/1-Recommendations Accessed November July 20, 2020. 22. Robinson A, Kardos M, Kimball AB. Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI): why do both? A systematic analysis of randomized controlled trials of biologic agents for moderate to severe plaque psoriasis. J Am Acad Dermatol. 2012;66(3):369-375. 23. Ashcroft DM, Wan Po AL, Williams HC, Griffiths CE. Clinical measures of disease severity and outcome in psoriasis: a critical appraisal of their quality. The British journal of dermatology. 1999;141(2):185-191. 24. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Official journal of the American College of Gastroenterology | ACG. 2018;113(4):481-517. 25. National Institute for Health and Care Excellence (NICE) Crohn’s Disease: Management. May 3, 2019. https://www.nice.org.uk/guidance/ng130 Accessed July 20, 2020. 26. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG Clinical Guideline: Ulcerative Colitis in Adults. The American journal of gastroenterology. 2019;114(3):384-413. 27. National Institute for Health and Care Excellence (NICE) Ulcerative Colitis: Management. May 2019. https://www.nice.org.uk/guidance/ng130 Accessed July 20, 2020. 28. Kahwati L eaTIMCsdaUCP, OR: Center for Evidence-based Policy, Oregon Health & Science University; February 2020. 29. Cosyntex® (Secukinumab) Injection. Prescribing Information. East Hanover, NJ: Novartis. June 2020. 30. Taltz® (ixekizumab) injection. Prescribing Information. Indianapolis, IN: Eli Lilly and Company. May 2020. 31. Ilaris® (canakinumab) for injection. Prescribing information. East Hanover, NJ: Novartis. June 2020. 32. Tremfya® (guselkumab) for injection. Prescribing Information. Horsham, PA: Janssen. July 2020.

Author: Moretz October 2020 243

Appendix 1: Current Preferred Drug List

Generic Brand Route Form PDL adalimumab HUMIRA PEN SUB-Q PEN IJ KIT Y adalimumab HUMIRA PEN CROHN'S-UC-HS SUB-Q PEN IJ KIT Y HUMIRA PEN PSOR-UVEITS-ADOL adalimumab HS SUB-Q PEN IJ KIT Y adalimumab HUMIRA(CF) PEN SUB-Q PEN IJ KIT Y adalimumab HUMIRA(CF) PEN CROHN'S-UC-HS SUB-Q PEN IJ KIT Y adalimumab HUMIRA(CF) PEN PSOR-UV-ADOL HS SUB-Q PEN IJ KIT Y adalimumab HUMIRA SUB-Q SYRINGEKIT Y adalimumab HUMIRA(CF) SUB-Q SYRINGEKIT Y adalimumab HUMIRA(CF) PEDIATRIC CROHN'S SUB-Q SYRINGEKIT Y etanercept ENBREL MINI SUB-Q CARTRIDGE Y etanercept ENBREL SURECLICK SUB-Q PEN INJCTR Y etanercept ENBREL SUB-Q SYRINGE Y etanercept ENBREL SUB-Q VIAL Y secukinumab COSENTYX PEN SUB-Q PEN INJCTR Y secukinumab COSENTYX PEN (2 PENS) SUB-Q PEN INJCTR Y secukinumab COSENTYX (2 SYRINGES) SUB-Q SYRINGE Y secukinumab COSENTYX SYRINGE SUB-Q SYRINGE Y abatacept ORENCIA CLICKJECT SUB-Q AUTO INJCT N abatacept ORENCIA SUB-Q SYRINGE N abatacept/maltose ORENCIA IV VIAL N anakinra KINERET SUB-Q SYRINGE N apremilast OTEZLA ORAL TAB DS PK N apremilast OTEZLA ORAL TABLET N baricitinib OLUMIANT ORAL TABLET N belimumab BENLYSTA IV VIAL N belimumab BENLYSTA SUB-Q AUTO INJCT N belimumab BENLYSTA SUB-Q SYRINGE N brodalumab SILIQ SUB-Q SYRINGE N canakinumab/PF ILARIS SUB-Q VIAL N certolizumab pegol CIMZIA SUB-Q KIT N certolizumab pegol CIMZIA SUB-Q SYRINGEKIT N golimumab SIMPONI ARIA IV VIAL N golimumab SIMPONI SUB-Q PEN INJCTR N golimumab SIMPONI SUB-Q SYRINGE N

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guselkumab TREMFYA SUB-Q AUTO INJCT N guselkumab TREMFYA SUB-Q SYRINGE N infliximab REMICADE IV VIAL N infliximab-abda RENFLEXIS IV VIAL N infliximab-dyyb INFLECTRA IV VIAL N ixekizumab TALTZ AUTOINJECTOR SUB-Q AUTO INJCT N ixekizumab TALTZ AUTOINJECTOR (2 PACK) SUB-Q AUTO INJCT N ixekizumab TALTZ AUTOINJECTOR (3 PACK) SUB-Q AUTO INJCT N ixekizumab TALTZ SYRINGE SUB-Q SYRINGE N natalizumab TYSABRI IV VIAL N risankizumab-rzaa SKYRIZI SUB-Q SYRINGE N risankizumab-rzaa SKYRIZI (2 SYRINGES) KIT SUB-Q SYRINGEKIT N rituximab RITUXAN IV VIAL N rituximab-abbs TRUXIMA IV VIAL N rituximab-pvvr RUXIENCE IV VIAL N sarilumab KEVZARA SUB-Q PEN INJCTR N sarilumab KEVZARA SUB-Q SYRINGE N tildrakizumab- asmn ILUMYA SUB-Q SYRINGE N tocilizumab ACTEMRA IV VIAL N tocilizumab ACTEMRA ACTPEN SUB-Q PEN INJCTR N tocilizumab ACTEMRA SUB-Q SYRINGE N tofacitinib citrate XELJANZ XR ORAL TAB ER 24H N tofacitinib citrate XELJANZ ORAL TABLET N upadacitinib RINVOQ ORAL TAB ER 24H N ustekinumab STELARA IV VIAL N ustekinumab STELARA SUB-Q SYRINGE N vedolizumab ENTYVIO IV VIAL N

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Appendix 2: Prior Authorization Criteria

Biologics for Autoimmune Diseases

Goal(s):  Restrict use of biologics to OHP funded conditions and according to OHP guidelines for use.  Promote use that is consistent with national clinical practice guidelines and medical evidence.  Promote use of high value products.

Length of Authorization:  Up to 12 months

Requires PA:  All biologics for autoimmune diseases (both pharmacy and physician-administered claims)

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Table 1. Approved and Funded Indications for Biologic Immunosuppressants. Drug Name Ankylosing Crohn’s Juvenile Plaque Psoriatic Rheumatoid Ulcerative Other Spondylitis Disease Idiopathic Psoriasis Arthritis Arthritis Colitis Arthritis Abatacept ≥2 yo ≥18 yo ≥18 yo (ORENCIA) Adalimumab ≥18 y ≥6 yo ≥2 yo ≥18 yo ≥18 yo ≥18 yo ≥18 yo Uveitis (non- (HUMIRA) and (Humira) (Humira) infectious) ≥2 yo biosimilars ≥18 yo ≥4 yo (Humira) (biosimilars) (biosimilars) HS ≥ 12 yo Anakinra ≥18 yo NOMID (KINERET) Apremilast ≥18 yo ≥18 yo Oral Ulcers (OTEZLA) associated with BD ≥ 18 yo Baricitinib ≥18 yo (OLUMIANT) Brodalumab ≥18 yo (SILIQ) Canakinumab ≥2 yo FCAS ≥4 yo (ILARIS) MWS ≥4 yo TRAPS ≥ 4 yo

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Drug Name Ankylosing Crohn’s Juvenile Plaque Psoriatic Rheumatoid Ulcerative Other Spondylitis Disease Idiopathic Psoriasis Arthritis Arthritis Colitis Arthritis HIDS ≥ 4 yo MKD ≥ 4 yo FMF ≥ 4 yo Stills Disease Certolizumab ≥18 yo ≥18 yo ≥18 yo ≥18 yo ≥18 yo Nr-axSpA ≥ 18 yo (CIMZIA) Etanercept ≥18 yo ≥2 yo ≥4 yo ≥18 yo ≥18 yo (ENBREL) and (Enbrel) biosimilars ≥18 yo (biosimilars) Golimumab ≥18 yo ≥18 yo ≥18 yo ≥18 yo (SIMPONI and (Simponi) SIMPONI ARIA) Guselkumab ≥18 yo ≥18 yo (TREMFYA) Infliximab ≥18 yo ≥6 yo ≥18 yo ≥18 yo ≥18 yo ≥6 yo (REMICADE) and biosimilars Ixekizumab ≥ 18 yo ≥6 yo >18 yo Nr-axSpA ≥ 18 yo (TALTZ) Risankizumab- ≥18 yo rzaa (SKYRIZI) Rituximab ≥18 yo CLL ≥18 yo (RITUXAN) NHL ≥18 yo and GPA ≥2yo biosimilars MPA ≥ 2 yo Pemphigus Vulgaris ≥18 yo (Rituxan only) Sarilumab >18 yo (KEVZARA) Secukinumab ≥18 yo ≥18 yo ≥18 yo Nr-AxSpA ≥18 yo (COSENTYX) Tildrakizumab- ≥18 yo asmn (ILUMYA) Tocilizumab ≥2 yo ≥18 yo CRS >2 yo (ACTEMRA) GCA >18 yo Tofacitinib >18 yo ≥18 yo ≥18 yo (XELJANZ) Upadacitinib ≥18 yo (RINVOQ) Ustekinumab ≥ 18 yo ≥12 yo ≥18 yo ≥18 yo (STELARA) Author: Moretz October 2020 247

Drug Name Ankylosing Crohn’s Juvenile Plaque Psoriatic Rheumatoid Ulcerative Other Spondylitis Disease Idiopathic Psoriasis Arthritis Arthritis Colitis Arthritis Vedolizumab ≥18 yo ≥18 yo (ENTYVIO) Abbreviations: BD = Bechet’s Disease; CLL = Chronic Lymphocytic Leukemia; CRS = Cytokine Release Syndrome; FCAS = Familial Cold Autoinflammatory Syndrome; FMF = Familial Mediterranean Fever; GCA = Giant Cell Arteritis; GPA = Granulomatosis w ith Polyangiitis (Wegener’s Granulomatosis); HIDS: Hyperimmunoglobulin D Syndrome; HS: Hidradenitis Suppurativa; MKD = Mevalonate Kinase Deficiency; MPA = microscopic polyangiitis; MWS = Muckle-Wells Syndrome; NHL = Non-Hodgkin’s Lymphoma; NOMID = Neonatal Onset Multi-Systemic Inflammatory Disease; nr-axSpA = non-radiographic axial spondyloarthritis; TRAPS = Tumor Necrosis Factor Receptor Associated Periodic Syndrome; yo = years old.

Approval Criteria

1. What diagnosis is being treated? Record ICD-10 code.

2. Is the diagnosis funded by OHP? Yes: Go to #3 No: Pass to RPh. Deny; not funded by the OHP.

3. Is this a request for continuation of therapy? Yes: Go to Renewal Criteria No: Go to #4

4. Is the request for a non-preferred product and will the Yes: Inform prescriber of No: Go to #5 prescriber consider a change to a preferred product? preferred alternatives.

Message:  Preferred products are reviewed for comparative effectiveness and safety by the Oregon Pharmacy and Therapeutics Committee.

5. Has the patient been annually screened for latent or active Yes: Go to #6 No: Pass to RPh. Deny; medical tuberculosis and if positive, started tuberculosis treatment? appropriateness. May approve for up to 3 months to allow time for screening.

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Approval Criteria

6. Is the diagnosis Juvenile Idiopathic Arthritis, non-Hodgkin Yes: Approve for length of No: Go to #7 Lymphoma, Chronic Lymphocytic Leukemia, Non- treatment. infectious Posterior Uveitis, or one of the following syndromes:  Familial Cold Autoinflammatory Syndrome  Muckel-Wells Syndrome  Neonatal Onset Multi-Systemic Inflammatory Disease  Tumor Necrosis Factor Receptor Associated Periodic Syndrome  Hyperimmunoglobulin D Syndrome  Mevalonate Kinase Deficiency  Familial Mediterranean Fever  Giant Cell Arteritis  Cytokine Release Syndrome  Non-radiographic axial spondyloarthritis  Oral ulcers associated with Behcet’s Disease  Still’s disease

AND Is the request for a drug FDA-approved for one of these conditions as defined in Table 1?

7. Is the diagnosis ankylosing spondylitis and the request for Yes: Go to #8 No: Go to #9 a drug FDA-approved for this condition as defined in Table 1?

8. If the request is for a non-preferred agent, has the patient Yes: Approve for up to 6 No: Pass to RPh. Deny; medical failed to respond or had inadequate response to a months. appropriateness. Humira® product or an Enbrel® product after a trial of at least 3 months? Document therapy with dates.

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Approval Criteria

9. Is the diagnosis plaque psoriasis and the request for a Yes: Go to #10 No: Go to #12 drug FDA-approved for this condition as defined in Table 1?

Note: Only treatment for severe plaque psoriasis is funded by the OHP.

10. Is the plaque psoriasis severe in nature, which has Yes: Go to #11 No: Pass to RPh. Deny; not resulted in functional impairment (e.g., inability to use funded by the OHP. hands or feet for activities of daily living, or significant facial involvement preventing normal social interaction) and one or more of the following:  At least 10% body surface area involvement; or  Hand, foot or mucous membrane involvement?

11. Has the patient failed to respond or had inadequate Yes: Approve for up to 6 No: Pass to RPh. Deny; medical response to each of the following first-line treatments: months. appropriateness.  Topical high potency corticosteroid (e.g., betamethasone dipropionate 0.05%, clobetasol propionate 0.05%, fluocinonide 0.05%, halcinonide Document each therapy with 0.1%, halobetasol propionate 0.05%; triamcinolone dates. 0.5%); and  At least one other topical agent: calcipotriene, tazarotene, anthralin; and  Phototherapy; and  At least one other systemic therapy: acitretin, cyclosporine, or methotrexate; and  One biologic agent: either a Humira® product or an Enbrel® product for at least 3 months?

Author: Moretz October 2020 250

Approval Criteria

12. Is the diagnosis rheumatoid arthritis or psoriatic arthritis Yes: Go to #13 No: Go to #16 and the request for a drug FDA-approved for these conditions as defined in Table 1?

13. Has the patient failed to respond or had inadequate Yes: Go to #14 No: Pass to RPh. Deny; medical response to at least one of the following medications: appropriateness.  Methotrexate, leflunomide, sulfasalazine or

hydroxychloroquine for ≥ 6 months; or Document each therapy with  Have a documented intolerance or contraindication dates. Biologic therapy is recommended to disease-modifying antirheumatic drugs in combination with DMARDs (DMARDs)? (e.g. methotrexate) for those who AND If applicable, document have had inadequate response  Had treatment failure with at least one biologic intolerance or with DMARDs. agent: a Humira® product or an Enbrel® product for contraindication(s). at least 3 months?  AND  Is the patient on concurrent DMARD therapy with plans to continue concomitant use?

14. Is the request for tofacitinib, baricitinib, or upadacitinib? Yes: Go to #15 No: Approve for up to 6 months

Author: Moretz October 2020 251

Approval Criteria

15. Is the patient currently on other biologic therapy or on a Yes: Pass to RPh. Deny; No: Approve baricitinib or potent immunosuppressant like azathioprine, tacrolimus or medical appropriateness. upadacitinib for up to 6 months. cyclosporine? Approve tofacitinib for up to 6 months at a maximum dose of 10 Note: Tofacitinib, baricitinib, and upadacitinib may be used or 11 mg daily for Rheumatoid concurrently with methotrexate or other nonbiologic Arthritis OR DMARD drugs. Tofacitinib, baricitinib, or upadacitinib are 10 mg twice daily for 8 weeks not recommended to be used in combination with other then 5 or 10 mg twice daily for JAK inhibitors, biologic DMARDs, azathioprine, or Ulcerative Colitis cyclosporine.

16. Is the request for adalimumab in an adult with moderate- Yes: Go to # 17 No: Go to # 18 to-severe Hidradenitis Suppurativa (HS)?

17. Has the patient failed to respond, had inadequate Yes: Approve for up to 12 weeks No: Pass to RPh. Deny; medical response, or do they have an intolerance or of therapy appropriateness. contraindication to a 90 day trial of conventional HS therapy (e.g. oral antibiotics)?

Note: Treatment of moderate-to-severe HS with adalimumab is funded on the Prioritized List of Health Services per Guideline Note 198

18. Is the diagnosis Crohn’s disease or ulcerative colitis and Yes: Go to # 19 No: Go to # 20 the request for a drug FDA-approved for these conditions as defined in Table 1?

Author: Moretz October 2020 252

Approval Criteria

19. Has the patient failed to respond or had inadequate Yes: Approve for up to 12 No: Pass to RPh. Deny; medical response to at least one of the following conventional months. appropriateness. immunosuppressive therapies for ≥6 months:  Mercaptopurine, azathioprine, or budesonide; or  Have a documented intolerance or contraindication to Document each therapy with conventional therapy? dates. AND  Has the patient tried and failed a 3 month trial of a Humira® product? If applicable, document intolerance or contraindication(s).

20. Is the diagnosis for an FDA approved diagnosis and age Yes: Approve for length of No: Pass to RPh. Deny; medical as outlined in Table 1, and is the requested drug rituximab treatment. appropriateness. for induction or maintenance of remission?

Renewal Criteria

1. Is the request for treatment of psoriatic arthritis or Yes: Go to # 4 No: Go to # 2 rheumatoid arthritis?

2. Is the request for continuation of adalimumab to treat Yes: Go to # 3 No: Go to # 5 moderate-to-severe Hidradenitis Suppurativa in an adult?

Author: Moretz October 2020 253

Renewal Criteria

3. Has the patient had clear evidence of response to Yes: Approve for an additional No: Pass to RPh. Deny; medical adalimumab therapy as evidenced by: 12 weeks of therapy appropriateness. A) a reduction of 25% or more in the total abscess and inflammatory nodule count, AND B) no increase in abscesses and draining fistulas.

4. Has the patient been adherent to both biologic and Yes: Go to #5 No: Pass to RPh. Deny; medical DMARD therapy (if DMARD therapy has been prescribed appropriateness. in conjunction with the biologic therapy)?

5. Has the patient’s condition improved as assessed by the Yes: Approve for 6 months. No: Pass to RPh; Deny; medical prescribing provider and provider attests to patient’s appropriateness. Document baseline assessment improvement. and provider attestation

received.

P&T/DUR Review: 10/20 (DM); 2/20; 5/19; 1/19; 1/18; 7/17; 11/16; 9/16; 3/16; 7/15; 9/14; 8/12 Implementation: TBD; 7/1/2019; 3/1/19; 3/1/18; 9/1/17; 1/1/17; 9/27/14; 2/2

Natalizumab (Tysabri®) Goal(s):  Approve therapy for covered diagnosis which are supported by the medical literature.

Length of Authorization:  Up to 12 months

Requires PA:  Natalizumab (Tysabri®)

Covered Alternatives:  Preferred alternatives listed at www.orpdl.org

Author: Moretz October 2020 254

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Has the patient been screened for Jason Cunningham Yes: Go to #3 No: Pass to RPH; Deny for (JC) Virus? medical appropriateness

3. Does the patient have a diagnosis of relapsing multiple Yes: Go to #4 No: Go to #6 sclerosis (CIS, RRMS, or SPMS)?

4. Has the patient failed trials for at least 2 drugs indicated Yes: Document drug and dates trialed: No: Pass to RPh. Deny; for the treatment of RRMS? 1.______(dates) medical appropriateness. 2.______(dates)

Go to #5

5. Is the medication being prescribed by or in consultation Yes: Approve for 12 months No: Pass to RPH; Deny for with a neurologist? medical appropriateness.

6. Does the patient have Crohn’s Disease? Yes: Go to #7 No: Pass to RPH; Deny for medical appropriateness.

7. Has the patient been screened for latent or active Yes: Go to #8 No: Pass to RPH; Deny for tuberculosis and if positive, started tuberculosis treatment? medical appropriateness.

Author: Moretz October 2020 255

Approval Criteria

8. Has the patient failed to respond to at least one of the Yes: Approve for up to 12 months. No: Pass to RPh. Deny; following conventional immunosuppressive therapies for ≥6 medical appropriateness. months: Document each therapy with dates.  Mercaptopurine, azathioprine, or budesonide; or  Have a documented intolerance or contraindication If applicable, document intolerance or to conventional therapy? contraindication(s).  AND  Has the patient tried and failed a 3 month trial of Humira? P&T / DUR Action: 10/20 (DM); 11/17 Implementation: 1/1/18

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Policy Evaluation: Provider Administered Biologics for Autoimmune Conditions

Purpose of the Evaluation: This policy evaluation examines the impact of implementing a prior authorization (PA) for provider administered drugs in the Biologics for Autoimmune Conditions preferred drug list (PDL) class. This PA requierement was implemented in October 2018, and prior to this date PA had only been required for claims when billed through pharmacies rather than provider offices.

Research Questions: 1. Since implementation of the PA for provider administered biologics, has utilization of biologics for autoimmune conditions changed for new start patients? 2. Has prior utilization of Disease-Modifying Anti-Rheumatic Drug (DMARD) therapy increased for patients initiating therapy with a biologic agent? 3. Has utilization of concurrent DMARD therapy changed significantly for patients prescribed biologics? 4. What proportion of patients on prior biologic treatment had an interruption in therapy after implementation of the PA? 5. Was there any change in overall hospitalization or ER visits for the total population or for patients with an interruption in therapy?

Conclusions: 1. Biologic utilization: o Overall, the total number of patients with a paid or denied claim for a biologic decreased from 229 in the year prior to the policy implementation to 154 patients in the year after the PA requirement for provider administered biologic therapies for autoimmune conditions. o In new start patients, the proportion of patients with paid claims decreased after the policy implementation from 47% to 39%. New start patients with an initial denied claim accounted for 52% and 61% of patients in the year before and after implementation of the PA. 2. History of systemic DMARD therapy in new start patients: o In patients newly started on a biologic therapy, the number of patients with claims for prior DMARD therapy decreased from 36.7% (n=84) in the year before to 22.1% (n=34) in the year after the policy implementation. 3. Concurrent DMARD therapy: o The proportion of patients with combination biologic and DMARD therapy for at least 3 weeks decreased slightly after implementation of the PA policy for provider administered drugs from 19% to 15% in patients with an initial paid claim. 4. Interruptions in therapy: o In patients with a prior history of biologic use, only 2 patients (10%) with an initial denial after implementation of the PA policy for provider administered drugs did not have a subsequent paid claim within 90 days. o Of new start patients with an initial denied biologic claim, the proportion of patients who did not have a subsequent paid claim for a biologic and had not switched to a DMARD was unchanged after implementation of the PA for provider administered drugs. Approximately 48% to 50% of Author: Sarah Servid, PharmD October 2020 257 patients did not have a subsequent paid claim for a biologic and had not switched to a systemic DMARD. The majority of these patients did not have a PA requested submitted by their provider, and it is unclear what specific diagnosis was associated with these claims. However, the most common diagnoses identified in patients with a biologic claim included psoriasis and rheumatoid arthritis. Psoriasis is classified only as funded on the Health Evidence Review Commission prioritized list when defined as severe disease which causes functional impairment and affects either more than 10% body surface area or involves mucus membranes. 5. Frequency of hospitalizations and emergency department visits: o Hospitalizations were infrequent in patients with claims for biologic therapy, but emergency department visits were slightly more common in the year after policy implementation. However, the proportion of emergency department visits was similar upon comparison of patients with a paid or denied index event in the year after the policy implementation (20% vs. 21%), and visits associated with autoimmune conditions occurred in only 1-3% of the population. No patients with a denied provider administered claim had a subsequent hospitalization or emergency department visit for the same diagnosis within 90 days of the denial.

Recommendations:  No policy changes recommended based on current data. Continue to monitor trends in utilization.

Background: In October 2018, prior authorization was implemented for biologics for autoimmune conditions when billed as a provider administered drug. Prior to October 2018, PA had only applied if the drug was billed as a pharmacy claim. However a significant proportion of drugs in this class are administered intravenously and can be billed by a provider when administered to a patient as part of an office visit. In order to minimize interruptions in therapy, the PA for provider administered claims applied only to patients initiating new therapy with a biologic. For patients with previous history of fee-for-service (FFS) claims for a provider administered biologic medication, patients are allowed to continue on their current therapy if the prescriber provides documentation of disease improvement. This review evaluates the impact of administering a PA for provider administered claims in this drug class.

Medications in this class include biologics for treatment of rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, Crohn’s disease and ulcerative colitis. Individual medications are listed in Appendix 1, and the preferred biologic medications at the time of the FFS provider administered drug policy implementation were adalimumab and etanercept. Because preferred therapies are primarily self-administered, they are typically billed as a pharmacy claim, whereas non-preferred therapies may be billed via pharmacies or in provider offices depending on the drug. Current PA criteria are indication specific and require documentation of the all following information:  Documentation that the requested agent be approved by the Food and Drug Administration for the condition,  Documentation that the diagnosis is funded on the prioritized list (e.g., moderate to severe plaque psoriasis)  Documentation of trial and failure or contraindication to other DMARD treatments and preferred biologic therapies when indicated  Documented use of concomitant DMARD therapy if appropriate (e.g., rheumatoid or psoriatic arthritis)

Methods: This uncontrolled before-and-after analysis compared utilization of biologics in a historical control group in the year prior to implementation of the PA (from 10/1/17 to 9/30/18) to patients after implementation of the policy (from 10/1/18 to 9/30/19). The index event (IE) was defined as the first biologic medication claim in the reporting period. Patients were included if they had a paid or denied FFS pharmacy claim, outpatient medical claim, or professional medical claim for a biologic in Appendix 1 (PDL class: Biologics for Autoimmune Conditions; Table A1). Patients with denied pharmacy claims were only included if denial was due to a PA requirement (error 3002 ‘NDC requires PA’ or error 3022 ‘Non-preferred drug’). Patients were excluded if they had denied pharmacy claims with denials Author: Servid October 2020 258 due to other reasons listed in Appendix 1 (Table A5). Patients with denied provider administered claims were included only if they had a denial indicating the claim was stopping for PA (error 4173) and did not have a denial for other reasons listed in Appendix 1 (Table A4). Patients were excluded if they had less than 75% Medicaid enrollment during the 6 months before to 6 months after the IE to ensure completeness of reporting. Patients were excluded if they had benefit plans indicating Medicare coverage (BMM, BMD, MED) or limited drug coverage (CWM, MND, SMF, SMB).

The following definitions were used for the analysis:  New start patients: no prior biologic therapy (based on both pharmacy and provider administered claims) in the 6 months before the IE  Patients with a prior history of biologic therapy: patients with pharmacy or provider administered claims for a biologic in the 6 months before the IE  Prior DMARD therapy: Prior DMARD therapy was assessed based on pharmacy claims in the 6 months before the IE. DMARD therapy was evaluated based on proportion of patients with prior claims and average duration of therapy. Systemic DMARDs of interest are listed in Appendix 1 (Table A1).  Relevant diagnoses: For provider administered claims, the relevant diagnosis was identified using the diagnosis submitted with the IE. For pharmacy claims, relevant conditions were identified based on ICD-10 codes within the 6 months before or 6 months after the IE (Table A2). For pharmacy claims, patients may be counted more than once if they have multiple diagnoses.  Days’ Supply: Days’ supply for pharmacy claims was defined based on information submitted with the claim, and days’ supply for medical claims was defined based on the estimated maintenance dose for each agent (Table A3). If maintenance dose varied by condition, the longest estimate of days’ supply was used to provide a more conservative estimate of treatment adherence.  Duration of therapy: Duration was defined using the number of covered days in the 6 months following the IE.  Combination DMARD therapy: Combination therapy was defined as patients with paid claims for at least 21 days of overlapping therapy for both a systemic DMARD and biologic in the 6 months following the index event with no more than a 7 day gap in coverage. Analysis of concomitant DMARDs was limited to pharmacy claims as most therapies oral or self-injectable.

Author: Servid October 2020 259 Results: Figure 1 shows the month over month trend of patients with paid claims for a biologic. The PA policy for provider administered drugs was implemented in October 2018. Compared to the number of patients prescribed biologic therpy in the year prior to policy implementation, since October 2018 the number of patients with paid claims for biologic therapy has decreased.

Figure 1. Per-member per-month (PMPM) count of unique patients with paid pharmacy or provider administered claims for a biologic

Patients with a FFS Pharamcy or Provider Administered Drug Claim for a Biologic (PMPM x10,000, duals excluded) 14.0

12.0

10.0

8.0

6.0

4.0

2.0 Unique Patients PMPM PA 0.0

Author: Servid October 2020 260 Baseline demographics for patients prescribed a biologic for an autoimmune condition are listed in Table 1. The majority of patients identified were female adults. Sixty-five to 75% of patients were classified as new starts with no history of biologic therapy within the 6 months before their first claim. Provider administered claims accounted for 35% of all biologic claims before and 27% of claims after the policy implementation.

Table 1. Baseline demographics Before After Total IE Total IE N= 303 % 235 %

Age (years) Average (min - max) 37 (3-64) 38 (6-63) <18 years 33 10.9% 15 6.4% ≥19 years 270 89.1% 220 93.6%

Female 204 67.3% 154 65.5%

Ethnicity White 117 38.6% 89 37.9% American Indian/Alaskan Native 89 29.4% 80 34.0% Unknown 70 23.1% 54 23.0% Other 27 8.9% 12 5.1%

New Start 229 75.6% 154 65.5% Prior Biologic Therapy 74 24.4% 81 34.5%

Index Event Type Pharmacy 196 64.7% 170 72.3% Provider Administered 107 35.3% 65 27.7%

Table 2 shows the proportion of paid and denied claims before and after policy implementation. Overall, the total number of patients prescribed a biologic decreased in the year after policy implementation (229 vs. 154 patients in the year after implementation). Similarly, the proportion of patients with paid claims decreased after implementation of the policy from 47% to 39% in new start patients and from 89% to 75% in patients with a prior history of biologic therapy.

Table 2. Changes in proportion of paid and denied biologic claims before and after policy implementation New Start Patients Prior Biologic Therapy Before After Before After N= 229 % 154 % 74 % 81 % Paid IE 108 47.2% 60 39.0% 66 89.2% 61 75.3% Denied IE 121 52.8% 94 61.0% 8 10.8% 20 24.7%

Author: Servid October 2020 261 Approval and denial rates in a subgroup of patients with a prior history of DMARD therapy are shown in Table 3. In new start patients, there were fewer patients with a history of DMARD therapy in the year after policy implementation (n=34 vs. 84 patients in the year before the policy) and a greater proportion of those patients had denied claims compared to before the policy implementation (75% vs. 57%). In patients with a prior history of biologic therapy, the proportion of patients with a denied claim increased by 24% after policy implementation. In accordance with current guidelines, renewal criteria for ongoing treatment of rheumatoid or psoriatic arthritis requires concomitant use of both a biologic and DMARD therapy unless the patient has contraindications or intolerances to systemic DMARDs.

Table 3. Use of prior DMARD therapy New Start Patients Prior Biologic Therapy Before After Before After N= 84 34 28 29 Paid IE 36 42.9% 8 23.5% 28 100% 22 75.9% Denied IE 48 57.1% 26 76.5% 0 0% 7 24.1%

Common diagnoses in patients with claims for biologic therapy are listed in Table 4. Diagnoses must be submitted on provider administered claims, but are not present on pharmacy claims. Therefore, diagnoses were categorized by the first 3 digits of the ICD-10 code on the IE for provider administered claims and based on any relevant diagnosis of interest in the 6 months before or 6 months after the IE for pharmacy claims. The most common conditions included psoriasis, rheumatoid arthritis, and Crohn’s disease. Overall, there was a larger proportion of denied claims for patients with a diagnosis of psoriasis. Psoriasis is classified only as funded on the Health Evidence Review Commission prioritized list when defined as severe disease which causes functional impairment and affects either more than 10% body surface area or involves mucus membranes. The proportion of patients with paid versus denied claims for each condition was overall similar before and after the policy implementation.

Table 4. Common diagnosis occurring in at least 1% of patients during the reporting period Before After Total IE Paid IE Denied IE Total IE Paid IE Denied IE 30 N= 3 % 174 % 129 % 235 % 121 % 114 % Diagnosis 1 L40 Psoriasis 75 24.8% 27 15.5% 48 37.2% 59 25.1% 24 19.8% 35 30.7% 2 M06 Other rheumatoid arthritis 68 22.4% 41 23.6% 27 20.9% 50 21.3% 27 22.3% 23 20.2% 3 M05 Rheumatoid arthritis with rheumatoid factor 47 15.5% 21 12.1% 26 20.2% 40 17.0% 17 14.0% 23 20.2% 4 K50 Crohn's disease [regional enteritis] 52 17.2% 38 21.8% 14 10.9% 37 15.7% 19 15.7% 18 15.8% 5 M45 Ankylosing spondylitis 11 3.6% 3 1.7% 8 6.2% 15 6.4% 6 5.0% 9 7.9% 6 K51 Ulcerative colitis 21 6.9% 18 10.3% 3 2.3% 12 5.1% 9 7.4% 3 2.6% 7 M08 Juvenile arthritis 13 4.3% 2 1.1% 11 8.5% 8 3.4% 4 3.3% 4 3.5% 8 G35 Multiple sclerosis 9 3.0% 9 5.2% 0.0% 8 3.4% 8 6.6% 0.0% 9 Z51 Encounter for other aftercare and medical care 3 1.0% 3 1.7% 0.0% 5 2.1% 5 4.1% 0.0% 10 C83 Non-follicular lymphoma 2 0.7% 2 1.1% 0.0% 3 1.3% 3 2.5% 0.0% 11 M32 Systemic lupus erythematosus (SLE) 3 1.0% 3 1.7% 0.0% 2 0.9% 2 1.7% 0.0% Author: Servid October 2020 262 Table 5 shows changes in utilization for preferred and non-preferred products. PA is required for both preferred and non-preferred therapies, but preferred therapies are subcutaneously administered and more likely to be billed as a pharmacy claim compared to some non-preferred IV therapies which are more likely to be administered in a provider office. Overall, the proportion of requests for preferred and non-preferred products did not change for either new start patients or patients with a history of biologic use after implementation of the PA for provider administered drugs. For new start patients, preferred biologics accounted for 42-44% of patient requests and non-preferred therapies represented 56-58% of requests. Interestingly, in patients with a prior history of biologic use, there was a higher proportion of patients with claims for preferred therapy (54-56%) compared to the new start population.

After implementation of the policy, there was little change in the proportion of new start patients with a paid claim for a preferred or non-preferred biologic. Preferred subcutaneous products are most likely to be dispensed via pharmacy claims and may be unaffected by implementation of this policy. However, for new start patients requesting a non-preferred product, the proportion of denials was slightly higher after implementation of the policy (37%) compared to before PA implementation (26%). Many non-preferred products are intravenous and are more likely to be affected by a PA for provider administered drugs. The largest changes were observed in patients with claims for adalimumab and infliximab.

In patients with a history of biologic use, the proportion of patients with paid claims was unchanged for preferred and non-preferred. Prior to policy implementation, providers were encouraged to submit PA requests for patients on current therapy, and patients were grandfathered if the provider attested to ongoing benefit with their current therapy. For patients with a history of biologic use, patients with denied claims were infrequent but more than doubled after implementation of a PA for provider administered claims (n=8 patients before and 20 patients after the policy implementation). After implementation of PA for provider administered drugs, 11 patients had denials for preferred products and 9 had denials for non-preferred products. The small number of patients included in this analysis significantly limits interpretation of these results.

Table 5. Preferred and non-preferred utilization of pharmacy and provider administered claims Before After Total IE Paid IE Denied IE Total IE Paid IE Denied IE New Start Patients N= 229 % 108 % 121 % 154 % 560 % 94 % Preferred biologics 101 44.1% 11 10.2% 90 74.4% 65 42.2% 6 10.0% 59 62.8% adalimumab 71 31.0% 9 8.3% 62 51.2% 37 24.0% 4 6.7% 33 35.1% etanercept 30 13.1% 2 1.9% 28 23.1% 28 18.2% 2 3.3% 26 27.7%

Non-preferred biologics 128 55.9% 97 89.8% 31 25.6% 89 57.8% 54 90.0% 35 37.2% rituximab 21 9.2% 21 19.4% 0.0% 21 13.6% 21 35.0% 0.0% infliximab 47 20.5% 45 41.7% 2 1.7% 20 13.0% 16 26.7% 4 4.3% certolizumab pegol 9 3.9% 2 1.9% 7 5.8% 7 4.5% 1 1.7% 6 6.4% secukinumab 2 0.9% 0.0% 2 1.7% 6 3.9% 1 1.7% 5 5.3% vedolizumab 8 3.5% 8 7.4% 0.0% 4 2.6% 3 5.0% 1 1.1% natalizumab 6 2.6% 5 4.6% 1 0.8% 5 3.2% 3 5.0% 2 2.1% tocilizumab 6 2.6% 6 5.6% 0.0% 1 0.6% 1 1.7% 0.0% other non-preferred biologics* 29 12.7% 10 9.3% 19 15.7% 25 16.2% 8 13.3% 17 18.1%

Author: Servid October 2020 263 Patients with a prior history of biologic use N= 74 % 66 % 8 % 81 % 61 % 20 % Preferred biologics 40 54.1% 37 56.1% 3 37.5% 45 55.6% 34 55.7% 11 55.0% adalimumab 18 24.3% 17 25.8% 1 12.5% 21 25.9% 17 27.9% 4 20.0% etanercept 22 29.7% 20 30.3% 2 25.0% 24 29.6% 17 27.9% 7 35.0%

Non-preferred biologics 34 45.9% 29 43.9% 5 62.5% 36 44.4% 27 44.3% 9 45.0% infliximab 12 16.2% 12 18.2% 0.0% 12 14.8% 11 18.0% 1 5.0% other non-preferred biologics* 22 29.7% 17 25.8% 5 62.5% 24 29.6% 16 26.2% 8 40.0%

* The proportion of patients with claims for other biologics in the class was less than 2% for each other drug

Table 6 describes duration of combination DMARD therapy. Of the patients with a claim for a biologic drug for an autoimmune condition, approximately 15% to 19% of patients had concomitant use of a systemic DMARD for at least 21 days. The average duration of combination therapy was 73 to 80 days in the 6 months following a paid index event. The majority of patients with combination DMARD therapy had a diagnosis of rheumatoid or psoriatic arthritis. However, these patients accounted for only 29% to 33% of all patients with a diagnosis of rheumatoid or psoriatic arthritis who were prescribed biologic therapy.

Table 6. Concurrent DMARD therapy in the 6 months after the IE (new start and continuous users). Before After Paid IE Denied IE Paid IE Denied IE N= 174 % 129 % 121 % 114 %

All patients with combination DMARD therapy 33 19.0% 13 10.1% 18 14.9% 11 9.6% Mean duration of combination DMARD therapy (days) 80 54 73 52 Median duration (days) (interquartile range) 52 (30-138) 53 (30-62) 57 (28-89) 33 (29-57)

Patients with diagnosis of rheumatoid or psoriatic arthritis 72 41.4% 72 55.8% 52 43.0% 60 52.6% …And with combination DMARD therapy 24 33.3% 10 13.9% 15 28.8% 7 11.7%

Of new start patients with an initial denied claim, approximately 41% to 43% of patients had a paid claim for a biologic within 30 days (Table 7). In patients with a history of prior biologic use, the proportion of patients with a subsequent paid claim for a biologic was slightly higher (62-65%). Only a small proportion of patients (1-2%) switched to a systemic DMARD therapy after requesting a biologic drug. In the majority of patients without a subsequent paid claim, a PA was never requested. In new start patients, about 12-15% of patients had a PA approved, but no claims were ever billed in the 90 days following an initial denial. Hospitalizations were infrequent, but for patients who never received therapy, emergency department visits occurred in 8% of patients (n=10) before implementation of the policy and 11% of patients (n=10) after implementation of the policy.

Author: Servid October 2020 264 Table 7. PA status for denied IE Before After New Start Prior Biologic New Start Prior Biologic N (Denied IE) = 121 % 8 % 94 % 20 %

IE Denied Claim Biologic claim paid within 30 days 49 40.5% 5 62.5% 40 42.6% 13 65.0% Biologic claim paid within 31-90 days 10 8.3% 2 25.0% 4 4.3% 4 20.0%

IE Denied with no paid biologic claim within 90 days 62 51.2% 1 12.5% 50 53.2% 3 15.0% Switch to DMARD* within 30 days 2 1.7% 0 0.0% 1 1.1% 0 0.0% Switch to DMARD* within 31-90 days 2 1.7% 0 0.0% 2 2.1% 0 0.0%

IE Denied with no paid biologic AND not switched to DMARD within 90 days 58 47.9% 1 12.5% 47 50.0% 3 15.0% PA not requested 5 days before or 90 days after the denied claim 40 33.1% 1 12.5% 36 38.3% 2 10.0% PA denied in the 5 days before or 90 days after the initial denied claim 0 0.0% 0 0.0% 0 0.0% 0 0.0% PA approved in the 5 days before or 90 days after the initial denied claim 18 14.9% 0 0.0% 11 11.7% 1 5.0%

Never received drug and had diagnosis of cancer on the IE¥ 0 0.0% 0 0.0% 0 0.0% 0 0.0% Hospitalization within 90 days of the denied IE 0 0.0% 0 0.0% 1 1.1% 0 0.0% Emergency department visit within 90 days of the denied IE 10 8.3% 1 12.5% 10 10.6% 0 0.0%

*Switching therapy was defined as patients having a paid pharmacy claim for a new DMARD following a biologic denial in patients with no prior DMARD therapy in the 6 months before the denial. ¥Cancer diagnoses defined as ICD-10 codes beginning with C

Overall incidence of hospitalizations and emergency department visits in the 90 days following the IE are listed in Table 8. Hospitalizations were infrequent, and emergency department visits were only slightly more common in patients with a denied IE the year after policy implementation. However, the proportion of emergency department visits was similar between patients with paid or denied index events in the year after the policy implementation, and the proportion of visits due to autoimmune conditions was small with similar rates before and after the policy implementation. No patients with a denied provider administered claim had a subsequent hospitalization or emergency department visit for the same diagnosis. For provider administered claims, diagnoses were matched based on the first 3 letters of the ICD-10 code. This indicates that emergency department visits and hospitalizations were likely unrelated to the current policy.

Author: Servid October 2020 265 Table 8. Assessment of potential unintended harms and safety signals after implementation of the policy. Before After Paid IE Denied IE Paid IE Denied IE N= 174 % 129 % 121 % 114 %

Any hospitalization 8 4.6% 0 0.0% 7 5.8% 1 0.9% Any emergency department visit 40 23.0% 20 15.5% 24 19.8% 24 21.1%

Hospitalization due to an autoimmune condition 4 2.3% 0 0.0% 2 1.7% 0 0.0% Emergency department visit due to an autoimmune condition 2 1.1% 1 0.8% 3 2.5% 1 0.9%

Provider Administered Claims Only Hospitalization with same diagnosis as IE 5 2.9% 0 0.0% 3 2.5% 0 0.0% Emergency Department visit with same diagnosis as IE 4 2.3% 0 0.0% 2 1.7% 0 0.0%

Limitations: There are several inherent limitations for claims-based analyses:  Potential for inaccurate or missing data: This analysis was based on paid and denied claims for biologic therapy. However, provider administered claims can only be billed after administration of the medication to the patient. In order to get a guarantee of payment from an insurance, the provider will request a prior authorization before administering the medication. However, if this PA request is denied, the provider likely will not bill for the service. Because this analysis was based on paid or denied claims, there is potential for missing data in which a provider submitted a PA and no subsequent provider administered claims were billed. The observed decrease in utilization after implementation of the policy may be at least partially due to this data, which was not captured in this analysis. An evaluation was conducted for patients with denied PAs, and no patients were identified who were not already captured in this analysis. However, it is possible that there could be methodological limitations with identification of denied provider administered PAs.  Delays in billing: Decrease in utilization after implementation of the policy may be due to lag in billing rather than change in prescribing patterns. While the majority of provider administered claims are billed within 6 months of the provider visit and should be captured in this analysis, providers may continue to submit medical claims after that date. Similarly, there may be a lag in billing for medical visits including emergency department visits and hospitalizations.  Days’ supply estimates: Days’ supply for medical claims was defined based on the estimated maintenance dose for each agent which may be inaccurate. For pharmacy claims, duration of therapy estimates were based on the days’ supply submitted by the pharmacy, and for medications with infrequent dosing, there could be variability in how pharmacies estimate days’ supply for the medication. In particular, days’ supply for concomitant DMARD therapy may be inaccurate (e.g., methotrexate is typically given weekly rather than daily).  Limitations for combination DMARD therapy: Many systemic DMARDs are self-administered, and evaluation of combination DMARD and biologic use did not include patients who were getting provider administered DMARD therapy such as injectable methotrexate.  Diagnostic accuracy: Diagnoses are required on provider administered claims, but are not available for pharmacy claims. For pharmacy claims, diagnoses identified may not accurately reflect the patient’s true diagnoses and may be inaccurate or incomplete. For provider administered claims, claims are submitted with a single primary diagnoses which may not reflect all relevant conditions for patients with multiple diagnoses. Author: Servid October 2020 266  Confounding factors: There may be many other, unidentified factors associated with billing or prescribing patterns which could impact or influence the observed trends in claims. For example, this analysis does not account for changes in Medicaid provider enrollement or the patient’s disease severity, both of which may have a significant impact on prescribing. Because this population is small, a few prescribers may have a significant impact on prescribing patterns in this population, and analysis of individual prescribers was not assessed in this policy evaluation. Similarly, changes in overall Medicaid or FFS enrollment could influence the number of patients with claims for a biologic for autoimmune conditions. In order to assess for changes in Medicaid enrollment, the rough number of enrolled FFS members and the number of members with FFS medical claims for an autoimmune condition was evaluated. Overall, the monthly average number of enrolled FFS members per month was unchanged in the year before and after the policy implementation. There was a slight decrease in the number of patients with at least one FFS medical claim for an autoimmune condition (1045 in the year before implementation and 953 in the year after implementation). While this difference is not substantial, it may account for some of the prescribing trends observed in this population.  Population size: This analysis included only a small number of patients with provider administered claims. In the year before and after policy implementation, the number of patients with claims for a provider administered biologics for an autoimmune condition was only 107 and 65, respectively. The majority of claims in this class continue to be billed through the pharmacy rather than in provider offices, which limits the ability to discern changes in prescribing for provider administered drugs.  Switching therapy: The number and proportion of patients who switched therapy from one biologic treatment to another was not evaluated. Changing therapy may be due to ineffectiveness of treatment, adverse events, comorbid conditions, or patient preference.

Author: Servid October 2020 267 Appendix 1. Coding Information Table A1. Coding for biologics and DMARDs Category HSN Generic Biologics for Autoimmune Conditions 037825 abatacept Biologics for Autoimmune Conditions 033411 abatacept/maltose Biologics for Autoimmune Conditions 024800 adalimumab Biologics for Autoimmune Conditions 022953 anakinra Biologics for Autoimmune Conditions 040967 apremilast Biologics for Autoimmune Conditions 044296 baricitinib Biologics for Autoimmune Conditions 037462 belimumab Biologics for Autoimmune Conditions 044102 brodalumab Biologics for Autoimmune Conditions 036497 canakinumab/PF Biologics for Autoimmune Conditions 035554 certolizumab pegol Biologics for Autoimmune Conditions 018830 etanercept Biologics for Autoimmune Conditions 036278 golimumab Biologics for Autoimmune Conditions 044418 guselkumab Biologics for Autoimmune Conditions 018747 infliximab Biologics for Autoimmune Conditions 044432 infliximab-abda Biologics for Autoimmune Conditions 043249 infliximab-dyyb Biologics for Autoimmune Conditions 043193 ixekizumab Biologics for Autoimmune Conditions 026750 natalizumab Biologics for Autoimmune Conditions 016848 rituximab Biologics for Autoimmune Conditions 044183 sarilumab Biologics for Autoimmune Conditions 041715 secukinumab Biologics for Autoimmune Conditions 044823 tildrakizumab-asmn Biologics for Autoimmune Conditions 036466 tocilizumab Biologics for Autoimmune Conditions 039768 tofacitinib citrate Biologics for Autoimmune Conditions 036187 ustekinumab Biologics for Autoimmune Conditions 036187 ustekinumab Biologics for Autoimmune Conditions 041146 vedolizumab Systemic DMARDs 004523 azathioprine Systemic DMARDs 004524 cyclosporine Systemic DMARDs 010086 cyclosporine, modified Systemic DMARDs 007827 acitretin Systemic DMARDs 003906 methotrexate Systemic DMARDs 003905 methotrexate sodium Systemic DMARDs 024819 methotrexate sodium/PF Systemic DMARDs 040683 methotrexate/PF Systemic DMARDs 004074 sulfasalazine Author: Servid October 2020 268 Systemic DMARDs 004151 hydroxychloroquine sulfate Systemic DMARDs 018694 leflunomide Systemic DMARDs 003908 mercaptopurine

Table A2. Diagnosis Codes for relevant conditions of interest Condition ICD-10 Diagnosis Codes Ankylosing spondylitis M45xxx Crohn’s Disease K50xxx Juvenile Idiopathic Arthritis M08xxx Plaque psoriasis L400x-L404x, L408x, L409x Psoriatic arthritis L405x Rheumatoid Arthritis M05xxx, M06xxx Ulcerative colitis K51xxx

Table A3. Days’ Supply Estimates for Medical Claims Procedure Code Drug Name Procedure Description Days’ Supply C9026 vedolizumab Injection, Vedolizumab, 1 Mg 56 days C9029 guselkumab Injection, Guselkumab, 1 Mg 56 days C9487 ustekinumab Ustekinumab, For Intravenous Injection, 1 Mg 56 days J0129 abatacept Injection, Abatacept, 10 Mg (Code May Be Used For Medicare When Drug 7 days Administered Under The Direct S J0129 abatacept/maltose Injection, Abatacept, 10 Mg (Code May Be Used For Medicare When Drug 28 days Administered Under The Direct S J0135 adalimumab Injection, Adalimumab, 20 Mg 14 days J0490 belimumab Injection, Belimumab, 10 Mg 28 days J0638 canakinumab/PF Injection, Canakinumab, 1 Mg 28 days J0717 certolizumab pegol Injection, Certolizumab Pegol, 1 Mg (Code May Be Used For Medicare 28 days When Drug Administered Under The J0718 certolizumab pegol Injection, Certolizumab Pegol, 1 Mg 28 days J1438 etanercept Injection, Etanercept, 25 Mg (Code May Be Used For Medicare When 7 days Drug Administered Under The Direct J1602 golimumab Injection, Golimumab, 1 Mg, For Intravenous Use 56 days J1745 infliximab Injection, Infliximab, Excludes Biosimilar, 10 Mg 56 days J2323 natalizumab Injection, Natalizumab, 1 Mg 28 days J3262 tocilizumab Injection, Tocilizumab, 1 Mg 28 days J3357 ustekinumab Ustekinumab, For Subcutaneous Injection, 1 Mg 84 days J3358 ustekinumab Ustekinumab, For Intravenous Injection, 1 Mg 56 days

Author: Servid October 2020 269 J3380 vedolizumab Injection, Vedolizumab, 1 Mg 56 days J9310 rituximab Injection, Rituximab, 100 Mg 168 days J9312 rituximab Injection, Rituximab, 10 Mg 168 days Q2044 belimumab Injection, Belimumab, 10 Mg 28 days Q4079 natalizumab Injection, Natalizumab, 1 Mg 28 days Q5102 infliximab-abda Injection, Infliximab, Biosimilar, 10 Mg 56 days Q5102 infliximab-dyyb Injection, Infliximab, Biosimilar, 10 Mg 56 days Q5103 infliximab-dyyb Injection, Infliximab-Dyyb, Biosimilar, (Inflectra), 10 Mg 56 days Q5104 infliximab-abda Injection, Infliximab-Abda, Biosimilar, (Renflexis), 10 Mg 56 days Q9989 ustekinumab Ustekinumab, For Intravenous Injection, 1 Mg 56 days

Table A4. Error Codes to Exclude for Denied Provider Administered Drug Claims Error Code Description 3334 CAWEM: not emergency 4244 COVERAGE/RULE NOT FOUND FOR THE DIAGNOSIS/BP 4021 COVERAGE/RULE NOT FOUND FOR THE PROCEDURE/BP 4227 COVERAGE/RULE NOT FOUND FOR THE REVENUE/BP 264 DETAIL FROM DATE OF SERVICE IS MISSING 526 DETAIL FROM DOS IS AFTER HEADER THROUGH DATE 400 DETAIL UNITS OF SERVICE MUST BE GREATER THAN ZERO 3542 DIAGNOSIS REIMBURSABLE W/DIAGNOSTIC PROCEDURES ONL 4024 INVALID HCPCS/NDC COMBINATION 2807 MATCH CODE INVALID 3320 MEDICARE SERVICE NOT COVERED FOR QMB RECIPIENT 1036 PERFORMING PROV TYPE/CLAIM TYPE MIS MATCH 2504 RECIPIENT COVERD BY PRIVATE INSURANC(NO ATTACHMNT) 2502 RECIPIENT COVERED BY MEDICARE B (NO ATTACHMENT) 2503 RECIPIENT COVERED BY MEDICARE B (WITH ATTACHMENT) 2003 RECIPIENT INELIGIBLE ON DETAIL DATE OF SERVICE 2017 RECIPIENT SERVICES COVERED BY HMO PLAN 1007 RENDERING PROVIDER I.D. NOT ON FILE

Table A5. Error Codes to Exclude for Denied Pharmacy Claims Error Code Description 1000 BILLING PROVIDER ID NOT ON FILE

Author: Servid October 2020 270 576 CLAIM HAS THIRD-PARTY PAYMENT 503 DATE DISPENSED AFTER BILLING DATE 502 DATE DISPENSED EARLIER THAN DATE PRESCRIBED 500 DATE PRESCRIBED AFTER BILLING DATE 2809 DOB IS INVALID 2807 MATCH CODE INVALID 3022 Non-Pref Drug. Prior Authorization Required. 1026 PRESCRIBING PHYSICIAN ID NOT ON FILE 1040 PRESCRIBING PHYSICIAN NOT ENROLLED 1033 PRESCRIBING PROV TYPE/CLAIM TYPE MIS MATCH 2509 RECIPIENT COVERED BY MEDICARE 2508 RECIPIENT COVERED BY PRIVATE INSURANCE (PHARMACY) 2507 RECIPIENT HAS MORE THAN ONE INSURANCE CARRIER 513 RECIPIENT NAME AND NUMBER DISAGREE 238 RECIPIENT NAME IS MISSING 2002 RECIPIENT NOT ELIGIBLE FOR HEADER DATE OF SERVICE 2017 RECIPIENT SERVICES COVERED BY HMO PLAN 505 THIRD PARTY PAYMENT AMOUNT MORE THAN CLAIM CHARGE 4999 THIS DRUG IS COVERED BY MEDICARE PART D

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Drug Use Evaluation: Modafinil/Armodafinil Safety

Research Questions: 1. Is modafinil or armodafinil therapy associated with increased risk of harm based on medical claims data in the adult Oregon Medicaid population? 2. How frequently is modafinil or armodafinil therapy prescribed to women during pregnancy or in women of child-bearing age who do not have evidence of birth control? 3. What proportion of patients have a mental health comorbidity (psychosis, depression, or mania) which may put them at increased risk of adverse events with modafinil or armodafinil therapy? 4. How frequently do patients prescribed modafinil or armodafinil in the Oregon Medicaid adult population have hospitalizations or emergency department visits for adverse drug events?

Conclusions:  Modafinil and/or armodafinil adverse events that resulted in recent European Medicines Agency (EMU), Heath Canada and/or FDA labeling changes were: risk of congenital malformations including cardiac anomalies, reproductive toxicity, serious dermatologic reactions, angioedema and anaphylactic reactions, drug rash with eosinophilia and systemic symptoms (DRESS), suicidal ideation, and psychiatric adverse reactions some of which have resulted in hospitalization.  In 2018-2019, less than 2% of Oregon Medicaid adult females ages 18-39 had claims indicating they were pregnant in the 3 months prior to modafinil/armodafinil treatment initiation.  Over three-quarters (77%) of female patients ages 18-39 prescribed continuous modafinil/armodafinil therapy did not have evidence of claims for a contraceptive agent (diaphragms, condoms, nonoxynol 9/spermicide, or oral contraceptives) up to 4 months before and up to 4 months after starting therapy. Other contraceptive products either not obtained at pharmacy point of sale or non-prescription contraceptive mechanisms were not captured in the claims data. Given the documented drug interaction with modafinil/armodafinil and hormonal contraception, alternative methods of birth control may have been more common in this population.  Overall, roughly 18% of patients had ER visit claims and 2.4% had a hospitalization up to 3 months after modafinil/armodafinil therapy initiation which were similar rates to ER/hospitalizations within 90 days prior to starting modafinil/armodafinil. Over three quarters (77%) of new-start patients had at least 1 high-risk comorbidity present prior to therapy initiation including cardiovascular disease (29%), psychosis (5%), anxiety disorders (42%), and/or mood disorders (62%). Subgroup analysis by comorbidity revealed that in those with preexisting cardiovascular disease, there was a 10% increase in ER visits in the 3 months after therapy initiation compared to the 3 months before.  The most common adverse event reported up to 30 days after modafinil/armodafinil therapy initiation were psychiatric (29%) and cardiovascular (2%) symptoms.

Author: David Engen, PharmD October 2020 272  Within 6 months of modafinil/armodafinil initiation, roughly 9% of individuals had new psychiatric symptoms and 3-4% of patients had new cardiovascular symptoms with no prior history of claims for a similar diagnosis.

Recommendations:  Modify modafinil/armodafinil prior authorization criteria to prevent inappropriate use during pregnancy and in women of childbearing age.

Background: Modafinil and armodafinil (generic and branded products) are carve-out medications, paid for by fee-for-service (FFS), and designated as preferred agents on the Oregon Health Plan (OHA) preferred drug list (PDL). These agents are indicated for the treatment of excessive daytime sleepiness in both narcolepsy and obstructive sleep apnea (OSA) conditions. 1,2 Documented off-label uses of modafinil and armodafinil include fatigue associated with cancer, multiple sclerosis (MS) and other neurological conditions, depression, and other mood disorders.3 Modafinil and armodafinil are regulated as class IV-controlled substances in the United States (US).1,2 Both agents require a prior authorization (PA) to ensure medically appropriate use in adults for treatment of OHP-funded conditions. Previous reviews failed to identify any clinically significant comparative differences in efficacy or harms between modafinil, armodafinil, or other narcolepsy treatment agents.4 However, in patients with OSA who were adherent to continuous positive airway pressure (CPAP), one systematic review with meta-analysis reported that modafinil or armodafinil therapy plus CPAP resulted in an increased proportion of patient dropouts due to adverse events compared to CPAP alone (6.2% vs. 2.8% respectively; RR 2.03; 95% CI 1.12 to 3.67; moderate quality evidence).4,5 The most commonly reported adverse events were headache, vertigo and anxiety.4,5

Current FDA labeling designate both Provigil™ (modafinil) and Nuvigil™ (armodafinil) as Pregnancy Category C and advise that patients notify their physician if they become pregnant or intend to become pregnant.1,2 These warnings were based on developmental toxicity observed at clinically relevant exposures in animal studies.1,2 In 2009, the manufacturer of modafinil and armodafinil created a pregnancy registry currently linked on the FDA website to assist in data collection of adverse effects reported in pregnancy and fetal development.6 In 2019, the EMA announced that they suspected congenital malformations were associated with modafinil use in pregnancy and recommended that the product should not be used in women who are pregnant, are planning to be pregnant, or are breastfeeding. 7 The alerts were identified by the manufacturer based on analysis of data from post-marketing pregnancy registry reports where congenital malformations were noted in up to 15% of children with modafinil exposure during pregnancy compared to 3% who were not exposed (see Table 1).8 TEVA Canada Innovation released similar findings to Health Canada and cited a higher frequency of major congenital anomalies (17.3%) and cardiac anomalies (4%) in modafinil and/or armodafinil exposed patients compared to the general population (3% and 1%, respectively).9 Health Canada has since updated their Canadian Product Monograph to include pregnancy as a contraindication to the use of modafinil.9 Both Health Canada and the EMA also note that female patients of reproductive potential must instructed to use “effective contraception” during modafinil therapy but did not elaborate. The manufacturer has not issued such a warning to the FDA despite the data having been obtained through the US Nuvigil/Provigil Pregnancy Registry. At least one recent observational study has confirmed a similar association of exposure to modafinil and risk of major congenital malformations. 10

Author: Engen October 2020 273 Table 1. Recent Warnings for Modafinil and Armodafinil Use in Pregnancy Year Source Warning Recommendation 2019 Health Canada9 Risk of Congenital Anomalies - Healthcare professionals are advised to: Based on international post-  discuss with all female patients treated or to be treated with modafinil the potential risks marketing reports, modafinil may associated with modafinil to a fetus during pregnancy cause fetal harm and is  ensure all female patients of reproductive potential have a negative pregnancy test within a week contraindicated in women who are before starting treatment with modafinil pregnant or may become pregnant.  instruct all female patients of reproductive potential that they must use effective contraception during therapy with modafinil, and for two months after discontinuation of modafinil treatment;  inform female patients that modafinil may reduce the effectiveness of steroidal [hormonal] contraceptives and that alternative or concomitant methods of contraception, other than steroidal [hormonal], are required during the modafinil treatment, and for two months after discontinuation of modafinil 2019 European New product information wording - Updated warning in prescribing information: Medicines Based on limited human experience  modafinil is suspected to cause birth defects if taken during pregnancy. 7 Agency from a pregnancy registry and  Women of childbearing potential have to use effective contraception as modafinil may reduce the spontaneous reporting modafinil is effectiveness of oral contraception, alternative additional methods of contraception are required. suspected to cause congenital  If you are pregnant (or think that you may be), are planning to become pregnant, or are breast malformations when administered feeding, you should not take modafinil. during pregnancy.

There have been post-marketing reports of serious adverse effects with armodafinil use.11 Post-marketing reports have included 2 fatalities associated with drug hypersensitivity including drug reaction with eosinophilia and systemic symptoms.11 Patients are advised to discontinue armodafinil at the first sign of rash, skin or mouth sores, blistering or ulceration.11 In addition, hypersensitivity reactions such as Stevens-Johnson Syndrome have been documented with modafinil therapy.12,13 Clinical trials and post market data noted increased rates of suicidal ideation associated with modafinil and armodafinil.1,2 FDA labeling was updated to highlight the risk of psychiatric symptoms, including suicidal ideation, with armodafinil use.1,2 Therefore, caution is advised when prescribing either of these agents in patients with a history of psychiatric symptoms such as documented psychosis, depression, and mania. 1,2 Prescribers are warned that these symptoms may result in hospitalization and to consider discontinuation of modafinil or armodafinil if psychiatric symptoms develop upon administration. 1,2

Methods: All adult patients (18 years or older) with a unique FFS claim for modafinil (HSN = 010865) or armodafinil (HSN = 034868) from January 2016 to May 2020 were included in the trend analysis (see Figure 1). Patients were only counted once total for analysis depending upon the first paid claim for either drug. Only patients with a new FFS claim for modafinil or armodafinil from 1/1/2018 to 12/31/2019 were included in the demographics, diagnostic, and safety analysis. The first FFS claim in the reporting period was classified as the index event (IE). Both FFS and CCO patients > 18 years of age were included in the analysis if they had a FFS claim. Patients were excluded if they had Medicaid coverage for less than 75% of days in the 6 months before or after the first reference claim. Baseline characteristics, including patient age, were assessed at the time of the IE.

The following definitions and categories were used for the analysis of new start patients:  New start patients were defined as patients without modafinil or armodafinil use in the 90 days prior to the IE.  Prior history of modafinil/armodafinil use was evaluated in the 90 days prior to the IE. Author: Engen October 2020 274  Comorbid diagnoses were identified using ICD-10 codes on medical claims in the 12 months before the IE (see Appendix 1 for relevant ICD-10 codes).  Drugs of Other Stimulant PDL class (modafinil, armodafinil) were identified based on HSN (010865 and 034868, respectively).  Number of female patients of childbearing age (18-39) with no claims (Pharmacy or PAD) for a contraceptive agent in Standard Therapeutic Class 36 or 63 (e.g. diaphragms, condoms, nonoxynol 9/spemicide, or oral contaceptives [norgestrel, levonorgestrel, desogestrel, drospirenone, norethindrone, ethinyl estradiol, etc and combination products]) 4 months prior or 4 months after the first reference claim of reporting period in patients prescribed continuous modafinil/armodafinil therapy from January 1, 2018 to December 31, 2019.  Continuous therapy patients were defined as those with sustained modafinil or armodafinil therapy for at least 90 days on either drug after index event in reporting period with no greater than 7 days between successive claim  Patients with at least 1 medical claim for an adverse event within 30 days of therapy initiation.  Patients with adverse events were identified 6 months prior to IE and up to 6 months after IE.  New start patients with a pre-existing comorbidity who had an emergency room visit or hospitalization within 90 days following the IE.

Results: Figure 1 indicates that after an initial decline in 2016, there have been roughly 150 to 200 unique patients with monthly FFS claims for modafinil or armodafinil for the past 3 years.

Figure 1 - Unique Patient Count with Drug Claim for Modafinil or Armodafinil

After exclusion of Medicare patients and patients without continuous Medicaid benefits (see Appendix 2), a total of 541 patients were identified as new start patients from 1/1/2018 to 12/31/2019. Table 2 describes characteristics of patients prescribed modafinil or armodafinil with no prior history of use in the prior Author: Engen October 2020 275 90 days. Patients were primarily white females (65%) and approximately 44% were patients less than 40 years of age. Almost 75% of patients were prescribed modafinil compared to roughly 25% with armodafinil as their first index claim.

Table 2. Demographics for new start modafinil or armodafinil patients between 1/1/2018 to 12/31/2019.

N= 541 %

Age (years) Average (min - max) 41.5 (18-64) 18-28 75 13.9% 29-39 164 30.3% 40-50 179 33.1% 51 or older 123 22.7%

Female Female 352 65.1% Male 189 34.9%

Race White 321 59.3% Black 4 0.7% Native American 25 4.6% Other 8 1.5% Unknown 183 33.8%

Index Drug Modafinil (HSN: 010865) 402 74.3% Armodafinil (HSN: 034868) 139 25.7%

Of the patients with new start prescriptions for modafinil or armodafinil, 157 patients were identified as females of childbearing age (18 to 39 years). Less than 2% (3/157) of females with childbearing potential had claims indicating a pregnancy diagnosis within 3 months of starting modafinil/armodafinil treatment.

Table 3 describes the number of female patients of childbearing age (18-39 years) who were identified as having continuous modafinil or armodafinil therapy. All included females were prescribed modafinil or armodafinil for at least 90 days after the first reference claim in the reporting period with no greater than 7 days between successive claims. Over three-quarters (77%) of these patients prescribed continuous modafinil/armodafinil therapy did not have evidence of birth control up to 4 months before and up to 4 months after starting therapy. Most of these women (60%) were 29-39 years of age, and 17% were 18-28 years of age. Author: Engen October 2020 276 Table 3. Continuous prescribing of Modafinil or Armodafinil therapy to women of childbearing age.

Female Patients Ages 18-39 on Continuous Therapy: N= 42 %

Patients with sustained therapy and without birth control by age: 18-28 7 17% 29-39 25 60%

Table 4a shows that the overall rate of patient ER visits within 3 months after starting modafinil/armodafinil was just over 18%, while the rate of hospitalizations was 2.4%. The rate of ER visits and hospitalizations prior to treatment were similar to post treatment rates. Based on clinical trial data, the FDA has identified several comorbidities associated with a high-risk of adverse outcomes when prescribed modafinil/armodafinil. Table 4b shows that over three-quarters of new- start patients (77%) had at least 1 claim to indicate the presence of a high-risk comorbidity present prior to therapy initiation. The most common high-risk comorbidity was mood disorder (62%), followed by anxiety disorder (42%), cardiovascular disease (29%), and psychosis (5%). In Table 4c, a subgroup analysis by comorbidity revealed that 27% of those with preexisting cardiovascular disease had an ER visit, whereas the rate in the 3 months before therapy was 17%. Interestingly, the rates of hospitalization for psychosis appeared to decrease with the initiation of modafinil/armodafinil therapy but the overall numbers were relatively small. All the other comparisons showed a 5% or less difference in the 90 day pre- and- post therapy initiation time period.

Table 4a. Patients with an ER visit or hospitalization up to 90 days after starting modafinil/armodafinil claim compared to 90 days prior to treatment.

ER Visit Hospitalization

New start patients up to 90 N N % N % days after therapy initiation 541 99 (18.3%) 13 (2.4%) New start patients in the 90 days prior to therapy initiation 541 91 (16.8%) 20 (3.6%)

Table 4b. Pre-existing high-risk comorbidities in new start modafinil/armodafinil patients.

N 541 %

Pre-existing comorbidity 416 77% Cardiovascular disease 158 29% Psychosis 25 5% Other anxiety disorders 225 42% Mood disorders 334 62%

Author: Engen October 2020 277

Table 4c. Patients with preexisting comorbidity and ER visit or hospitalization rate 90 days before and after starting modafinil.

ER Visit ER Visit Hospitalization Hospitalization Pre-existing comorbidity N Prior After Before After

Cardiovascular disease 158 27 (17%) 43 (27%) 9 (6%) 8 (5%) Psychosis 25 7 (28%) 8 (32%) 5 (20%) 3 (12%) Other anxiety disorders 225 48 (21%) 43 (19%) 13 (6%) 5 (2%) Mood disorders 334 59 (18%) 58 (17%) 15 (4%) 8 (2%)

Table 5a lists adverse events identified within 30 days of modafinil/armodafinil therapy initiation. Of all patients with an adverse event within 30 days after therapy initiation, psychiatric symptoms were the most frequently reported (29% or 159/541) followed by 2% (10/541) with cardiovascular symptoms. No patients with hypersensitivity reactions or hepatic were identified. Upon subgroup analysis (Table 5b), most (143/159) of the psychiatric events were identified in patients 29 years or older with 40-50 year-olds having the highest proportion (56/159 or 35%) of all age subcategories. Only 10% of the cases were identified in patients 18 to 28 years of age. There were 4 deaths within the first month of therapy, 3 of whom were females and all of whom were 40 years or older. The causes of death were unknown.

Table 5a. New start patients with adverse event within 30 days of starting modafinil or armodafinil.

Total Male Female Adverse Event Type Patients (N=189) (N=352) (N=541)

Psychiatric Symptoms 159 (29%) 52 107

Cardiovascular Symptoms 10 (2%) 4 6

Death 4 (<1%) 1 3

Author: Engen October 2020 278 Table 5b. Adverse Events within 30 days of Modafinil/Armodafinil Therapy Initiation Separated by Age and Sex

Patients with >=1 Adverse Events by Age and Sex

18-28 years 29-39 years 40-50 years 50+ years

N=75 N=164 N=179 N=123

M =28 F=47 M=54 F=110 M=58 F=121 M=49 F=74 7 9 18 30 15 41 12 27 Psychiatric Symptoms (N=159) 16 (10%) 48 (30%) 56 (35%) 39 (25%)

1 1 1 0 1 3 1 2 Cardiovascular Symptoms (N=10) 2 (20%) 1 (10%) 4 (40%) 3 (30%)

0 0 0 0 0 2 1 1 Death (N=4) 0 0 2 (50%) 2 (50%)

As stated previously, the FDA has identified numerous adverse events associated with modafinil/armodafinil use. Table 6 identifies new adverse events reported up to 6 months after modafinil/armodafinil therapy initiation in patients without a prior history of the diagnosis. Medical claims for one or more of these adverse events occurred in about 12% of patients. Roughly 9% of individuals with a documented psychiatric adverse event after modafinil/armodafinil therapy initiation had no prior claims history of these symptoms in the 6 months prior to treatment initiation. New cardiovascular events were noted in 3-4% of patients. There were few to no claims for new hypersensitivity reactions or hepatic symptoms.

Table 6. Number of Patients with Adverse Events in the 6 months after Index Event, but no adverse event in 6 months prior.

Modafinil Armodafinil Adverse Event Type 402 % 139 %

Hypersensitivity reactions 1 0.2% 0.0% Psychiatric Symptoms 34 8% 12 9% Cardiovascular Symptoms 14 4% 4 3%

Total number of patients with Adverse Event 49 12.2% 16 12%

Author: Engen October 2020 279

Limitations:

Data presented in this report is based on Medicaid claims history and has several inherent limitations.  Definitions for new start patients: Prior use of modafinil/armodafinil was only evaluated in the 90 days prior to the IE. Patients could have had a remote history of modafinil/armodafinil use beyond this date which could influence choice in current therapy.  Diagnostic accuracy: Diagnoses based on claims history may be inaccurate or incomplete. Many patients in this analysis may have been enrolled in coordinated care organizations and delays in submission and processing of medical claims data may result in missed diagnoses. Diagnosis codes for pregnancy may not have been fully captured as miscarriages and/or elective termination of pregnancy were not analyzed. Assumptions regarding childbearing potential may have led to incomplete data as women 40 years of age or older of gestational viability were excluded from analysis. In addition, contraceptive mechanisms through other payment sources (eg. third-party payors), health status (eg. prior hysterectomy or sterile), male partner status (eg. vasectomy), life-choices (eg. not sexually active), or other contraceptive products either not obtained at pharmacy point of sale or non-prescription (eg. intrauterine device, barrier) were not captured in the claims data. These alternative forms of contraception may be more common in this population as there is a drug interaction with modafinil/armodafinil and hormonal contraception.  Adverse events: This study did not analyze all reported adverse events, or every high-risk comorbidity identified by FDA or post-marketing data. Psychiatric adverse events included the broad categories of psychosis, anxiety, and mood disorders which made it difficult to detect the frequency of specific reactions possibly associated with modafinil/armodafinil use.  Correlation of adverse events: There is no way to determine if the adverse events identified via claims were definitively associated with modafinil/armodafinil use.  Small sample size: more patients may be needed to observe correlations between modafinil/armodafinil exposure and adverse outcomes.

Author: Engen October 2020 280 References:

1. Provigil prescribing information. Cephalon Inc., Frazier, PA. January 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf. Accessed June 29, 2020. 2. Nuvigil prescribing information. Cephalon Inc., Frazier, PA. April 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021875s021lbledt.pdf. Accessed June 29, 2020. 3. Micromedex Healthcare Series [internet database]. Greenwood Village, CO: Truven Health Analytics, Inc. Updated periodically. Accessed July 30, 2020 4. Drug Class Update with New Drug Evaluation: Narcolepsy Agents, Author: Servid S, February 2020. 5. Avellar ABCC, Carvalho LBC, et al. Pharmacotherapy for residual excessive sleepiness and cognition in CPAP-treated patients with obstructive sleep apnea syndrome: A systematic review and meta-analysis. Sleep Med Rev. 2016;30:97-107. 6. Food and Drug Administration. List of Pregnancy Exposure Registries. Updated June 12, 2020. https://www.fda.gov/science-research/womens- health-research/list-pregnancy-exposure-registries. Accessed June 18, 2020. 7. European Medicines Agency. PRAC recommendations on signals. May 6, 2019. https://www.ema.europa.eu/en/documents/prac- recommendation/prac-recommendations-signals-adopted-8-11-april-2019-prac-meeting_en.pdf. Accessed June 18, 2020. 8. Teva Pharmaceuticals Ireland. Direct Healthcare Professional Communication (DHPC). Modafinil: potential risk of congenital malformations when administered during pregnancy. June 7, 2019. http://www.hpra.ie/docs/default-source/default-document-library/important-safety-information--- modafinil99170c2697826eee9b55ff00008c97d0.pdf?. Accessed June 18, 2020. 9. Government of Canada, Health Canada. ALERTEC (modafinil) and the Risk of Congenital Anomalies. June 20, 2019. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70201a-eng.php. Accessed June 18, 2020. 10. Damkier P, Broe A. First-Trimester Pregnancy Exposure to Modafinil and Risk of Congenital Malformations. JAMA. 2020;323(4):374–376. 11. Nuvigil (Armodafinil) FDA Safety-related labeling changes Approved by FDA Center for Drug Evaluation and Research (CDER) Feb 07 2017 (SUPPL-23). https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm?event=searchdetail.page&DrugNameID=828. Accessed June 18, 2020. 12. Holfinger S, Roy A, Schmidt M. Stevens-Johnson syndrome after armodafinil use. J Clin Sleep Med. 2018;14(5):885–887. 13. Prince V, Philippidou M, et al. Stevens-Johnson syndrome induced by modafinil. Clin Exp Dermatol. 2018;43(2):191-192.

Author: Engen October 2020 281 Appendix 1: Definitions

ICD-10 Definitions

Diagnoses indicating pregnancy O00-O9Ax, Z331, Z34x

Comorbidities Cardiovascular Hypertension diagnosis I10, I15x Myocardial infarction I21x Unstable angina I20x Psychosis F20x-F29x Other Anxiety disorders F41x Mood disorder F30x-F39x

Adverse Events Hypersensitivity Reactions Drug rash L27x Stevens-Johnson Syndrome L511 Toxic Epidermal Necrolysis L512 Stevens-Johnson-toxic epidermal necrolysis overlap syndrome L513 Angioedema T783x Anaphylaxis T782x Unspecified adverse effect of drug T887x Multi-organ hypersensitivity R652 Psychiatric Symptoms Stimulant dependence w/ stimulant-induced psychotic disorder w/ hallucinations F15251 Psychosis F20x-F29x Anxiety F41x Mood disorders F30x-F39x Hallucinations and symptoms w/ general sensations and perceptions R44x Suicidal ideation or suicide attempt R4585x, T1491x Cardiovascular Symptoms Angina I20x Palpitations R002 Dyspnea R060x Transient ischemia G459 Hepatic Symptoms Hepatitis K72x Toxic liver disease K71x

Author: Engen October 2020 282 Appendix 2: Exclusions

DUE Benefit Package Exclusion List BMM – QMB + OHP with Limited Drug Package BMD – OHP with Limited Drug CWM – Emergency services only – Citizen Alien Waived Emergent Medical (CAWEM) MED – Qualified Medicare Beneficiary (Dual) MND – Transplant Package SMF – Special Low Income Medicare Beneficiary Only (no Medicaid drug benefit) SMB – Special Low Income Medicare Beneficiary Only (no Medicaid drug benefit)

Appendix 3: Proposed Prior Authorization Criteria Updates Sleep-Wake Medications

Goal(s):  To promote safe use of drugs for obstructive sleep apnea and narcolepsy.  Limit use to diagnoses where there is sufficient evidence of benefit and uses that are funded by OHP. Excessive daytime sleepiness related to shift-work is not funded by OHP.  Limit use to safe doses.

Length of Authorization:  Initial approval of 90 days if criteria met; approval of up to 12 months with documented benefit

Requires PA: Payment for drug claims for modafinil or armodafinil without previous claims evidence of narcolepsy or obstructive sleep apnea Solriamfetol Pitolisant

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Author: Engen October 2020 283 Table 1. Funded Indications. Indication Modafinil Armodafinil Solriamfetol Pitolisant (Provigil™) (Nuvigil™) (Sunosi™) (Wakix™)  Excessive daytime sleepiness in FDA approved for FDA approved for FDA approved for FDA approved for narcolepsy Adults 18 and older Adults 18 and older Adults 18 and older Adults 18 and older  Residual excessive daytime FDA approved for FDA approved for FDA approved for Not FDA approved; sleepiness in obstructive sleep apnea Adults 18 and older Adults 18 and older Adults 18 and older insufficient evidence patients treated with CPAP.

 Depression augmentation (unipolar or Not FDA approved; Not FDA approved; Not FDA approved; Not FDA approved; bipolar I or II acute or maintenance Low level evidence insufficient evidence insufficient evidence insufficient evidence phase) of inconsistent  Cancer-related fatigue benefit  Multiple sclerosis-related fatigue  Drug-related fatigue Not FDA approved; Not FDA approved; Not FDA approved; Not FDA approved;  Excessive daytime sleepiness or insufficient insufficient evidence insufficient evidence insufficient evidence fatigue related to other neurological evidence disorders (e.g. Parkinson’s Disease, traumatic brain injury, post-polio syndrome)  ADHD  Cognition enhancement for any condition

Table 2. Maximum Recommended Dose (consistent evidence of benefit with lower doses). Generic Name Minimum Age Maximum FDA-Approved Daily Dose Armodafinil 18 years 250 mg Modafinil 18 years 200 mg Solriamfetol 18 years 150 mg Pitolisant 18 years 17.8 mg (poor CYP2D6 metabolizers)

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

Author: Engen October 2020 284 Approval Criteria

2. Is the patient 18 years of age or older? Yes: Go to #3 No: Pass to RPh. Deny; medical appropriateness. Providers for patients 7 to 17 years of age may also submit a request for sodium oxybate as it is FDA-approved for narcolepsy in this age group.

3. Is this a funded diagnosis? Yes: Go to #4 No: Pass to RPh. Deny; not funded by OHP Non-funded diagnoses:  Shift work disorder (ICD10 G4720-4729; G4750-4769; G478)  Unspecified hypersomnia (ICD10 G4710)

4. Is the request for continuation of therapy at maintenance Yes: Go to Renewal Criteria No: Go to #5 dosage previously approved by the FFS program?

5. Is the drug prescribed by or in consultation with an Yes: Go to #6 No: Pass to RPh. Deny; appropriate specialist for the condition (e.g., sleep medical appropriateness specialist, neurologist, or pulmonologist)?

6. Will prescriber consider a preferred alternative? Yes: Inform prescriber of No: Go to #7 preferred alternatives (e.g., preferred methylphenidate)

7. Is the prescribed daily dose higher than recommended in Yes: Go to #8 No: Go to #9 Table 2?

Author: Engen October 2020 285 Approval Criteria

8. Is the request for pitolisant in a patient with documentation Yes: Go to #9 No: Pass to RPh. Deny; of all the following: medical appropriateness.  CYP2D6 testing which indicates the patient is not a Max dose for pitolisant is 35.6 mg poor metabolizer daily.  Chart notes or provider attestation indicating lack of hepatic or renal impairment

9. Is there baseline documentation of fatigue severity using a Yes: Go to #10 No: Pass to RPh. Deny; validated measure (e.g., Epworth score, Brief Fatigue medical appropriateness Inventory, or other validated measure)? Document baseline scale and score

10. Is the request for solriamfetol or pitolisant? Yes: Go to #11 No: Go to #15

11. Does the patient have a diagnosis of end stage renal Yes: Pass to RPh. Deny; medical No: Go to #12 disease? appropriateness

12. Is the request for solriamfetol? Yes: Go to #13 No: Go to #15

13. Is the request for concurrent use with a monoamine Yes: Pass to RPh. Deny; medical No: Go to #14 oxidase inhibitor? appropriateness

14. Is there documentation of a recent cardiovascular risk Yes: Go to #17 No: Pass to RPh. Deny; assessment (including blood pressure) with physician medical appropriateness attestation that benefits of therapy outweigh risks? Document recent blood pressure within the last 3 months and Use of solriamfetol is not physician attestation of recommended in patients with cardiovascular risk assessment uncontrolled hypertension or serious heart problems.

15. Is the patient a woman with childbearing potential? Yes: Go to #16 No: Go to #17

16. Is there documentation of a negative pregnancy test as Yes: Go to #17 No: Pass to RPh. Deny; well as reliable contraception OR documentation that medical appropriateness. provider has assessed pregnancy risk and discussed contraceptive use with the patient?

Author: Engen October 2020 286 Approval Criteria

17. Is the request for treatment of narcolepsy for a drug FDA- Yes: Approve for 90 days and No: Go to #18 approved for the condition (Table 1)? inform prescriber further approval will require documented evidence of clinical benefit.

18. Is the request for treatment of obstructive sleep apnea Yes: Go to #19 No: Go to #20 (OSA) (without narcolepsy) for a drug FDA-approved for the condition (see Table 1)?

19. Is the patient compliant with recommended first-line Yes: Approve for 90 days and No: Pass to RPh; Deny; treatments (e.g., CPAP or other primary therapy)? inform prescriber further approval medical appropriateness will require documented evidence of clinical benefit.

20. Is the request for off-label use of armodafinil, solriamfetol, Yes: Pass to RPh. Deny; medical No: Go to #21 or pitolisant (see Table 1)? appropriateness.

There is insufficient evidence for off-label use.

21. Is the primary diagnostic indication for modafinil fatigue Yes: Inform prescriber of first-line No: Go to #22 secondary to major depression (MDD), MS or cancer- options available without PA. related fatigue? May approve for 90 days and inform prescriber further approval Note: Methylphenidate is recommended first-line for cancer. will require documented evidence of clinical benefit and assessment of adverse effects.

Author: Engen October 2020 287 Approval Criteria

22. All other diagnoses must be evaluated as to the OHP-funding level and evidence for clinical benefit.

 Evidence supporting treatment for excessive daytime sleepiness (EDS) or fatigue as a result of other conditions is currently insufficient and should be denied for “medical appropriateness”.  Evidence to support cognition enhancement is insufficient and should be denied for “medical appropriateness”. If new evidence is provided by the prescriber, please forward request to Oregon DMAP for consideration and potential modification of current PA criteria.

Renewal Criteria

1. Is the request for solriamfetol? Yes: Go to #2 No: Go to #3

2. Is there documentation of a recent blood pressure Yes: Go to #3 No: Pass to RPh. Deny; medical appropriateness evaluation (within the last 3 months)?

3. Is the request for treatment of obstructive sleep Yes: Go to #4 No: Go to #5 apnea?

4. Is the patient adherent to primary OSA treatment Yes: Go to #5 No: Pass to RPh. Deny; medical appropriateness (e.g.,CPAP) based on chart notes?

5. Is there documentation of clinical benefit and Yes: Approve for up to No: Pass to RPh. Deny; medical appropriateness tolerability from baseline? 12 months

The same clinical measure used to diagnose excessive daytime sleepiness (EDS), fatigue secondary to MS and/or cancer, major depressive disorder (MDD) is recommended to document clinical benefit. For Epworth Sleepiness Scale, and improvement of at least 3 points is considered clinically significant.

P&T Review: 10/1/2020(DE); 2/2020; 7/19; 03/16; 09/15 Implementation: 3/1/2020; 8/19/19; 8/16, 1/1/16

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Policy Proposal: Drug Discontinuation Safety Net

Purpose of the Proposal: Identify patients with gaps in therapy for maintenance medications and offer patient case management services to identify reasons for gaps in care, provide patient education, and connect patients with appropriate resources.

Background: The current COVID-19 pandemic has changed how many people receive medical care in Oregon. Provider offices may be closed, operating with limited staffing, or have limited office hours. Some providers may be prioritizing urgent or emergency services or only providing remote or virtual services, and patients may be hesitant to schedule routine office visits during the pandemic. Because of these changes, some patients may be unable to see a provider or unable to get to the pharmacy to have their prescription filled in a timely manner. Many pharmacies have begun offering mail delivery or drive-through services to accommodate patient needs. However, with so many changes, there is potential for gaps in care where patients may be unable to fill their routine prescriptions.

In order to support prescription needs for FFS members during the current pandemic, a pilot program was created to provide patient outreach and case management for members with discontinuation of a high-risk medication. High-risk medications were defined based on medication type and patient diagnoses (see methods below), and referrals were prioritized based on case manager availability and medication importance. The program was intended to ensure members were able to fill essential prescriptions particularly when they may be unable to physically pick up their prescription or when their provider office may have been closed. Case managers can help ensure that members have adequate access to essential medications by connecting patients with additional resources, assisting in care coordination, communicating with provider offices, and providing patient education.

While this initiative was started to provide patient support during the current pandemic, many factors can cause barriers to care and delay access to necessary medications. In particular, care coordination can often be improved during transitions of care. The FFS population has a significant number of patients transitioning to and from coordinated care organizations (CCOs). Because CCOs are location-based, if patients move locations or loose Medicaid coverage, they may be disenrolled from their current CCO and re-enrolled in a different CCO. Because members are typically eligible for FFS coverage before CCO enrollment occurs, FFS serves as a safety net to provide Medicaid coverage when members are first enrolled or moving between CCOs. Ensuring access to essential maintenance medications for patients with transitional FFS coverage can improve care for Medicaid members. Similarly, delays in obtaining appropriate medications can arise from other system-wide issues. The following are just a few examples of scenarios that have the potential to cause delays in therapy:  Changes in a patient’s primary care provider  Referrals to a specialist  Drug shortages  Changes in claims edits or Medicaid drug coverage  Changes in other insurance policies  Prior authorizations which are not submitted in a timely manner or are lacking necessary information for approval Author: Sarah Servid, PharmD October 2020 289 Patient outreach may be able to mitigate some of these issues by identifying the reason for the delay in therapy, providing patient education, and supporting care coordination.

Methods: Patients were targeted for outreach if they had previously filled more than 84 days of a routine maintenance medication and had a recent gap in therapy of more than 14 days (Appendix 1). Patients were excluded if they were deceased, not currently enrolled in FFS, enrolled in Medicare, or had other primary insurance. Patients were also excluded if they had a more recent paid claim for medication in the same PDL class, indicating a switch to a different therapy. Patients were prioritized for case management referral based on patient and medication characteristics. Types of referrals have included the following categories:  Insulin in patients with a diagnosis of type 1 diabetes  Anticoagulants, statins, or antihypertensive medications in patients with established cardiovascular disease  Antiepileptics in patients with a seizure disorder  Maintenance asthma or COPD inhalers  HIV medications  Medications for opioid use disorder

Patients were identified weekly and information on the patient, medication history, prescribing provider, and most recent pharmacy were sent to case managers who called patients to offer support and case management services if needed (Appendix 2). There are several inherent limitation with using claims data to identify gaps in therapy. For example, patients may have paid cash for a prescription, had a recent hospitalization, or have an excess supply of medication on hand from previous prescriptions. Insurance coverage or Medicaid enrollment may change resulting in missing or delayed claims data. Changes in directions or dose may result in inaccurate days’ supply on billed claims. These limitations may result in inaccurate identification of patients. Additionally, enrollment with case management services is voluntary and members can opt out of receiving calls from the case management program. However, providing the opportunity for patient education and support for patients with an actual gap in therapy has the potential to improve adherence and prevent utilization of emergency services and hospitalizations.

Planned assessments to evaluate impact of this policy include evaluation for re-initiation of therapy after referral, medication adherence before and after referral, and utilization of emergency services.

Discussion and Preliminary Results: In total, 90 patients were referred for case management outreach in the first 5 weeks of the pilot program. Because this is a recently initiated pilot program, outcomes are not yet available for all patients. Outcomes for initial outreach have been documented for 52 patients. Of these patients, case management services were able to contact 36 patients (69%). Nineteen patients (37%) were enrolled in a partial case management program. Patients in the partial case management program decline to be actively enrolled with a case manager, but agree to receive quarterly health-related newsletters and reminders for healthy activities such as flu shots. Three patients (6%) were enrolled in full case management services for a chronic condition (smoking cessation, diabetes, and asthma/COPD). With full enrollment in case management services, patients are matched with a case manager who performs an initial assessment to identify medication issues, gaps in care, social determinants of health, and patient needs. Based on this initial assessment, case managers work to connect the patient with community resources, communicate with their providers and pharmacies, and provide education regarding their medications, non-pharmacological treatments, and diagnoses.

Author: Servid October 2020 290 Even though claims data indicated that many patients may have a gap in therapy, most patients identified still had an adequate supply of their medication or were about to refill the medication. However, some patients were identified who may not have been taking their medications routinely or may have missed doses. In a few cases, gaps in care, changes in insurance coverage, or individual patient circumstances resulted in delayed access to routine medications. For these patients, case management outreach can help provide patient education regarding importance of medication adherence, assist in coordination with provider offices, and provide resources in order to connect members with adequate services to enhance care and avoid adverse events. Outreach to members can also increase awareness of case management services and provide an additional resource if members encounter issues or wish to be engaged in the future.

Recommendations:  Implement a case management referral program for patients with gaps in therapy for high-risk maintenance medications.

Appendix 1: RetroDUR Inclusion and Exclusion Criteria Inclusion Criteria - Patients previously on stable therapy, defined as patients with >=84 days and <=180 supply for a drug in past 150 days AND - Recent >2 week gap in therapy in the prior month for a “high-risk drug” in the drug categories below. Gap in therapy was defined as 2 weeks of no covered days for the drug. o Anticoagulants o Platelet Inhibitors o HIV o Diabetes, Insulins o Antipsychotics (exclude drugs which are typically prescribed for sleep) o Antidepressants (exclude drugs which are typically prescribed for sleep) o Benzodiazepines o Substance Use Disorders, Opioid and Alcohol o Immunosuppressants o Maintenance asthma/COPD inhalers (anticholinergic, long-acting beta-agonist, corticosteroid, and combination inhalers) o Antiepileptics in patients with a seizure disorder in past 2 years (ICD-10 G40x) o Blood pressure medications (ACE inhibitors, ARBs, beta-blockers, diuretics) in patients with cardiovascular disease o Statins in patients with cardiovascular disease

Exclusion criteria - Patients who are: o Deceased o Enrolled in a CCO o Enrolled in Medicare OR o Have other primary insurance - Patients with a more recent paid claim for the same drug or a paid claim for a different drug in the same PDL class (indicating therapy was switched) - Patients previously identified and referred to case management in the past 3 months

Author: Servid October 2020 291 Appendix 2: Patient, Drug and Problem Solving Information Collected for Case Management

Patient Information:

- Patient ID - Patient Name - Patient phone number - Number and list of conditions which may increase risk for COVID-related complications (e.g. age, diabetes, pulmonary diagnoses, chronic kidney disease, liver disease, immunosuppression, etc)

Drug Information:

- PDL Class of identified drug with a gap in therapy - Generic drug name - Drug strength - Total days’ supply in last 6 months - Med possession ratio (MPR) in the past 6 months - Last filled date - Last fill days’ supply - Duration of gap in therapy

Potential problem-solving issues:

- Recent denied claims for the drug indicating a pharmacy tried to fill a prescription - PA submission needed based on error codes associated with denied claims - Issues with prescriber enrollment based on error codes associated with denied claims - Possible new prescription needed based on the prescription number, refill number, and total days’ supply - Potential drug shortage based on the FDA drug shortage list

Appendix 3: Outcome Information for the RetroDUR Report

Case Management Referrals - Number of patients referred - Number of patients with subsequent paid claim within 1 month of referral for the identified drug - Number of patients with subsequent paid claim within 1 month of referral for a different drug in the same PDL class - Patients with an improvement of ≥10% in med possession ratio (MPR) in the 3 months after referral (compared to MPR in 3 months before referral) for identified drug (HSN)

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Policy Evaluation: Expert Consultation for Long-term Antipsychotics in Children

Research Questions:  What proportion of prescribers referred for expert consultation completed a consultation with the Oregon Psychiatric Access Line about Kids (OPAL-K)?  How many patients had a change in psychiatric therapy after referral for prescriber consultation?  Were there any differences in provider type or patients (e.g., medication therapy or demographics) who had a consult compared to those that did not?

Conclusions:  This preliminary analysis identified 77 patients with at least 6 months of use of a newly initiated antipsychotic who were referred to OPAL-K for peer-to- peer provider consultation from August to December 2019. Forty-four percent of prescribers successfully scheduled and completed a consultation for their patients.  Of the patients referred for consultation, 80% had more than 2 antipsychotics prescribed within a 60 day period, 84% lacked an appropriate diagnosis based on claims data, and 62% did not have documented glucose monitoring. Approximately 50% of patients were prescribed antipsychotics from a non- specialist prescriber. The most commonly prescribed antipsychotics were risperidone and aripiprazole.  Forty-four percent of patients (n=34) had no change in drug therapy or monitoring in the 3 months following consultation with a mental health specialist. In the 3 months following referral for consultation, 26% of patients (n=20) had a decrease in dose of their antipsychotic, and 19% (n=15) had a gap in therapy of more than 45 days indicating their antipsychotic may have been discontinued. Thirteen patients (17%) had new metabolic monitoring following referral for consultation. Changes in therapy were similar for those that scheduled a consultation compared to those who were only sent a letter. However, the small population size makes it difficult to discern differences between groups.  Pediatric physicians were the most commonly referred prescribers, followed by mental health nurse practitioners and psychiatrists. Overall differences in providers or patient characteristics were small upon comparison of those with consultation with those who were unable to schedule a consultation. The analysis was limited by the small number of patients identified for each group.

Recommendations:  Continue to monitor drug therapy changes after referral and consultation in pediatric patients on long-term antipsychotics.

Background: There is limited evidence on the use of antipsychotics in children. Many antipsychotics are not FDA-approved for young children and many guidelines recommend extreme caution when prescribing antipsychotics to young children. In addition, long-term use of antipsychotics can be associated with complications including increased risk for metabolic syndrome, diabetes, and movement disorders. Long-term use of antipsychotics is often recommended only in combination with non-pharmacological therapy, and only when benefit has been established.

Author: Sarah Servid, PharmD Date: October 2020 293

In order to improve care and promote medically appropriate use for young children on antipsychotics, this initiative targeted new-start patients less than 10 years of age who were initiating long-term antipsychotic therapy, defined as at least 6 months of covered days in the past 9 months. Patients were prioritized for referral based on relevant risk factors, including patients lacking relevant psychiatric diagnoses or glucose monitoring based on claims data or patients prescribed antipsychotics from a non-specialist. Mental health specialists were included in the program if their patient had other relevant risk factors. Two separate interventions were conducted as part of this process. First, a fax was sent to the prescribing provider notifying them that their patient had been identified based on long-term antipsychotic use. The fax included information on why their patient was being referred, and the prescribing provider was instructed to contact OPAL-K for a consultation on their patient in order to promote the best care for their patient. If providers did not call for a consultation, OPAL-K staff reached out to the provider to schedule a consultation. Consultation as part of this program is not required, and providers were allowed to refuse the offer for consultation. In some cases, patients may have changed providers and the current provider responsible for ongoing therapy was unable to be identified based on claim data or unable to be reached to schedule a consultation.

Methods:

This is a preliminary pre- and post-analysis to evaluate antipsychotic utilization in the 3 months before and after the referral date for each member. Both first- and second-generation antipsychotics were included in the analysis and were identified based on PDL class. Patients were included if a profile was sent to OPAL- K as part of this initiative. Patients were excluded if they had less than 60 days of Medicaid enrollment in the 3 months following referral for consultation.

Baseline characteristics including age, ethnicity, and relevant risk factors were identified at the time of the referral. Relevant psychiatric diagnoses were evaluated based on ICD-10 codes associated with medical claims the 1 year before the referral. Typically ICD-10 codes were categorized according to the first 3 characters. Prescriber type was based on primary provider taxonomy. Medication flags identified at the time of the referral are documented in Table 1. Patients were stratified based on completion of a consultation with OPAL-K experts from August to December 2019.

Changes in drug therapy were compared for the 3 months before and after referral to OPAL-K. The following definitions were used to evaluate therapy:

 Drug discontinuation was defined as a break in therapy of at least 45 days.  Switches in antipsychotic therapy were assessed based on the unique molecular entity (HSN code; Table A1).  Glucose monitoring was defined using the codes in Table A4.  Utilization of other psychotropic medications was classified by the number of unique molecular entities (HSNs). The analysis included any products in the psychiatric system. Oral antipsychotics were defined according to PDL class: first-generation antipsychotics and second-generation antipsychotics.  Concurrent use of more than one oral antipsychotic or other psychotropic was defined as at least 60 days of therapy with no more than a 2-week gap in coverage.  Average dose per day was evaluated in the 3 months before and after the OPAL-K referral. Changes in drug dose were categorized according to the relative decrease or increase per day. Relative percent change was calculated based on difference in the average dose for the before and after groups over 3 months divided by the average dose in the before group.

Author: Servid October 2020 294

 Outpatient medical visits were identified using codes in Table A5. All provider NPIs associated with these medical visits were evaluated to determine if the prescriber of the antipsychotic was involved in the visit. Results: Table 1 shows baseline demographics for patients referred to OPAL-K for expert consultation. Most patients referred were White and over 5 years of age. Patients were referred for expert consultation based on several criteria including duration of antipsychotic use, lack of metabolic monitoring, lack of FDA- approved diagnosis, use of more than 2 antipsychotics, and lack of mental health specialist prescribing. Eighty percent of referred patients had more than 2 antipsychotics prescribed within a 60 day period, 84% lacked an appropriate diagnosis based on claims data, and 62% did not have documented glucose monitoring. The most commonly prescribed antipsychotics were risperidone and aripiprazole. Approximately 50% of patients were prescribed antipsychotics from a non-specialist prescriber. Overall, 77 patients were identified, and 44% of prescribers successfully completed a consultation for their patients. Two groups were available for comparison: 1) patients whose provider had received a fax and completed a consultation AND 2) patients whose provider had received a fax but did not complete a consultation. Demographics were similar between patients who completed a consultation and those only notified via fax, though compared to patients whose provider did complete a consultation, patients without consultation were slightly more likely to be prescribed multiple antipsychotics (86% vs. 73.5%) and not have an FDA-approved diagnosis based on claims data (88.4% vs. 79.4%).

Table 2 describes the most common mental health diagnoses identified in children referred for consultation. The most common identified diagnoses were ADHD, severe stress and adjustment disorders (including PTSD), conduct disorders, and anxiety disorders. The majority of patients had more than one mental health diagnosis. For example, patients with a diagnosis of ADHD often had other mental health diagnoses such as mood or developmental disorders identified based on the patient’s medical claims. Providers who did not have a consultation were slightly more likely to prescribe antipsychotics in patients with diagnoses of severe stress and adjustment disorders, conduct disorders and anxiety disorders compared to providers who did complete an expert consultation. Provider types identified for referral for peer-to-peer consultation are described in Table 3. Pediatric physicians were the most commonly referred prescribers, followed by mental health nurse practitioners and psychiatrists. When categorizing providers by prescriber type, there were slight differences in the proportion of providers who were able to complete a consultation compared to those unable to complete a consultation, but any conclusions are significantly limited by the small population size.

Changes in drug therapy are described in Tables 4 and 5 for patients whose providers completed a consultation and providers without a consultation. While numbers of patients are small, screening for metabolic disorders was increased in both populations after referral for consultation. In the 3 months following referral for consultation, 26% of patients (n=20) had a decrease in dose of their antipsychotic, and 19% (n=15) had a gap in therapy of more than 45 days indicating their antipsychotic may have been discontinued (Table 4). Six patients were switched to a different antipsychotic, most commonly risperidone to aripiprazole (Table 5). There were only slight changes in numbers of other concurrently psychotropic medications, and numbers are too small to discern any reliable patterns (data not shown). In the 3 months following provider notification and outreach for a consultation, subsequent medical visits were slightly more common for providers who completed a peer-to-peer consultation (58.8%) compared to those without a consultation (46.5%). With a longer duration of follow- up more changes in therapy may be documented.

Author: Servid October 2020 295

Table 1. Baseline Demographics of Patients Referred to OPAL-K.

All Patients 77 % Age 0-5 9 11.7% 6-9 68 88.3%

Race White 47 61.0% Unknown 24 31.2% Other 6 7.8%

Criteria for Referral* No diabetes screen within the past year 48 62.3% ≥2 antipsychotics prescribed within prior 60 days 62 80.5% Non-psychiatrist prescriber 38 49.4% No diagnosis of schizophrenia, bipolar, or autism 65 84.4%

Antipsychotics prescribed in the 6 months before referral* 1 risperidone 57 74.0% 2 aripiprazole 24 31.2% 3 olanzapine 2 2.6% 4 paliperidone 1 1.3% 5 asenapine maleate 1 1.3% 6 chlorpromazine HCl 1 1.3%

Patients with a medical visit with their prescribing provider in the 3 months following OPAL-K referral 40 51.9%

*Patients may be counted more than once if they meet multiple criteria or were prescribed multiple medications

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Table 2. Common Diagnoses Identified in Children Referred to OPAL-K. Patients may be counted more than once if they have multiple diagnoses.

Patients Patients w/o All Patients w/consultation consultation 77 % 34 44% 43 56% Top 10 psychiatric diagnosis (categorized by the first 3 characters of the ICD-10 code) 1 F90 - Attention-deficit hyperactivity disorders 51 66.2% 22 64.7% 29 67.4% 2 F43 - Reaction to severe stress, and adjustment disorders 34 44.2% 13 38.2% 21 48.8% 3 F91 - Conduct disorders 30 39.0% 11 32.4% 19 44.2% 4 F41 - Other anxiety disorders 28 36.4% 9 26.5% 19 44.2% 5 F88 - Other disorders of psychological development 18 23.4% 11 32.4% 7 16.3% 6 F34 - Persistent mood [affective] disorders 16 20.8% 8 23.5% 8 18.6% 7 F84 - Pervasive developmental disorders (including autistic disorder) 11 14.3% 6 17.6% 5 11.6% 8 F80 - Specific developmental disorders of speech and language 11 14.3% 7 20.6% 4 9.3% 9 F93 - Emotional disorders with onset specific to childhood 10 13.0% 6 17.6% 4 9.3% 10 F32 - Major depressive disorder, single episode 6 7.8% 2 5.9% 4 9.3%

Table 3. Prescriber characteristics based on primary provider taxonomy for the most recent antipsychotic claim before the referral.

Patients Patients w/o All Patients w/consultation consultation Provider Type 77 % 34 44% 43 56%

PHYSICIAN-PEDIATRICS 21 27.3% 9 26.5% 12 27.9% NURSE PRACTITIONER - PSYCHIATRIC/MENTAL HEALTH 20 26.0% 12 35.3% 8 18.6% PHYSICIAN-PSYCHIATRY&NEUROLOGY-PSYCHIATRY 10 13.0% 4 11.8% 6 14.0% PHYSICIAN-PSYCHIATRY&NEUROLGY-CHILD&ADOLESCENT PSYCHIATRY 9 11.7% 2 5.9% 7 16.3% NURSE PRACTITIONER - PEDIATRICS: PEDIATRICS 5 6.5% 2 5.9% 3 7.0% NURSE PRACTITIONER - FAMILY 4 5.2% 0 0.0% 4 9.3% PHYSICIAN-PEDIATRICS-DEVELOPMENTAL BEHAVORIAL PEDIATRICS 2 2.6% 2 5.9% 0 0.0% PHYSICIAN-FAMILY MEDICINE 2 2.6% 1 2.9% 1 2.3% PHYSICIAN-PEDIATRICS-ADOLESCENT MEDICINE 1 1.3% 1 2.9% 0 0.0% STUDENT IN AN ORGANIZED HEALTH CARE EDUCATION/TRAINING PROGRAM 1 1.3% 1 2.9% 0 0.0% CLINICAL NURSE SPECIALIST - PSYCHIATRIC/MENTAL HEALTH 1 1.3% 0 0.0% 1 2.3% DENTIST 1 1.3% 0 0.0% 1 2.3%

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Table 4. Changes in drug utilization in the 3 months following OPAL-K referral compared to the 3 month before referral.

Patients Patients w/o All Patients w/consultation consultation 77 % 34 44% 43 56% No change in drug therapy or monitoring (patients not meeting any of the criteria below) 34 44.2% 14 41.2% 20 46.5%

Antipsychotic drug discontinuation 15 19.5% 7 20.6% 8 18.6% Discontinuation of other psychotropic drug 5 6.5% 3 8.8% 2 4.7% Change to a different antipsychotic 6 7.8% 3 8.8% 3 7.0% New glucose monitoring 13 16.9% 7 20.6% 6 14.0%

Change in Average Daily Dose No change or less than 25% change in dose 43 55.8% 18 52.9% 25 58.1% Decrease of >=25% 20 26.0% 9 26.5% 11 25.6% Increase of >=25% 14 18.2% 7 20.6% 7 16.3%

Table 5. Changes in antipsychotic therapy assessed in the 3 months following OPAL-K referral

Drug prescribed Drug prescribed before referral after referral Patient 1 aripiprazole haloperidol Patient 2 risperidone ziprasidone Patient 3 risperidone aripiprazole Patient 4 risperidone aripiprazole Patient 5 risperidone aripiprazole Patient 6 risperidone aripiprazole

Limitations:  This is a before/after analysis and does not control for potential confounding factors (of which there are many). Other characteristics may influence which prescribers contact OPAL-K for a consult (e.g., number of patients seen, familiarity with OPAL services, time available in the day, availability of administrative office staff, prior consults with specialists, or previous provider education or experience with antipsychotics). Similarly, there are many

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factors which can influence medication therapy including new diagnoses, disease severity, adverse events, involvement of parents/guardians in care, frequency of follow-up, or availability of providers for medical visits.  This analysis did not include a comparison to a similar patient population with no intervention (educational fax or consultation). The fax intervention notifying providers of the need for expert consultation includes patient specific information on why they are being contacted (e.g., long-term antipsychotic use, lack of metabolic monitoring, etc). It is possible that the fax intervention itself may result in changes in prescribing or glucose monitoring.  This analysis assesses only short-term changes in therapy within the 3 months following referral for consultation. The long-term impact of consultation and referral for peer-to-peer consultation is unknown at this time.  The count of patients with follow-up medical visits may be inaccurate as billing provider for medical visit may not match prescribing provider even if prescriber was involved in care for that visit. Codes identified are the most common codes associated with routine medical visits, but all types of medical visits may not be captured.  Prescriber type may not be accurate and may not reflect all specialties. Prescribers may change over time.  Diagnoses is identified via medical claims and may not accurately reflect the diagnosis for the identified antipsychotic prescription.  Dose changes were evaluated based on an average days’ supply for paid claims and may not accurately reflect what the patient is actually taking.  Blood glucose screening was identified based on medical claims. Patients may have access to glucose screening via other mechanisms which would not be identified via claims data.  The small number of patients in this analysis significantly limtis ability to identify changes in prescribing between groups.

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Appendix 1. Drug Coding Information Table A1. Antipsychotics

Class HSN Generic Antipsychotics, 1st Gen 001621 chlorpromazine HCl Antipsychotics, 1st Gen 001626 fluphenazine HCl Antipsychotics, 1st Gen 001662 haloperidol Antipsychotics, 1st Gen 001661 haloperidol lactate Antipsychotics, 1st Gen 039886 loxapine Antipsychotics, 1st Gen 001664 loxapine succinate Antipsychotics, 1st Gen 001627 perphenazine Antipsychotics, 1st Gen 001637 pimozide Antipsychotics, 1st Gen 001631 thioridazine HCl Antipsychotics, 1st Gen 001668 thiothixene Antipsychotics, 1st Gen 001667 thiothixene HCl Antipsychotics, 1st Gen 001630 trifluoperazine HCl Antipsychotics, 2nd Gen 024551 aripiprazole Antipsychotics, 2nd Gen 046175 asenapine Antipsychotics, 2nd Gen 036576 asenapine maleate Antipsychotics, 2nd Gen 042283 brexpiprazole Antipsychotics, 2nd Gen 042552 cariprazine HCl Antipsychotics, 2nd Gen 004834 clozapine Antipsychotics, 2nd Gen 046280 lumateperone tosylate Antipsychotics, 2nd Gen 037321 lurasidone HCl Antipsychotics, 2nd Gen 011814 olanzapine Antipsychotics, 2nd Gen 034343 paliperidone Antipsychotics, 2nd Gen 043373 pimavanserin tartrate Antipsychotics, 2nd Gen 014015 quetiapine fumarate Antipsychotics, 2nd Gen 008721 risperidone Antipsychotics, 2nd Gen 021974 ziprasidone HCl

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Table A2. Drug dosing for unique antipsychotic dosage forms

Class Generic GSN Route FormDesc TextDrugStr Strength Antipsychotics, 2nd Gen cariprazine HCl 075566 PO CAP DS PK 1.5 mg (1)-3 mg (6) 3 Antipsychotics, 2nd Gen clozapine 064429 PO ORAL SUSP 50 mg/mL 50 Antipsychotics, 2nd Gen asenapine 080406 TD PATCH TD24 3.8 mg/24 hour 3.8 Antipsychotics, 2nd Gen asenapine 080407 TD PATCH TD24 5.7 mg/24 hour 5.7 Antipsychotics, 2nd Gen asenapine 080408 TD PATCH TD24 7.6 mg/24 hour 7.6 Antipsychotics, 2nd Gen aripiprazole 058594 PO SOLUTION 1 mg/mL 1 Antipsychotics, 2nd Gen risperidone 026177 PO SOLUTION 1 mg/mL 1 Antipsychotics, 2nd Gen risperidone 071304 PO SYRINGE 1 mg/mL 1 Antipsychotics, 2nd Gen risperidone 071305 PO SYRINGE 2 mg/2 mL 1 Antipsychotics, 2nd Gen risperidone 071306 PO SYRINGE 3 mg/3 mL 1 Antipsychotics, 2nd Gen quetiapine fumarate 074076 PO TAB24HDSPK 50 mg (3)-200 mg (1)-300 mg (11) 300 Antipsychotics, 1st Gen fluphenazine HCl 003821 PO ELIXIR 2.5 mg/5 mL 0.5 Antipsychotics, 1st Gen chlorpromazine HCl 003794 PO ORAL CONC 100 mg/mL 100 Antipsychotics, 1st Gen chlorpromazine HCl 003795 PO ORAL CONC 30 mg/mL 30 Antipsychotics, 1st Gen fluphenazine HCl 003822 PO ORAL CONC 5 mg/mL 5 Antipsychotics, 1st Gen haloperidol lactate 003971 PO ORAL CONC 2 mg/mL 2 Antipsychotics, 1st Gen thioridazine HCl 003857 PO ORAL CONC 100 mg/mL 100 Antipsychotics, 1st Gen thioridazine HCl 003858 PO ORAL CONC 30 mg/mL 30 Antipsychotics, 1st Gen thiothixene HCl 003994 PO ORAL CONC 5 mg/mL 5

Table A4. Codes associated with glucose monitoring

CPT Code Description 80047 basic metabolic panel w/calcium, ionized 80048 basic metabolic panel w/calcium, total 80050 general health panel 80053 comprehensive metabolic panel 80065 metabolic panel 80069 renal function panel 82947 glucose assay 82948 reagent strip/blood glucose

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82950 glucose test 82951 glucose tolerance test 82952 glucose tolerance test –added samples 82953 glucose tolerance test 82961 glucose tolerance test, IV 82962 glucose test (home use) 83036 A1c 83037 A1c home use D0411 Hba1c in-office point of service testing 81506 endocrinology (T2DM), biochemical assays of seven analytes

Table A5. Codes associated with medical visits

CPT Code Description 90791 Psychiatric Diagnostic Evaluation 90792 Psychiatric Diagnostic Evaluation With Medical Services 90832 Psychotherapy, 30 Minutes 90833 Psychotherapy, 30 Minutes 90834 Psychotherapy, 45 Minutes 90836 Psychotherapy, 45 Minutes 90837 Psychotherapy, 60 Minutes 90839 Psychotherapy For Crisis, First 60 Minutes 90840 Psychotherapy For Crisis 90846 Family Psychotherapy, 50 Minutes 90847 Family Psychotherapy Including Patient, 50 Minutes 90849 Multiple-Family Group Psychotherapy 90853 Group Psychotherapy 90882 Environmental Intervention For Management Of Medical Conditions 90887 Explanation Of Psychiatric, Medical Examinations, Procedures, And Data To Other Than Patient 96110 Developmental Screening 96112 Developmental Test Administration By Qualified Health Care Professional With Interpretation And Repo 96113 Developmental Test Administration By Qualified Health Care Professional With Interpretation And Repo 96127 Brief Emotional Or Behavioral Assessment 96130 Psychological Testing Evaluation By Qualified Health Care Professional, First 60 Minutes Author: Servid October 2020 302

96131 Psychological Testing Evaluation By Qualified Health Care Professional, Additional 60 Minutes 96132 Neuropsychological Testing Evaluation By Qualified Health Care Professional, First 60 Minutes 96133 Neuropsychological Testing Evaluation By Qualified Health Care Professional, Additional 60 Minutes 96136 Psychological Or Neuropsychological Test Administration And Scoring By Qualified Health Care Profess 96137 Psychological Or Neuropsychological Test Administration And Scoring By Qualified Health Care Profess 96138 Psychological Or Neuropsychological Test Administration And Scoring By Technician, First 30 Minutes 96150 Health And Behavior Assessment Each 15 Minutes 96151 Health And Behavior Re-Assessment Each 15 Minutes 96152 Health And Behavior Intervention, Individual Each 15 Minutes 96154 Health And Behavior Intervention, Family And Patient Each 15 Minutes 97151 Behavior Identification Assessment By Qualified Health Care Professional, Each 15 Minutes 97153 Adaptive Behavior Treatment By Protocol, Administered By Technician Under Direction Of Qualified Hea 97155 Adaptive Behavior Treatment With Protocol Modification Administered By Qualified Health Care Profess 97156 Family Adaptive Behavior Treatment Guidance By Qualified Health Care Professional (With Or Without P 97157 Family Adaptive Behavior Treatment Guidance By Qualified Health Care Professional Without Patient Pr 97530 Therapeutic Activities To Improve Function, With One-On-One Contact Between Patient And Provider, Ea 98966 Telephone Assessment And Management Service, 5-10 Minutes Of Medical Discussion 98967 Telephone Assessment And Management Service, 11-20 Minutes Of Medical Discussion 99201 New Patient Office Or Other Outpatient Visit, Typically 10 Minutes 99202 New Patient Office Or Other Outpatient Visit, Typically 20 Minutes 99203 New Patient Office Or Other Outpatient Visit, Typically 30 Minutes 99204 New Patient Office Or Other Outpatient Visit, Typically 45 Minutes 99205 New Patient Office Or Other Outpatient Visit, Typically 60 Minutes 99211 Established Patient Office Or Other Outpatient Visit, Typically 5 Minutes 99212 Established Patient Office Or Other Outpatient Visit, Typically 10 Minutes 99213 Established Patient Office Or Other Outpatient Visit, Typically 15 Minutes 99214 Established Patient Office Or Other Outpatient, Visit Typically 25 Minutes 99215 Established Patient Office Or Other Outpatient, Visit Typically 40 Minutes 99215 Established Patient Office Or Other Outpatient, Visit Typically 40 Minutes 99354 Prolonged Office Or Other Outpatient Service First Hour 99383 Initial New Patient Preventive Medicine Evaluation, Age 5 Through 11 Years 99392 Established Patient Periodic Preventive Medicine Examination, Age 1 Through 4 Years 99393 Established Patient Periodic Preventive Medicine Examination, Age 5 Through 11 Years 99403 Preventive Medicine Counseling, Approximately 45 Minutes Author: Servid October 2020 303

99404 Preventive Medicine Counseling, Approximately 60 Minutes 99441 Physician Telephone Patient Service, 5-10 Minutes Of Medical Discussion 99442 Physician Telephone Patient Service, 11-20 Minutes Of Medical Discussion 99443 Physician Telephone Patient Service, 21-30 Minutes Of Medical Discussion 99492 Initial Psychiatric Collaborative Care Management, First 70 Minutes In The First Calendar Month 99493 Subsequent Psychiatric Collaborative Care Management, First 60 Minutes In Subsequent Month Of Behavi G0463 Hospital Outpatient Clinic Visit For Assessment And Management Of A Patient H0002 Behavioral Health Screening To Determine Eligibility For Admission To Treatment Program H0004 Behavioral Health Counseling And Therapy, Per 15 Minutes H0017 Behavioral Health; Residential (Hospital Residential Treatment Program), Without Room And Board, Per H0019 Behavioral Health; Long-Term Residential (Non-Medical, Non-Acute Care In A Residential Treatment Pro H0031 Mental Health Assessment, By Non-Physician H0032 Mental Health Service Plan Development By Non-Physician H0034 Medication Training And Support, Per 15 Minutes H0036 Community Psychiatric Supportive Treatment, Face-To-Face, Per 15 Minutes H0037 Community Psychiatric Supportive Treatment Program, Per Diem H0039 Assertive Community Treatment, Face-To-Face, Per 15 Minutes H2000 Comprehensive Multidisciplinary Evaluation H2011 Crisis Intervention Service, Per 15 Minutes H2012 Behavioral Health Day Treatment, Per Hour H2013 Psychiatric Health Facility Service, Per Diem H2014 Skills Training And Development, Per 15 Minutes H2027 Psychoeducational Service, Per 15 Minutes T1016 Case Management, Each 15 Minutes T1017 Targeted Case Management, Each 15 Minutes T1024 Evaluation And Treatment By An Integrated, Specialty Team Contracted To Provide Coordinated Care To T1040 Medicaid Certified Community Behavioral Health Clinic Services, Per Diem T2022 Case Management, Per Month T2023 Targeted Case Management; Per Month

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