PharmacologicupdatesinthemanagementofacutemigrainesandmigrainepreventionEmily Neddermeyer, PharmD, BCACPClinical Pharmacy Specialist, NeurologyUniversity of Iowa Hospitals & Clinics

03.31.20

Disclosures• No conflicts of interest• Off label use of medications will be discussed• Brand names will be used when needed for clarity

Migraine Fundamentals

Burch R, et al. Headache. 2018;58:496-505.GBD 2016 Headache Collaborators (Stovner LJ, et al). Lancet. 2018; 17:954-976.Stewart WF, et al. JAMA. 2003; 290(18): 2443-2454.

3 Billion People Globally

Highest burden in:• Elderly and Disabled• Unemployed• Low Income (<$35,000)

3rd leading cause of emergency department visits

(women of childbearing age)

Most common pain condition resulting in

lost productive time

1 in 6 Americans

of emergency dept. visits annually3%

Acute Treatment of Migraine

AcuteTreatment

Mayans L, Walling A.AAFP. 2018;97(4):243- 251.

OTCs Ergot alkaloids Triptans

NSAIDsAcetaminophen

ASA/APAP/Caffeine (Excedrin®)

Dihyroergotamine(Migranol®)

Almotriptan (Axert®)Eletriptan (Relpax®)

Naratriptan (Amerge®)Rizatriptan (Maxalt®) Sumatriptan (Imitrex®)Zolmitriptan (Zomig®)

18% ‐ 50% effective  2 hr migraine freedom

***

NNT: 7 ‐ 10  patients2 hr migraine freedom

SelectiveTriptan‐ Lasmiditan(ReyvowTM)

• Selective for 5‐HT1F ▫ Previous triptans non‐selective for subtypes: 1F, 1B, 1D, 1A, 5A, 7

• $700 per 8 tablets▫ Available in blister packages of 8 doses▫ Same price regardless of dose

J Pain Res. 2018; 11: 2221-2227 Eli Lilly and Company. Lilly’s REVOW (lastmiditan), Receives FDA Approval. 2019 Oct. https://investor.lilly.com/node/41861/pdf

Lasmiditan(ReyvowTM)2 Hour Freedom From 

Pain

28.3%50 mg

28.3% , 31.4%100 mg

31.8%, 38.8% 200 mg

15.3%, 21%Placebo

Trial #1, Trial #2Trial #2 only

Percent of Responders

Lasmiditan(ReyvowTM)2 Hour Freedom From 

Most Bothersome Symptoms

40.8%50 mg

41.2% , 44%100 mg

40.7%, 48.7% 200 mg

29.6%, 33.2%Placebo

Trial #1, Trial #2Trial #2 only

Percent of Responders

Lasmiditan(ReyvowTM)

Reyvow (Lasmiditan) [package insert]. Indianapolis, IN: Lilly, USA, LLC; Jan 2020

Dose: 50 mg, 100 mg, or 200 mg PO PRN• Second dose not shown to be effective• Unclear safety of >4 doses/month• Only available in 50 mg and 100 mg tablets

Adverse Effects: dizziness (9 – 17%), fatigue, sedation, parasthesia, nausea • Do not operate drive within 8 hours• Possibility of serotonin syndrome

Drug Interactions: Inhibits BCRP & P‐gp• CNS depressants• Serotonergic agents• Heart rate lowering drugs (e.g. propranolol)

CalcitoninGeneRelatedProtein(CGRP)

Durham P. N Engl J Med. 2004;350:11.

• 37 amino acid neurotransmitter• Released from trigeminal nerve• Wide distribution in CNS and non‐neuronal tissues• Potent dilator of  cerebral and dural vessels▫ Important in regulating blood flow to the brain▫ Release of inflammatory agents from meningeal mast cells

CalcitoninGeneRelatedProtein(CGRP)

Durham P. N Engl J Med. 2004;350:11.

Newtreatmentclass:“‐gepants”

Ubrogepant (Ubrelvy®)

Migraine Elimination at 2 hours

38.7%50 mg (n=883)

37.7%100 mg (n=883)

27.6%Placebo (n=910)

Lipton RB, Dodick DW, Ailani J et al. JAMA. 2019;322(19):1887‐1898. Dodick DW, Lipton RB, Ailani, et al. Ubrogepant for the treatment of migraine. N Engl J Med.Benemei S, Cortese F, Labastida‐Ramírez A, et al. J Headache Pain. 2017;18(1):103.

Ubrogepant (Ubrelvy®)

Ubrelvy (ubrogepant) [package insert] Madison, NJ: Allergan Pharmaceuticals International Limited; Dec 2019

Dose: 50 mg or 100 mg PO PRN•May repeat in 2 hours• Max of 200 mg / 24 hours

Adverse Effects: nausea, somnolence

Drug Interactions: CYP3A4, BCRP, P‐gp• Avoid strong 3A4 inhibitors: Itraconazole, ketoconazole, clarithromycin• Dose adjust: Verapamil, fluconazole, ciprofloxacin, grapefruit juice, carvedilol, quinidine, tumeric supplements, 

Priced similar to lasmiditan $90/tablet regardless of strength

Ubrogepant (Ubrelvy®)

Lipton RB, Dodick DW, Ailani J et al. JAMA. 2019;322(19):1887‐1898. Dodick DW, Lipton RB, Ailani, et al. Ubrogepant for the treatment of migraine. N Engl J Med.Mullin K, Kudrow D, Croop R, et al. Neurology. 2020 Jan 13.Benemei S, Cortese F, Labastida‐Ramírez A, et al. J Headache Pain. 2017;18(1):103.

Dose: 50 mg or 100 mg PO PRN•May repeat in 2 hours• Max of 200 mg / 24 hours

Adverse Effects: nausea, somnolence

Drug Interactions: CYP3A4, BCRP, P‐gp• Avoid: Itraconazole, ketoconazole, clarithromycin• Dose adjust: Verapamil, fluconazole, ciprofloxacin, grapefruit juice, carvedilol, quinidine, tumeric supplements, 

Rimegepant(NurtecTM)

Croop R, et al. Lancet. 2019; 394 (10200): 737-745.Nurtec (rimegepant) [package insert]. New Haven, CT: Biohaven Pharmaceuticals, Inc.; Feb 2020

2 Hour Freedom From Pain

21%Rimegepant

11% Placebo

2 Hour Freedom FromMost Bothersome Symptom

27%Placebo

35%Rimegepant

Rimegepant(NurtecTM)Dose: 75 mg PO PRN, dissolve on or under the tongue• Max of 75 mg / 24 hours; Max of 75 mg / 48 hours if CYP3A4 inhibitors• Unclear safety of >15 doses/month

Adverse Effects: nausea (2%)

Drug Interactions: CYP3A4, CYP2C9• Avoid strong 3A4 inhibitors: Itraconazole, ketoconazole, clarithromycin• Dose adjust: Verapamil, fluconazole, ciprofloxacin, grapefruit juice, carvedilol, quinidine, tumeric supplements 

Croop R, et al. Lancet. 2019; 394 (10200): 737-745.Nurtec (rimegepant) [package insert]. New Haven, CT: Biohaven Pharmaceuticals, Inc.; Feb 2020

Rimegepant(NurtecTM)

Croop R, et al. Lancet. 2019; 394 (10200): 737-745.Nurtec (rimegepant) [package insert]. New Haven, CT: Biohaven Pharmaceuticals, Inc.; Feb 2020

Single dose of 300 mg (4 x recommended)No clinically relevant QT prolongation

Sumatriptan SQ vs. Sumatriptan + RimegepantNo difference in blood pressure

Migraine Prevention

Reference

Antihypertensives Antiepileptics Antidepressants

PropranololTimolol

MetoprololVerapamil

TopiramateDivalproex

AmitriptylineVenlafaxine

BotulinumToxin• Increasing benefit with longer use▫ Patient may not see benefit until after 2 – 3 treatment (~4 – 9 months after initiation)

• Logistics and billing

Reference

Prefilled erenumab (Aimovig) syringe not available in U.S.

Eptinezumab (VyeptiTM)• 4th CGRP‐inhibitor for migraine prevention▫ Binds to CGRP ligand• Infused over 30 minutes every 3 months• Good option for patients with Medicare + supplement• Expected availability: April 2020

Lipton R, Saper J, Ashina M et al. PROMISE-2 trial. Neurology. 2018;90 (15 Supplement)Vyepti (eptinezumab) [package insert]. Bothell, WA: Lundbeck Seattle BioPharmaceuticals, Inc.; Feb 2020.

Erunumab(Aimovig)

Fremanezumab(Ajovy)

Galcanezumab(Emgality)

Eptinezumab(Vyepti)

Administration  SQ autoinjector SQ syringe SQ syringeSQ autoinjector IV

Frequency MonthlyMonthly

Or Quarterly(still 12/year)

Monthly Quarterly

Dose 70 mg or 140 mg

225 mg monthly675 mg quarterly 120 mg  100 mg 

or 300 mg

Target CGRP receptor CGRP ligand CGRP ligand CGRP ligand

Antibody Sequence

100 % humanized

>90% humanized

>90% humanized

>95% humanized

Approval Date May 2018 September 2018 September 2018 February 2020

Maasumi K, Michael RL, Rapoport AM. Drugs. 2018;78(9):913–928.

AdverseEffects

ISMP Medication Safety Report. Quarter Watch. Aug 2019: 24 (16):2-4.

• Injection site reactions ▫ Mostly common with Ajovy® monthly and quarterly (43% and 45%, respectively) versus placebo (38%)

• Constipation▫ Observed in clinical trials with Aimovig® 70 mg and 140 mg (1% and 3%, respectively) versus placebo (1%)

AmericanHeadacheSocietyPositionStatement• Consider starting:▫ Patient is 18 y/o +▫ Diagnosis of migraine +/‐ aura▫ Inability to tolerate evidence‐based prophylactic therapies▫ Inadequate response to 6 week trial of at least 2 evidence‐based prophylactic therapies

• Consider continuing:▫ ≥ 50% reduction in monthly headache days▫ Clinically meaningful improvement

American Headache Society. Headache. 2019;59:1-18.

OralCGRPinhibitor?

• Atogepant▫ Currently in Phase 3 trials▫ Oral CGRP inhibitor taken daily for prevention “gepant” for prevention

▫ Plans to file with FDA in 2020▫ Less liver toxicity compared to the daily gepants that failed in early 2000s

▫ First instance of class with preventative and acute treatment?

https://clinicaltrials.gov/ct2/show/NCT02848326?term=02848326&rank=1

DrugPipeline

PatientCW• 41 y/o high school teacher• Experiencing 15 – 17 migraines per month▫ Topiramate: Initial effect, but then less effective▫ Amitriptyline: Dry mouth▫ Magnesium: No effect▫ Botox: Currently helpful Down to 5 – 9 migraines per month Still regularly refilling sumatriptan (9 doses/month) Too expensive $$$$

PatientCW• November 2019▫ Started erenumab (Aimovig®) 70 mg monthly• February 2020▫ Reduction to 4 migraine per month 3 of which were less severe, and she was able to continue working

2 uses of sumatriptan in past month▫ More productive at work▫ Able to attend more personal and social events

Pharmacologicupdatesinthemanagementofacutemigrainesandmigraineprevention

Emily Neddermeyer, PharmD, BCACPAdult Neurology Clinic University of Iowa Hospitals & Clinics

emily‐neddermeyer@uiowa.edu