Utah Medicaid Dur Report June 2020 Cgrp Antagonists

UTAH MEDICAID DUR REPORT JUNE 2020

CGRP ANTAGONISTS FOR ACUTE TREATMENT OF MIGRAINE: NURTEC ODT (RIMEGEPANT) UBRELVY (UBROGEPANT)

Report Finalized in May 2020 Report Presented in June 2020

Drug Regimen Review Center

Valerie Gonzales, Pharm.D., Clinical Pharmacist Jeffrey Sperry, Pharm.D. Candidate Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Jacob Crook, MStat, Data and Statistical Analyst Joanne LaFleur, PharmD, MSPH, Associate Professor

Contents

Introduction ...... 3

Table 1. Nurtec ODT and Ubrelvy Indication and Dosing ...... 3

Methods ...... 4

Disease Overview ...... 4

Table 2. Migraine Diagnostic Criteria of the International Classification of Headache Disorders .... 5

Pharmacotherapy for Migraine Headache ...... 6

Table 3. American Headache Society Clinical Guidance for Treatment of Adults with Migraine ..... 9

Place in Therapy ...... 10

Table 4. Pharmacokinetic Parameters for Nurtec OCT and Ubrelvy ...... 10

Clinical Studies ...... 12

Safety ...... 15

Table 5. Safety Concerns for Oral CGRP Receptor Antagonists ...... 16

Prior Authorization Considerations ...... 19

Existing Prior Authorization Criteria for CGRP Antagonists ...... 20

Summary ...... 21

References ...... 22

Appendix ...... 26

Table 1. Dose Adjustments with Enzyme or Transport Inhibitors/Inducers ...... 26

Introduction

Rimegepant (Nurtec ODT) and ubrogepant (Ubrelvy) are among the relatively new drug class of calcitonin gene-related peptide receptor antagonists (CGRP-RAs) developed for the treatment of migraine. These two agents are approved for the relief of active migraine with or without aura in adults (ie, acute/abortive migraine therapies). Previously approved CGRP antagonists are indicated for the prevention of migraine (eptinezumab, erenumab, fremanezumab, galcanezumab). Rimegepant and ubrogepant are not indicated for migraine prevention; though rimegepant has positive preliminary results for migraine prevention in a recently completed phase 2/3 study, with sponsor plans to submit supplemental application for a label extension.1

Rimegepant (75 mg) and ubrogepant (50 mg or 100 mg) are taken at the onset of migraine symptoms. A second dose of ubrogepant can be taken if needed (eg, if symptoms persist or return) 2 hours following the first dose; the maximum dose of ubrogepant is 200 mg per 24 hours.2,3 Since the maximum dose per day of rimegepant is 75 mg, a second rescue dose a couple hours following the first dose is not an option. Safety is established for treating up to 8 migraines per month with ubrogepant, and up to 15 migraines per month with rimegepant. Nurtec ODT is an orally disintegrating tablet (ODT) to be placed on or under the tongue, whereas Ubrelvy is a conventional oral tablet. Dose adjustments or restrictions for each medication are dependent on drug interactions involving cytochrome P450 (CYP) 3A4 metabolism or breast cancer resistant protein (BCRP) and/or P-glycoprotein (P-gp) meditated pathways. Table 1 provides the strengths, indication, and dosing for the use of rimegepant and ubrogepant.

This report reviews the place-in-therapy for the acute CGRP-RAs for migraine treatment and outlines potential safety concerns. Prior authorization (PA) discussion points and potential criteria are provided. Abortive products for migraine with preferred status on the Utah Medicaid Preferred Drug List (PDL) include Relpax (eletriptan) tablets, and generic rizatriptan and sumatriptan tablets, with quantity limits in place for these agents. Nurtec ODT and Ubrelvy are designated as non-preferred on the PDL. A drug class-specific PA is currently in place for all CGRP antagonists, acute and preventive therapies. Details of the PA are discussed on page 20 of this report. There were less than 5 pharmacy claims for ubrogepant use in the fee-for-service Medicaid population and 0 for rimegepant (based on claims data from September 2019 through April 2020).

Table 1. Nurtec ODT and Ubrelvy Indication and Dosing Ubrelvy (ubrogepant) tablets Nurtec ODT (rimegepant) § Strengths: 50 mg, 100 mg § Strength: 75 mg Dosage § Configuration: boxes of single-unit § Configuration: blister pack with 8 orally Forms dose as a count of 6, 8, 10, 12, or 30 disintegrating tablets. tablets per box Approved Indicated for acute treatment of migraine with or without aura in adults Indication • Dosage: 50 mg or 100 mg; may take a • Dosage: 75 mg Dosinga second dose if needed, separated by at • Maximum is 75 mg/24-hours least 2 hours after the initial dose • Safety of treating > 15 migraines per 30-day • Maximum dose is 200 mg/24-hours period is not established

Table 1. Nurtec ODT and Ubrelvy Indication and Dosing • Safety of treating > 8 migraines per 30- • Open blister pack with dry hands; avoid day period is not established pushing the tablet through foil; take • Dose adjustments are required if used in immediately after opening the blister pack combination with CYP3A4 • Avoid use with strong inhibitors of CYP3A4; inducers/inhibitors; BCRP and/or P-gp avoid a second dose within 48 hours of the transport inhibitors; and for hepatic or first when used with moderate inhibitors of renal impairment (see Table 1 of the CYP3A4; avoid use with strong/moderate Appendix for details); avoid with strong inducers of CYP3A4 or inhibitors of P-gp or CYP3A4 inducers BCRP transporters a See Table 5 for dose adjustments related to renal or hepatic insufficiency. See Table 1 of the Appendix for dose adjustments related to concomitant medications. Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome P450 enzyme; ODT, orally disintegrating tablet; P-gp, P-glycoprotein

Methods

Background information regarding migraine disease state and guidance or position statements by key organizations regarding pharmacological treatment of migraine were sought at the following websites: I. For treatment guidelines we searched websites of the American Academy of Neurology (https://www.aan.com/policy-and-guidelines/guidelines/), and the American Headache Society (https://americanheadachesociety.org/resources/guidelines/). II. For professional prescribing information (ie, product labeling) we searched the drug sponsor’s website for each product’s most up-to-date package insert. III. Evidence-based drug information databases, Micromedex and Lexicomp

Literature searches for reviews and randomized controlled trial (RCT) information were performed in OvidMedline and in Epistemonikos, searching rimegepant OR ubrogepant as keywords; see the Appendix for search strategies.

Disease Overview

Migraine is a common primary headache disorder. Findings from the 2018 National Health Interview Survey (NHIS) showed that approximately 16% of American adults experienced migraine or severe headache over a 3-month recall period, with prevalence disproportionately higher in women than in men (21% vs. 11%, respectively).4 In the pediatric population, prevalence increases with increasing age.5 The estimated prevalence of migraine in children and adolescent males is 6% and in females is 9.7% according to population-based studies.6

Migraine symptoms can reduce quality of life, and negatively affect school and work productivity or social engagements.7,8 Most patients with migraine rate their pain level as severe.7 Approximately 20% of patients with episodic migraine suffer from moderate to severe headache-related disability.9 Of the subpopulation experiencing high-frequency migraines (chronic migraine), approximately 50% have moderate to severe disability.9 According to a 2017 survey (Migraine in America Symptoms and Treatment Study), 96% of patients (out of 3930 respondents) with migraine had at least 1 unmet need

4 despite using their acute migraine treatment.10 Common unmet needs included inadequate treatment response (eg, inadequate pain freedom at 2 hours, 48%; recurrent migraine within 24 hours of initial relief, 38%), rapid onset of attack (65%), and disability (56%). The percentage of patients with self- reported inadequate treatment response per drug class was reported as follows: triptans (44%), prescribed non-steroidal anti-inflammatory drugs (NSAIDs) (38%), opioids (36%), and barbiturates (12%).10

Migraines are classified according to symptoms (migraine with or without aura) and frequency (episodic or chronic migraine). The diagnosis and classification of migraine has been delineated in the International Classification of Headache Disorders-3 (ICHD-3), developed by the International Headache Society.11 Migraine without aura usually presents unilaterally and is often depicted as pulsating moderate-to-severe pain that can be aggravated by physical exertion. Patients may experience nausea, vomiting, cutaneous allodynia, and become sensitive to light (photophobia) and noise (phonophobia). Migraine without aura can last 4 to 72 hours in adults. Migraine with aura is characterized by transient neurological symptoms (of visual, sensory, speech, motor, brainstem, or retinal types) that usually precede the migraine within an hour but may also occur during the episode. Aura symptoms, which occur in about a third of migraineurs may include any of the following: visual disturbances, dysarthria, vertigo, feeling of pins and needles, numbness, impaired hearing, diplopia, or ataxia.11,12 Hemiplegic- type aura involves motor weakness and other reversible visual, sensory, or speech dysfunction presentations. A migraine may also be preceded by prodromal symptoms hours to days before the migraine (eg, hyper- or hypo-activity, depression, food cravings, repetitive yawning, fatigue, or neck stiffness/pain).

With respect to migraine frequency, patients who experience headache occurring ≥15 days per month for more than 3 months and with at least 8 days/month involving features of migraine headache are classified as having chronic migraine.11 Patients with migraines not meeting this frequency criteria are generally considered to have episodic migraine. Table 2 provides a detailed description of the criteria for classification of migraine according to the ICHD-3.

Table 2. Migraine Diagnostic Criteria of the International Classification of Headache Disorders, 3rd Edition11 Migraine Without Aura Migraine With Aura Chronic Migraine

A. At least 5 attacks fulfilling A. At least 2 attacks fulfilling A. Migraine-like or tension-type-like criteria B–D criteria B and C headache on ≥15 days/month for >3 months that fulfill criteria B and C B. Headache attacks lasting 4–72 B. One or more of the following hours (when untreated or fully reversible aura symptoms: B. Occurring in a patient who has had unsuccessfully treated) 1. visual at least 5 attacks fulfilling criteria B-D 2. sensory for migraine without aura and/or C. Headache has at least 2 of the 3. speech and/or language criteria B and C for migraine with following 4 characteristics: 4. motor aura 1. unilateral location 5. brainstem 2. pulsating quality C. On ≥8 days/month for >3 months, 6. retinal 3. moderate or severe pain fulfilling any of the following: intensity C. At least 3 of the following 6 1. Criteria C and D migraine 4. aggravation by or causing characteristics: without aura avoidance of routine physical 1. at least one aura symptom 2. Criteria B and C for migraine activity (eg, walking or climbing spreads gradually over ≥5 mins with aura

Table 2. Migraine Diagnostic Criteria of the International Classification of Headache Disorders, 3rd Edition11 Migraine Without Aura Migraine With Aura Chronic Migraine stairs) 2. two or more aura symptoms 3. Believed by the patient to be occur in succession migraine at onset and relieved by a D. During headache at least 1 of 3. each individual aura symptom triptan or ergot derivative the following: lasts 5–60 mins 1. nausea and/or vomiting D. Not better accounted for by 4. at least one aura symptom is 2. photophobia and another diagnosis unilateral phonophobia 5. at least one aura symptom is E. Not better accounted for by positive (ie, scintillations or pins another ICHD-3 diagnosis and needle feeling) 6. the aura is accompanied, or followed within 60 mins, by headache D. Not better accounted for by another ICHD-3 diagnosis Abbreviations: ICHD-3, International Classification of Headache Disorders, 3rd edition; mins, minutes

Pharmacotherapy for Migraine Headache

Migraine treatment strategies include acute or abortive therapies to rapidly halt symptoms, and preventive therapy to decrease the frequency of migraine episodes. Behavioral and lifestyle modifications are additionally considered in the management of migraine.6 Optimization of therapy for each patient is challenging due to intra- and inter-individual variability regarding migraine characteristics, severity, and frequency of attacks.12 Treatment strategies should be individualized based on patient preference; pregnancy status or plans to conceive; the frequency and intensity of migraine attacks; the patient’s symptom profile including disability; response to previous treatments; comorbidities such as cardiovascular disease; contraindications; and concurrent medications. The goals of acute treatment are to provide rapid and consistent pain relief, restore functional ability, and minimize symptom recurrence, adverse effects, and use of healthcare resources such as emergency room admission. All patients with migraine are to be considered for as needed treatment for migraine attacks with abortive therapy.12

According to the 2019 position statement by the American Headache Society, for mild-to-moderate migraine attacks, non-opioid analgesics are recommended (eg, NSAIDs, acetaminophen [APAP], or caffeinated analgesic [APAP and NSAID] combinations). Migraine-specific medications (triptans or dihydroergotamine [DHE]) are recommended for moderate-to-severe attacks or as second-line for mild- to-moderate attacks. Regarding the more recently approved agents, the AHS recommends considering lasmiditan, rimegepant, or ubrogepant for patients with contraindications to triptans, or who failed to respond or did not tolerated at least 2 oral triptans, as a cost-effective approach to treatment.12

A non-oral agent (eg, intranasal, injectable, or transdermal) or agents available as orally disintegrating or rapid melting tablets can be provided for patients with attacks accompanied with severe nausea or vomiting, for patients with swallowing difficulties, and for patients with inadequate response to traditional oral formulations.12,13 Intranasal or injectable triptans or DHE may be more effective than oral formulations in patients that have attacks reaching maximal intensity rapidly.13 Antiemetics may be co-

6 prescribed if needed. As part of the Choosing Wisely position statements by the American Academy of Neurology (AAN), in 2013, the AAN recommended that opioids and butalbital be reserved as last-resort options for abortive migraine treatment since there are more effective migraine-specific agents.14,15 The AHS recommends that opioid use should be limited to those with contraindications to other medications, or opioids can be used infrequently as a rescue medication when the patient does not respond to their initial treatment during a severe attack.13 Although opioid-containing migraine medications (eg, butorphanol, or APAP with codeine or tramadol) can be effective, they should be used sparingly due to potential risk of dependence, addiction, and occurrence of medication overuse headache.13 Butalbital-containing migraine medications do not have as strong of evidence for efficacy compared to other agents (eg, triptans, NSAIDs, ergots) and also have dependence and abuse risk.16,17

Treatment should be administered early, preferably at the first sign of migraine onset for best response.12,13 The AHS suggests that clinicians may need to try several different medications to find an optimal regimen.13 If a patient does not respond well to a particular triptan, a different triptan should be tried.13 A stratified approach to therapy is used when possible, in which the patient is instructed to use certain medications based on the severity of the attack.13 Thus, the patient is issued several prescriptions to have different medications on hand (eg, NSAIDs, triptans) for as needed use based the severity of the individual migraine attack. This approach works well when patients are able to differentiate, based on experience, which headaches will respond to an NSAID versus those that will need a triptan or other migraine-specific medication. Moreover, if initial treatment fails to provide relief, patients may need to take a second dose of their initial treatment (if allowed by product labeling) or use of a self-administered rescue option from a different medication class (eg, subcutaneous sumatriptan, DHE injection or intranasal spray), especially for those who have variable response to acute therapies. Combining both a triptan and an NSAID for migraine recurrence within 24 hours of the initial attack is a strategy that can improve response.13 It is important for patients to avoid overusing traditional acute medications (i.e., > 9 days per month for triptans, ergots, opioids, or combination analgesics containing these therapies; or >14 days per month for non-opioid analgesics (eg, acetaminophen, NSAIDs) because overuse can lead to medication-overuse headache and conversion to high-frequency migraines (ie, chronic migraine).12,13 Patients should generally limit the use of acute migraine treatments to an average of 2 days per week and be offered preventive therapy if exceeding this average.12

Regarding preventive therapies for the reduction of migraine frequency in adults, many agents in various pharmacological classes (eg, CGRP antagonists, antiepileptics, antidepressants, beta-blockers, calcium channel blockers, etc.) have been studied. The most recent (2012) American Academy of Neurology and the American Headache Society (AAN/AHS) guideline for long-term prevention of episodic migraine in adults classifies therapies based on the level of evidence supporting their use.18 Medications with established efficacy supported by the highest-quality evidence include divalproex, sodium valproate, topiramate, metoprolol, timolol, and propranolol.18 Agents that are probably effective include amitriptyline, venlafaxine, atenolol, and nadolol. Several CGRP antagonists (eptinezumab, erenumab, fremanezumab, galcanezumab), that either sequester the CGRP ligand or that antagonize the receptor, have also been approved for migraine prevention in more recent years than the 2012 guideline. These CGRP antagonists are approved for prevention of both episodic migraine and chronic migraine.19-22 Onabotulinumtoxin A (OBTA) is approved specifically for chronic migraine.23 Besides OBTA, topiramate was the only other agent shown to be efficacious in RCTs of patients specifically with chronic migraine until approval of the preventive CGRP antagonists.24,25

Preventive therapies can be considered for any of the following scenarios: migraines significantly impairing patient’s daily routine despite acute treatment, patient prefers preventive therapy, the frequency of attacks is at least 4 migraine days per month, or when there is contraindication, adverse effect, treatment failure, or medication overuse with acute treatments.12 However, there is some flexibility for when preventive therapy should be offered or when it can be considered based on the number of headache days per month (HDM) and degree of disability, according to the 2019 AHS position statement: i) preventive therapy should be offered when HDM are ≥3 with severe disability, ≥4 with some disability, or ≥6 with no disability; or ii) preventive therapy can be considered with 1 less HDM in each of these pairs. Regardless of migraine frequency, preventive options should be considered in those with hemiplegic migraine, migraine with brainstem aura, migraine with prolonged aura, or migrainous infarction.12

Nondrug therapies for migraine treatment include single-pulse transcranial magnetic stimulation, electrical trigeminal nerve stimulation, and noninvasive vagus nerve stimulation.12 The AHS describes that these can be considered “…in patients who prefer nondrug therapies and those who have failed to respond to, have contraindications to, or poor tolerability with pharmacotherapy…”12

Pregnancy

For treatment of migraine during pregnancy, the NICE guideline recommends offering acetaminophen.26 Triptans or NSAIDs can be considered for use upon discussion with the patient about the potential risks and if the benefits outweigh the risks for the patient.26 An expert review from the John. R Graham Headache Center of Brigham and Women’s Hospital notes that triptans have better safety evidence than butalbital during pregnancy, and of the triptan drug-class, evidence is strongest for sumatriptan, naratriptan, and rizatriptan; however, these two drug classes are second-line options. Preferred first-line options include acetaminophen, diphenhydramine, subcutaneous lidocaine, metoclopramide, and NSAIDs (eg, ibuprofen, naproxen, and diclofenac for use only in the second trimester).27

Children

Children and adolescents can benefit from nonprescription oral analgesics such as acetaminophen and ibuprofen.6 In particular, ibuprofen oral solution (10 mg/kg) is the recommended first-line option to alleviate pain for pediatric patients with migraine. In adolescents, triptans are also an option, though less often prescribed compared to use in adults. FDA-approved agents for the pediatric population 12 years or older include almotriptan, sumatriptan/naproxen, and zolmitriptan nasal spray. Rizatriptan is indicated for children 6 to 17 years of age.6 The 2015 NICE guideline recommends considering nasal triptans over oral triptans for patients 12 to 17 years.26

Table 3 provides information from recent American Headache Society guidelines or position statements regarding the acute treatment of migraine in adults.

Table 3. American Headache Society Clinical Guidance for Treatment of Adults with Migraine Position Statement on Integrating New Migraine Treatments Into Clinical Practice; 2019 Recommendations 12 • Acute treatment is indicated for all patients with migraines • Use NSAIDs, acetaminophen, nonopioid analgesics, or caffeinated analgesic combinations for mild-to- moderate migraine attacks. • Use triptans or dihydroergotamine for moderate-to-severe migraine attacks and mild-to-moderate migraine attacks that respond poorly to NSAIDs or caffeinated analgesic combinations. • May consider lasmiditan, rimegepant, or ubrogepant for patients with contraindications to triptans or who have failed at least 2 oral triptans • Provide coverage for at least 2 migraine attacks to assess efficacy and tolerability • Continue coverage according to migraine response (reduction in migraine days per month, improvement on validated patient outcome questionnaires, and/or provider attestation)

The Acute Treatment of Migraine in Adults, Evidence Assessment of Migraine Pharmacotherapies; 2015 Recommendations 16

Agents with Established Efficacy (Level A, evidence supported by ≥ 2 class I studies):

• Triptans: almotriptan 12.5 mg, eletriptan 20- 80 mg, frovatriptan 2.5 mg, naratriptan 1-2.5 mg, rizatriptan 5-10 mg, sumatriptan (oral 25-100 mg, nasal spray 10-20 mg, SC 4-6 mg, transdermal patch 6.5 mg), zolmitriptan (oral 2.5-5 mg; and nasal spray 2.5-5 mg) • Dihydroergotamine (nasal spray 2 mg, inhaler 1 mg) • APAP 1,000 mg for non-incapacitating attacks • NSAIDS: aspirin 500 mg, diclofenac 50-100 mg, ibuprofen 200-400 mg, naproxen 500 or 550 mg • Butorphanol nasal spray 1 mg (though this is not recommended for regular use) • Combinations: sumatriptan/naproxen 85/500 mg, APAP/ASA/CAF 500/500/130 mg

Agents Probably Effective (Level B, evidence supported by 1 class I studies or 2 Class II studies):

• Ergots: DHE as IV, IM, SC 1 mg, ergotamine/CAF 1/100 mg • Antiemetics: droperidol IV 2.75 mg, chlorpromazine IV 12.5 mg, metoclopramide IV 10 mg, prochlorperazine IV/IM 10 mg or suppository 25 mg, promethazine (listed in 2019 Position Statement) • NSAIDs: ketoprofen 100 mg, ketorolac IV/IM 30-60 mg, flurbiprofen 100 mg • Others: isometheptene 65 mg, codeine/APAP 25/400 mg, tramadol/APAP 75/650 mg, magnesium sulfate IV (for migraine with aura) o Opioids are not recommended for regular use

Agents Possibly Effective (Level C, evidence supported by 1 Class II and 2 Class III studies):

• Butalbital 50 mg, butalbital/APAP/CAF/codeine 50/325/40/30 mg, butalbital/APAP/CAF 50/325/40 mg • Phenazone 100 mg (NSAID) • Opioids: butorphanol IM 2 mg, codeine 30 mg, meperidine IM 75 mg, methadone IM 10 mg, tramadol IV o Opioids are not recommended for regular use • Others: lidocaine (intranasal), dexamethasone IV, valproate IV

Efficacy is Unclear (Level U, evidence is conflicting or inadequate to support or refute the efficacy of the following medications for migraine): celecoxib, lidocaine IV, hydrocortisone IV

Table 3. American Headache Society Clinical Guidance for Treatment of Adults with Migraine Definitions for level of evidence: Level A requires at least two Class I studies (randomized, controlled trials with masked outcome assessment, concealment of allocation, and adequate accounting for attrition). Level B requires one Class I study or two Class II studies (well-designed cohort studies or randomized, controlled trials that do not meet 1-2 criteria for Class I studies). Level C is supported by 1 Class II and 2 Class III studies (controlled studies, not meeting Class I or II, with outcome assessment masked) Abbreviations: ASA, aspirin, APAP, acetaminophen; DHE, dihydroergotamine; CAF, caffeine; IM, intramuscular; IV, intravenous; SC, subcutaneous

Place in Therapy

The calcitonin gene-related peptide (CGRP) antagonists target the CGRP receptor that is present in the trigeminal sensory system and which is thought to be activated by CGRP ligand during a migraine; though the exact mechanism in resolving a migraine is unknown.3,28 CGRP is thought to be a mediator of pain transmission when stimulating trigeminal sensory nerve fibers.29 It is also a “…vasodilatory neuropeptide involved in nociceptive transmission and modulation, and its receptors are widely expressed in central and peripheral regions of the nervous system.”30 Elevated CGRP levels have been observed during migraine attack, and migraine features can be precipitated by intravenously administered CGRP; moreover, CGRP levels have been observed to be normalized after triptan administration.29,31,32 Several small molecule drugs and monoclonal antibodies are approved and some are being further investigated for the treatment of migraine, both for acute treatment and as preventive therapy. Thus far, rimegepant and ubrogepant are approved for as needed use to relieve an active migraine (ie, acute/abortive treatments). Rimegepant is also being studied for migraine prevention and trigeminal neuralgia but is not yet approved for these indications.28

Table 4. Pharmacokinetic Parameters for Nurtec OCT and Ubrelvy Rimegepant (Nurtec ODT)

Tmax: 1.5 hours CYP3A4 (major metabolism pathway); CYP2C9 (minor pathway) T½: 11 hours • pharmacokinetics of rimegepant were Food effects: after high-fat meal, Tmax is delayed by unaffected by CYP2C9 genotype

1 hour and Cmax and AUC were reduced; the The medication is cleared primarily as unchanged medication was studied without regard to food drug (77%) via urine (51%) and feces (42%)

Ubrogepant (Ubrelvy)

Tmax 1.5 hours CYP3A4 (major metabolism pathway) T½: 5-7 hours Food effects: after high-fat meal, Tmax is delayed by The parent compound is cleared via urine (6%) 2 hours and Cmax is reduced but no change in AUC; and feces (42%) the medication was studied without regard to food Abbreviations: AUC, area under the curve; CYP, cytochrome P450 enzyme; ODT, orally disintegrating tablet; T½, drug elimination half-life; Tmax: time to reach the maximum concentration

As a cost-effective approach to therapy options, the American Headache Society recommends considering rimegepant and ubrogepant (along with lasmiditan) for patients with contraindications to triptans or who have had an inadequate response or intolerance to at least 2 oral triptans, per the prescriber’s attestation or as determined using a validated patient-reported outcome questionnaire. Coverage determinations based on response and tolerability to these new therapies should be made after the patient treats at least 2 migraine episodes with the medication. Furthermore, “Continuation of coverage should be based on the frequency of migraine attacks in an average month and response to a validated acute treatment patient-reported outcome questionnaire or clinical assessment of improvement by the healthcare provider.”12 Validated instruments that can be used to assess response to acute migraine therapy include the following: Migraine Treatment Optimization Questionnaire (mTOQ), Migraine Assessment of Current Therapy (Migraine-ACT), Patient Perception of Migraine Questionnaire (PPMQ-R), Functional Impairment Scale (FIS), or Patient Global Impression of Change (PGIC).12

Scenarios that preclude use of commonly used agents for moderate-to-severe migraine attacks are described below.

A. Triptans are contraindicated in patients with the following:33 i. Ischemic coronary artery disease (including angina pectoris, history of myocardial infarction, or documented silent ischemia) ii. Coronary artery vasospasm (including Prinzmetal’s angina) iii. Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders iv. History of stroke or transient ischemic attack v. Peripheral vascular disease vi. Ischemic bowel disease vii. Uncontrolled hypertension viii. Hemiplegic or basilar migraines (since patients are at higher stroke risk) ix. Severe hepatic impairment x. Triptans must also be avoided with recent use (ie, within 24 hours) of another triptan or with an ergot-containing medication; or if monoamine oxidase-A inhibitors (MAOIs) have been used within the past 2 weeks.33 • Triptans should be used with caution in patients with a history of epilepsy or with a lowered seizure threshold.34

B. Ergotamine derivatives are contraindicated in patients with the following:35-37 i. Ischemic coronary artery disease (including angina pectoris, history of myocardial infarction, or documented silent ischemia) ii. Coronary artery vasospasm (including Prinzmetal’s angina) iii. Peripheral vascular disease iv. Following vascular surgery v. Uncontrolled hypertension vi. Sepsis vii. Severe hepatic or renal dysfunction viii. Hemiplegic or basilar migraines (since patients are at higher stroke risk)

ix. Recent use (ie, within 24 hours) of triptans, peripheral and central vasoconstrictors, ergot derivatives, serotonin agonists, or with concurrent use of potent CYP3A4 inhibitors x. Pregnancy and breastfeeding • Long-term use is associated with cardiac valvular and pulmonary-related fibrosis • May cause vasospastic reactions; major adverse events have been reported with use including acute myocardial infarction, cardiac arrhythmia, and hemorrhagic cerebrovascular events

C. NSAIDs can cause serious gastrointestinal and cardiovascular side effects. i. Avoid use in patients with active GI bleeding; use with caution if there is history of GI ulcers, concurrent use of medications that increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, or in elderly or debilitated patients.38 ii. NSAIDs may contribute to new-onset hypertension, exacerbation of hypertension, fluid retention, and thrombotic events; NSAIDs should generally be avoided in heart failure or with recent MI unless benefits outweigh risk. Must be used with caution in patients, hypertension, edema, or significant CV-risk.38

D. Medication overuse headache (≥15 day/month with headache) as a result of >3 months of medication overuse: medication overuse is defined as (a) 10 or more days per month for which abortive treatments (ergot derivatives, triptans, opioids, combination opioid or caffeinated analgesics, or any combination of these individual drugs) were used for headache; or (b) use on 15 or more days per month of a non-opioid analgesic, NSAID, or APAP for the treatment of headache.12

Lasmiditan, the newly approved 5-HT1F receptor agonist for acute treatment of migraine, is a class V controlled substance and has a labeled restriction regarding driving due to its potential to cause CNS depression (ie, sleepiness, reduced metal alertness).39 Patients should avoid driving for 8 hours post dose as they may not be able to assess their own driving competence or degree of impairment. This agent must be used with caution in combination with other CNS depressants or serotonin reuptake inhibitors. No more than a single dose can be taken in a 24 hour period and safety is established for treating up to 4 migraines per 30 day period.39

Clinical Studies

In the phase 3 clinical studies with rimegepant and ubrogepant, patients were instructed to treat a moderate-to-severe migraine attack. With ubrogepant, patients could take a second dose between 2 to 48 hours after the initial dose if migraine pain was still of moderate intensity; whereas a second dose of rimegepant was not studied. Patients could enter the studies on stable preventive therapy, but none were on preventive CGRP-RAs since these preventive agents were not yet on the market at the commencement of these studies. Co-primary endpoints were the 2-hour post-dose effect on pain freedom, defined as a reduction of moderate or severe headache pain to no headache pain; and most bothersome symptom (MBS) freedom, defined as the absence of the self-identified MBS (eg, photophobia, phonophobia, or nausea). Other secondary measures included pain relief, defined as a

12 reduction in migraine pain from moderate or severe severity to mild or none; sustained pain freedom from 2 to 48 hours post dose; and use of rescue medication within 24 hours for the rimegepant study only.

There are no published studies directly comparing CGRP-RAs to triptans.40,41 A phase 2, dose-ranging trial for rimegepant capsules (non-approved formulation) included a treatment arm with oral sumatriptan, however, statistical analyses between the two active arms were not carried out.42 Numerically, slightly more patients who received sumatriptan 100 mg were pain free 2 hours post dose than those receiving rimegepant 75 mg (35% vs. 31.4%, respectively).42 Patients taking rimegepant did not experience any of the classic adverse events commonly experienced with triptans (such as chest pain, jaw pain, or muscle tightness), which occurred in 2% of patients in the sumatriptan group, nor did patients taking rimegepant experience any appreciable adverse event.42

Rimegepant

The pivotal, double-blind RCT evaluating the efficacy of rimegepant ODT 75 mg involved a total of 732 patients receiving the study drug.3,43 Eligible patients had a ≥ 1 year history of migraine with or without aura, 2 to 8 moderate to severe intensity migraines per month but less than 15 headache days per month over the previous 3 month. Patients were excluded with significant cardiovascular disease (unstable angina, myocardial infarction, transient ischemic attack, and stroke, within 6 months of the study) or with cerebral ischemia. Patients were allowed to enter the study with background migraine preventive therapy; 14% were on preventive agents at baseline. In the event of a non-responding or recurring migraine, patients were allowed to take certain acute migraine treatments (eg, NSAIDs, APAP, antiemetic, or baclofen) as rescue therapy 2 hours after rimegepant but were not allowed triptans or a second dose of rimegepant between 2 and 48 hours after the initial dose; about 14% of patients took rescue medication between 2 and 24 hours after rimegepant.43 After 48 hours, patients could use triptan rescue medication.44

Upon treatment of moderate-to-severe migraine pain, rimegepant significantly outperformed placebo for the effect on 2-hour post-dose pain freedom (21% were responders with rimegepant) and MBS freedom (35% were responders with rimegepant), a significant difference from placebo for each (10% and 8% difference, respectively). Approximately 60% of rimegepant-treated patients had pain relief at 2 hours post dose (ie, pain reduced to mild or no pain). There were significantly more patients on treatment than with placebo who had sustained pain relief 2 to 24 hours (13.5% vs 5.4%, p<0.001) and 15% fewer patients with rimegepant than placebo using rescue medication within 24 hours (a significant reduction).3,43 With the ODT formulation designed for quick onset, there was differentiation from placebo (ie, p<0.05) for pain relief and ability to function normally at 60 minutes post dose and response was persistent out to 48 hours post dose.43 Another similarly designed phase 3 study with a conventional tablet form (non-ODT) of rimegepant 75 mg resulted in comparable findings, showing superiority over placebo for pain freedom and freedom from MBS at 2 hours post dose. Additionally, differences were significant from placebo for secondary endpoints including freedom from photophobia, phonophobia, and pain relief 2 hours post dose.45

Ubrogepant

There were two phase 3, double-blind RCTs evaluating the efficacy of ubrogepant with a total of 1439 patients receiving the study drug.46,47 Eligible patients had a ≥ 1 year history of migraine with or without aura and 2 to 8 moderate to severe intensity migraines per month in the preceding 3 months (but with less than 15 headache days per month over the previous 6 months). Patients could have a previous diagnosis of chronic migraine and enter the study if they were having fewer than 15 headache days per month while on preventive therapy.46,47 Patients were allowed to enter the studies with stable background migraine preventive therapy; 23% to 24% had preventive therapy onboard at baseline (eg, beta-blocker, tricyclic antidepressant, topiramate, valproic acid, onabotulinumtoxinA).2,48 Patients with cardiovascular risk, including some at high risk (ie, ≥20% 10 year CV risk per Framingham risk score), were allowed to participate; however, patients with significant cardiovascular disease were excluded*.46,48 In the event of a non-responding or recurring migraine following the initial ubrogepant dose, after 2 hours, a second dose could be taken of ubrogepant or of the patient’s usual acute migraine treatment (eg, acetaminophen, NSAIDs, opioids, anti-emetics or triptans).48 In the study using both approved ubrogepant doses (50 mg and 100 mg), close to 44% of patients who received an initial dose of ubrogepant elected to take a second dose 2 to 48 hours after; percentages of patients in each dosage group electing for a second dose were similar (43% in the 50 mg group and 44% in the 100 mg group).46 About 16% of patients taking ubrogepant elected to use their usual rescue medication 2 to 48 hours after the initial ubrogepant dose (similar proportions of patients in each each dosage group: 16% in the 50 mg group and 15% in the 100 mg group).46 Statistical evaluations for efficacy endpoints used data based on the initial dose of ubrogepant.

Upon treatment of moderate to severe migraine pain, ubrogepant was significantly more effective than placebo with respect to the primary outcomes, pain freedom 2 hours post dose and MBS freedom 2 hours post dose. About 20% of patients treated with ubrogepant were pain free at 2 hours post dose (difference from placebo: 7.5% with 50 mg ubrogepant and 9.4% with 100 mg; p<0.05 for each). About 38% of patients treated with ubrogepant had MBS freedom 2 hours post dose, significantly different from placebo. Approximately 60% of patients had pain relief at 2 hours post dose (pain reduced to mild or no pain). There were significantly more patients on treatment than with placebo who had sustained pain relief 2 to 24 hours following the 100 mg dosage (15.4% vs 8.6% with placebo, p=0.002); however, the effect on this endpoint with the 50 mg dosage was only significantly different from placebo in one of the two studies.46,47At 2 to 8 hours post dose of ubrogepant 50 mg or 100 mg, patients were nearly twice as likely, than with placebo, to have normalized functional ability (using the Functional Disability Scale).30 Regarding the time to effect onset, based on pooled analysis of phase 3 studies, with ubrogepant 50 mg, statistically significant differentiation from placebo was achieved by 1 hour post dose for pain relief, and 1.5 hours post dose for pain freedom and MBS freedom.48 The phase 3 study with the 100 mg dosage showed significant differentiation from placebo by 1.5 hours post dose for pain

* For ubrogepant studies, exclusion criteria included clinically significant CV or cerebrovascular disease: ischemic heart disease (eg, unstable angina pectoris); cardiac rhythm or conduction abnormalities (eg, atrial fibrillation, second- or third-degree heart block) or considerable risk factors for Torsade de Pointes (eg, heart failure, hypokalemia, bradycardia); myocardial infarction, transient ischemic attack, or stroke within 6 months prior; and heart failure defined as New York Heart Association functional classification system, Class III or IV.

14 relief and MBS freedom, and 2 hours post dose for pain freedom.48

Safety

The most common side effects of oral ubrogepant were nausea (4%) and somnolence (3%), occurring in at least 2% of patients receiving the medication in phase 3 studies and greater than the occurrence in the placebo arm.2 Meta-analysis of the phase 3 studies showed that treatment-related adverse events between ubrogepant and placebo were similar.41 Similarly, phase 3 RCTs for rimegepant abortive migraine treatment showed that the safety and tolerability profile of rimegepant was similar to placebo.49 The most common adverse reaction in the pivotal study for the rimegepant ODT formulation was nausea, occurring in 2% of patients receiving the drug and higher than in the placebo arm (0.4%).3

Both rimegepant and ubrogepant are primarily metabolized by CYP3A4. Table 1 of the Appendix summarizes the dose adjustments related to concomitant medications that influence CYP3A4. Concomitant administration with strong CYP3A4 inhibitors and strong CYP3A4 inducers should be avoided with these CGRP-RAs.2,3 High-end dosing (100 mg per dose) is recommended when ubrogepant is co-administered with moderate or weak CYP3A4 inducers. Rimegepant should be avoided with moderate CYP3A4 inducers. Rimegepant and ubrogepant are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters. Concomitant use with inhibitors of P-gp and BCRP is recommended against with rimegepant and dose reduction is recommended for ubrogepant. The time frame in which a subsequent dose can be administered depends on potential drug-drug interactions.2,3 A subsequent dose of rimegepant should not be administered until 48 hours after the first dose when used in combination with a moderate CYP3A4 inhibitor. A second dose of ubrogepant must be avoided within 24 hours of the first dose when used with a moderate CYP3A4 inhibitor.2,3 Phase 1 pharmacokinetic studies showed that co-administration of ubrogepant with sumatriptan, acetaminophen, or naproxen was well tolerated with no safety concerns and no clinically relevant changes in the systemic exposure of either administered drug.50,51 Similarly, a drug interaction study of rimegepant at steady-state (75 mg daily for 5 days) with sumatriptan (12 mg, given in two doses of 6 mg one hour apart) had no clinical relevant effect on systemic exposure of either medication.52

Dose adjustments are not required for rimegepant with mild-to-severe renal impairment, or mild-to- moderate hepatic impairment.3 The safety of rimegepant ODT in patients with end-stage renal disease (ESRD), creatinine clearance (CrCL) < 15 mL/min, or on dialysis has not been studied; use is not recommended with ESRD. Severe hepatic impairment (Child–Pugh Class C) elevates exposure of rimegepant 2-fold; the medication is not recommended for use with severe hepatic impairment.3 With ubrogepant, dose adjustment to 50 mg per dose is recommended with severe renal impairment (CrCL 15 to 29 mL/min) and with severe hepatic impairment (Child-Pugh Class C).2 Ubrogepant is not recommended in ESRD.2

Table 5 summarizes the main labeled safety concerns for rimegepant (Nurtec ODT) and ubrogepant (Ubrelvy), including special population information.

Table 5. Safety Concerns for Oral CGRP Receptor Antagonists 2,3,53 Rimegepant (Nurtec ODT) Ubrogepant (Ubrelvy)

Pregnancy: There is a lack of data from Pregnancy: There is a lack of data from Special human studies to inform of potential human studies to inform of potential Populationsa developmental risk during pregnancy with developmental risk during pregnancy. In the MRHD of 75 mg/day. In animal studies rabbits with plasma exposure 8 times the with plasma exposures 45 times and 10 usual human exposure there were no adverse times the MRHD, in rats and rabbits effects on embryofetal development. The no- respectively, there were no adverse effects effect dose for adverse effects on pre- and on embryofetal development. At even postnatal development in rats was higher exposures (eg, 300 mg/kg/day in 25 mg/kg/day, or about 15 times the MRHD. rats), there were adverse outcomes. At even higher exposures, there were adverse “Published data have suggested that outcomes. women with migraine may be at increased “Published data have suggested that women risk of preeclampsia and gestational with migraine may be at increased risk of hypertension during pregnancy.” preeclampsia and gestational hypertension Lactation- it is unknown if drug is excreted during pregnancy.” into human breast milk or animal milk Lactation- it is unknown if drug is excreted Renal Impairment – avoid in end-stage into human breast milk, but drug was renal impairment (CrCL<15 mL/min); no excreted into animal milk at significant levels dose adjustment for mild to severe Renal Impairment – dose limit of 50 mg/dose impairment for severe impairment (CrCL 15 to 29 Hepatic Impairment- avoid with severe mL/min). Has not been studied in end-stage impairment (Child-Pugh C); no dose renal impairment (CrCL<15 mL/min); no dose adjustment for mild or moderate adjustment for mild or moderate impairment impairment Hepatic Impairment- dose limits of 50 mg/dose with severe impairment (Child-Pugh C); no dose adjustment for mild or moderate impairment

Contraindications

• Rimegepant: contraindicated in patients with a hypersensitivity to the active drug or Warnings any components of the product • Ubrogepant: concomitant use of strong CYP3A4 inhibitor is contraindicated Hypersensitivity reactions were reported in clinical trials with rimegepant, with symptoms of dyspnea and rash. Serious hypersensitivity reactions can be delayed, occurring days after administration of rimegepant

Drug Interactions • Both agents should be avoided with strong inducers or strong inhibitors of CYP3A4 • Additionally, with rimegepant o Avoid concomitant use of moderate or strong CYP3A4 inducers, or with inhibitors of BCRP and P-gp transporters o Avoid taking a second dose within 48 hours of the first dose, if using a moderate CYP3A4 inhibitor concomitantly • Additionally, with ubrogepant o 50 mg per dosage is the maximum dosage for the first or second dose if used concomitantly with weak CYP3A4 inhibitor, or with inhibitors of BCRP and/or P-gp only.

Table 5. Safety Concerns for Oral CGRP Receptor Antagonists 2,3,53 o With moderate CYP3A4 inhibitors, 50 mg per 24 hours is the maximum dosage o 100 mg per dose is to be used with a concomitant weak or moderate CYP3A4 inducer § BCRP transport inhibitors: curcumin, cyclosporine A, eltrombopag § P-gp transport inhibitors: amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil § CYP3A4: o Strong inhibitors: certain azole antifungals such as ketoconazole, protease inhibitors, clarithromycin o Moderate inhibitors: verapamil, diltiazem, fluconazole, ciprofloxacin, fluvoxamine, grapefruit juice o Weak inhibitors: chlorzoxazone, clotrimazole, ivacaftor, ranitidine, ranolazine, ticagrelor o Strong inducers: rifampin, carbamazepine, phenytoin o Moderate inducers: bosentan, efavirenz, etravirine, phenobarbital, primidone o Weak inducers: armodafinil, modafinil, rufinamide Abbreviations: BCRP, breast cancer resistance protein; CrCL, creatinine clearance; CYP, cytochrome P450 enzyme; ODT, orally disintegrating tablet; P-gp, P-glycoprotein

Cardiovascular-Related Information

Since endogenous CGRP is involved in vasodilation during ischemia, there was concern for potential cardiovascular (CV) adverse outcomes during the development of CGRP antagonists.31,32,54 However, no CV safety signals were detected during the clinical reviews of these medications based on pivotal clinical studies and long-term follow-up data (out to 1 year) submitted for drug approval. Clinical trials excluded patients with clinically significant cardiovascular or cerebrovascular disease†.55,56 While the FDA did not require further cardiovascular safety investigations beyond the data provided, the respective pharmaceutical companies are required to perform post-marketing surveillance focused on tracking stroke or myocardial infarction events. Other CGRP antagonists approved for migraine prevention— where the patient is under continuous medication exposure and CGRP antagonism— are also not known to be associated with increased CV risk thus far.57

Regarding ubrogepant, the phase 3 trials included patients with cardiovascular risk (11% [n=311] with moderate to high risk [10-20% 10 year CV risk, Framingham]; and 32% [n=920] with low CV-risk [<10%

† For ubrogepant studies, exclusion criteria included clinically significant CV or cerebrovascular disease: ischemic heart disease (eg, unstable angina pectoris); cardiac rhythm or conduction abnormalities (eg, atrial fibrillation, second- or third-degree heart block) or considerable risk factors for Torsade de Pointes (eg, heart failure, hypokalemia, bradycardia); myocardial infarction, transient ischemic attack, or stroke within 6 months prior; and heart failure defined as New York Heart Association functional classification system, Class III or IV. For rimegepant studies, excluded patients were with history of uncontrolled, unstable, or recently diagnosed cardiovascular disease including ischemic heart disease, coronary artery disease, cerebral ischemia; and patients with a history of myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, cardiac surgery, stroke, or transient ischemic attack during the 6 months prior to screening.

10 year risk, Framingham]).46,48 The safety profile (eg, serious adverse events) among the group with high CV-risk was comparable to those with low or no CV-risk. There were no treatment-related serious cardiovascular adverse events in the trials.48 The FDA Summary Review for Ubrelvy describes in vitro studies using human coronary, meningeal, and cerebral arteries where CGPR-induced vasodilation was inhibited by ubrogepant without inducing vasoconstriction.57 Additionally, there were no significant changes from baseline in the mean heart rate or electrocardiogram parameters (eg, QTc, QRS, PR intervals) in treated patients of controlled trials.57

This was also true for rimegepant, with no clinically significant changes from baseline in heart rate or electrocardiogram parameters with the marketed dosage during controlled trials.58 Based on pooled clinical data from phase 3 studies with rimegepant (as the ODT and traditional tablet formulations) there were no treatment-related CV adverse events.59 In monkeys exposed to supratherapeutic doses of rimegepant, (10 or 20 times the therapeutic exposure in humans), there were no effects on hemodynamic or electrocardiographic parameters.28 While triptans were not allowed until after 48 hours of rimegepant in the clinical trial, the labeling describes that in a study assessing effects of sumatriptan 12 mg administered 1 hour after rimegepant (to mimic a rescue dose) there were no clinically relevant differences in resting blood pressure compared to taking sumatriptan alone.3

Concomitant Use with CRRP-RA Preventive Therapies

There is limited data from case reports regarding the safety and efficacy of concomitant use of CGRP antagonists for acute treatment and anti-CGRP monoclonal antibodies for preventive treatment of migraine. There are two published case reports derived from the long-term safety extension trial for rimegepant (NCT03266588).60 In both instances, patients initiated erenumab following its approval in 2018. Each patient experienced a reduction in monthly migraine headache days (46% and 59% decrease with patient 1 and 2, respectively) with erenumab preventive therapy. Residual migraines were relieved with rimegepant with no reported adverse effects related to concomitant use.60 Additionally, there is a phase 1 study expected to be published soon that assessed the safety, tolerability, and whether there is any pharmacokinetic interaction when ubrogepant is co-administered with preventive CRGP antagonists, erenumab and galcanezumab.61

Prior Authorization Considerations

• Patients should be 18 years of age or older based on the approved indication for these therapies. • Consider diagnosis of migraine accompanied with moderate-to-severe pain intensity. o Patients included in pivotal studies for the approvals of rimegepant and ubrogepant had a migraine diagnosis consistent with the International Classification of Headache Disorders-3rd edition (ICHD-3), developed by the International Headache Society.43,47 o In clinical trials, patients were instructed to treat moderate-to-severe migraine attacks.43,47 • Consider step therapy with trial and failure (or contraindication) to 2 triptans as suggested by the American Headache Society’s 2019 Position Statement12 o The panel proposed consideration for rimegepant or ubrogepant for patients with a contraindication to triptans, or with inadequate response or intolerance to at least 2 oral triptans according to the provider’s attestation or by considering response history using validated patient-reported outcome questionnaires (eg, mTOQ, Migraine-ACT, PPMQ-R, FIS, PGIC). o When considering continuation of a CGRP-abortive treatment, the panel advised that response and tolerability be considered after the patient treats at least 2 migraine episodes. Additionally, “Continuation of coverage should be based on the frequency of migraine attacks in an average month and response to a validated acute treatment patient-reported outcome questionnaire or clinical assessment of improvement by the healthcare provider.”12 • Quantity limits can be considered based on the number of doses studied per migraine episode (or 24-hr period) and description in labeling of unclear efficacy/safety beyond treating so many migraines per month o For ubrogepant, studies were conducted allowing for a second dose 2 hours after the initial dose if needed. The efficacy/safety is unclear for treating more than 8 migraines per 30 days.2,62 § Ubrogepant: 2 doses max per migraine X 8 migraines/30 days => 16 doses max/30 days (ie, 16 units of the 50 mg tabs OR 16 units of the 100 mg tabs per 30 days) o For rimegepant, the efficacy/safety of only a single dose per migraine was studied in the phase 3 trials. The efficacy/safety is unclear for treating more than 15 migraines per 30 days.3 § Rimegepant: 1 dose max per migraine X 15 migraines/30 days => 15 doses max/30 days (ie, 15 units of 75 mg ODT per 30 days) o Quantity limits may need adjustment in the future if label extension is granted. Rimegepant is being studied as ongoing dosing, 75 mg every other day, for migraine prevention plus supplemental dosing as needed for residual migraines.63

Potential Educational Notes

• Reevaluate therapy and dosages whenever weak to strong CYP3A4 inducers/inhibitors, or BCRP and/or P-gp inhibitors are initiated or discontinued. Severe hepatic impairment or severe renal impairment require either dose adjustment or may preclude use (see prescribing information).

• The patient should be warned of potential hypersensitivity reaction with rimegepant, as serious events have been reported with manifestations of dyspnea and rash; hypersensitivity reaction may present days after administration.2

Existing Prior Authorization Criteria for CGRP Antagonists

The current PA document addresses both preventive and acute CGRP antagonists for the treatment of migraine (last updated 3/31/2020). Open bullet points in this section delineate potential areas for modification of the current PA criteria.

For acute CGRP-RAs, the current PA requires that patients must be 18 years or older with diagnosis of migraine according to the criteria set forth from the International Headache Guidelines. Patients must have a trial and failure of at least 1 preferred agent (ie, with preferred status on the PDL) from 2 of the 3 following drug classes: triptans, NSAIDs, and APAP. Documentation is required for the dates of use and details of treatment failure. o Consider adding contraindication as exception to trial and failure of the designated agents o Consider maintaining trial of at least 2 of the 3 listed drug classes, but may consider adding a specification regarding the triptan class, to try at least 2 different triptans § The AHS 2016 guidance document describes that if a particular triptan fails, other triptans should be tried since there is variable response among patients between acute agents.13 § The 2019 AHS guidance describes step therapy through inadequate response, intolerance, or contraindication to at least 2 oral triptans, according to the provider’s attestation or by considering response history with validated questionnaires.

Re-authorization submission is required at 6 months following initial authorization, then yearly thereafter, with documentation of improved headache severity at each re-authorization submission.

In the notes section of the PA document, the following restrictions are described: concomitant use of two CGRP antagonists (one for acute treatment [eg, rimegepant or ubrogepant] and one for prevention [eptinezumab, erenumab, fremanezumab, or galcanezumab]) is not permitted; also, concomitant use of a CGRP antagonist (unspecified) with botulinum toxin A is not permitted.

o Consider specifying that the note pertaining to botulinum toxin A applies to concomitant use of migraine preventive CGRP antagonists, since the abortive CGRP antagonists may be combined with botulinum toxin A. § In the clinical trials with ubrogepant and rimegepant, patients were allowed to take preventive therapies.30,43,46,62 OnabotulinumtoxinA was among those described particularly in study with ubrogepant. Authors of the rimegepant ODT pivotal study did not specify the particular preventive therapy drug classes used as background therapy, other than stating that preventive therapies were allowed. Patients who had a past diagnosis of chronic migraine could enter these studies as long as they had fewer than 15 monthly headache days on average, modified by preventive medication.30,43,46,62 There is no labeled restriction for combined use with these new acute CGRP antagonists and onabotulinumtoxinA, perhaps since there was no particular safety signal identified during the FDA clinical review.2,3 Ubrogepant and rimegepant are approved for the abortive treatment of migraine headache regardless of the patient’s diagnosis

history of chronic migraine or episodic migraine.2,3 The approved migraine preventive options with demonstrated efficacy specifically in the chronic migraine population include only OBTA, CGRP antagonists (eptinezumab, erenumab, fremanezumab, or galcanezumab), and topiramate.

Summary

Rimegepant and ubrogepant are two newly approved CGRP antagonists for the treatment of migraine, which are to be used intermittently as abortive therapy. They are not yet approved for the prevention of migraine; however, rimegepant is being studied for preventive therapy as there have been several other CGRP antagonists that have proven benefit for reducing migraine headache days per month when patients are under constant exposure to CGRP antagonism.

Rimegepant and ubrogepant serve as additional treatment options when patients experience intolerability, contraindication, insufficient relief, or development of medication overuse headache that are at times issues and unmet needs when using traditional migraine abortive agents (triptans and analgesics). Patients were allowed to take migraine preventive medications in the clinical trials of rimegepant and ubrogepant; however, no patients were on preventive CGRP antagonists since these preventive agents were not yet approved or marketed when the pivotal clinical studies for rimegepant and ubrogepant began. Prescribing information labeling for rimegepant and ubrogepant does not advise against or preclude concomitant use with any particular agent that is effective for preventing episodic migraine (eg, divalproex, eptinezumab, erenumab, fremanezumab, galcanezumab, metoprolol, propranolol, timolol, topiramate, etc.) or agents effective for preventing chronic migraine (eg, eptinezumab, erenumab, fremanezumab, galcanezumab, onabotulinumtoxinA, and topiramate).

While studies with rimegepant and ubrogepant excluded patients with significant cardiovascular disease (see footnote of page 17), a subgroup of patients (n=311) in the phase 3 studies for ubrogepant had moderate to high cardiovascular risk. The safety profile among the group with high CV-risk was comparable to those with low or no CV-risk and there were no treatment-related serious cardiovascular adverse events in the trials.48 There has not yet been a signal for negative cardiovascular effect by these acute agents or by the migraine preventive CGRP antagonists used for continuous exposure. Until a clear signal emerges, for patients with CV-risk factors, CGRP antagonists may be preferable to some traditional acute therapies, as the AHS has described, “Unlike triptans and ergotamine derivatives, these novel treatment options [CGRP antagonists and lasmiditan] do not result in constriction of blood vessels and may have a special role in patients with cardiovascular contraindications to triptans.”12 Pharmacovigilance monitoring for major cardiovascular events will be carried out by pharmaceutical manufacturers of Nurtec ODT and Ubrelvy in case a signal manifests with use in the larger population.

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Appendix

OvidMedline Literature Search § (rimegepant or ubrogepant).ti,ab,kw,kf. => results 55 on May 6th 2020

Epistemonikos Literature Search § (title:(ubrogepant OR rimegepant) OR abstract:(ubrogepant OR rimegepant)) => 4 results § (title:((CGRP OR (calcitonin gene-related peptide)) AND ((acute treatment) OR (acute migraine) OR abort*)) OR abstract:((CGRP OR (calcitonin gene-related peptide)) AND ((acute treatment) OR (acute migraine) OR abort*))) => 21 results on May 6th

Table 1. Dose Adjustments with Enzyme or Transport Inhibitors/Inducers Ubrogepant1 Rimegepant2 50 mg or 100 mg (with or without food); a second dose may be taken at least 2 hours Usual Dosing 75 mg/ 24 hours after the initial dose if needed. (max 200 mg/24 hours). Weak CYP3A4 Initial dose: 100 mg No change Inducers Second dose: 100 mg

Moderate Initial dose: 100 mg Avoid use CYP3A4 Inducers Second dose: 100 mg

Strong CYP3A4 Avoid use Avoid use Inducers

Weak CYP3A4 Initial dose: 50 mg No change Inhibitors Second dose: 50 mg

Moderate Initial dose: 50 mg Avoid a second dose of 75 mg within a 48 CYP3A4 Second dose: Avoid within 24 hours hours of the initial dose Inhibitors

Strong CYP3A4 Contraindicated Avoid use Inhibitors

BCRP or P- Initial dose: 50 mg Glycoprotein Avoid use Second dose: 50 mg Inhibitors