Upload
others
View
6
Download
0
Embed Size (px)
Citation preview
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‐[email protected]