NEW DRUG UPDATE

Mark S. Johnson, Pharm.D., BCPS Professor of Pharmacy Practice Director of Postgraduate Education Bernard J. Dunn School of Pharmacy Shenandoah University Financial Disclosures

• Mark S. Johnson, Pharm.D., BCPS • Name of commercial interest(s) • Stockholder in Merck, Express Scripts and various mutual funds Objectives

• Identify the new drugs approved by the FDA that are most clinically relevant to general practice in the first half of 2018 • Discuss relevant indications, efficacy, pharmacokinetics, safety, and dosing of the new drugs • Discuss how the new drugs differ from existing drugs on the market • Describe how to best incorporate the new drugs into clinical practice using a case-based format Self Assessment Questions

1. Coagulation factor Xa (recombinant), inactivated-zhzo (andexanet alfa) (Andexxa™) is FDA-approved as a reversal agent for which of the following? A. Rivaroxaban (Xarelto™) B. Apixaban (Eliquis™) C. Dabigatran (Pradaxa™) D. Enoxaparin (Lovenox™)

2. Plazomicin (Zemdri™) belongs to which of the following antibiotic classes? A. Quinolones B. Tetracyclines C. Macrolides D. Aminoglycosides Self Assessment Questions

3. Baricitinib (Olumiant™) is a inhibitor that’s FDA-approved for which of the following conditions? A. B. Inflammatory bowel disease C. Rheumatoid arthritis D. Lupus

4. -aooe (Aimovig™) is a new drug for migraine prophylaxis. How should it be administered? A. Orally B. Subcutaneously C. Intramuscularly D. Sublingually Self Assessment Questions

5. Sodium Zirconium Cyclosilicate (Lokelma™) is a new drug for treating hyperkalemia. What is its most common adverse effect? A. Hypertension B. Dehydration C. Edema D. Hypercalcemia

6. -asmn (Ilumya™) is a new drug for treating psoriasis. What is its mechanism of action? A. 12 antagonist B. antagonist C. antagonist D. TNF inhibitor

FDA Approvals

• 2018 to date (as of 8/17/18) • 31 New Molecular Entities / New Biolologics • 19 New Dosage Forms • 1 Withdrawal Withdrawals

• (Zinbryta™)—Biogen/AbbVie • Humanized for relapsing remitting multiple sclerosis • MOA: modulator of interleukin-2-mediated activation of lymphocytes by binding to the alpha subunit CD25 of the interleukin-2 receptor • Manufacturer voluntarily removed from the worldwide market on March 2, 2018 due to safety concerns • Severe liver damage including autoimmune hepatitis and liver failure • Immune-related disorders including skin reactions, lymphadenopathy, non-infectious colitis, other immune- mediated disorders SIGNIFICANT NEW MOLECULAR ENTITIES/BIOLOGICS Cardiovascular Drugs Coagulation factor Xa (recombinant), inactivated-zhzo (andexanet alfa) (Andexxa™): Portola Pharm

• Anticoagulation reversal agent for the direct factor Xa inhibitors rivaroxaban (Xarelto™) and apixaban (Eliquis™) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding • First reversal agent for the factor Xa inhibitors (but not for edoxaban [Savaysa™] or betrixaban [Bevyxxa™] • (Praxbind™) was approved in 2015 for reversal of the anticoagulant effect of the direct thrombin inhibitor dabigatran (Pradaxa™) • Studies suggest that the anticoagulant effect of factor Xa inhibitors may be reversed by prothrombin complex concentrates as well

https://www.empr.com Coagulation Factor Xa (Andexxa™) MOA • Genetically modified variant of human factor Xa (alanine substituted for serine) produced in Chinese hamster ovary cells • Exerts procoagulant effect by binding and sequestering the Factor Xa inhibitors rivaroxaban and apixaban • Also exerts procoagulant effect by binding and inhibiting the activity of Tissue Factor Pathway Inhibitor, which can lead to increase tissue factor-initiated thrombin generation

https://www.nejm.org/doi/full/10.1056/NEJMoa1510991 Coagulation Factor Xa (Andexxa™) Efficacy • FDA approval based on 2 randomized, placebo-controlled trials in healthy volunteers 50-75yo (ANNEXA-A and ANNEXA-R) • Evaluated mean change from baseline in anti-factor Xa activity following administration of andexanet alfa • Patients had received either apixaban or rivaroxaban • In phase 2 trials and animal studies, andexanet alfa shown to reduce the anti-factor Xa activity of other direct or indirect factor Xa inhibitors • FDA requiring Portola Pharm to conduct a randomized, controlled trial comparing andexanet alfa with usual care (including prothrombin complex concentrates) in patients taking factor Xa inhibitors with active bleeding Coagulation Factor Xa (Andexxa™) Efficacy: ANNEXA-A • N=66 healthy subjects • Received apixaban 5mg twice daily for 3.5 days • 3 hours after the last dose of apixaban andexanet alfa 400-mg IV bolus with or without a subsequent 4 mg/min continuous infusion for 2 hours vs. placebo • Anti-factor Xa activity reduced within 2-5 minutes by 94% with an andexanet alfa IV bolus vs. 21% placebo • Thrombin generation was fully restored within 2-5 minutes in 100% of andexanet-treated patients vs. 11% placebo • Effects sustained throughout the continuous 2h infusion Coagulation Factor Xa (Andexxa™) Efficacy: ANNEXA-R • N=80 healthy subjects • Received rivaroxaban 20mg once daily for 4 days • 4 hours after the last dose of rivaroxaban andexanet alfa 800-mg IV bolus with or without a subsequent 8 mg/min continuous infusion for 2 hours vs. placebo • Anti-factor Xa activity reduced within 2-5 minutes by 92% with an andexanet alfa IV bolus vs. 18% placebo • Thrombin generation was fully restored within 2-5 minutes in 96% of andexanet-treated patients vs. 7% placebo • Effects sustained throughout the continuous 2h infusion Coagulation Factor Xa (Andexxa™) Efficacy: ANNEXA-4 Interim Analysis • Ongoing single-arm trial • N=238 patients with acute major bleeding (61% intracerebral, 27% gastrointestinal) • Received andexanet alfa (89% low-dose regimen and 11% high-dose regimen) within 18h after taking factor Xa inhibitor (apixaban, rivaroxaban, edoxaban, enoxaparin) • Reduction of anti-factor Xa activity by 91% apixaban, by 88% rivaroxaban, by 75% enoxaparin • Effective hemostasis achieved in 83% of patients within 12h Coagulation Factor Xa (Andexxa™) Safety • Warnings/Precautions • Arterial and venous thromboembolic events, ischemic events, and cardiac events, including sudden death, have occurred during treatment • Interim analysis of ANNEXA-4: 11% of patients had thrombotic event and 12% died within 30 days with median time to the first event of 6 days • No thromboembolic events in 223 healthy volunteers • Resume anticoagulant therapy as soon as medically appropriate following treatment • Re-elevation or incomplete reversal of anticoagulant activity can occur

• ADR’s • Most common adverse reactions (≥ 5%): urinary tract infections and pneumonia • Most common adverse reactions (≥ 3%) in healthy volunteers: infusion-related reactions Coagulation Factor Xa (Andexxa™) Availability/Dosing/Cost • Availability: Cartons containing four 100-mg single-use vials; limited supply until early 2019 • Dosing: Recommended dosage is based on the factor Xa inhibitor taken, its dose, and the time since the last factor Xa inhibitor dose.

• Cost: High dose=$49,500; Low dose=$24,750 Coagulation Factor Xa (Andexxa™) Conclusion • Coagulation Factor Xa is an anticoagulation reversal agent for the direct factor Xa inhibitors rivaroxaban and apixaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding • Can rapidly reverse the anticoagulant effect of apixaban and rivaroxaban in patients with active major bleeding, based on an interim analysis of an ongoing single-arm trial • It may also be effective in reversing the anticoagulant effect of other direct factor Xa inhibitors and indirect factor Xa inhibitors but data are lacking • Arterial and venous thromboembolic events, ischemic events, and cardiac events, including sudden death, have occurred • How it compares with prothrombin complex concentrates is not established • Costly Case

• A 65yo F with atrial fibrillation on rivaroxaban (Xarelto™) falls coming down her steps and hits her head. An intracranial bleed is seen on CT scan. How should this patient best be treated? Infectious Diseases Drugs Vancomycin Oral Solution (Firvanq™) Cutis Pharma • A glycopeptide antibacterial indicated in adults and pediatrics < 18yo for treatment of Clostridium difficile- associated diarrhea and enterocolitis caused by Staphylococcus aureus (including MRSA) • Only FDA-approved vancomycin oral solution available • Replaced vancomycin compounding (FIRST™ Vancomycin Kit) • Oral capsule formulation (Vancocin™) also available • IV formulation has been used in past to compound the oral solution as less costly than capsules Vancomycin Oral Solution (Firvanq™) Efficacy • No new clinical trials were required for approval of Firvanq™ by the FDA • Approval was based on two trials conducted earlier with Vancocin™ oral capsules showing efficacy for treatment of Clostridium difficile infections • Oral vancomycin now recommended as first line therapy for CDI in 2017 Guidelines Vancomycin Oral Solution (Firvanq™) ADRs • Poorly absorbed, but significant systemic absorption can occur in patients with renal insufficiency and/or colitis who have taken multiple oral doses. • Also some patients with inflammatory disorders of the intestinal mucosa also may have significant systemic absorption • Most common adverse reactions (≥ 10%): • nausea (17%) • abdominal pain (15%) • hypokalemia (13%) Vancomycin Oral Solution (Firvanq™) Dosing • C. difficile-associated diarrhea: • Adults (>18 yo): 125mg orally 4 times daily for 10 days • Pediatrics (<18 yo): 40 mg/kg in 3 or 4 divided doses for 7-10 days • Total daily dosage should not exceed 2 g • Staphylococcal enterocolitis: • Adults (>18 yo): 500 mg to 2 g orally in 3 or 4 divided doses for 7- 10 days • Pediatrics (< 18 yo): 40 mg/kg in 3 or 4 divided doses for 7 to 10 days • Total daily dosage should not exceed 2 g Vancomycin Oral Solution (Firvanq™) Availability/Cost • Availability • Available in kits containing a bottle of vancomycin hydrochloride powder (3.75g, 7.5g, 10.5g, 15g) and a bottle of grape-flavored diluent • Must be reconstituted by a healthcare provider to a final concentration of 25 or 50 mg/ml • Should be refrigerated before and after reconstitution, and the solution should be discarded after 14 days • Cost • $125 / 10 days Vancomycin Oral Solution (Firvanq™) Conclusion • Only FDA-approved oral solution of vancomycin for Clostridium difficile-associated diarrhea and enterocolitis caused by Staphylococcus aureus (including MRSA) in adults and pediatrics • Does not require compounding • Costs much less than oral vancomycin capsules Case

• A 45yo M develops CDI after 5 days of levofloxacin for CAP. WBC 12,000 SCr 0.9. What would be the best treatment for CDI in this patient? -uiyk (Trogarzo™) Thera Technologies • CD4-directed monoclonal antibody post-attachment HIV-1 inhibitor, in combination with other antiretroviral(s) • FDA-approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen • First biologic approved by the FDA for treatment of HIV-1 infection • Current guidelines advise against adding a single fully active antiretroviral drug to a nonsuppressive regimen because of the risk of rapid development of resistance

https://www.webmd.com Ibalizumab-uiyk (Trogarzo™) MOA • Recombinant humanized monoclonal antibody that blocks entry of HIV-1 into CD4+ cells and prevents its transmission via cell-cell fusion by binding to the second extracellular domain of the CD4+ receptor • Does not interfere with normal CD4+ cell activity • No cross-resistance between ibalizumab and other FDA- approved antiretroviral drugs has been observed to date

https://www.researchgate.net Ibalizumab-uiyk (Trogarzo™) Efficacy • Unpublished single-arm trial (TMB-301) • N=40 heavily treatment-experienced patients with MDR-HIV infection, a viral load >1000 copies/mL, and documented resistance to at least 1 NRTI, 1 NNRTI, and 1 PI—patients were taking a failing antiretroviral regimen or had taken one within the previous 8 weeks • After 1-week observation, patients received ibalizumab 2000mg while continuing their failing antiretroviral regimen (if any)

• Primary Endpoint: partial virologic suppression (≥0.5-log10reduction in viral load from baseline) achieved in 83% of patients at day 13 • Then ibalizumab 800mg on day 21 and every 2 weeks thereafter through week 25 in addition to optimized background therapy • At week 25, full virologic suppression achieved in 61% of patients with a baseline CD4+ count ≥50 cells/μL and in 18% of those with a baseline count <50 cells/μL • Extension trial (TMB-311) • N=27 patients who had completed the TMB-301 trial • All 15 patients who had achieved full virologic suppression with ibalizumab at week 24 maintained suppression with continued treatment through week 48 Ibalizumab-uiyk (Trogarzo™) ADR’s • Most (90%) ADR’s were mild or moderate in severity • Severe ADR’s: one severe rash and one immune reconstitution inflammatory syndrome manifested as an exacerbation of progressive multifocal leukoencephalopathy • Most Common • Diarrhea 8% • Dizziness 8% • Nausea 5% • Rash 5% • Severe (grade ≥3) laboratory abnormalities • Elevated serum creatinine (10%) • Elevated lipase (5%) • Leukopenia (5%) • Neutropenia (5%) • Hyperbilirubinemia (5%) Ibalizumab-uiyk (Trogarzo™) Dosing • Recommended dose: 2000 mg (10 vials) once, then 800 mg (4 vials) every two weeks • Solution should be diluted in 250 mL of normal saline and administered as an IV infusion in the cephalic vein • Loading dose should be infused over ≥30 minutes; subsequent doses can be given over ≥15 minutes if no infusion-related adverse reactions occur • Patients should be observed for at least 1 hour after the first infusion and for at least 15 minutes after subsequent infusions • If a dose is missed by ≥3 days, a 2000-mg dose should be given as soon as possible; regular maintenance dosing can resume thereafter Ibalizumab-uiyk (Trogarzo™) Availability/Cost • Availability: • Sterile colorless to slightly yellow and clear to slightly opalescent solution with no visible particles for intravenous infusion • Packaged in a single-dose 2 mL clear glass vial containing 200 mg/1.33 mL (150 mg/mL) of ibalizumab-uiyk • Available in a carton containing two single-dose vials • Store vials under refrigeration at 2 to 8ºC (36-46 ºF). Do not freeze and protect from light • Once diluted, should be administered immediately • Cost • $118,000 / 1 year Ibalizumab-uiyk (Trogarzo™) Conclusion • First biologic drug to be approved by the FDA for treatment of HIV-1 infection • Reduced viral loads in heavily treatment-experienced patients with multidrug-resistant infection in a single-arm trial • Most ADR’s mild to moderate but severe adverse effects including rash and immune reconstitution inflammatory syndrome have occurred along with lab abnormalities • Long-term efficacy and safety remain to be determined • Costly Other HIV Drugs

• //Tenofovir/Alafenamide (Biktarvy™): Gilead Sciences • A once-daily, fixed-dose combination of bictegravir, a new integrase strand transfer inhibitor (INSTI), and the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine and (TAF), for treatment of HIV-1 infection in adults • Indicated for use in patients who are antiretroviral-naive or who have been virologically suppressed on a stable antiretroviral regimen for ≥3 months with no history of treatment failure and no known substitutions associated with resistance to any component of the combination Other HIV Drugs

• , , Emtricitabine, Tenofovir alafenamide (Symtuza™): Janssen Pharmaceuticals, Inc. • A four-drug combination of darunavir (DRV), a human immunodeficiency virus (HIV-1) protease inhibitor, cobicistat (COBI), a CYP3A inhibitor, and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults: who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. • Once daily, single-tablet regimen Plazomicin (Zemdri™) Achaogen • An aminoglycoside antibacterial indicated for the treatment of patients > 18 yo with complicated urinary tract infections (cUTI) including pyelonephritis • Spectrum includes gram negative aerobic bacilli: E. coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae • Active vs. ESBL’s, KPC’s, other aminoglycoside modifying enzymes • In vitro activity vs. many other Enterobacteriaceae but limited clinical experience • Activity against Pseudomonas aeruginosa variable; no activity against Acinetobacter baumanni, Stenotrophomonas maltophila, or anaerobes; no activity vs. gram positive aerobes

https://biosupply.fffenterprises.com Plazomicin (Zemdri™) MOA/Resistance • MOA • Bind to bacterial 30S ribosomal subunit, thereby inhibiting protein synthesis • Concentration-dependent bactericidal activity as measured by time kill studies • In vitro studies demonstrated a post-antibiotic effect ranging from 0.2 to 2.6 hours at 2X MIC against Enterobacteriaceae • Resistance • Production of aminoglycoside modifying enzymes (AMEs), alteration of the ribosomal target through production of 16S rRNA methyltransferases, up-regulation of efflux pumps and reduced permeability into bacterial cell due to loss of outer membrane porins Plazomicin (Zemdri™) Efficacy • Evaluating Plazomicin In cUTI (EPIC) • Phase 3 cUTI trial; plazomicin 15mg/kg QD vs. meropenem 1g Q8h; N=609, multinational, double-blind, noninferiority trial • Non-inferior vs. meropenem for co-primary efficacy endpoints of composite cure (clinical cure and microbiological eradication) in the microbiological modified intent-to-treat population (N=388) (day 5) and test-of-cure (TOC) visit (Day 17 + 2) • Composite cure rates (day 5): 88.0%P vs. 91.4%M (diff -3.4%, CI -10.0- 3.1) • Composite cure rates (at TOC visit): 81.7%P vs. 70.1%M (diff 11.6%, CI 2.7- 20.3) • Composite cure in patients with concomitant bacteremia at baseline (at TOC visit): 72.0%P vs. 56.5%M • CURE Trial • FDA issued a Complete Response Letter stating that CARE does not provide substantial evidence of effectiveness of plazomicin for the treatment of blood stream infections at this time Plazomicin (Zemdri™) ADR’s • Boxed Warning • Nephrotoxicity: risk greater in patients with impaired renal function, elderly, those receiving concomitant nephrotoxic • Ototoxicity: manifested as hearing loss, tinnitus, and/or vertigo; may be irreversible and may not become evident until after completion • Neuromuscular blockade possible • Can cause fetal harm when administered to a pregnant woman • Contraindicated in hypersensitivity to aminoglycosides Plazomicin (Zemdri™) ADR’s • ADR’s • Decreased renal function 3.6% • Diarrhea 2.3% • Hypertension 2.3% • Headache 1.3% • Nausea 1.3% • Vomiting 1.3% • Hypotension 1.0% • Ototoxicity • Based on pure tone audiometry, ototoxicity could not be definitively excluded according to the American Speech-Language Hearing Association criteria in 2.2% plazomicin vs. 2.0% comparator or placebo Plazomicin (Zemdri™) Dosing • 15 mg/kg every 24 hours by IV infusion over 30 minutes to >18 yo with CrCl > 90ml/min • Recommended duration: 4-7 days for cUTI, including pyelonephritis • Assess CrCl (Cockcroft-Gault) in all patients prior to therapy and daily • Dose adjustment based on renal function • > 60-89 ml/min: 15mg/kg q24h • > 30-59 ml/min: 10mg/kg q24h • > 15-29 ml/min: 10mg/kg q48h • Dose based on TBW or ABW if obese • For cUTI patients with CrCl > 15-89 ml/min, TDM is recommended to maintain plasma trough concentrations below 3 mcg/mL • Measure trough within approximately 30 minutes before administration of the second dose • Adjustment of dose based on TDM involves extending the dosing interval by 1.5 fold (i.e., from every 24 hours to every 36 hours or from every 48 hours to every 72 hours) for patients with trough > 3 mcg/mL Plazomicin (Zemdri™) Availability/Dilution/Stability/Cost • Availability • 500 mg/10 mL (50 mg/mL) in single-dose vial containing plazomicin sulfate equivalent to 500 mg plazomicin free base • Dilution/Stability • Should be diluted in 0.9% Sodium Chloride or Lactated Ringer’s to achieve a final volume of 50 mL for intravenous infusion • Stable for 24 hours at room temperature at concentrations of 2.5 mg/mL to 45 mg/mL in 0.9% Sodium Chloride and Lactated Ringer’s • Cost • ?$325-$350 / 500mg Plazomicin (Zemdri™) Conclusion • An aminoglycoside antibacterial indicated for the treatment of patients > 18 yo with complicated urinary tract infections (cUTI) including pyelonephritis • Spectrum includes gram negative aerobic bacilli: E. coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae • Active vs. ESBL’s, KPC’s, other aminoglycoside modifying enzymes • Noninferior vs. meropenem for cUTI • Recommended duration 4-7days • Similar ADR’s to other aminoglycosides • Consider when limited option exist Case

• A 80yo F develops a complicated UTI due to ESBL E.Coli. CrCl 40ml/min. Is this patient a candidate for plazomicin (Zemdri™)? If used, what labs should be monitored? Rheumatology Drugs Baricitinib (Olumiant™) Lilly • Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) inhibitors • Second JAK inhibitor to be approved for treatment of RA after tofacitinib (Xeljanz™, Xeljanz XR™) • JAK signaling is a critical step in hematopoiesis and immune activation

https://www.olumiant.com/ Baricitinib (Olumiant™) Mechanism of Action • JAKs are intracellular enzymes which transmit signals arising from or -receptor interactions on the cellular membrane • JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which are intracellular mediators of gene expression and are involved in immune response and inflammation leading to joint destruction • Baricitinib inhibits the signaling pathway at JAKs, thereby preventing phosphorylation and activation of STATs

http://www.skintherapyletter.com/conditions/psoriasis/small-molecules/ Baricitinib (Olumiant™) Efficacy • Four randomized, double-blind trials (N=73-457) +/- DMARD’s vs. placebo in patients with active RA that had not responded adequately to other DMARDs (methotrexate, other cDMARD’s, TNF inhibitors) • More patients achieved 20% improvement from baseline at 12 weeks on American College of Rheumatology Scale (ACR20) • ACR20 response rates from 49%-83% with baricitinib vs. 27%-41% placebo • Also showed early symptom relief, with ACR20 responses as early as week 1 • RA-BEACON trial (2mg vs 4mg vs placebo) • N=527 with inadequate response to or unacceptable ARR’s associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both • 4mg “larger treatment benefits” at 12 weeks but more serious ADR’s (2 nonmelanoma skin cancers and 2 major adverse cardiovascular events, including a fatal stroke) • Significant improvements in physical function based on Health Assessment Questionnaire Disability Index (HAQ-DI) (1.71 before treatment and 1.31 at Week 12) vs. placebo (1.78 before treatment and 1.59 at Week 12) Baricitinib (Olumiant™) ADR’s • Boxed Warning: Serious infections, malignancy, thrombosis • Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections have occurred--if a serious infection develops, interrupt baricitinib until the infection is controlled • Prior to starting, perform a test for latent tuberculosis; if it is positive, start treatment for tuberculosis prior to starting baricitinib • Monitor all patients for active tuberculosis during treatment, even if the initial latent tuberculosis test is negative • Lymphoma and other malignancies have been observed • Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, some fatal, have occurred and symptoms of thrombosis should be evaluated promptly Baricitinib (Olumiant™) ADR’s • Common • Dermatologic: Herpes zoster (1% ) • Gastrointestinal: Nausea (2.7% ) • Hepatic: increased ALT/SGPT (1.7% ), AST/SGOT (1.3%) • Respiratory: Upper respiratory infection (16.3% ) • Other: Infectious disease (29% to 42% ) • Serious • Gastrointestinal: GI perforation • Hematologic: Arterial thrombosis (0.4% to 0.6% ), Venous thromboembolism (up to 0.4% ) • Other: Infectious disease, Serious (1% to 3% ) (including TB) • Other • Thromboembolic events, malignancy, neutropenia, lymphopenia, anemia, thrombocytosis, elevations in CPK’s, elevations in lipid levels Baricitinib (Olumiant™) Drug Interactions • Not recommended in patients taking strong Organic Anion Transporter 3 (OAT3) inhibitors (probenecid has increased baricitinib 2x) • Concomitant use with other immunosuppressants could increase the risk of serious infection • Live vaccines should not be administered Baricitinib (Olumiant™) Dosing • The recommended dosage is one tablet (2mg) once daily, taken with or without food, alone or in combination with methotrexate or other conventional DMARDs • Treatment should be withheld if the absolute lymphocyte count < 500 cells/mm3, ANC < 1000 cells/mm3, or the hemoglobin level < 8 g/dL, or if sepsis or a serious or opportunistic infection develops • Use with biologic DMARDs, other JAK inhibitors, or potent immunosuppressants such as cyclosporine is not recommended • Renal/Hepatic Impairment • Should not be used in patients with severe hepatic impairment (Child- Pugh C) or moderate or severe renal impairment (eGFR <60 mL/min/1.73 m2) Baricitinib (Olumiant™) Availability/Cost • Availability • Available in 2mg tablets • Lilly had sought FDA approval of a 4mg dose (approved in Europe) for use in patients who had an inadequate response to the 2mg dose, but an FDA advisory committee considered the risk-to-benefit profile of this higher dose unacceptable

• Cost • $2054.70 / 30 days Baricitinib (Olumiant™) Conclusion • Baricitinib is a Janus kinase (JAK) inhibitor • More effective than placebo for treatment of refractory rheumatoid arthritis, but active-comparator trials and convincing radiographic data with the FDA-approved dosage are lacking • Fatal adverse effects including infection and thrombosis have occurred with its use • Should be used only when biologic agents such as TNF inhibitors have failed • Had not been compared to tofacitinib Case

• An 25yo M with RA has been on methotrexate but is no longer responding. Is baricitinib (Olumiant™) an option for this patient? Neurology Drugs Case

• A 25yo M present with opioid use disorder. What are some options to manage withdrawal symptoms? Lofexidine (Lucemyra™) US WorldMeds

• Centrally acting alpha2 receptor agonist to manage opioid withdrawal symptoms in adults to facilitate abrupt opioid discontinuation in adults • Has been available in United Kingdom since 1992 • First nonopioid to be approved for opioid withdrawal—clonidine used off-label to reduce withdrawal symptoms related to noradrenergic overactivity (GI, hyperhidrosis, anxiety, and irritability) but can cause bradycardia and hypotension • Partial opioid agonist buprenorphine is DOC and comparable to methadone

https://www.empr.com Lofexidine (Lucemyra™) Efficacy • FDA approval based on two randomized, double-blind trials vs. placebo • Patients physically dependent on short-acting opioids • Were receiving inpatient treatment for withdrawal management • Lofexidine significantly improved Subjective Opiate Withdrawal Scale (SOWS-Gossop) patient rating scores (0-30 scale) and treatment completion rates • N=264: 2.88mg/d SOWS-Gossop 7 (completion rate 49%) vs. placebo SOWS-Gossop 8.9 (completion rate 33%) • N=602: 2.88mg/d SOWS-Gossop 6.1 (completion rate 40%) vs. 2.16mg/d SOWS-Gossop 6.5 (completion rate 41%) vs. placebo SOW- Gossop 8.8 (completion rate 28%) Lofexidine (Lucemyra™) ADR’s • Insomnia: 51%-55% • Orthostatic Hypotension: 29%-42% • Bradycardia: 24%-32% • Hypotension: 30%-30% • Dizziness: 19%-23% • Somnolence: 11%-13% • Sedation: 13%-12% • Dry Mouth: 10%-11% • Syncope/Tinnitus: 0.9%/0.9%-1.4%/3.2% • Also QT prolongation in postmarketing studies Lofexidine (Lucemyra™) ADR’s • Blood pressure elevations after stopping therapy • ≥ 140 mmHg and ≥ 20 mmHg increase from baseline • 2.88 mg/d (N = 134): 23/58 = 39.7% • Placebo (N=129): 6/37=16.2%

• ≥ 170 mmHg and ≥ 20 mmHg increase from baseline • 2.88 mg/d (N=134): 5/58 = 8.6% • Placebo (N=129): 0/37= 0%

• Gender-specific • Serious CV (2.88mg/d): females 4/101 (4%); males 3/289 (1%) • Discontinuations and Dose Holds for Bradycardia and Orthostatic Hypotension (2.16mg/d and 2.88mg/d): females 9/67 (13%) and 20/64 (31%); males 22/162 (14%) and 29/158 (18%) Lofexidine (Lucemyra™) Precautions • Risk of Hypotension, Bradycardia, and Syncope: • Monitor vital signs before dosing and advise patients on how to minimize the risk of these CV effects and manage symptoms. Monitor symptoms related to bradycardia and orthostasis. • In outpatients, ensure patients can self-monitor signs/symptoms • Avoid use in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, or chronic renal failure, marked bradycardia. • Risk of QT prolongation: • Monitor EKG with electrolyte abnormalities, CHF, bradyarrhythmias, hepatic or renal impairment, with other QT prolonging drugs. Lofexidine (Lucemyra™) Drug Interactions • Methadone: • Both prolong QT interval. • EKG monitoring is recommended when used concomitantly. • Oral Naltrexone: • Concomitant use may reduce efficacy of oral naltrexone. • CYP2D6 Inhibitors: • Paroxetine resulted in increased plasma levels of lofexidine (28%). • Monitor for symptoms of orthostasis and bradycardia with concomitant use of a CYP2D6 inhibitor. • Other drugs that cause bradycardia or hypotension: should not be used in combination Lofexidine (Lucemyra™) Dosing • Usual dose: three 0.18 mg tablets taken orally 4 times daily at 5- to 6-hour intervals • May be continued for up to14 days with dosing guided by symptoms • After the period of peak withdrawal (first 5-7 days after last opioid use), can be reduced by one tablet per dose every 1 to 2 days. Discontinue with a gradual dose reduction over 2 to 4 days • Renal/hepatic dose adjustment: • CrCl ≥30 and <90 mL/min or moderate hepatic impairment (Child- Pugh B): two tablets four times daily • CrCl <30 mL/min or severe hepatic impairment (Child-Pugh C): one tablet four times daily Lofexidine (Lucemyra™) Availability/Cost • Availability • Available as 0.18mg tablets • Bottles of 36 and 96 tablets • Cost • $1738 / 1 week Lofexidine (Lucemyra™) Conclusion

• Lofexidine is a central alpha2 receptor agonist • First nonopioid to be approved by the FDA for management of opioid withdrawal symptoms • Appears to have similar efficacy and causes less

hypotension vs. clonidine (another central alpha2 receptor agonist that has been used off-label for this indication) • More costly than clonidine • Buprenorphine still remains the drug of choice for management of opioid withdrawal in most patients Erenumab-aooe (Aimovig™) • A calcitonin gene-related peptide receptor antagonist for the preventive treatment of migraine in adults • First drug in its class to be approved by the FDA • Other drugs used for migraine prevention: beta blockers (propranolol*, timolol*, metoprolol, nadolol, atenolol), antiepileptic drugs (valproic acid*, topiramate*), onabotulinumtoxinA* (Botox™), tricyclic antidepressants (), serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine)

https://www.aimovig.com/taking-aimovig/ Erenumab-aooe (Aimovig™) Mechanism of Action • A human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function • CGRP is a neuropeptide common in trigeminal ganglia but also distributed throughout the central and peripheral nervous systems, and is a potent vasodilator and pain- signaling neurotransmitter • Serum levels of CGRP increase during migraine attacks and IV CGRP injection has induced migraine-like headaches with a history of migraines Erenumab-aooe (Aimovig™) Efficacy • Episodic Migraine (4-14 monthly migraine days [MMD]; mean 8 MMD) • Goadsby et al • N=955, 6 months • Change in MMD: -3.2 (70mg), -3.7 (140mg), -1.8 (placebo) • >50% reduction in MMD: 43.3% (70mg), 50% (140mg), 26.6% (placebo) • Dodick et al • N=577, 3 months • Change in MMD: -2.9 (70mg), -1.8 (placebo) • >50% reduction in MMD: 39.7% (70mg), 29.5% (placebo) • Reuter et al (abstract) • N=246, failed 2-4 preventive migraine treatments • >50% reduction in MMD: 30.3% (140mg), 13.7% (placebo) Erenumab-aooe (Aimovig™) Efficacy • Chronic Migraine (≥15 headache days per month with ≥8 MMD; mean frequency 18 MMD) • Tepper et al • N=677, 3 months • Change in MMD: -6.6 (70mg), -6.6 (140mg), -4.2 (placebo) • >50% reduction in MMD: 39.9% (70mg), 41.2% (140mg), 23.5% (placebo) Erenumab-aooe (Aimovig™) ADR’s • Most common • Injection-site reactions (5-6%) • Constipation (1-3%) • Other • Cramps, muscle spasms: <1% (70mg), 2% (140mg) • Anti-erenumab antibodies: 6.2% (70mg), 2.6% (140mg) • 1 patient with CV risk factors died from a CV event Erenumab-aooe (Aimovig™) Dosing • For subcutaneous use only, administer in the abdomen, thigh, or upper arm • Recommended dosage is 70mg once monthly • Some patients may benefit from a dosage of 140 mg once monthly • 140 mg dose is administered once monthly as two consecutive injections of 70 mg each • Needle shield within the white cap of prefilled autoinjector and the gray needle cap of prefilled syringe contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex Erenumab-aooe (Aimovig™) Availability/Cost • Availability • Injection: 70 mg/mL solution in a single-dose prefilled SureClick® autoinjector • Injection: 70 mg/mL solution in a single-dose prefilled syringe

• Cost: $575 / 70mg Erenumab-aooe (Aimovig™) Conclusion • First antibody against the calcitonin gene-related peptide (CGRP) receptor to receive FDA approval for the preventive treatment of migraine in adults • Reduces migraine frequency in patients with episodic and chronic migraine vs. placebo, and may be effective when other therapies have failed • Self injected subcutaneously once monthly • Long-term efficacy and safety unknown, especially in those with cardiac risk factors • No direct comparisons to other migraine preventative drugs • Costly Case

• A 35yo F with episodic migraines (about 3-4 monthly) wants to consider a prophylactic drug and has heard of the new drug erenumab (Aimovig™). Would this be a reasonable agent to use in this patient? Cannabidiol (Epidiolex™) Greenwich Biosciences • Cannabidiol (CBD) oral solution for seizures with Lennox- Gastaut syndrome or Dravet syndrome in patients > 2yo • First FDA-approved drug that contains a purified drug substance derived from marijuana and first FDA approval of a drug for the treatment of patients with Dravet syndrome • CBD is chemical component of the Cannabis sativa plant (marijuana), but does not cause intoxication or euphoria that comes from tetrahydrocannabinol (THC)

http://fortune.com/2018/06/25/fda-cannabis-epidiolex/ Cannabidiol (Epidiolex™) Efficacy • 3 randomized, double-blind, placebo-controlled clinical trials • 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome • Cannabidiol taken along with other medications was effective in reducing the frequency of seizures compared with placebo Cannabidiol (Epidiolex™) ADR’s/DI’s • Most common (10% or more) ADR’s • somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections

• Drug Interactions: • Moderate or strong inhibitors of CYP3A4 or CYP2C19 • Strong inducer of CYP3A4 or CYP2C19 • Consider a dose reduction of substrates of UGT1A9, UGT2B7, CYP2C8, CYP2C9, and CYP2C19 (e.g., clobazam) • Substrates of CYP1A2 and CYP2B6 may also require dose adjustment. Cannabidiol (Epidiolex™) Availability/Dispensing • Availability: Oral solution: 100 mg/mL • Must be dispensed with a patient Guide that describes important information about the drug’s uses and risks • Most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks • Also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury and more severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine. • Under the Controlled Substances Act (CSA), CBD is currently a Schedule I substance because it is a chemical component of the cannabis plant Cannabidiol (Epidiolex™) Dosing/Cost • Recommended starting dosage is 2.5 mg/kg taken twice daily (5 mg/kg/day) orally • After one week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day) • Based on individual clinical response and tolerability, can be increased up to a maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day) • Dosage adjustment is recommended for patients with moderate or severe hepatic impairment • Obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment • Cost: Estimated $32,500/year Cannabidiol (Epidiolex™) Conclusion • Cannabidiol (CBD) oral solution for seizures with Lennox- Gastaut syndrome or Dravet syndrome in patients > 2yo • First FDA-approved drug that contains a purified drug substance derived from marijuana and first FDA approval of a drug for the treatment of patients with Dravet syndrome • Watch for drug interactions • Costly Renal Drugs Sodium Zirconium Cyclosilicate (Lokelma™) AstraZeneca • A highly-selective, oral potassium-removing agent • FDA-approved for the treatment of hyperkalemia in adults

https://www.empr.com Sodium Zirconium Cyclosilicate (Lokelma™) MOA • A non-absorbed zirconium silicate that preferentially captures K in exchange for H and Na • Has a high affinity for K ions, even in the presence of other cations such as Ca and Mg • Increases fecal K excretion through binding of K in the lumen of the GI tract • Binding of K reduces the concentration of free K in the GI lumen, thereby lowering serum K

https://www.researchgate.net Sodium Zirconium Cyclosilicate (Lokelma™) Efficacy • FDA approval is supported by data from three double-blind, placebo-controlled trials and two open-label trials • PKS: Onset of action was 1 hour and the median time to achieving normal potassium levels in the blood was 2.2 hours • 92% of patients achieving normal potassium levels within 48 hours from baseline • In one 2-part, double-blind, randomized, placebo-controlled trial (N=753), a greater reduction in serum potassium levels was observed compared with placebo (2.5g 3 times daily [TID]: -0.5; 5g TID: -0.5; 10g TID: -0.7 vs placebo:-0.2; P<.001) • The treatment effect was maintained for up to 12 months in an open-label study (N=751) Sodium Zirconium Cyclosilicate (Lokelma™) ADR’s • Warnings and Precautions • Gastrointestinal Adverse Events in Patients with Motility Disorders—has not been studied in these patients • Edema • ADR’s • Edema (8-11%): Each 5 g dose contains approximately 400 mg of sodium; edema was generally mild to moderate in severity and was more commonly seen in patients treated with 15 g once daily Sodium Zirconium Cyclosilicate (Lokelma™) Drug Interactions • Can transiently increase gastric pH, and as a result can change the absorption of co-administered drugs that exhibit pH-dependent solubility, potentially leading to altered efficacy or safety of these drugs when taken • Other oral medications should be administered at least 2 hours before or 2 hours after Sodium Zirconium Cyclosilicate Sodium Zirconium Cyclosilicate (Lokelma™) Availability/Administration/Dosing • Availability • For oral suspension: 5 g per packet • For oral suspension: 10 g per packet • Administration • Other oral medications should be administered at least 2 hours before or 2 hours after • Empty the entire contents of the packet(s) into a drinking glass containing approximately 3 tablespoons of water or more if desired. Stir well and drink immediately. If powder remains in the drinking glass, add water, stir and drink immediately. Repeat until no powder remains to ensure the entire dose is taken. • Dosing • Recommended starting dose is 10g TID for up to 48 hours • For maintenance treatment, recommended dose is 10g QD • Adjust dose at one-week intervals as needed (by 5g daily) to obtain desired serum potassium target range Sodium Zirconium Cyclosilicate (Lokelma™) Conclusion • Sodium Zirconium Cyclosilicate is a non-absorbed zirconium silicate that preferentially captures K in exchange for H and Na • FDA-approved for the treatment of hyperkalemia • Has been shown to be effective vs. placebo, unknown how compares to other drugs for hyperkalemia • ADR of edema due to sodium content • Separate administration from other drugs by 2 hours • ? Cost Case

• A 55yo M with CKD and CHF presents with K 5.5. Would Sodium Zirconium Cyclosilicate be a good option to treat this patient’s hyperkalemia? OB/GYN Drugs Elagolix (Orilissa™) AbbVie Inc. • Gonadotropin-releasing hormone (GnRH) antagonist for the management of moderate to severe pain associated with endometriosis • First FDA-approved oral treatment for the management of moderate to severe pain associated with endometriosis in over 10 years

https://www.womenshealthmag.com ElagolixElagolix (Orilissa™)(Orilissa™) MOAMOA • AnAn gonadotropingonadotropin-releasingreleasing hormonehormone (GnRH)(GnRH) antagonistantagonist • InhibitsInhibits endogenousendogenous GnRHGnRH signalingsignaling byby bindingbinding competitivelycompetitively toto GnRHGnRH receptorsreceptors inin thethe pituitarypituitary glandgland • AdministrationAdministration resultsresults inin dosedose-dependentdependent suppressionsuppression ofof luteinizingluteinizing hormonehormone (LH)(LH) andand folliclefollicle-stimulatingstimulating hormonehormone (FSH),(FSH), leadingleading toto decreaseddecreased bloodblood concentrationsconcentrations ofof ovarianovarian sexsex hormones,hormones, estradiolestradiol andand progesteroneprogesterone Elagolix (Orilissa™) Efficacy • Two phase 3 multinational double-blind, placebo-controlled trials in 1686 premenopausal women, moderate to severe endometriosis pain • Significantly reduced most common types of endometriosis pain: daily menstrual pelvic pain, non-menstrual pelvic pain, pain with sex • Responders for daily menstrual pain and non-menstrual pelvic pain vs. placebo in a dose-dependent manner (150mg QD and 200mg BID) at month three • Both treatment groups showed statistically significant greater mean decreases from baseline vs. placebo in daily menstrual pain and non- menstrual pelvic pain at month six • Reduced baseline numeric rating scale (NRS) scores vs. placebo at month 3 (p <0.001) • Statistically significant greater reduction in pain with sex from baseline to month 3 (200mg BID) vs. placebo Elagolix (Orilissa™) Safety • Contraindications • Pregnancy • Known osteoporosis • Severe hepatic impairment • Strong organic anion transporting polypeptide (OATP) 1B1 inhibitors • Warnings and Precautions • Loss: dose- and duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible • Reduced Ability to Recognize Pregnancy: may alter menstrual bleeding, which may reduce the ability to recognize pregnancy, discontinue if pregnancy is confirmed • Suicidal Ideation and Mood Disorders • Hepatic Transaminase Elevations: Dose-dependent elevations in serum alanine aminotransferase (ALT) • Potential for Reduced Efficacy with Estrogen-Containing Contraceptives: Use non- hormonal contraception during treatment and for one week after discontinuing Elagolix (Orilissa™) ADR’s • Most common adverse reactions (>5%) in clinical trials included: • Hot flushes and night sweats (24-46%) • Headache (17-20%) • Nausea (11-16%) • Insomnia (6-9%) • Mood altered, mood swings (5-6%) • Amenorrhea (4-7%) • Depressed mood, depression, depressive symptoms and/or tearfulness (3-6%) • Anxiety (3-5%) • Arthralgia (3-5%) Elagolix (Orilissa™) Drug Interactions • Weak to moderate inducer of CYP 3A—may decrease concentrations of substrates of CYP3A • Inhibitor of efflux transporter P-glycoprotein—may increase concentrations of P-gp substrates (digoxin) • Substrate of CYP3A, P-gp, and OATP1B1 • Concomitant elagolix 200mg BID and strong CYP3A inhibitors for > 1 month is not recommended • Limit concomitant elagolix 150mg QD and strong CYP3A inhibitors to 6 months • Co-administration with drugs that induce CYP3A (rifampin) may decrease elagolix plasma concentrations • Effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of elagolix is unknown • Co-administration with drugs that inhibit OATP1B1 may increase elagolix concentrations—concomitant use of elagolix and strong OATP1B1 inhibitors (cyclosporine and gemfibrozil) is contraindicated Elagolix (Orilissa™) Availability/Cost/Dosing • Availability/Cost • Oral tablets: 150 mg and 200 mg • Cost: $844.87/month or $10,138.44/year • Dosing

https://www.rxabbvie.com Elagolix (Orilissa™) Conclusion

• Gonadotropin-releasing hormone (GnRH) antagonist for the management of moderate to severe pain associated with endometriosis • Effective in decreasing endometrial pain vs. placebo, unknown how compares to other therapies • Do not use with contraindications: pregnancy, known osteoporosis, severe hepatic impairment, strong organic anion transporting polypeptide (OATP) 1B1 inhibitors • High potential for drug interactions • Costly Dermatology Drugs Tildrakizumab-asmn (Ilumya™) Merck • An interleukin-23 antagonist indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy • Other interleukin inhibitors for psoriasis: • and 23 (IL-12/23) inhibitor: (Stelara™). • Interleukin 17 (IL-17) inhibitors: (Cosentyx™), (Taltz™), (Siliq™) • Interleukin 23 (IL-23) inhibitors: (Tremfya™)

https://www.sunpharma.com Tildrakizumab-asmn (Ilumya™) MOA • A humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor • IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses • Tildrakizumab inhibits the release of proinflammatory and

https://www.semanticscholar.org/ Tildrakizumab-asmn (Ilumya™) Efficacy • Two multicenter, randomized, double-blind, placebo- controlled trials, N=926 • Tildrakizumab-asmn 100mg (N=616) at Week 0, Week 4, and every twelve weeks thereafter (Q12W) up to 64 weeks vs. placebo (N=310) • Inclusion criteria • Physician Global Assessment (PGA) score of ≥3 (moderate) on a 5-point scale of overall disease severity • Psoriasis Area and Severity Index (PASI) score ≥12, and a minimum body surface area (BSA) involvement of 10% Tildrakizumab-asmn (Ilumya™) Efficacy

• Week 28: PASI 75 (74%) • Week 64: PASI 75 (84%), PGA 0 or 1 (69%) Tildrakizumab-asmn (Ilumya™) Safety/Drug Interactions • Warnings and Precautions • Hypersensitivity: If a serious allergic reaction occurs, discontinue immediately and initiate appropriate therapy • Infections: May increase the risk of infection. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, consider discontinuing until the infection resolves • Tuberculosis (TB): Evaluate for TB prior to initiating treatment

• ADR’s • Most common (≥1%): upper respiratory infections (14%), injection site reactions (3%), diarrhea (2%)

• Drug Interactions • Avoid use of live vaccines Tildrakizumab-asmn (Ilumya™) Availability/Dosing/Cost • Availability • Injection: 100 mg/mL solution in a single-dose prefilled syringe • Storage: Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Can be kept at room temperature at 25°C (77°F) for up to 30 days in the original carton to protect from light. Once stored at room temperature, do not place back in the refrigerator. If not used within 30 days, discard. • Dosing • Administer by subcutaneous injection • Recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter • Cost • Approx $40,000/year Tildrakizumab-asmn (Ilumya™) Conclusion • An interleukin-23 antagonist indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy • Has shown to be effective vs. placebo • ADR’s: upper respiratory infections (14%), injection site reactions (3%), diarrhea (2%) • Has not been compared to other interleukin inhibitors • Costly Self Assessment Questions

1. Coagulation factor Xa (recombinant), inactivated-zhzo (andexanet alfa) (Andexxa™) is FDA-approved as a reversal agent for which of the following? A. Rivaroxaban (Xarelto™) B. Apixaban (Eliquis™) C. Dabigatran (Pradaxa™) D. Enoxaparin (Lovenox™)

2. Plazomicin (Zemdri™) belongs to which of the following antibiotic classes? A. Quinolones B. Tetracyclines C. Macrolides D. Aminoglycosides Self Assessment Questions

3. Baricitinib (Olumiant™) is a Janus kinase inhibitor that’s FDA-approved for which of the following conditions? A. Psoriasis B. Inflammatory bowel disease C. Rheumatoid arthritis D. Lupus

4. Erenumab-aooe (Aimovig™) is a new drug for migraine prophylaxis. How should it be administered? A. Orally B. Subcutaneously C. Intramuscularly D. Sublingually Self Assessment Questions

5. Sodium Zirconium Cyclosilicate (Lokelma™) is a new drug for treating hyperkalemia. What is its most common adverse effect? A. Hypertension B. Dehydration C. Edema D. Hypercalcemia

6. Tildrakizumab-asmn (Ilumya™) is a new drug for treating psoriasis. What is its mechanism of action? A. Interleukin 12 antagonist B. Interleukin 17 antagonist C. Interleukin 23 antagonist D. TNF inhibitor Informational Slides

• These medications will not be discussed in detail during the lecture based on time limitations • The use of these medications will be more in specialty areas of practice and less use in general practice but are provided to the audience as a reference Infectious Diseases Drugs

• Tecovirimat (TPOXX™): SIGA Technologies, Inc. • An orthopoxvirus-specific antiviral indicated for the treatment of human smallpox disease

• Tafenoquine (Krintafel™): SIGA Technologies, Inc. • An 8-aminoquinoline derivative antimalarial for the radical cure (prevention of relapse) of Plasmodium vivax malaria

• Tafenoquine (Arakoda™): 60 Degrees Pharmaceuticals • An 8-aminoquinoline antimalarial drug indicated for the prophylaxis of malaria in patients aged 18 years and older

• Moxidectin (Moxidectin™): Medicines Development for Global Health • Anthelmintic for onchocerciasis (river blindness) Oncology/Hematology Drugs

• (Braftovi™): Array BioPharma • Kinase inhibitor for metastatic melanoma

• Apalutamide (Erleada™): Janssen • Androgen receptor inhibitor for non-metastatic, castration-resistant prostate cancer

• Lutetium Lu 177 dotatate (Lutathera™): Advanced Accelerator Applications • Radiopharmaceutical for gastroenteropancreatic neuroendocrine tumors Oncology/Hematology Drugs

• (Mektovi™): Array BioPharma • Kinase inhibitor for metastatic melanoma

• (Tibsovo™): Agios Pharmaceuticals Inc. • Isocitrate dehydrogenase-1 (IDH1) inhibitor for the treatment of patients with relapsed or refractory acute myeloid leukemia with an IDH1 mutation

• Fosnetupitant/Palonosetron (Akynzeo™): Helsinn • Injectable formulation for prevention of chemo-induced nausea and vomiting Oncology/Hematology Drugs

• Avatrombopag (Doptelet™): Dova Pharm • receptor agonist for thrombocytopenia in patients with chronic liver disease prior to undergoing a procedure

• Fostamatinib (Tavalisse™): Rigel Pharm. • Kinase inhibitor for chronic immune thrombocytopenia

• Lusutrombopag (Mulpleta™): Shionogi Inc. • Once-daily oral thrombopoietin (TPO) receptor agonist for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a medical or dental procedure Oncology/Hematology Drugs

• -jmdb (Fulphila™): Mylan • A recombinant human granulocyte colony-stimulating factor biosimilar to Neulasta™ indicated for the treatment of neutropenia associated with and related conditions

• -aafi (Nivestym™): Pfizer • A recombinant human granulocyte colony-stimulating factor biosimilar to Neupogen™ indicated for the treatment of neutropenia associated with chemotherapy and related conditions

• -kpkc (Poteligeo™): Kyowa Kirin • A humanized monoclonal antibody (mAb) directed against CC receptor 4 (CCR4) for the treatment of (MF) and Sézary Syndrome (SS), the most common subtypes of cutaneous T-cell lymphoma (CTCL) Renal Drugs

• Epoetin alfa-epbx (Retacrit™): Hospira • Biosimilar to Epogen™/Procrit™ OB/GYN Drugs

• Ethinyl estradiol and segesterone acetate (Annovera Vaginal System™): The Population Council • An estrogen and progestin vaginal contraceptive system indicated to prevent pregnancy for up to a year Miscellaneous Drugs

• Pegvaliase-pqpz (Palynzig™): Biomarin Pharm • Enzyme to reduce blood phenylalanine levels in patients with phenylketonuria

• Burosumab-twza (Crysvita™): Ultragenyx • 23 blocking antibody for X-linked hypophosphatemia

• Tezacaftor/Ivacaftor (Symdeko™): Vertex Pharm • Combination formulation for cystic fibrosis in patients with a specific gene mutation Miscellaneous Drugs

• Patisiran (Onpattro™): Alnylam Pharmaceuticals • A small interfering ribonucleic acid (siRNA) therapeutic for the treatment of polyneuropathy caused by hereditary transthyretin- mediated amyloidosis (hATTR)

• Migalastat (Galafold™): Amicus Therapeutics • An alpha-galactosidase A (alpha-Gal A) pharmacological chaperone indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant

• Glycopyrronium Cloth for Topical Use (Qbrexza™): Dermira • A topical anticholinergic contained in a single-use, pre-moistened, medicated cloth for the treatment of primary axillary hyperhidrosis (excessive underarm sweating) in adults and children > 9 years of age Miscellaneous Drugs

• Epinephrine auto-injector (0.3 mg and 0.15 mg): Teva Pharmaceuticals USA • First generic version of EpiPen and EpiPen Jr (epinephrine) auto- injector for the emergency treatment of allergic reactions, including those that are life-threatening (anaphylaxis), in adults and pediatric patients who weigh more than 33 pounds Selected References

• Various online references, databases, and review/primary literature were used in preparation of this lecture that were accessed August 2018. These included but were not limited to: The Medical Letter, Pharmacist’s Letter, Clinical Pharmacology, Lexicomp, Micromedex, FDA.gov website, Drugs.com, primary literature. New Drug Update