"Hot Off the Patients“ What's New with Bugs & Drugs

10/1/2019

David T. Bearden, Pharm.D., FIDP, FCCP Clinical Professor, Department of Pharmacy Practice Associate Dean for Academic Integration and Clinical Advancement Clinical Assistant Director, Department of Pharmacy Services Oregon State University/Oregon Health & Science University College of Pharmacy

New Drugs – quick hits

DISCLAIMER –

“New systemic antibacterials that I like.” • Approved in the last 5 years • Excluding • TB • Topical • Anti-virals

1 10/1/2019

2/3 rule: Two (plus 1) “X”s and 1 (plus 2) “Z”

2015 2018 ceftazidime-avibactam (Avycaz) plazomicin (Zemdri) eravacycline (Xerava) 2017 omadacycline (Nuzyra) delafloxacin (Baxdela) mero/vaborbactam (Vabomere) 2019 secnidazole (Solosec) imi/relebactam (Recarbrio) lefamulin (Xenleta)

https://www.centerwatch.com/drug-information/fda-approved-drugs/therapeutic- area/25/infections-and-infectious-diseases

Resistant Gram-negative Pathogens - Added β-lactamases 2015 2018 Ceftazidime/avibactam (Avycaz) plazomicin (Zemdri) eravacycline (Xerava) 2017 omadacycline (Nuzyra) delafloxacin (Baxdela) mero/vaborbactam (Vabomere) 2019 secnidazole (Solosec) imi/relebactam (Recarbrio) lefamulin (Xenleta)

2 10/1/2019

Bad (East Coast) GNRs

ESBLs KPCs • Extended spectrum β- • Klebsiella pneumoniae lactamases carbapenemases • Oregon E. coli 8.3% , US 13.4% • Oregon K. pneumonia 6.6%, US 20% • Oregon 0%, national 8.7% • Resistance to most • Generally provide resistance to cephalosporins, penicillins, and all β-lactams, including β- aztreonam lactamase inhibitors combinations • Carbapenems are generally resistant to ESBL hydrolysis

https://gis.cdc.gov/grasp/PSA/MapView.html

Quick Drug Facts – IV only, ESBLs, KPCs

Cephalosporin/β-lactamase inhibitor Carbapenem/β-lactamase inhibitor • Ceftazidime/avibactam • Meropenem/vaborbactam • Improved activity against • Imipenem/relebactam • Pseudomonas sp. • Improved activity against • Carbapenem-resistant Enterobactericeae (CRE) • ESBLs • KPCs • AmpC β-lactamases • Pseudomonas (*imi/relebactam only*)

https://commons.wikimedia.org/w/index.php?curid=40665787

Pharmacotherapy. 2015 Aug; 35(8): 755–770. Drugs. 2018 Jan;78(1):65-98.

3 10/1/2019

Resistant Gram-negative Pathogens - New Tetracyclines 2015 2018 ceftazidime-avibactam (Avycaz) plazomicin (Zemdri) eravacycline (Xerava) 2017 omadacycline (Nuzyra) delafloxacin (Baxdela) mero/vaborbactam (Vabomere) 2019 secnidazole (Solosec) imi/relebactam (Recarbrio) lefamulin (Xenleta)

Quick Drug Facts – restores tetracycline spectrum

Omadacycline (IV and PO) Eravacycline (IV only) • Targeted CAP and SSTI • Targeted intra-ab organisms pathogens • MRSA, VRE • MRSA, S. pneumoniae, VRE • MDR GNR – CRE & ESBLs • H. flu, Moraxella, ESBL/CRE • No Pseudomonas! • Atypical respiratory pathogens • True anaerobes

Drugs. 2016 Apr;76(5):567-88 Clin Infect Dis. 2019 Aug 1;69(Supplement_1):S1-S5

4 10/1/2019

New fluoroquinolone

https://www.centerwatch.com/drug-information/fda-approved-drugs/therapeutic- area/25/infections-and-infectious-diseases

Quick Drug Facts – Delafloxacin

• IV & PO • “Usual” FQ activity, plus… • Covers MRSA! (though concerns about future resistance) • Pseudomonas • Anaerobes • Typical FQ warnings

Infect Dis Ther. 2018 Jun; 7(2): 197–217.

5 10/1/2019

Fluoroquinolones – adverse reactions

• Common* • Gastrointestinal • Nausea • Central nervous system • HA, dizziness, insomnia

The Pharmaceutical Journal 22 JAN 2015

* Side effects led FDA 2016 to recommend against FQ use in uncomplicated UTI, sinusitis, and bronchitis

Fluoroquinolones – adverse reactions

• Less common* • Cartilage toxicity: AVOID children/pregnancy • CNS: confusion, seizures, hallucinations, delirium* • Severe hypoglycemia* • Peripheral neuropathy • Prolonged cardiac QT interval • Increased with other similar drugs *2018 FDA Black Box Warnings

6 10/1/2019

NO FQ’s?

• Look for alternatives • Search deeper in guidelines • Newer guidelines will start to tackle these issues • Presently, push listed alternatives (sometimes less data)

New aminoglycoside

7 10/1/2019

Quick Drug Facts – nudged activity aminoglycoside

• Plazomicin • Currently approved for complicated UTI • Typical aminoglycoside coverage – GNR focus! • Added activity for Enterobacteriacea w/ AG resistance

• May have benefits for systemic infections with carbapenem resistant isolates!

Drugs. 2019 Feb;79(3):243-269.

UTI - epidemiology of E. coli resistance

NW Regional HMO, primary care • Ampicillin ~66% • Ciprofloxacin ~94% • Nitrofurantoin ~97% • TMP / SMX ~85%

McGregor JC, et al. BMC Fam Pract. 2013 Feb 22;14:25

8 10/1/2019

New imidazole (think metronidazole)

Bacterial Vaginosis Therapy

Current CDC Recommendations Secnidazole “Recommended” • 2g PO granules X 1 dose • Metronidazole 500 mg PO BID for • 17h t 1/2 7 days • No disulfiram-like reaction • Topical – metronidazole or clindamycin

“Alternatives” • Tinidazole 2g PO QD for 2 days • Tinidazole 1g PO QD for 5 days • Clindamycin PO or topical

MMWR Recomm Rep 2015;64(No. RR-3): 1-137.

9 10/1/2019

NEW ENTITY! - pleuromutilin

Drug Facts – lefamulin (IV & PO)

• First pleuromutilin – 50S ribosomal protein synthesis inhibitor • Spectrum of Activity • GPC – including MRSA, S. pneumonia • GNR – H. flu, Moraxella catarrhalis • Atypical respiratory pathogens

• Targeted for community-acquired pneumonia (maybe SSTI)

Pharmacotherapy. 2018 Sep;38(9):935-946

10 10/1/2019

"Hot Off the Patients“ What's New with Bugs & Drugs

11 10/1/2019

Updates in Diabetes Management: 2019

Andrew Bzowyckyj, PharmD, BCPS, CDE Associate Professor Pacific University Oregon School of Pharmacy [email protected]

Session Objectives • Summarize key updates to the American Diabetes Association Standards of Medical Care in Diabetes • Describe new agents approved and in the pipeline for type 1 and type 2 diabetes • Discuss factors to consider when adding these new medications for specific patient populations

1 10/1/2019

Session Outline: Top 10 Updates

1. Designing medication 6. New medication updates – Oral semaglutide regimens – SGLT inhibitors in type 1 2. SGLT-2 inhibitors in renal diabetes – New formulations of glucagon insufficiency 3. What’s the deal with 7. Continuous Glucose aspirin? Monitoring (CGM) 4. Blood pressure treatments 8. Use of language in diabetes 5. De-prescribing & care & education simplifying regimens in the 9. ADA Consensus Report on elderly Nutrition 10. Insulin price wars & resources

GUIDELINE UPDATES

2 10/1/2019

Diabetes Care 2019;42 (Suppl. 1):S90-S102. 5

1. Intensifying Injectable Therapies (Basal / GLP-1)

Diabetes Care 2019;42 (Suppl. 1):S90-S102.

3 10/1/2019

1. Intensifying Injectable Therapies (Prandial Insulin)

Diabetes Care 2019;42 (Suppl. 1):S90-S102.

1. Intensifying Injectable Therapies

Diabetes Care 2019;42 (Suppl. 1):S90-S102.

4 10/1/2019

1. Considering oral & injectable combinations?

Diabetes Care 2018;41(12):2669-701.

1. Considering oral & injectable combinations?

Diabetes Care 2018;41(12):2669-701.

5 10/1/2019

2. SGLT-2 Inhibitors in Renal Insufficiency

Use Not Studied in CV Drug Dosing Recommended Type 1 Indication 100-300mg QAM Canagliflozin eGFR 45-59: max 100 mg eGFR <45ml/min Yes Yes daily Dapagliflozin 5-10mg QAM eGFR <45ml/min Yes No Empagliflozin 10-25 mg QAM eGFR <45ml/min Yes Yes

Ertugliflozin 5-15mg QAM eGFR <60ml/min No No

UPDATE: Consider SGLT2i in people with eGFR ≥ 30 and particularly in those with >300 mg/g albuminuria to reduce risk of CKD progression, cardiovascular events, or both. (Level A)

Diabetes Care 2019;42 (Suppl. 1):S124-8.

3. What’s the deal with aspirin?

Secondary YES Prevention

Primary Prevention NO (<50 years)

Primary Consider if Not high CV risk Prevention recommended (50-69 years) and low GI risk

Primary Prevention NO (70+ years)

Diabetes Care 2019;42 (Suppl. 1):S113-4.

6 10/1/2019

4. What are we doing with blood pressure?

Secondary 10-year ASCVD 10-year ASCVD Prevention risk > 15% risk < 15% • Less than • Less than • Less than 130/80 may be 130/80 may be 140/90 appropriate if it appropriate if it can be safely can be safely attained attained

Diabetes Care 2019;42 (Suppl. 1):S104.

4. What are we doing with blood pressure?

*ACEI or ARB suggested if UACR 30-299, and strongly recommended for UACR > 300 **Thiazide-like diuretic; long-acting agents shown to reduce CV events preferred (chlorthalidone, indapamide) ***Dihydropyridine calcium channel blocker

Diabetes Care 2019;42 (Suppl. 1):S108.

7 10/1/2019

4. What are we doing with blood pressure?

**Thiazide-like diuretic; long-acting agents shown to reduce CV events preferred (chlorthalidone, indapamide) ***Dihydropyridine calcium channel blocker

Diabetes Care 2019;42 (Suppl. 1):S108.

5. De-prescribing in older adults

Diabetes Care 2019;42 (Suppl. 1):S144.

8 10/1/2019

5. De-prescribing in older adults

Diabetes Care 2019;42 (Suppl. 1):S144.

6. NEW MEDICATION UPDATES

9 10/1/2019

Oral Semaglutide • Barriers to GLP-1 oral absorption: – Degradation by gastrointestinal enzymes – pH induced conformational changes – Limited protein permeability of the intestinal membrane • Semaglutide co-formulated with Sodium N-(8-[2- hydroxybenzoyl] Amino) Caprylate (SNAC), an absorption enhancer • Advantages: – long half-life – lower molecular weight – high potency – molecular stability • Submitted to the FDA in March, 2019 with priority review voucher

Clin Pharmacokinet 2019;58(6):781-91.

PIONEER 4: Compared to GLP-1 agonist • Oral semaglutide vs. SC liraglutide (n=711)

Nausea: 20%(S), 18%(L), 4%(P) | Diarrhea: 15%(S), 11%(L), 8%(P) Vomiting: 9%(S); 5%(L); 2%(P)

Lancet 2019;394(10192):39-50.

10 10/1/2019

PIONEER 6: CV Outcomes

• RCT comparing oral semaglutide 14mg vs placebo, n=3183 adults • Primary outcome: first occurrence of CV death, nonfatal MI, nonfatal stroke (MACE) • Median follow-up: 15.9 months – 84.7% were over 50 with CVD or CKD • Demonstrated non-inferiority of major CV events (MACE) – Overall MACE • 61/1591 (3.8%) oral semaglutide vs. 76/1592 (4.8%), HR 0.79, 95% CI: 0.57-1.11 – CV death • 15/1591 (0.9%) vs 30/1592 (1.9%), HR 0.49, 95% CI: 0.27-0.92 – Nonfatal MI • 37/1591 (2.3%) vs. 31/1592 (1.9%), HR 1.18, 95% CI: 0.73-1.90 – Nonfatal stroke • 12/1591 (0.8%) v 16t/1592 (1.0%), HR 0.74, 95% CI 0.35-1.57 – Death from any cause • 23/1591 (1.4%) vs 45/1592 (2.8%), HR: 0.51, 95% CI 0.31-0.84

1. N Engl J Med 2019;381:841-51 2. Diabetes Obes Metab 2019;21(3):499-508

Sotagliflozin: inTandem Trials (T1DM)

Trial N Trial Population Efficacy 46 years; 91% white A1C ~ 7.57%; BMI ~ 29 kg/m2 A1C change vs. placebo: inTandem 1 793 Insulin pump: 60% 200 mg: -0.36% (p<0.001) (USA) Sota 200 or 400 vs. PBO x 52 400 mg: -0.41% (p<0.001) weeks 41 years; 96% white A1C: ~7.8%; BMI: ~ 30 kg/m2 A1C change vs placebo: inTandem 2 782 Insulin pump: 25% 200 mg: -0.37% (p<0.001) (Europe) Sota 200 or 400 vs. PBO x 52 400 mg: -0.35% (p<0.001) weeks 43 years; 88.4% white Percent achieving A1c < 7% with A1C ~8.2%; BMI: ~ 28 kg/m2 no severe hypoglycemia or DKA inTandem 3 1402 Insulin pump: 40% Sota: 28.6% vs. PBO: 15.2% (Global) Sota 400 mg vs PBO x 24 (p<0.001) weeks NNT: 8 people x 6 months

1. Diabetes Care 2018;41(9):1970-80 2. Diabetes Care 2018;41(9):1981-90 3. N Engl J Med 2017;377:2337-48

11 10/1/2019

Sotagliflozin & DKA: inTandem Trials (T1DM)

Trial N PBO Sota NNH Sota NNH 200 mg (vs. 200 mg) 400 mg (vs. 400 mg) inTandem 1 793 0.4% 3.4% 33 4.2% 26 (USA) inTandem 2 782 0% 2.3% 43 3.4% 29 (Europe) inTandem 3 1402 0.6% N/A N/A 3.0% 41 (Global)

1. Diabetes Care 2018;41(9):1970-80 2. Diabetes Care 2018;41(9):1981-90 3. N Engl J Med 2017;377:2337-48

Updates: SGLT Use in T1DM

• Dapagliflozin submitted to EU • Sotagliflozin submitted to EU and FDA and FDA – EMA recommends approval for – Jan 2019: FDA advisory those who meet criteria: committee votes 8-8 if benefits • Adjunct to insulin therapy outweigh risks • BMI > 27kg/m2 – Feb 2019: EU approves with same • Supplemental ketone monitoring criteria as dapagliflozin • Additional patient selection criteria – Mar 2019: FDA issues Complete • Patient Alert Card Response Letter (not approved) – July 2019: FDA issues Complete • Ipragliflozin approved for use in Response Letter (not approved) T1DM in Japan • Empagliflozin (?) – EASE trials

12 10/1/2019

Mitigating DKA Risk – STICH Protocol

ST • STop SGLT Inhibitor

I • Inject bolus insulin

• Consume 30 grams C carbohydrates

H • Hydrate with water

Diabetes Technol Ther 2018;20:571-5.

Glucagon Nasal Powder • Indicated for severe hypoglycemia in patients over 4 years old • Stable at room temp • Shelf-life: 18 months • Non-inferior to 1mg injectable glucagon • Studied in patients with nasal congestion: dosing found to be consistent • Single-use dose 3mg

www.baqsimi.com

13 10/1/2019

Time to Administer Nasal Glucagon • 16 instructed caregivers and 15 non-instructed acquaintances administered nasal vs injectable glucagon to manikins • Lots of mistakes with IM glucagon – Injected partial dose, injected diluent only, bent needle, injected empty syringe

Diabetes Technol Ther 2017;19(7):423-32.

Glucagon Pen

• Proprietary formulation technology (XeriSol™) – Non-aqueous liquid form of glucagon – Long-term stability at room temperature • Pre-mixed solution in auto-injector – Doses: 0.5mg, 1mg • NDA submitted to FDA – Decision expected 9/10/19 • Phase 2 trials for other indications – Post-bariatric hypoglycemia, exercise induced hypoglycemia

https://www.xerispharma.com/pipeline/

14 10/1/2019

How Effective is the Glucagon Pen? • Phase-3 randomized, controlled, crossover clinical trial compared usual emergency glucagon kit to glucagon rescue pen (n=81)

Clinical Comparison Pen Kit P-Value Drug preparation and 27.3 ± 19.7 97.2 ± 45.1 <0.0001 administration seconds seconds Mean time to resolution of 11.6 ± 6.5 13.1 ± 7.9 NS hypoglycemia symptoms minutes minutes Mean time to resolution of 12.7 ± 6.5 15.3 ± 8.0 0.02 symptoms from decision to dose minutes minutes

https://investors.xerispharma.com/static-files/328c34b0-0ed1- 42d1-85a1-5d8921ab6024

15 10/1/2019

DIABETES TECHNOLOGY

7. Important CGM Terminology

Trend Arrow Dexcom Freestyle Libre

Increasing > 3 N/A ⬆⬆ mg/dL/min Real-time vs. Warm-up Increasing 2-3 Increasing > 2 Flash Time ⬆ mg/dL/min mg/dL/min Increasing 1-2 Increasing 1-2 ↗ mg/dL/min mg/dL/min Not increasing or Not increasing or ➡ decreasing > 1 decreasing > 1 mg/dL/min mg/dL/min Time in Personal vs. ↘ Decreasing 1-2 Decreasing 1-2 range Professional mg/dL/min mg/dL/min Decreasing 2-3 Decreasing >2 ⬇ mg/dL/min mg/dL/min Decreasing > 3 N/A ⬇⬇ mg/dL/min

1. J Endocr Soc. 2018;2(12):1320-37. 2. J Endocr Soc. 2017;1(12):1461-76.

16 10/1/2019

7. Personal CGM Comparisons

FDA- FDA- Minimum Device Sensor Real-time approved for Manufacturer approved Calibration Model duration vs. Flash treatment age Frequency decision

Dexcom G5 Every 12 > 2 years 7 days Real-time Yes* Dexcom Mobile hours Dexcom G6 > 2 years Not required 10 days Real-time Yes* Guardian 14-75 Every 12 Medtronic 7 days Real-time No Connect years hours Freestyle Abbott > 18 years N/A 14 days Flash Yes* Libre 14 day Eversense Senseonics > 18 years Twice daily 90 days Real-time No (implant)

*Assumes symptoms are consistent with reading and there are no concurrent interactions

User guides of individual products

NEW RESOURCES

17 10/1/2019

8. Use of Language in Diabetes Care & Education Guiding Principles

Person-first, Every member of Stigma that has strengths-based, the health care historically been empowering Diabetes is a team can serve attached to a language can complex and people with diagnosis of improve challenging diabetes more diabetes can communication disease involving effectively through contribute to and enhance the many factors and a respectful, stress and feelings motivation, health, variables inclusive, and of shame and and well-being of person-centered judgment people with approach diabetes

Diabetes Care 2017;40:1790-9.

8. Use of Language in Diabetes Care & Education

Language with potentially Suggested replacement Rationale negative connotation language

Diabetes Care 2017;40:1790-9.

18 10/1/2019

9. ADA Nutrition Update

• Update to the 2014 report • Do not advocate for a “one size fits all” eating plan • Person-specific eating plans that take into consideration: • person’s medical conditions • cultural background • personal preferences • socioeconomic setting

Diabetes Care 2019;42:731–54.

9. ADA Nutrition Update • Helpful information for: • Macronutrient distribution • Eating patterns • Energy balance / weight management • Sweeteners • Alcohol consumption • Micronutrients / herbal supplements • Medication-associated deficiencies • Prevention/Management of diabetes complications

Diabetes Care 2019;42:731–54.

19 10/1/2019

10. The Rising Cost of Insulin

• GENERIC insulin lispro (Lilly) • Sanofi VALyou program – Interchangeable at pharmacy – Valid on all Sanofi insulins – $137.35 per vial (~$0.14/unit) (except Toujeo Max or Soliqua) – $262.50 per 5 pens (~$0.18/unit) – $99 for up to 10 boxes of pens – Cash price and/or 10 vials per month • Can apply to multiple insulin types • Novo Nordisk/Walmart ReliOn • MUST be filled together at same time Insulin (N/R) – Guaranteed price x 12 consecutive – $25 per vial monthly fills – Max 4 vials per transaction – Registration required – Cash price – Cash pay (UNINSURED) only • Cigna / Express Scripts • Copay cards – Non-government plans ONLY (must – Multiple manufacturers opt-in) – $25 copay cap for a 30-day supply

10. The Rising Cost of Insulin

https://www.diabeteseducator.org/practice/educator- tools/app-resources/affordability-resources

20 10/1/2019

THANK YOU!

QUESTIONS | COMMENTS

Andrew Bzowyckyj, PharmD, BCPS, CDE Associate Professor Pacific University Oregon School of Pharmacy [email protected]

21 10/1/2019

From Tabs to mAbs: An Overview of Migraine Prophylaxis

Kelsey H. Blom, PharmD, BCACP Clinical Pharmacy Specialist – Neurology Kaiser Permanente Northwest

DISCLOSURE

• I have nothing to disclose and no conflicts of interest

1 10/1/2019

Which of the below statements is true regarding time to effect for oral migraine prophylactic medications? A. Patients should expect to have a full response to treatment after 2 weeks PRE-TEST B. It may take 2-6 months to realize a full response QUESTIONS to treatment C. If a patient does not realize a response to treatment after 3 weeks, it should be discontinued D. Patients may begin to see improvement after one week of treatment

Out of the list below, which is NOT a Level A recommended migraine prophylactic medication? A. Candesartan PRE-TEST B. Topiramate QUESTIONS C. Metoprolol D. Propranolol

2 10/1/2019

Clinical trials have demonstrated that erenumab, galcanezumab, and fremanezumab decrease migraine headache days by ___ days per month, on average. PRE-TEST A. 4-6 QUESTIONS B. 3-4 C. 2-3 D. 1-2

The most common side effects of erenumab, galcanezumab, and fremanezumab include: A. Decreased blood pressure PRE-TEST B. Injection site reactions QUESTIONS C. Hypersensitivity reactions D. Chest pressure

3 10/1/2019

Describe time to effect for migraine prophylactic Describe medications

Recognize the most effective (Level A) migraine Recognize prophylactic medications LEARNING OBJECTIVES Define the efficacy of calcitonin-gene related peptide Define (CGRP) antagonists in terms of reduction in monthly migraine days

List List adverse effects of CGRP antagonists

OVERVIEW

OVERVIEW OF MIGRAINE MIGRAINE CGRP PROPHYLACTIC MEDICATIONS ANTAGONISTS

4 10/1/2019

Headache that is unilateral and pulsating

Moderate to severe in intensity and lasts 4-72 hours WHAT IS A MIGRAINE Worsens with activity

Associated with nausea or vomiting, and/or sensitivity to light or sound

Ha. Am Fam Physician. 2019;99(1):17-24.

Second most disabling neurologic condition globally

Affects women more than men 3:1

DISEASE Fifth leading cause of Emergency Department BURDEN visits

Prevalence ~ 16%

50% of patients require bed rest or report severe impairment

Ha. Am Fam Physician. 2019;99(1):17-24. Lipton. Neurology. 2007;68(5):343-349. American Headache Society. Headache. 2019;59(1):1-18.

5 10/1/2019

MIGRAINE TREATMENT

Abortive Therapy Preventative therapy

• Medications: • Patients who may benefit: ~38% • Triptans, dihydroergotamines • Prophylaxis prescribed: ~12.4% • NSAIDs, acetaminophen • Combined analgesics

Lipton. Neurology. 2007;68(5):343-349. Silberstein. Neurology. 2000;55(6):754-762.

Type of chronic headache

Overuse of acute medications for 3 months or more • Butalbital products: 5 days / month • Triptans, combined analgesics: 10 days / month • Non-opioid analgesics: 15 days / month MEDICATION OVERUSE Treatment HEADACHE • Medication withdrawal

Prevention

• Limit use to 2 days per week

Silberstein. Neurology. 2000;55(6):754-762. Tepper. Cleve Clin J Med. 2010;77(4):236-242. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1). 1–211.

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MIGRAINE PROPHYLAXIS

• Four or more migraines per month • Significantly interfere with quality of life or daily routines WHEN TO • Side effects, contraindication, overuse, TREAT or failure of acute medications • Patient preference

Ha. Am Fam Physician. 2019;99(1):17-24. Silberstein. Neurology. 2000;55(6):754-762. Silberstein. Continuum. 2015;21(4):973-989.

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• Reduce attack frequency, severity, and disability from migraine • Reduce migraine duration TREATMENT GOALS • Enhance response to and reduce use of acute medication • Improve quality of life

Ha. Am Fam Physician. 2019;99(1):17-24. Silberstein. Neurology. 2000;55(6):754-762. Silberstein. Continuum. 2015;21(4):973-989.

MIGRAINE PROPHYLACTIC MEDICATION OPTIONS

Antiepileptics Beta-Blockers Antidepressants Antihypertensives/ Others Divalproex / Metoprolol Amitriptyline Lisinopril Valproate

Topiramate Propranolol Venlafaxine Candesartan

Carbamazepine Atenolol Nicardipine

Cyproheptadine

Level A: Medication with established efficacy Level B: Medications are probably effective

Silberstein. Neurology. 2012;78(17):1337-1345.

8 10/1/2019

Success = 50% reduction or more in migraine frequency

TIME TO EFFECT Time to effect

Some Full Response 2 month trial improvement ~ 2-6 months required 6-8 weeks

Ha. Am Fam Physician. 2019;99(1):17-24. Silberstein. Continuum. 2015;21(4):973-989. 17

CHOICE OF MEDICATION AND EFFECTIVENESS

Choice of agent based on: Reduce headache days by 1 or 2 patient characteristics, preference, days per month and co-morbidities

Jackson. PLoS One. 2015;10(7):e0130733. Silberstein. Continuum. 2015;21(4):973-989. 18

9 10/1/2019

PROPHYLAXIS: CGRP ANTAGONISTS

Calcitonin gene-related peptide (CGRP)

• Neuropeptide involved in migraine pathophysiology • Potent vasodilator

Available products

• Erenumab (Aimovig) CGRP • Galcanezumab (Emgality) ANTAGONISTS • Fremanezumab (Ajovy)

Monoclonal antibodies (mAbs)

• Erenumab: • Fully human • Binds to CGRP receptor • Galcanezumab and fremanezumab • Humanized (>90%) • Bind to CGRP ligand

Maasumi. Drugs. 2018;78(90):913-928. 20

10 10/1/2019

ADMINISTRATION

Erenumab Galcanezumab Fremanezumab Route SubQ SubQ SubQ 225 mg or Maintenance Dose 70 mg or 140 mg 120 mg 675 mg Loading Dose No Yes – 240 mg No Monthly (225 mg) Frequency Monthly Monthly or Every 3 months (675 mg) • 70 mg/mL and 140 • 120 mg/mL mg/mL • 225 mg/ 1.5 mL Dosage Forms • Pre-filled pen • Pre-filled autoinjector • Pre-filled syringe • Pre-filled syringe • Pre-filled syringe Refrigerator Refrigerator Refrigerator Storage Room temp for 7 days Room temp for 7 days Room temp for 24 hours

SubQ = subcutaneous; temp = temperature 21

• Efficacy • Decreases monthly migraine headache days by 1 to 2 days per month • Common side effects • Injection reactions – pain, redness, swelling, itching EFFICACY • Erenumab – constipation AND • Hypersensitivity reaction SAFETY • Rash, pruritis, urticaria • Angioedema, anaphylaxis • May occur within hours to weeks

Skljarevski. Cephalagia. 2018;38(8):1442-1454. Goadsby. N Engl J Med. 2017;377(22):2123-2132. Dodick. JAMA. 2018;319(19):1999-2008. Stauffer JAMA Neurol. 2018;75(9):1080-1088. 22

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CGRP ANTAGONISTS: PROS AND CONS

Potential Benefits Concerns

• Improved adherence • Cost: $575 / syringe • Mild side effect profile • Similar effectiveness to current • No dose titration medications • May be effective earlier • Long term effects unknown • Low risk of drug interactions

Red Book Online. 2019.

PLACE IN THERAPY

Consider Using Consider Avoiding

• Failed alternative migraine prophylaxis • Pregnant/nursing • Only continue if effective • Cardiovascular or cerebrovascular • Re-assess after 3 months (monthly disease injection) or 6 months (quarterly • Alcohol or drug abuse injection) • Severe mental disorder

American Headache Society. Headache. 2019;59(1):1-18. Sacco S. J Headache Pain. 2019;20(1):6.

12 10/1/2019

Educate patients about prophylactic medication

Recommend limit use of acute medication to 2 days per week PHARMACIST PEARLS Full benefit from prophylactic medication can take 2-6 months

CGRP antagonists may be an option for patients who have failed alternative prophylaxis medications

ADDITIONAL RESOURCES

• Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the quality standards subcommittee of the American Academy of Neurology and the American Headache Society. 2012;78(17):1337-45.

• American Headache Society. The American Headache Society position statement on integrating new migraine treatment into clinical practice. Headache. 2019;59(1):1-18.

13 10/1/2019

QUESTIONS

REFERENCES

• Aimovig [package insert]. Thousand Oaks, CA: Amgen; 2019. • Ajovy [package insert]. North Wales, PA: Teva Pharmaceuticals; 2018. • American Headache Society. The American Headache Society position statement on integrating new migraine treatment into clinical practice. Headache. 2019;59(1):1-18. • Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319(19):1999-2008. • Emgality [package insert]. Indianapolis, IN: Eli Lily & Co; 2019. • Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123-2132. • Ha H, Gonzalez A. Migraine headache prophylaxis. Am Fam Physician. 2019;99(1):17-24. • Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1). 1–211. • Jackson JL, Cogbill E, Santana-Davila R, et al. A comparative effectiveness analysis of drugs for the prophylaxis of migraine headaches. PLoS One. 2015;10(7):e0130733. • Lipton BB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventative therapy. Neurology. 2007;68(5):343-349. • Lupi C, Guerzoni S, Negro A, Benemei S. Once-monthly galcanezumab for the prevention of migraine in adults: an evidence-based descriptive review and potential place in therapy. Ther Clin Risk Manag. 2019;15:557-569. • Maasumi K, Michael RL, Rapoport AM. CGRP and migraine: the role of blocking calcitonin gene-related peptide ligand and receptor in the management of migraine. Drugs. 2018;78(90):913-928.

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REFERENCES CONTINUED

• Red Book Online. Truven Health Analytics; 2019. https://www.micromedexsolutions.com/micromedex2/librarian/CS/FA4606/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/2EE271/ND_PG/ evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/redbook.FindRedBook?navitem=topRedBook&isToolPage=true. Accessed July 27, 2019. • Sacco S, Bendtsen L, Ashina M, et al. European headache federation guidelines on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. J Headache Pain. 2019;20(1):6. Doi • Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):754-762. • Silberstein SD, Holland S, Freitag F, Dodrick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the quality standards subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345. • Silberstein SD. Preventive migraine treatment. Continuum (Mineap Minn). 2015;21(4):973-989. • Skljarevski V, Matharu M, Millen BA, Ossipov MH, KIM BK, Yang Jy. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalagia. 2018;38(8):1442-1454. • Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. • Tepper SJ, Tepper DE. Breaking the cycle of medication overuse headache. Cleve Clin J Med. 2010;77(4):236-242.