Utah Medicaid Pharmacy and Therapeutics Committee Drug

Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Agents for the Acute Treatment of Migraine

Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists Ubrogepant Rimegepant

Selective Serotonin Agonists Almotriptan Eletriptan Frovatriptan Lasmiditan Naratriptan Rizatriptan Sumatriptan Zolmitriptan

Other Miscellaneous and Combinations Ergot derivatives: dihydroergotamine, ergotamine Nonsteroidal anti-inflammatory drugs: diclofenac potassium, celecoxib Opioids: butorphanol Combinations: butalbital combinations, ergotamine/caffeine, sumatriptan/naproxen

Report finalized in May 2020 Report presented in June 2020

Review prepared by: Elena Martinez Alonso, B.Pharm., Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Jeffrey Sperry, Pharm.D. Candidate Yen Ngoc Ma, Pharm.D. Candidate Joanne LaFleur, Pharm.D., MSPH, Associate Professor

University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2020 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved Contents Executive Summary ...... 3 Introduction ...... 7 Table 1. Comparison Table for FDA-Approved Agents for the Acute Treatment of Migraine and Other Types of Primary Headache Disorders ...... 8 Methods ...... 11 Disease Overview ...... 12 Table 2. Diagnostic Criteria for Migraine from the International Classification of Headache Disorders, 3rd Edition ...... 13 Pharmacotherapy and Clinical Practice Guideline Recommendations ...... 14 Table 3. Acute Migraine Treatment Options in Adults ...... 16 Table 4. Clinical Practice Guidelines for the Acute Treatment of Migraine ...... 18 Table 5. Clinical Practice Guidelines for the Treatment of Cluster Headache ...... 20 Table 6. Clinical Practice Guidelines for the Treatment of Tension-type Headache ...... 20 Pharmacology ...... 21 Table 7. Mechanism of Action of Agents for the Acute Treatment of Migraine ...... 22 Table 8. Pharmacokinetics of Agents for the Acute Treatment of Migraine ...... 23 Special Populations ...... 25 Table 9. Special Population Considerations of Selective Serotonin Agonists ...... 26 Table 10. Special Population Considerations of Ergot Derivatives, CGRP Receptor Antagonists, and NSAIDs ...... 27 Table 11. Special Population Considerations of Butorphanol and Butalbital Combinations ...... 28 Direct Comparative Evidence...... 29 Figure 1. PRISMA Flow Chart for Publication Screening ...... 29 Table 12. Randomized Controlled Trials of Lasmiditan, Rimegepant, and Ubrogepant Compared to Placebo ...... 32 Table 13. Randomized Controlled Trials of Celecoxib Oral Solution Compared to Placebo ...... 34 Safety ...... 40 Table 14. Warnings and Precautions for Triptans and Lasmiditan ...... 44 Table 15. Warnings and Precautions for Ergot Derivatives ...... 46 Table 16. Warnings and Precautions for Nonsteroidal Anti-inflammatory Drugs ...... 46 Summary ...... 47 References ...... 49 Appendix A – Additional Product Information...... 56 Appendix B – Literature Search Strategies ...... 68 Appendix C – Included and Excluded References ...... 74 Appendix D – Evidence Tables ...... 77

Executive Summary Introduction: Migraine is a common primary headache disorder with a prevalence of 16% in American adults. It is characterized by intermittent attacks, typically of pulsating unilateral headache associated with photophobia, phonophobia, nausea, vomiting, and occasionally auras. This report will review agents for the acute treatment of migraine. Recently approved agents include lasmiditan, a highly selective serotonin (5-HT)1F receptor agonist; rimegepant and ubrogepant, 2 calcitonin gene-related peptide (CGRP) receptor antagonists; and celecoxib oral solution, a nonsteroidal anti-inflammatory drug (NSAID). Older agents include the 5-HT1B and 5-HT1D receptor agonists or ‘triptans’, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan; ergot derivatives, dihydroergotamine (DHE) and ergotamine; the opioid, butorphanol; the oral NSAID solution, diclofenac potassium; and combination products (butalbital combinations, sumatriptan/naproxen, and ergotamine/caffeine). Formulations include tablets, capsules, orally disintegrating tablets (ODT), oral solutions, nasal spray, rectal suppositories, and injections (subcutaneous [SQ], intramuscular, or intravenous), which are product specific. Agents approved by the U.S. Food and Drug Administration (FDA) for the acute treatment of migraine include triptans, sumatriptan/naproxen, lasmiditan, rimegepant, ubrogepant, diclofenac potassium and celecoxib oral solutions, DHE, ergotamine, and ergotamine/caffeine. Use of nasal butorphanol for migraine-related pain is within the scope of its broad indication regarding pain, as its efficacy for migraine is described in the labeling. All are labeled for use in the adult population, except DHE, ergotamine, and butorphanol that do not specify the population. In the pediatric population, almotriptan tablets, zolmitriptan nasal spray, and sumatriptan/naproxen tablets are labeled for use in pediatric patients 12 years and older; rizatriptan tablets and ODT are labeled for use in pediatric patients 6 years and older. Butalbital-containing products do not have a migraine-specific indication but can be used off-label for the treatment of migraine since there is some evidence supporting their use. Pharmacologic treatment strategies for the management of migraine include acute therapies to rapidly halt symptoms, and preventive therapies to decrease the frequency of migraine episodes. The 2019 American Headache Society (AHS) position statement recommends non-opioid analgesics (eg, NSAIDs, acetaminophen [APAP], and caffeinated analgesic combinations) for acute treatment of mild to moderate migraine attacks. Migraine-specific agents (triptans or dihydroergotamine) are recommended for moderate to severe migraine attacks and mild to moderate attacks that respond inadequately to non-opioid analgesics. Triptans are usually preferred over DHE. However, some patients may experience inadequate response or adverse events, or have contraindications to these traditional acute therapies (eg, triptans and ergot derivatives are contraindicated in patients with cardiovascular diseases due to their vasoconstrictive properties). As the novel agents lasmiditan, rimegepant, and ubrogepant do not induce vasoconstriction, the AHS suggests their use when triptans are contraindicated or when at least 2 oral triptans are ineffective or not tolerated. Non-specific analgesic medications such as barbiturates (butalbital), opioids (butorphanol), and APAP with codeine or tramadol are generally not recommended for regular use in migraine patients due to their potential risk for dependence and addiction, and occurrence of medication overuse headache. They are usually reserved as a “back-up plan” for patients who do not respond or have contraindications to the initial acute treatment. The 2019 American Academy of Neurology (AAN) guideline for acute treatment of migraine in pediatric patients recommends ibuprofen oral solution as initial therapy in children and adolescents. For

adolescents, several other medications including sumatriptan/naproxen oral tablets, sumatriptan nasal spray, zolmitriptan nasal spray, rizatriptan ODT, or almotriptan oral tablets have evidence supporting their use in reducing migraine pain and should be offered in this population. The aim of this report is to provide head-to-head efficacy and safety comparisons among the acute treatments of migraine from systematic reviews (SRs) and randomized controlled trials (RCTs). Comparative Efficacy Evidence: Nine SRs and 1 additional RCT were identified following a systematic search in Ovid MEDLINE and Embase for direct head-to-head comparisons. Listed below is a summary of key findings: Comparative Evidence for Lasmiditan, Rimegepant, and Ubrogepant No clinical trial to date has directly compared lasmiditan, ubrogepant, or rimegepant versus each other or versus other acute treatments of migraine. Clinical trials with ubrogepant, rimegepant, and lasmiditan showed efficacy of these agents compared to placebo for the acute treatment of migraine. Comparative Evidence for Triptans and Triptan Combinations Head-to-head RCTs are not available for all possible triptan comparisons. The majority of identified RCTs compared oral sumatriptan with other triptans (mostly as oral tablet formulations). Evidence suggests that most triptans perform similarly in terms of efficacy and safety with some exceptions. Eletriptan and rizatriptan tablets were significantly better than other oral triptans (eg, sumatriptan, zolmitriptan, and naratriptan) in providing headache relief or achieving pain freedom in patients with migraine. Naratriptan tablets performed more poorly than other triptans regarding pain relief. Sumatriptan/naproxen was significantly more efficacious than sumatriptan monotherapy regarding pain freedom and pain relief at 2 hours after treatment. Sumatriptan 22 mg nasal powder (Onzetra) produced an earlier onset of migraine efficacy compared with oral sumatriptan 100 mg; however, pain relief or pain freedom at 2 hours and sustained pain relief or pain freedom from 2 hours to 48 hours were comparable between treatment groups. Comparative Evidence for Ergot Derivatives Comparative trials, rated as poor quality, suggest that sumatriptan (intranasal or SQ) was significantly better or similar to DHE (intranasal or SQ) at relieving headache pain within 1 or 2 hours. Oral sumatriptan, eletriptan, and almotriptan were more efficacious than ergotamine/caffeine with respect to headache relief and pain freedom at 2 hours after treatment. Comparative Evidence for NSAIDs There was no direct-comparative information for the oral NSAID solutions, diclofenac potassium (Cambia) or celecoxib (Elyxyb) versus each other or other acute treatments of migraine. Pharmacokinetic studies comparing the oral solutions with the capsule or tablet counterpart showed a more rapid absorption and shorter time to peak plasma concentration with the oral solutions. Diclofenac potassium oral solution also appeared to outperform the tablet in terms of migraine-related pain freedom at 2 hours after treatment in 1 RCT. An RCT comparing oral sumatriptan 100 mg with diclofenac potassium (oral tablets) showed no significant differences for the primary endpoint of headache pain relief at 2 hours post dose.

Comparative Evidence for Butorphanol or Butalbital-Containing Products An RCT demonstrated butorphanol nasal spray was more efficacious than butalbital/caffeine/aspirin/ codeine (Fiorinal with codeine) at reducing pain intensity at 2 hours post dose in adults with migraine. Another RCT compared sumatriptan/naproxen vs. butalbital/APAP/caffeine in patients with moderate to severe migraine attacks. There were no differences for the primary efficacy endpoint of sustained pain freedom from 2 to 24 hours, but significant differences for most secondary endpoints (eg, pain-free, pain relief, and associated symptoms) in favor of sumatriptan/naproxen. Adverse Drug Reactions: CGRP-receptor antagonists appear to be well tolerated and do not carry any black box warning. Rimegepant can cause hypersensitivity reactions (eg, dyspnea and rash) and prescribing information for ubrogepant does not specify any warnings aside from a contraindication with concomitant use of strong cytochrome P450 (CYP)3A4 inhibitors. Lasmiditan is a schedule V controlled substance and prescribing information warns about the potential for development of medication overuse headache, risk of serotonin syndrome, central nervous system (CNS) depression such as dizziness and sedation, and driving impairment. Unlike triptans and ergot derivatives (that are contraindicated in patients with cardiovascular disease), lasmiditan, rimegepant, and ubrogepant are not known to be associated with cardiovascular adverse events since 5-HT1F stimulation or CGRP receptor inhibition do not induce vasoconstriction. Similar to other NSAIDs, celecoxib and diclofenac potassium oral solutions carry a black box warning regarding the risk of serious cardiovascular and gastrointestinal events. Opioids and butalbital combinations are associated with risk of dependence and abuse. Overuse of traditional acute migraine agents (eg, ergotamine, triptans, opioids, NSAIDs, or combination or these agents), celecoxib oral solution, and lasmiditan may lead to medication overuse headache and development of chronic migraine. Rimegepant and ubrogepant have not been associated with medication overuse headache. Rimegepant is being studied for prevention of migraine as other CGRP antagonists have been approved for reducing migraine frequency. Summary: No direct evidence was identified for the new acute, migraine-specific treatments (lasmiditan, rimegepant, ubrogepant, and celecoxib oral solution) versus each other or versus other acute treatments of migraine. There are limited head-to-head comparisons among the traditional acute treatments for migraine (eg, triptans, ergot derivatives, and NSAIDs). Regarding triptans, direct evidence suggests that eletriptan and rizatriptan perform better than other oral triptans (eg, sumatriptan, zolmitriptan, and naratriptan) regarding headache relief or pain freedom in patients with migraine. There are similarities in efficacy between oral sumatriptan and other oral triptans (zolmitriptan, almotriptan, and naratriptan). Clinical practice guidelines by the AHS do not state a preference for 1 triptan over another; however, the AHS states that non-oral formulations (eg, subcutaneous injection, nasal spray) and agents available as orally disintegrating or rapid melting tablets should be offered for patients with migraine accompanied by severe nausea or vomiting, for patients who have swallowing difficulties, and for patients with inadequate response to traditional oral formulations. Comparative trials with ergot derivatives suggest that sumatriptan (intranasal or SQ) has comparable or better efficacy with respect to headache relief compared to DHE (intranasal or SQ); oral triptans (sumatriptan, eletriptan, and almotriptan) are more efficacious than ergotamine/caffeine at relieving pain or achieving pain freedom in patients with migraine. Triptans are usually preferred over DHE in clinical practice. The AHS considers that ubrogepant, rimegepant, and lasmiditan should be offered when triptans are 5

contraindicated or when at least 2 oral triptans are inadequately effective or not tolerated, as a cost- effective approach. Prior authorization criteria are currently in place for the 2 CGRP-receptor antagonists requiring failure of at least 1 preferred agent from 2 or 3 drug classes (triptans, NSAIDs, APAP) before accessing a CGRP-receptor antagonist. Initial selection of migraine therapy should be individualized based on patient preference; the frequency and intensity of attacks; the profile of associated symptoms; disability; considerations regarding pregnancy, lactation, or plans to conceive; response to previous treatments; comorbidities; contraindications such as cardiovascular disease; other factors such as blood pressure and heart rate; and concurrent medications. The Utah Medicaid Preferred Drug List (PDL) currently includes 3 triptans (Relpax [eletriptan tablets], generic rizatriptan [tablets and ODT], and generic sumatriptan tablet) and 1 CGRP-receptor antagonist (Nurtec [rimegepant]) as preferred under the Migraine Agents, Abortive Therapy category. Several oral NSAIDs (eg, generic diclofenac potassium, ibuprofen, and naproxen tablet, and Zipsor [diclofenac potassium capsule]) are listed as preferred on the PDL under the NSAID category. Among Medicaid fee-for-service (FFS) pharmacy claims data, from January 2018 through April 2020, 2305 unique patients utilized a PDL-listed abortive migraine agent; 161 were pediatric patients (< 18 years of age). In the overall population, the most highly utilized agents in order of frequency during this period were sumatriptan tablets (utilized by more than 70% of patients), rizatriptan (oral tablets and ODT), the combination butalbital/APAP/caffeine, and Relpax (eletriptan tablets). In the pediatric population, the most highly utilized agents were sumatriptan tablets and rizatriptan (oral tablets and ODT). Regarding preference of acute treatments for migraine in the Utah Medicaid PDL, the P&T Committee may consider the following recommendations: - Consider at least 2 triptans as preferred agents, with at least 1 of them being a non-traditional oral formulation (eg, ODT) or a non-oral formulation (eg, intranasal or injectable formulation) that can be administered in the event of nausea/vomiting or with swallowing difficulty. - Consider butalbital-containing products and butorphanol as non-preferred products since the AHS highlights that these products are generally not recommended for regular use in patients with migraine due to the availability of more effective migraine-specific agents and the risk of dependence, abuse, and medication overuse headache. Additionally, the P&T Committee may wish to discuss the following points: - Potential inclusion of at least 1 CGRP-receptor antagonist (rimegepant or ubrogepant) as preferred in the PDL. CGRP-receptor antagonists can be used in some populations with contraindications to triptans and they appear to have fewer safety concerns than lasmiditan. Prior authorization is required for rimegepant and ubrogepant. - Allowance of pediatric patients to receive a triptan formulation recommended by the American Academy of Neurology for this population if they have previously failed or have contraindication to ibuprofen oral solution.

Introduction The scope of this review encompasses the agents for the acute treatment of migraine. These include serotonin (5-HT)1B and 5-HT1D receptor agonists or ‘triptans’ (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan); 5-HT1F receptor agonists or ‘ditans’ (lasmiditan); calcitonin gene-related peptide (CGRP) receptor antagonists or ‘gepants’ (rimegepant and ubrogepant); ergot derivatives (dihydroergotamine [DHE] and ergotamine); 2 nonsteroidal anti-inflammatory drugs (NSAIDs; diclofenac potassium and celecoxib oral solutions); opioids (butorphanol); and combination products (butalbital combinations, sumatriptan/naproxen, and ergotamine/caffeine). Agents are available as tablets, capsules, orally disintegrating tablets (ODT), oral solutions, nasal spray, rectal suppositories, and injections (subcutaneous [SQ], intramuscular, or intravenous).1-34 Triptans, sumatriptan/naproxen, lasmiditan, rimegepant, ubrogepant, diclofenac potassium and celecoxib oral solutions, DHE, ergotamine, and ergotamine/caffeine are approved by the U.S. Food and Drug Administration (FDA) for the acute treatment of migraine. Use of nasal butorphanol for migraine- related pain is within the scope of its broad indication regarding pain, as its efficacy for migraine is described in the labeling. Agents are labeled for use in the adult population, except DHE, ergotamine, and butorphanol that do not specify the population. Four triptan-containing products are additionally approved for the pediatric population (almotriptan, zolmitriptan nasal spray, and the combination product sumatriptan/naproxen are labeled for use in pediatric patients 12 years and older; rizatriptan is labeled for use in pediatric patients 6 years and older). Butalbital-containing products do not have a migraine-specific indication but can be used off-label for the treatment of migraine since there is some evidence supporting their use. Injectable formulations of sumatriptan and DHE are additionally approved for the acute treatment of cluster headache.1-34 Rimegepant is currently being studied for migraine prevention, with preliminary positive results in a recently completed phase 2/3 study.35 Table 1 summarizes the disease states and age groups for which the agents included in this report are approved. Appendix A includes complete information regarding the available drug formulations, labeled indications, dosage recommendations, and special population considerations for these agents. The research objective of this report is to determine whether there are key efficacy or safety differences between the available agents indicated for the acute treatment of migraine listed in Table 1. The Utah Medicaid Preferred Drug List (PDL), published in June 2020, groups these products under the category, Migraine Agents, Abortive Therapy. Preferred products include 3 triptans (Relpax [eletriptan tablet], generic rizatriptan [tablet and ODT], and generic sumatriptan tablet) and 1 CGRP-receptor antagonist (Nurtec [rimegepant]). The remaining agents included in Table 1 are listed as non-preferred abortive migraine agents in the PDL, except Elyxyb (celecoxib oral solution) that is not included in the PDL yet due to its recent approval in May 2020. Quantity limits apply for all triptans, butalbital-containing products, butorphanol, and diclofenac oral solution (Cambia). The novel products Nurtec ODT (rimegepant), Ubrelvy (ubrogepant), and Reyvow (lasmiditan) require prior authorization. Regarding the Medicaid fee-for-service (FFS) pharmacy data for January 2018 through April 2020, utilization in the overall population was highest for generic sumatriptan (tablets), followed by generic rizatriptan (tablets and ODT), the combination butalbital/APAP/caffeine, and then Relpax (eletriptan tablets). Novel agents were approved in 2019 and 2020. Utilization was very low for ubrogepant and there was no utilization for lasmiditan, rimegepant, or celecoxib oral solution. In the pediatric population, the most highly utilized agents were generic sumatriptan (tablets) and rizatriptan (tablets and ODT). 7

Table 1. Comparison Table for FDA-Approved Agents for the Acute Treatment of Migraine and Other Types of Primary Headache Disorders Treatment of Treatment of pain Treatment or tension headache severe enough to Generic Name prevention of vascular Acute treatment of Acute treatment Treatment when other non- require an opioid Preparations headache (eg, migraine, migraine with or of cluster of tension opioid analgesics analgesic and for (Brand Name, if Available on the migraine variants, or so- without aura headache headache and alternative which alternative Market) called "histaminic treatments are treatments are cephalalgia”) inadequate inadequate Selective Serotonin Receptor Agonists 1 X (adults and pediatric Almotriptan tablets patients 12-17 y) Eletriptan tablets2 (Relpax) X (adults) Frovatriptan tablets3 (Frova) X (adults) Lasmiditan tablets5 (Reyvow) X (adults) Naratriptan tablets6 (Amerge) X (adults)

4 Rizatriptan tablets and ODT X (adults and pediatric

(Maxalt and Maxalt-MLT) patients 6-17 y) Sumatriptan tablets, nasal 28-30 X (adults; ONLY spray, SQ injection X (adults) (Imitrex) for SQ injection) Sumatriptan nasal powder (Onzetra Xsail)31 X (adults) Sumatriptan nasal spray (Tosymra)32 X (adults) Sumatriptan SQ injection (Zembrace SymTouch)33 X (adults) Zolmitriptan tablets and ODT17,18 X (adults) (Zomig, Zomig-ZMT)

Table 1. Comparison Table for FDA-Approved Agents for the Acute Treatment of Migraine and Other Types of Primary Headache Disorders Treatment of Treatment of pain Treatment or tension headache severe enough to Generic Name prevention of vascular Acute treatment of Acute treatment Treatment when other non- require an opioid Preparations headache (eg, migraine, migraine with or of cluster of tension opioid analgesics analgesic and for (Brand Name, if Available on the migraine variants, or so- without aura headache headache and alternative which alternative Market) called "histaminic treatments are treatments are cephalalgia”) inadequate inadequate 17 Zolmitriptan nasal spray X (adults and pediatric

(Zomig) patients ≥ 12 y) CGRP Receptor Antagonist Ubrogepant tablets7 (Ubrelvy) X (adults)

Rimegepant ODT8 (Nurtec ODT) X (adults) Ergot Derivatives Dihydroergotamine mesylate 14 X (population X (population injectable (IV, IM, SQ) (D.H.E. 45) unspecified) unspecified) Dihydroergotamine mesylate 15 X (population nasal spray (Migranal) unspecified)

9 Ergotamine SL tablets X (population

(Ergomar) unspecified) NSAIDs

Celecoxib oral solution34 (Elyxyb) X (adults)

Diclofenac powder for oral 10 solution X (adults) (Cambia)

Table 1. Comparison Table for FDA-Approved Agents for the Acute Treatment of Migraine and Other Types of Primary Headache Disorders Treatment of Treatment of pain Treatment or tension headache severe enough to Generic Name prevention of vascular Acute treatment of Acute treatment Treatment when other non- require an opioid Preparations headache (eg, migraine, migraine with or of cluster of tension opioid analgesics analgesic and for (Brand Name, if Available on the migraine variants, or so- without aura headache headache and alternative which alternative Market) called "histaminic treatments are treatments are cephalalgia”) inadequate inadequate Other Miscellaneous and Combinations Butalbital/APAP tablets and X 19,20 capsules (population (Allzital, Butapap) unspecified) Butalbital/APAP/caffeine X 21- tablets, capsules, oral solution (population 23 unspecified) Butalbital/APAP/ 24 X (population caffeine/codeine capsules (Fioricet with codeine) unspecified)

Butalbital/aspirin/ caffeine X 25,27 capsules and tablets (population (Fiorinal) unspecified) Butalbital/aspirin/ 26 X (population caffeine/codeine capsules (Fiorinal with codeine) unspecified)

13 X (population Butorphanol nasal spray unspecified) Ergotamine/caffeine tablets 11,12 and rectal suppositories X (adults) (Cafergot, Migergot)

16 Sumatriptan/naproxen tablets X (adults and pediatric

(Treximet) patients ≥ 12 y) Abbreviations: APAP, acetaminophen; CGRP, calcitonin gene-related peptide; DHE, dihydroergotamine; FDA, U.S. Food and Drug Administration; IM, intramuscular; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; ODT, orally disintegrating tablet; SL, sublingual; SQ, subcutaneous; y, years

Methods

Literature Search Search strategies were developed for Ovid MEDLINE and Embase. Strategies consisted of controlled vocabulary, such as Medical Subject Headings (MeSH), and keyword phrases. Methodological filters were used for systematic reviews (SRs) and randomized controlled trials (RCTs). The Embase search excluded conference abstracts and results were limited to English language. Databases were searched from 2010 to present for SRs, from 2019 to present for RCTs including the newly approved agents (ubrogepant, rimegepant, and lasmiditan), and from 2016 to present for RCTs including the remaining agents listed on Table 1. Search dates for RCTs were selected following the identification of high-quality SRs from the Ovid MEDLINE and Embase results.36-39 Searches were conducted in March, April, and May 2020. At the time of the literature search undertaking, celecoxib oral solution was not yet approved so was not included in the complete search strategy. Following its approval in May, information for this medication was added based on the prescribing information and an Ovid MEDLINE search. The complete search strategies and terms are available in Appendix B. Authors additionally screened the reference lists of related systematic reviews and other relevant websites for further information: 1. For guidelines or position statements addressing acute treatment of migraine: websites of the American Academy of Neurology (AAN), the American Headache Society (AHS), and the National Institute for Health and Care Excellence (NICE) 2. For prescribing information: The Food and Drug Administration website (Drugs@FDA: FDA Approved Drug Products: https://www.accessdata.fda.gov/scripts/cder/daf/) and DailyMed website (https://dailymed.nlm.nih.gov/dailymed/) 3. Evidence-based drug information databases: Micromedex and Lexicomp Screening Two review authors screened titles and abstracts. Conflicts were resolved via discussion between reviewers. The full texts for all citations receiving 2 inclusion votes were retrieved; screening and inclusion were determined by the lead author. Figure 1 on page 29 shows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart for the review process.40 Inclusion and Exclusion Criteria Systematic reviews (SRs) of RCTs and RCTs providing direct head-to-head efficacy or safety comparisons among the agents for the acute treatment of migraine were included. For product comparisons where an SR provided robust data, we examined only those trials or systematic reviews published after the search date of the robust systematic review. Network meta-analyses (NMAs) including standard pairwise meta-analyses of an agent for migraine vs. another were included. Excluded references met the following exclusion criteria: 1) review articles not using SR methodology, 2) NMAs including indirect comparisons only, 3) SRs or RCTs comparing agents for migraine vs. placebo, 4) SRs or RCTs evaluating agents administered in the emergency room (eg, parenteral formulations), or 5) post-hoc analyses of studies, pilot studies, switching studies, and observational studies. A list containing the included and excluded references is provided in Appendix C.

Disease Overview Migraine

Migraine is a common primary headache disorder characterized by intermittent attacks of typically pulsating unilateral headache associated with photophobia, phonophobia, nausea, vomiting, and occasionally auras.41-43 Migraine is thought to occur following stimulation of the trigeminovascular system and subsequent release of vasodilating neuropeptides (eg, CGRP, substance P, and neurokinin A), which are associated with inflammation and pain.43,44 The specific etiology of migraine is currently unknown, although some frequently reported triggers of migraine include stress, hormones in women, not eating, weather changes, and sleep problems.45

Migraine episodes vary in intensity and frequency among individuals and even within each individual over time.42 Severe attacks can lead to disability affecting social relationships, reducing the capability to function at work or school, and increasing health care costs (eg, emergency department visits).42,46 The 2015 Global Disease Burden Study listed migraine as the third most common cause leading to disability worldwide in people less than 50 years of age.41 Migraine is 3 times more common in women than in men and prevalence reaches a peak between ages 25 and 55 years.42 Based on the 2018 National Health Interview Survey (NHIS), approximately 16% of American adults had migraine or severe headaches in a 3-month recall period.47 Among them, migraine or severe headache prevalence was 21.0% in females and 10.7% in males.47 The estimated prevalence of migraine in children and adolescents younger than 20 years of age is 7.7% (9.7% in females and 6% in males), according to population-based studies.46,48

Diagnosis of primary headache disorders is determined based on the clinical criteria detailed in the 3rd edition of the International Classification of Headache Disorders (ICHD-3), developed by the International Headache Society.41,46 Migraines are classified according to symptoms (eg, migraine with aura or migraine without aura) and frequency (episodic or chronic migraine). The ICHD-3 categorizes migraine into 2 main categories based on symptoms: migraine without aura (previously termed as common migraine or hemicranias simplex) and migraine with aura (previously termed as classic migraine, hemiplegic migraine, or complicated migraine).41 Classic features of migraine without aura include headache episodes lasting 4 to 72 hours (if untreated or inadequately treated), moderate to severe pain, unilateral location, pulsating headache, worsening symptoms with physical activity, and occurrence of associated symptoms (eg, nausea, vomiting, photophobia, and phonophobia).41,42 Cutaneous allodynia can appear in some patients.41,42 Approximately 33% of patients experience migraine with an “aura” preceding the headache attacks or occurring during some attacks.41,42 Aura symptoms are transitory, reversible focal neurological symptoms including visual disturbances, sensory disturbances (eg, feeling of pins and needles, numbness), speech and/or language problems (eg, aphasia, dysarthria), and motor symptoms, among others.41 The majority of aura symptoms last 1 hour although motor symptoms may last up to 72 hours. Visual impairment is the most common type of aura symptom.41 Approximately 75% of migraneurs experience premonitory symptoms hours or 1-2 days before the onset of symptoms (ie, prior to the aura in migraine with aura and prior to headache in migraine without aura). These symptoms include hyperactivity, hypoactivity, neck stiffness, depression, food cravings, nausea, light or sound sensitivity, recurrent yawning, and fatigue.41,49

The frequency of monthly migraine days (MMDs) and monthly headache days (MHDs) are also key features for the diagnosis of migraine. Patients with ≥15 MHDs for more than 3 months (including ≥8

days/month with migraine headache) are classified as having chronic migraine, while patients with migraine not meeting the chronic migraine criteria are considered to have episodic migraine.41,42 Table 2 describes diagnostic criteria for the classification of migraine with or without aura and chronic migraine based on the ICHD-3.

Table 2. Diagnostic Criteria for Migraine from the International Classification of Headache Disorders, 3rd Edition41 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 B. One or more of the following 4-72 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 (e.g. walking or climbing spreads gradually over ≥5 mins with aura 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 another ICHD-3 diagnosis 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

Tension-Type Headache

Tension-type headache is a commonly diagnosed primary headache disorder with a prevalence between 30% and 78%, based on several studies.41 This disorder is characterized by a mild to moderate pain that is bilateral, persistent, or tightening, and that lasts minutes to days.41 Headache does not aggravate with physical activity and is not accompanied by nausea, but photophobia or phonophobia may occur. Tension-type headache is classified by the ICHD-3 as episodic (infrequent and frequent type) and chronic. Most people suffer from infrequent episodic tension-type headache, which has a small impact on quality of life and does not require medical management. Frequent episodic tension-type headache and chronic tension-type headache can result in substantial disability and reduced quality of life; prescribed pharmacotherapies are commonly required.41

Differentiating between tension-type headache and mild forms of migraine without aura is challenging.41 People suffering recurrent headaches often have both disorders at the same time.41 Regarding monthly headache days (MHDs), diagnosis criteria for the infrequent episodic tension-type headache includes “at least 10 episodes of headache occurring on <1 day/month on average (<12 days/year)”, while frequent episodic tension-type headache includes “at least 10 episodes of headache occurring on 1–14 days/month on average for >3 months (≥12 and <180 days/year).”41 Chronic tension-type headache is a “headache occurring on ≥15 days/month on average for >3 months (≥180 days/year).”41 Trigeminal Autonomic Cephalalgias

Trigeminal Autonomic Cephalalgias (TCAs) are clinically characterized by a unilateral headache and, often, significant cranial parasympathetic autonomic features, which occur on the same side as the headache.41 An example of TCA is cluster headache, which is described by the ICHD-3 as attacks of severe, exclusively unilateral pain that is orbital, supraorbital, temporal, or any combination of these, lasts 15–180 minutes, and occurs once every-other-day to 8 times daily. The pain is accompanied by “ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis and/or eyelid edema, and/or with restlessness or agitation.”41 Cluster headaches may be episodic or chronic.41 Attacks appear in series that last weeks or months (also called “cluster periods”) separated by pain-free periods that usually last months or years.41 Cluster headaches are more common in men than in women and age of onset is typically 20 to 40 years. Alcohol, histamine, or nitroglycerin may trigger cluster headaches.41

Pharmacotherapy and Clinical Practice Guideline Recommendations Migraine

Pharmacologic treatment strategies for the management of migraine include acute therapies (also known as abortive therapies) to rapidly halt symptoms, and preventive therapies to decrease the frequency of migraine episodes.42 Non-pharmacologic interventions are additionally considered in the management of migraine and may include behavioral therapies (eg, cognitive behavioral therapy, biofeedback, and relaxation therapies) and lifestyle modifications related to trigger factors, diet, exercise, and hydration.42,46

Goals of acute treatment encompass rapid decrease of pain and associated symptoms, reduce migraine- related disability, decrease the need for rescue medication, and minimize adverse events. All patients with migraine should be considered for as needed treatment for migraine attacks with acute/abortive therapy.42 The 2015 American Headache Society (AHS) expert review of migraine pharmacotherapies in adults evaluated the evidence for efficacy of each treatment for migraine compared to placebo.50 Medications such as triptans, DHE nasal spray, NSAID (eg, diclofenac, ibuprofen, and naproxen), butorphanol nasal spray, acetaminophen [APAP], APAP/aspirin/caffeine, and sumatriptan/naproxen are established as effective (Level A evidence) in treating migraine in adults. Other medications such as ergotamine/caffeine and injectable DHE are considered probably effective (Level B evidence). Butalbital, butalbital combinations, and intramuscular butorphanol, among others, are considered possibly effective (Level C evidence).50 Authors stated that opioid medications including butorphanol,

codeine/acetaminophen, and tramadol/acetaminophen, although probably effective, are not recommended for regular use. The 2 CGRP receptor antagonists, ubrogepant and rimegepant, the 5-HT1F receptor agonist lasmiditan, and the NSAID celecoxib (oral solution) have been recently approved in 2019 and 2020 and are not included in this guideline.5,7,8

According to the 2019 AHS position statement, pharmacotherapy for mild to moderate migraine attacks includes non-opioid analgesics (eg, NSAIDs such as diclofenac; APAP; or caffeinated analgesic combinations such as aspirin/APAP/caffeine). Migraine-specific agents (triptans or DHE) are recommended for moderate to severe migraine attacks and mild to moderate attacks that respond inadequately to NSAIDs or caffeinated combinations.42

Non-oral formulations (eg, SQ/intranasal sumatriptan or SQ/intranasal DHE) and agents available as orally disintegrating or rapid melting tablets can be offered for patients with migraine accompanied with severe nausea or vomiting, for patients who have swallowing difficulties, and for patients with inadequate response to traditional oral formulations.42 Intranasal or injectable triptans or DHE may be more effective than oral formulations in patients with migraine attacks that rapidly reach maximal intensity.51 Antiemetics may be co-prescribed if needed. Tolerability, safety issues, and comorbidities should additionally be considered when choosing a product. For example, NSAIDs are associated with gastrointestinal and cardiovascular adverse reactions; triptans and ergot derivatives should not be administered or should be used with caution “in patients with coronary artery disease, peripheral vascular disease, uncontrolled hypertension, and other vascular risk factors and disorders”36 because they induce vasoconstriction.42,52,53 In general, triptans have a more specific mechanism of action and favorable safety profile compared to ergot derivatives.52 Triptans are usually preferred over DHE.51 Nevertheless, approximately 33% of patients do not respond to triptans and medication-overuse headache can occur.1-3,5,8,17,18,28-33,52 Use of ergotamine for the management of migraine is challenging due to poor oral absorption, vasoconstrictive adverse events, and frequent incidence of nausea that impedes achievement of optimal dose in many patients.52 The 2013 American Academy of Neurology (AAN) and Choosing Wisely joint statement recommends opioids and butalbital be reserved as last resort options for abortive migraine treatment since there are more effective migraine-specific agents and frequent utilization can aggravate headache.54 They are generally reserved as a “back-up plan” for patients who do not respond or have contraindications to acute medications.51,54,55 The 2016 AHS expert opinion guidance states that opioids and APAP with codeine or tramadol, although efficacious in migraine attacks, are generally not recommended for regular use in migraine patients due to potential risk for dependence, addiction, and occurrence of medication overuse headache.51 AHS authors recommend opioids be limited to patients with contraindications to other medications, or can be offered for infrequent use as a rescue medication when the patient does not respond to their initial treatment during a severe attack.51 Regarding butalbital-containing analgesic medications, there is no strong evidence demonstrating benefits of these combination products over other traditional agents for the acute treatment of migraine (eg, triptans and NSAIDs).52 In addition, these products have the risk of dependence, abuse, medication overuse headache, and withdrawal.25,52

Limitations of the traditional migraine treatments have led to the development of new antimigraine 53 agents with different targets (eg, 5-HT1F and CGRP receptors). The novel CGRP-receptor antagonists (ubrogepant and rimegepant) and selective 5-HT1F receptor agonist (lasmiditan) do not have

vasoconstrictor activity and may play an important role in patients with cardiovascular-related contraindications to triptans (eg, ischemic heart disease, uncontrolled hypertension, and certain types of migraine such as hemiplegic migraine).42,43,53 To ensure cost-effective care while warranting access to the most appropriate treatments, the 2019 AHS position statement considers that ubrogepant, rimegepant, and lasmiditan should be offered when triptans are contraindicated or when at least 2 oral triptans are inadequately effective or not tolerated.42

Treatment should be initiated as soon as the first sign of pain occurs to increase the likelihood of achieving pain freedom and reduce migraine-related disability.42,51 Initial selection of migraine therapy should be individualized based on patient preference; considerations regarding pregnancy, lactation, or plans to conceive; the frequency and intensity of attacks; associated symptoms; disability; response to previous treatments; comorbidities; agent-specific contraindications such as cardiovascular disease; other factors such as blood pressure and heart rate; and concurrent medications.42 Optimization of therapy for each patient is challenging due to intra- and inter-individual variability regarding migraine characteristics, severity, and frequency of attacks.42 A “trial and error” approach is usually needed to determine the optimal therapy for a specific patient.42 For instance, it may be appropriate to try different triptans in a patient.52 Clinical trials suggest that patients with an insufficient response to a triptan may adequately respond to a different triptan.52 A stratified approach to therapy is usually used when possible, in which the patient is instructed by their provider to use certain medications based on the severity of the attack, presence of accompanied symptoms (eg, nausea), and magnitude of migraine- related disability.51 Although treatment should be administered early in the attack, it is important for patients to avoid overusing traditional acute medications (ie, > 9 days per month for triptans, ergot derivatives, opioids, or combination analgesics containing these therapies; or > 14 days per month for non-opioid analgesics such as APAP or NSAIDs), as this can lead to medication-overuse headache and the development of chronic migraine.42,51 Patients should generally limit use of acute migraine treatments to an average of 2 days per week and be offered preventive therapy if exceeding this average.42

Table 3 provides a summary of treatment approaches for migraine in adults, based on expert opinion statements from the AHS.42,51

Table 3. Acute Migraine Treatment Options in Adults42,51 Non-opioid analgesics: • NSAIDs Mild to moderate migraine attacks • Acetaminophen • Caffeinated analgesic combinations Migraine-specific agents: Moderate to severe migraine attacks • Triptans (generally preferred over DHE) or refractory mild to moderate • DHE migraine attacks • Gepants (rimegepant, ubrogepant) or ditans (lasmiditan) can be considered if triptans are contraindicated or not tolerated • Combinations of triptans plus NSAIDs • Gepants (rimegepant, ubrogepant) Refractory moderate to severe • Ditans (lasmiditan) migraine attacks (ie, initial • Combinations of analgesics with codeine or tramadol can be medications have failed) considered, if used infrequently (not recommended for regular use) • Opioids (eg, butorphanol) can be considered, if used infrequently (not recommended for regular use)

Table 3. Acute Migraine Treatment Options in Adults42,51 For migraine associated with: (a) severe nausea/vomiting, difficulties swallowing oral • Non-oral formulations (eg, nasal spray, injectable formulation) formulations, or • (b) symptoms that reach Consider antiemetics if nausea/vomiting is present (eg, maximal intensity rapidly prochlorperazine, metoclopramide) (c) inadequate response to traditional oral therapies Abbreviations: AHS, American Headache Society; DHE, dihydroergotamine; NSAIDs, nonsteroidal anti- inflammatory drugs

Children and Adolescents

The American Academy of Neurology produced a 2019 practice guideline update for the acute treatment of migraine in children and adolescents.46 For both children and adolescents, ibuprofen oral solution is recommended as initial therapy. For adolescents, several other medications including sumatriptan/naproxen combination oral tablets, sumatriptan nasal spray, zolmitriptan nasal spray, rizatriptan oral disintegrating tablets, or almotriptan oral tablets have evidence supporting their use in reducing migraine pain and should be offered for the treatment of migraine in this population.46 Cluster Headache

For the acute treatment of cluster headache, the 2016 American Headache Society evidence-based guidelines include subcutaneous sumatriptan, nasal spray zolmitriptan, and high flow oxygen as medications with established efficacy (level A recommendation). Nasal spray sumatriptan and oral zolmitriptan are considered probably effective (level B recommendation).56 Tension-type Headache

For the treatment of tension-type headache (TTH), clinicians should consider offering aspirin, APAP, or an NSAID. Combinations of analgesics plus caffeine are an alternative choice. Triptans, muscle relaxants, and opioids should not be offered for the treatment of TTH.57,58

Tables on pages 18 to 20 provide clinical practice guideline recommendations regarding acute treatment of migraine in children, adolescents, and adults (Table 4), cluster headache management (Table 5), and treatment of tension-type headache (Table 6).

Table 4. Clinical Practice Guidelines for the Acute Treatment of Migraine Professional Organization Recommendations  Guideline Title American Academy of • For children and adolescents, ibuprofen 10 mg/kg oral solution should be Neurology and the prescribed as an initial treatment option to decrease pain (Level B, high American Headache confidence) Society • For adolescents, sumatriptan/naproxen 10/60 mg – 85/500 mg oral tablet, sumatriptan 20 mg nasal spray, zolmitriptan 5 mg nasal spray, rizatriptan  Practice guideline 5 mg – 10 mg oral disintegrating tablet, or almotriptan 6.25 mg – 12.5 mg oral update: Acute tablet should be prescribed to reduce headache pain ( treatment of migraine Level B, high in children and confidence) adolescents (2019)46 • If one triptan fails to provide pain relief, a different triptan should be offered (Level B, high confidence) • For adolescents who incompletely respond to a triptan, ibuprofen or naproxen should be offered in addition to a triptan (Level B, moderate confidence) • A non-oral route of administration may be prescribed for migraines that peak quickly in severity, are accompanied by nausea and/or vomiting, or do not respond to oral formulations (Level C, moderate confidence) • Contraindications/Precautions to Triptan Use: triptans must not be offered to patients with a history of ischemic vascular disease or accessory conduction pathway disorders (Level A, high confidence)

American Headache Agents with Established Efficacy (Level A, evidence supported by ≥ 2 class I Society studies): • Triptans: almotriptan 12.5 mg, eletriptan 20- 80 mg, frovatriptan 2.5 mg,  The acute treatment of naratriptan 1-2.5 mg, rizatriptan 5-10 mg, sumatriptan (oral 25-100 mg, nasal migraine in adults: the spray 10-20 mg, SC 4-6 mg, transdermal patch 6.5 mg), zolmitriptan (oral 2.5- American Headache 5 mg; and nasal spray 2.5-5 mg) Society evidence • DHE (nasal spray 2 mg, inhaler 1 mg) assessment of migraine • APAP 1,000 mg for non-incapacitating attacks pharmacotherapies • NSAIDS: aspirin 500 mg, diclofenac 50-100 mg, ibuprofen 200-400 mg, (2015)50 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 2018 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

Table 4. Clinical Practice Guidelines for the Acute Treatment of Migraine Professional Organization Recommendations  Guideline Title 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 National Institute for Acute treatment of migraine with or without aura Health and Care • Combination therapy with an oral triptan and an NSAID or an oral triptan and Excellence (NICE) paracetamol should be offered considering the patient’s preference, comorbidities, and risk for adverse events  Headaches in over • For patients 12-17 years old, a nasal triptan should be considered over an oral 12s: diagnosis and triptan management; 2012 • If monotherapy is preferred, an oral triptan, NSAID, aspirin, or paracetamol (updated 2015)57 should be offered considering the patient’s preference, comorbidities, and risk for adverse events • If a triptan is prescribed, try the less expensive triptan first. If poor response, try other triptans • Consider an anti-emetic drug in addition to acute treatment, even in the absence of nausea • Ergots or opioids should not be offered Canadian Headache Recommendations for agents approved in the US: Society • “Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are recommended for the acute treatment of  Canadian Headache migraine attacks that are likely to become moderate or severe” (Strong Society guideline: recommendation) acute drug therapy for • If patients do not adequately respond or are intolerant to one triptan, other migraine headache; triptans should be tried after 24 hours (Strong recommendation) 201352 • If patients do not adequately respond to sumatriptan, adding naproxen to the triptan should be considered (Strong recommendation) • If patients do not adequately respond to another triptan, adding an NSAID to the triptan should be considered (Strong recommendation) • Patients with moderate to severe migraine should be advised to take triptans early during their migraine episodes while pain is mild. Patient should be advised concerning medication overuse headache (Strong recommendation) • DHE (intranasal or subcutaneous self-injection) may be considered for the treatment of moderate to severe migraine (Weak recommendation) • Ergotamine should NOT be used regularly for migraine due to inferior efficacy in comparison to triptans, and the potential for more adverse reactions (Strong recommendation) • Ergotamine may be considered in some patients when triptans are not available or not effective (Weak recommendation)

Table 4. Clinical Practice Guidelines for the Acute Treatment of Migraine Professional Organization Recommendations  Guideline Title • “Diclofenac potassium (50 mg tablet or powder for oral solution) is recommended for the acute treatment of migraine attacks of all severities” (Strong recommendation) • Diclofenac powder for oral solution is recommended for the treatment of migraine when patients desire a faster onset of action in comparison to diclofenac oral tablets (Strong recommendation) • Intranasal butorphanol and barbiturates (eg, butalbital containing products) should be avoided for migraine due to lack of evidence for superiority to standard drugs (NSAIDs or triptans), dependence/abuse potential, risk of medication overuse headache, and possible withdrawal syndrome (Strong recommendation) Abbreviations: ASA, aspirin, APAP, acetaminophen; DHE, dihydroergotamine; CAF, caffeine; IM, intramuscular; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; SC, subcutaneous; US, United States

Table 5. Clinical Practice Guidelines for the Treatment of Cluster Headache American Headache Society Agents with a Level A recommendation for acute treatment of CH (established as effective, supported by 2 Class I RCTs):  Treatment of Cluster • Sumatriptan (subcutaneous) Headache: The American • Zolmitriptan (nasal spray) Headache Society • High flow oxygen Evidence-Based Agents with a Level B recommendation for acute treatment of CH (established Guidelines; 201656 as probably effective, supported by 1 class I RCT): • Sumatriptan (nasal spray) • Zolmitriptan (oral) • Sphenopalatine ganglion stimulation Agents with insufficient evidence for acute treatment of CH: • Dihydroergotamine (nasal spray) • Somatostatin • Prednisone National Institute for Health Acute treatment of CH and Care Excellence (NICE) • Offer oxygen and/or a subcutaneous or nasal triptan • APAP, NSAIDS, opioids, ergots, or oral triptans should not be offered  Headaches in over 12s: diagnosis and management; 2012 (updated 2015)57 Abbreviations: APAP, acetaminophen; CH, cluster headache; NSAID, nonsteroidal anti-inflammatory drug; RCT, randomized controlled trial

Table 6. Clinical Practice Guidelines for the Treatment of Tension-type Headache National Institute for Health Treatment of acute TTH and Care Excellence (NICE) • Consider aspirin, paracetamol, or an NSAID • Opioids should not be offered  Headaches in over 12s: diagnosis and management; 2012 (updated 2015)57 Abbreviation: TTH, tension-type headache; NSAID, nonsteroidal anti-inflammatory drug

Pharmacology Mechanism of Action

Ergot derivatives (ie, ergotamine and DHE) have a less specific mechanism of action compared to 52 triptans. Ergot derivatives bind with high affinity to 5-HT1D receptors, other serotonin receptors (ie, 5- 14,15 HT1A, 5-HT2A, and 5-HT2C), alpha adrenergic receptors, and dopamine receptors. The therapeutic effect of ergotamine and DHE in migraine is linked to the activation of 5-HT1D receptors that leads to intracranial vasoconstriction, inhibition of pro-inflammatory neuropeptide release, and subsequent 14,15 relief of migraine headache. Activation of other receptors (eg, 5-HT2) can cause adverse events such as coronary and peripheral vasoconstrictive side effects and nausea.52

Triptans display high affinity for serotonin receptors in the trigeminovascular system, particularly the 1-3,5,8,17,18,28-33,53 5-HT1B and 5-HT1D receptor subtypes. They have lower affinity for other serotonin receptors (eg, 5-HT1A) and no significant affinity for adrenergic receptors. Stimulation of 5-HT1B and 5-HT1D receptors on intracranial blood vessels and nerves of the trigeminal complex is thought to reduce pro-inflammatory neuropeptide release from trigeminal nerves, alter pain transmission in the trigeminal complex, and cause cranial vessel vasoconstriction, helping reduce migraine headache.1-3,5,8,17,18,28-33 However, activation of other receptors can cause adverse events such as coronary and peripheral vasoconstrictive side effects. As triptans have high specificity for 5-HT1B and 5-HT1D receptors, they are effective at reducing pain and associated symptoms (eg, nausea, vomiting, photophobia, and phonophobia) for many patients, with fewer adverse events than ergot derivatives.52

Lasmiditan is a novel agent with different chemical structure and receptor-binding activity compared to triptans, making lasmiditan the first agent in the drug class named as ‘ditans’.59 It acts as a selective 5-HT1F receptor agonist with low or minimal affinity to other receptors (5-HT1A, 1B, 1D, 5-HT2, 5-HT7, adrenergic, dopaminergic, histaminergic and muscarinic receptors).53 Although the exact mechanism of action of lasmiditan in migraine is unknown, it is thought that activation of 5-HT1F receptor is responsible for its therapeutic effect in migraine.4 Notably, lasmiditan does not produce the coronary 43,53 vasoconstrictor effects observed with 5-HT1B receptor stimulation. In clinical trials with lasmiditan, dizziness and somnolence were frequently reported adverse events. Unlike most triptans, the occurrence of these adverse effects suggests that lasmiditan crosses the blood-brain barrier and possibly binds to receptors in the brain.43

Rimegepant and ubrogepant, also known as ‘gepants’, are oral small molecule CGRP receptor antagonists that inhibit the effect of the pro-inflammatory, vasoactive neuropeptide CGRP and consequently reduce the pain associated with migraine.43 Similar to ergot derivatives and triptans, it is believed that gepants probably exert their action outside of the blood-brain barrier because they do not easily penetrate it due to their size and structures.43,44

The mechanism of action of diclofenac and celecoxib during migraine attacks is not well understood, but they are thought to exert their therapeutic effects by blocking prostaglandin synthesis via inhibition of cyclooxygenase.10,34

Butorphanol is an opioid analgesic with partial agonistic properties at mu opioid receptors and full agonistic properties at kappa opioid receptors.13

Butalbital is a barbiturate that activates gamma-aminobutyric acid (GABAA) receptors. It has anxiolytic and muscle relaxant properties. Butalbital is usually available as part of fixed dose combinations with other agents such as APAP, caffeine, aspirin, and codeine for the treatment of symptoms of tension-type headache (“headache pain, psychic tension, and muscle contraction in the head, neck, and shoulder region”26,27).19-27 APAP, aspirin, and codeine (mu-opioid receptor agonist) have analgesic properties; caffeine is a central nervous system stimulant with vasoconstriction activity.19-27

Table 7 describes the mechanism of action of agents for the acute treatment of migraine.

Table 7. Mechanism of Action of Agents for the Acute Treatment of Migraine43,52,60 Drug Classes Mechanism of Action/Effects in Migraine Attacks Non-selective 5-HT receptor agonist Ergotamine derivatives (activates 5-HT1B/1D/1F and 5-HT2 receptors) Blocks neuropeptide release and alpha adrenergic receptor agonist Alters communication between peripheral and central trigeminovascular neurons. Triptans 5-HT1B/1D/1F receptor agonist Vasoconstriction of cerebral blood vessels and inhibition of neuropeptide (eg, CGRP and substance P) Ditans 5-HT1F receptor agonist Blocks neuropeptide release Gepants CGRP receptor antagonist Blocks CGRP receptor Diclofenac and celecoxib inhibit prostaglandin synthesis, which COX-1 and COX-2 inhibition (diclofenac) reduces inflammation.10,34 In animal NSAIDs COX-2 inhibition (celecoxib) models diclofenac has shown a reduction of bradykinin action in inducing pain10 Anxiolytic and muscle Barbiturates GABAA receptor activation relaxant effects19-27 Mu-opioid receptor partial agonist and Opioids Analgesic effects13 kappa-opioid receptor full agonist Abbreviations: 5-HT, hydroxytryptamine (serotonin); CGRP, calcitonin gene-related peptide; COX, cyclooxygenase; GABA, gamma-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drug

Pharmacokinetic Properties

Table 8 includes pharmacokinetic (PK) properties for the acute treatments of migraine. Rimegepant and ubrogepant are both oral formulations achieving maximum concentration at 1.5 hours. Half-lives range from 5 to 7 hours with ubrogepant to 11 hours with rimegepant. Both agents are metabolized in the liver, primarily via CYP3A4. Dose adjustments or restrictions for each CGRP antagonist are dependent on drug interactions involving CYP3A4 metabolism or breast cancer resistant protein (BCRP) and/or P-glycoprotein (P-gp) meditated pathways.6,7

Lasmiditan is an oral formulation that achieves maximum concentration at 2 hours, has a half-life of 6 hours, and undergoes hepatic and extrahepatic metabolism mainly by non-CYP enzymes.4

There are some pharmacokinetic differences among triptans and their formulations. Time to maximum concentration (Tmax) ranges from 10 minutes with sumatriptan nasal spray to 4 hours with naratriptan. Subcutaneous sumatriptan has a faster onset of action (less than 10 minutes) in comparison to oral or intranasal sumatriptan.52 Frovatriptan has longer terminal elimination half-life compared to other triptans. Triptans are metabolized in the liver primarily via cytochrome P450 (CYP) enzymes or monoamine oxidase A (MAO-A).

Diclofenac potassium (powder for oral solution) is rapidly absorbed reaching maximum plasma levels in 15 min. An RCT in patients with migraine attacks showed that diclofenac potassium 50 mg oral solution provided significantly faster onset of headache relief compared to diclofenac potassium 50 mg tablets (15 minutes vs. 60 minutes).61,62 Compared to celecoxib 400 mg oral capsules, the novel oral solution formulation of celecoxib at doses of 120 mg, 180 mg, and 240 mg has shown a higher bioavailability, more rapid absorption rate, higher peak plasma levels of celecoxib, and shorter time to peak concentration (1 hour vs. 2.5 hours), in a pharmacokinetic study of fasting healthy volunteers.63

Table 8. Pharmacokinetics of Agents for the Acute Treatment of Migraine64,65 Generic Name Onset of Action/Tmax Metabolism Half-life Selective Serotonin Agonists and Combinations Tmax: 1-3 hours after Hepatic, predominantly Almotriptan3 3-4 hours administration via MAO-A and CYP3A4 and 2D6 Eletriptan2 Tmax: 2 hours Hepatic, predominantly via CYP3A4 4 hours Frovatriptan8 Tmax: 2-4 hours Hepatic, predominantly via CYP1A2 26 hours Hepatic and extrahepatic Onset: 30-60 minutes Lasmiditan4 metabolism primarily by non-CYP 5.7 hours Tmax: 1.8 hours enzymes Onset: 1-2 hours Naratriptan5 Hepatic via CYP isoenzymes 6 hours Tmax: 2-4 hours Rizatriptan1 Tmax: 1-1.5 hours Oxidative deamination by MAO-A 2-3 hours Imitrex Oral Tablet Onset: Within 30 minutes Tmax 2.5 hours Sumatriptan28-33 Hepatic, predominantly via MAO-A 2-3 hours Imitrex Nasal Spray Onset: 15-30 minutes Tmax: 10 minutes

Table 8. Pharmacokinetics of Agents for the Acute Treatment of Migraine64,65 Generic Name Onset of Action/Tmax Metabolism Half-life Tosymra Nasal Spray Tmax: 10 minutes Onzetra Xsail Nasal Powder Tmax: 45 minutes Imitrex Subcutaneous Sumatriptan28-33 Injection Onset: Less than 10 minutes Tmax: 12 minutes Zembrace SymTouch Subcutaneous Auto-Injector Onset: Less than 10 minutes Tmax: 12 minutes Tmax tablet: 1.5 hours Converted to an active N-desmethyl Zolmitriptan17,18 Tmax ODT and nasal spray: metabolite (2-6 times more potent 3 hours 3 hours than zolmitriptan) Sumatriptan: Hepatic, predominantly Sumatriptan: 1 hour (range: Sumatriptan: via MAO-A 0.3 to 4.0 hours) 2 hours

Sumatriptan/naproxen16 Naproxen: Extensively metabolized Naproxen: 5 hours (range: 0.3 Naproxen: in the liver to 6-0-desmethyl to 12 hours) 19 hours naproxen CGRP Receptor Antagonist Primarily hepatic via CYP3A4 and to Rimegepant7 Tmax: 1.5 hours 11 hours a lesser extent by CYP2C9 Ubrogepant6 Tmax: 1.5 hours Primarily hepatic via CYP3A4 5-7 hours Ergot Derivatives and Combinations Tmax: SQ: 15 to 45 minutes Extensively hepatic (one major Dihydroergotamine14,15 IM: 24 minutes active metabolite, 8'-β- 9 hours Intranasal: 30 to 60 minutes hydroxydihydroergotamine) IV: 1 to 2 minutes Ergotamine and Ergotamine: Tmax (ergotamine): 2 hours Ergotamine: Extensively hepatic ergotamine/caffeine9,11,12 2-2.5 hours NSAIDs Hepatic; undergoes first-pass Tmax for oral solution: Diclofenac Potassium10 metabolism; forms several 2 hours 15 minutes metabolites (1 with weak activity) Tmax for oral solution (under Celecoxib34 Primarily hepatic via CYP2C9 6 hours fasting conditions): 1 hour Other Miscellaneous Butalbital combinations Peak concentration: 1.5 hours NR 35 hours (data for butalbital only)27 Extensively hepatic (major Butorphanol13 Tmax (nasal): 30-60 minutes 18 hours metabolite: hydroxibutorphanol) Abbreviations: CGRP, calcitonin gene-related peptide; CYP, cytochrome P450; IM, intramuscular; IV, intravenous; MAO-A: monoamine oxidase A; NR, not reported; NSAID, nonsteroidal anti-inflammatory drug; ODT, orally disintegrating tablet; SQ, subcutaneous; Tmax, time to reach the maximum concentration

Special Populations Table 9, Table 10, and Table 11 include special population considerations for acute treatments of migraine. Table 2 of Appendix A includes detailed information regarding special populations. Pregnancy and Lactation Regarding pregnancy, prescribing information for triptans, lasmiditan, and gepants includes that these agents may cause fetal harm because animal studies have shown fetal developmental toxicities such as increased fetal mortality, fetal abnormalities, and decreased fetal weight (though at exposures higher than that by the maximum recommended human dose).1-8,17,18,28-33 Observational data in pregnant women exposed to sumatriptan suggest no increased frequency of birth defects.28-33 Ergot derivatives and ergotamine/caffeine are contraindicated or should be avoided during pregnancy.9 Diclofenac, celecoxib, and sumatriptan/naproxen should be avoided after week 30 of gestation (third trimester) due to potential premature closure of the ductus arteriosus in the fetus.10,16,34 Butorphanol and the combinations of butalbital with codeine carry a black box warning regarding the risk of neonatal opioid withdrawal syndrome in pregnant women using opioids long-term.13,24,25 An expert review from the John. R Graham Headache Center of Brigham and Women’s Hospital considers the following agents as preferred options for the treatment of migraine in pregnant women due to their established safety: APAP, diphenhydramine, subcutaneous lidocaine, metoclopramide, and NSAIDs such as ibuprofen, naproxen, and diclofenac. NSAIDs should be used during the second trimester only. Triptans and butalbital are second-line alternatives during pregnancy. Triptans have better safety data than butalbital, with sumatriptan, naratriptan, and rizatriptan having the strongest evidence for use in pregnancy. Opioids should be avoided when possible and ergot derivatives should not be used due to an increased risk of spontaneous abortion.66 During breastfeeding, DHE and combinations of butalbital with codeine are the only products among all agents indicated for migraine treatment with a labeled contraindication or avoidance of use in nursing mothers.14,15,24,25 Ergotamine and the combination ergotamine/caffeine are present in human milk and may cause gastrointestinal and cardiovascular symptoms in nursing infants. Thus, breastfeeding or drug discontinuation should be considered.9,11,12 Pediatric Population Almotriptan, rizatriptan, zolmitriptan nasal spray, and sumatriptan/naproxen are the only products approved for use in pediatric patients with migraine.1,3,17,18 Patients with Hepatic and Renal Impairment Considering the most recently approved products, lasmiditan is not recommended in patients with severe hepatic impairment, rimegepant should be avoided with severe hepatic impairment and end- stage renal disease, and patients receiving ubrogepant require dosage adjustment if severe hepatic or renal impairment is present.4,6,7 Celecoxib (Elyxyb) requires dose reduction in patients with moderate hepatic impairment and is not recommended in patients with severe hepatic or renal impairment.34 Poor Metabolizers of CYP2C9 Substrates Dose reduction is required when celecoxib is administered to patients who are known or suspected to be CYP2C9 poor metabolizers, according to genotype or prior history or experience with other CYP2C9 substrates.34

Table 9. Special Population Considerations of Selective Serotonin Agonists Selective Serotonin Agonists Special Populations ALM3 ELE2 FRO8 LAS4 NAR5 RIZ1 SUM28-33 SUM/NAP16 ZOL17,18 Pregnant women • Human data suggest no X increased frequency of birth defects • The drug may cause fetal harm (animal studies showed X X X X X X X X X developmental toxicity) X (3rd • Drug is contraindicated trimester) Nursing mothers • Unknown if drug is excreted X X X X X X in human milk. Weigh potential benefits and risks • Drug is present in human milk. Weigh potential X X X benefits and risks X (6- X (nasal spray: Approval for pediatric patients X (≥12y) X (≥12y) 17y) ≥12y) NR with CI with severe HI CI with severe HI moderate to Dose NR with Use with Dosage Dose reduction CI with Patients with hepatic NR with severe HI (nasal reduction severe caution in adjustment in with mild to severe HI impairment (HI) severe HI spray/ ODT) in HI HI severe HI mild to moderate HI Dose reduction in moderate HI (oral SUM) HI (tablet) CI with severe RI Dose Dosage Patients with renal reduction adjustment in impairment (RI) in severe mild to RI moderate RI Abbreviations: ALM, almotriptan; CI, contraindicated; ELE, eletriptan; FRO, frovatriptan; HI, hepatic impairment; LAS, lasmiditan; NAR, naratriptan; NR, not recommended; ODT, orally disintegrating tablet; RI, renal impairment; RIZ, rizatriptan; SUM, sumatriptan; SUM/NAP, sumatriptan/naproxen; y, years; ZOL, zolmitriptan

Table 10. Special Population Considerations of Ergot Derivatives, CGRP Receptor Antagonists, and NSAIDs Ergot Derivatives CGRP Receptor Antagonist NSAID Special Populations DHE14,15 ERG9 ERG/CAF11 RIM7 UBR6 CEL34 DIC-K10 Pregnant women • The drug may cause fetal harm X X (animal studies showed developmental toxicity) • Drug is contraindicated or should X (avoid from X (avoid from X X X be avoided week 30) week 30) Nursing mothers • Unknown if drug is excreted in X X X human milk. Weigh potential benefits and risks • Drug is present in human milk. X Weigh potential benefits and risks • Drug is present in human milk and may cause symptoms in nursing infants. Breastfeeding or drug X X discontinuation should be considered • Drug is contraindicated X Pediatric patients: safety and X X X X X X X efficacy not established Avoid use Dosage NR with severe HI Patients with hepatic impairment CI in severe HI CI in HI CI in HI with severe adjustment in Dose reduction (HI) HI severe HI with moderate HI Dosage NR in Avoid use Patients with renal impairment (RI) CI in severe RI CI in RI CI in RI adjustment in NR with severe RI advanced with ESRD severe RI renal disease Dose reduction is CYP2C9 poor metabolizers required Abbreviations: CEL, celecoxib; CI, contraindicated; DHE, dihydroergotamine; DIC-K, diclofenac potassium; ERG, ergotamine; ERG/CAF, ergotamine/caffeine; ESRD, end-stage renal disease; HI, hepatic impairment; NR, not recommended; NSAID, non-steroidal antiinflammatory drug; ODT, orally disintegrating tablet; RI, renal impairment; y, years

Table 11. Special Population Considerations of Butorphanol and Butalbital Combinations13,14,19,21,24-26 Opioids Butalbital Combinations Special Populations BUTOR BUT/APAP BUT/APAP/CAF BUT/APAP/CAF/COD BUT/ASA/CAF BUT/ASA/CAF/COD Pregnant women • The drug may cause fetal harm (animal X (see individual X (see individual X studies showed adverse effects). Weigh agents) agents) potential benefits and risks • Long-term use of opioids during pregnancy may lead to neonatal opioid withdrawal X X X syndrome after birth, which may be fatal if not recognized or left untreated • Drug should is not recommended during labor or delivery because opioids may cause X X X respiratory depression in neonates • No animal studies were conducted with the combination. Weigh potential benefits and X X X X X risks Nursing mothers • Drug is present in human milk. Weigh X potential benefits and risks

• Drug is present in human milk. Breastfeeding X X X or drug discontinuation should be considered • Drug is present in human milk. Breastfeeding X X not recommended Pediatric patients: safety and efficacy not X X X X X X established No dosage No dosage No dosage Dosage No dosage adjustment. adjustment. Caution adjustment. adjustment. Patients with hepatic impairment (HI) changes Caution in severe HI in HI and monitor Caution in Caution in HI and in HI carefully severe HI monitor carefully No dosage No dosage No dosage Dosage No dosage adjustment. adjustment. Caution adjustment. adjustment. Patients with renal impairment (RI) changes Caution in severe RI in RI and monitor Caution in Caution in RI and in RI carefully severe RI monitor carefully Abbreviations: BUT/APAP, butalbital/acetaminophen; BUT/APAP/CAF, butalbital/acetaminophen/caffeine; BUT/APAP/CAF/COD, butalbital/acetaminophen/ caffeine/codeine; BUT/ASA/CAF, butalbital/aspirin/caffeine; BUT/ASA/CAF/COD, butalbital/aspirin/caffeine/codeine; BUTOR, butorphanol; HI, hepatic impairment; RI, renal impairment; y, years a Boxes outlined in black indicate a black box warning

Direct Comparative Evidence Literature searches for SRs and RCTs identified 714 unique records, of which 9 SRs and 1 RCT directly comparing the acute treatments of migraine included in Table 1 met inclusion criteria for the qualitative synthesis. Most of the identified evidence compared oral triptans with each other in adult patients with a diagnosis of migraine, as specified by the International Headache Society. No comparative evidence was found in the pediatric population with migraine. The most common primary endpoints that were used in clinical trials included pain-free (ie, from moderate or severe pain to no pain) and headache relief (ie, reduction in headache intensity from moderate or severe to mild or none) at pre-specified time points (eg, 1 hour or 2 hours). Another important efficacy outcome used in clinical trials, but less frequently, was the percentage of patients with sustained freedom from migraine pain over 24 or 48 hours. Common secondary endpoints were reduction in headache-associated symptoms (eg, nausea, vomiting, photophobia, and phonophobia), reduction in functional disability, use of rescue medication, recurrence of migraine attacks, and incidence of any adverse events. Figure 1 shows the PRISMA flow diagram for the review process.

Figure 1. PRISMA Flow Chart for Publication Screening

• Records identified in Ovid Medline: 190 SRs, 116 RCTs, 19 records (for celecoxib) • Records identified in Embase: 272 SRs, 404 RCTs

Identification

Records after duplicates removed (325 SRs and 370 RCTs)

Screening Records excluded Records screened (714) (660)

Full-text articles excluded, with Full-text articles assessed for reasons (45) eligibility 20 Wrong study design Eligibility (54) 14 Wrong comparator 4 A more recent SR is available 2 Duplicate 1 Non-English article Publications included in qualitative 1 Unavailable 1 Wrong indication synthesis

Included 1 Wrong intervention (10 publications: 9 SRs and 1 RCT) 1 Wrong outcomes

Abbreviations: RCT, randomized controlled trials; SRs, systematic reviews

Summary of Comparative Evidence in the Acute Treatment of Migraine

1. Comparative Evidence Among Lasmiditan, Rimegepant, and Ubrogepant Head-to head comparisons among the newly approved agents lasmiditan, ubrogepant, and rimegepant were not identified. These agents have been compared to placebo in phase III RCTs showing efficacy for the treatment of moderate to severe migraine attacks. In the absence of head-to-head studies, a 2020 network meta-analysis (NMA) from the Institute for Clinical and Economic Review (ICER) was summarized as additional information. However, well- conducted head-to-head studies are needed to differentiate the effect of these drugs in patients with migraine. The NMA suggests that lasmiditan was comparable or inferior to rimegepant or ubrogepant in terms of net health benefit (ie, balance between clinical benefits and risks). Rimegepant and ubrogepant had a comparable net health benefit. Lasmiditan, rimegepant, and ubrogepant were similar or inferior to triptans (sumatriptan and eletriptan) in terms of net health benefit, in adults with migraine who had an inadequate response to non-prescription medicines. In this population, rimegepant and ubrogepant appeared to have a lower efficacy but similar incidence of short-term adverse reactions compared to triptans (sumatriptan and eletriptan). Lasmiditan appeared to have a lower efficacy compared to sumatriptan and eletriptan, comparable efficacy to sumatriptan, and higher incidence of adverse reactions in comparison to triptans. A limitation of this NMA includes the combination of RCTs studying non-FDA approved formulations of rimegepant and lasmiditan.

2. Comparative Evidence of Celecoxib Oral Solution Versus Other Acute Medications No head-to-head efficacy comparisons were identified between celecoxib oral solution and other acute treatments of migraine. This agent has been compared to placebo in 2 phase III RCTs showing efficacy for the treatment of moderate to severe migraine attacks.

3. Comparative Evidence Among Triptans Several SRs and MAs of RCTs have analyzed the comparative efficacy and safety among triptans. Head- to-head RCTs are not available for all possible triptan comparisons. Most of the head-to-head RCTs reported in SRs and MAs compared oral sumatriptan with other oral triptans. Direct comparisons among triptans are complex due to the availability of different doses and formulations, and multiple efficacy outcomes. Based on pairwise MAs of RCTs and considering the most common primary efficacy endpoints used in migraine clinical trials, Xu et al (2016) reported that rizatriptan (compared to sumatriptan or naratriptan) and eletriptan (compared to sumatriptan or zolmitriptan) were significantly more efficacious at relieving pain at 1 or 2 hours post dose and/or achieving pain freedom at 1 or 2 hours post dose. Almotriptan, naratriptan, and zolmitriptan were not significantly different compared to sumatriptan regarding pain relief or pain freedom at different time points. Diclofenac potassium (tablets) was similar to sumatriptan concerning pain freedom at 1 hour. Sumatriptan/naproxen was significantly more efficacious than sumatriptan monotherapy regarding pain freedom and pain relief at 2 hours after treatment. With respect to ‘all-adverse-event’ outcome, similar results were found among triptans and between diclofenac potassium and sumatriptan. Xu et al included direct MAs that combined RCTs assessing different doses and formulations for each triptan. Most RCTs evaluated oral tablet formulations.

The pairwise MA by Cameron et al (2015) reported comparative efficacy results among the triptan tablets (at standard doses). Due to limited data regarding the characteristics of included studies, it is unclear if direct MAs included traditional tablets only or both traditional tablets and ODT for rizatriptan and zolmitriptan. Overall, eletriptan and rizatriptan tablets were associated with more favorable outcomes compared with many of the other triptan tablets in terms of pain relief at 2 hours and/or pain freedom at 2 hours. Less favorable results were reported for naratriptan tablets compared with many of the other triptan tablets regarding pain relief at 2 hours and/or pain freedom at 2 hours. An RCT comparing sumatriptan 22 mg nasal powder (Onzetra) vs. oral sumatriptan 100 mg showed significantly higher reduction of migraine pain intensity within the first 30 minutes with sumatriptan nasal powder, but pain relief or pain freedom at 2 hours and sustained pain relief or pain freedom from 2 hours to 48 hours were comparable between treatment groups. Incidence of atypical sensations (ie, tingling and chest, jaw, or neck tightness) was significantly lower with sumatriptan nasal powder.

4. Comparative Evidence of Triptans Versus Ergot Derivatives Comparative trials, rated as poor quality, suggest that sumatriptan (intranasal or SQ) was significantly better or similar to DHE (intranasal or SQ) at relieving headache pain within 1 or 2 hours. Oral sumatriptan, eletriptan, and almotriptan were more efficacious than ergotamine/caffeine with respect to headache relief and pain freedom at 2 hours after treatment.

5. Comparative Evidence of Sumatriptan Versus Diclofenac Potassium (Oral Tablets) Oral sumatriptan was similarly efficacious at relieving headache pain compared to diclofenac potassium (oral tablets) in 1 RCT including adults with migraine. Note that diclofenac potassium oral tablets are not specifically approved for the acute treatment of migraine. The FDA-approved diclofenac potassium for the acute treatment of migraine is available as a powder for oral solution (Cambia).

6. Comparative Evidence of Butorphanol Versus Butalbital Combinations An RCT demonstrated butorphanol nasal spray was more efficacious than butalbital/caffeine/aspirin/ codeine (fiorinal with codeine) at reducing pain intensity at 2 hours post-dose (primary efficacy endpoint) in adults with migraine.

7. Comparative Evidence of Sumatriptan/Naproxen Versus Butalbital Combinations An RCT compared sumatriptan/naproxen vs. butalbital/APAP/caffeine in patients with moderate to severe migraine attacks. There were no differences for the primary efficacy endpoint of sustained pain freedom from 2 to 24 hours, but significant differences for most secondary endpoints (eg, pain-free, pain relief, and associated symptoms) in favor of sumatriptan/naproxen. Butalbital combinations are associated with risk of dependence, abuse, withdrawal syndrome, and development medication-overuse headache. Sumatriptan/naproxen is also associated with medication overuse headache.

8. Comparative Evidence Between Diclofenac Potassium Powder for Oral Solution and Tablets Based on an RCT, diclofenac potassium oral solution outperformed the tablet form in terms of migraine- related pain freedom at 2 hours and other endpoints such as headache intensity reduction at 4 hours post dose, sustained headache response within 24 hours, and sustained pain freedom within 24 hours. The following section describes head-to-head evidence in further detail. Appendix D includes Table 1 with key findings reported in the 9 included SRs, and Table 2 with the RCTs reported in the included SRs.

Detailed Information Regarding Comparative Evidence in the Acute Treatment of Migraine

1. Comparative Evidence Among Lasmiditan, Rimegepant, and Ubrogepant for the Acute Treatment of Migraine No head-to-head comparisons among lasmiditan, rimegepant, and ubrogepant were identified.36,38,67 Three randomized controlled trial (RCTs) of lasmiditan, 4 RCTs of rimegepant, and 3 RCTs of ubrogepant were identified.36,67 Each RCT was a placebo-controlled trial. There was only a phase II RCT of rimegepant capsules (a non-approved dosage form) that additionally included sumatriptan as an active comparator; however, statistical analyses between the 2 active arms were not carried out.36,67,68 Patients were 18 years and older, had at least 1-year history of migraine with or without aura (based on the ICHD diagnostic criteria), and were instructed to take one of the antimigraine agents at home to treat moderate to severe attacks. The majority of patients had moderate headache pain at baseline. A commonly used primary efficacy endpoint was pain freedom at 2 hours after treatment. The 2 phase III RCTs of lasmiditan included a high percentage of patients who had at least 1 cardiovascular risk factor.69,70 Ubrogepant studies also included patients with cardiovascular risk.71,72 Having a cardiovascular risk was not an exclusion criterion in the phase III study of rimegepant ODT (the FDA approved formulation).73 Table 12 includes headache pain freedom and pain relief 2 hours post-dose results from identified RCTs of lasmiditan, rimegepant, and ubrogepant compared with placebo.

Table 12. Randomized Controlled Trials of Lasmiditan, Rimegepant, and Ubrogepant Compared to Placebo Pain freedom at Pain relief at 2 h Agent RCT Design (author, year) Intervention 2 h (% of patients) (% of patients) Lasmiditan rapidly LAS 200 mg: 19 LAS 200 mg: 51 disintegrating tabletb LAS 100 mg: 14 LAS 100 mg: 64 Phase II (Farkkila 2012)74 50 mg, 100 mg or 200 mg LAS 50 mg: 14 LAS 50 mg: 43 vs. placebo PLA: 7.4 PLA: 25.9 LAS 200 mg: 38.8 LAS 200 mg: 65 Lasmiditan tablet 200 mg, Lasmiditan LAS 100 mg: 31.4 LAS 100 mg: 64.8 Phase III (Goadsby 2019)69 100 mg, or 50 mg vs. LAS 50 mg: 28.6 LAS 50 mg: 59.0 placebo PLA: 21.3 PLA: 47.7 LAS 200 mg: 32.2 LAS 200 mg: 59.5 Lasmiditan tablet 200 mg Phase III (Kuca 2018)70 LAS 100 mg: 28.2 LAS 100 mg: 59.4 or 100 mg vs. placebo PLA: 15.3 PLA: 42.2 Rimegepant capsulesb 10 mg, 25 mg, 75 mg, RIM 75 mg: 31.4 RIM 75 mg: 72.1 Phase IIb (Marcus 2014)68a 150 mg, 300 mg, or SUM: 35 SUM: 72 600 mg, or sumatriptan PLA: 15.3 PLA: 51.2 100 mg vs. placebo Phase III (Lipton 2018) – Rimegepant 60th Annual Scientific Rimegepant tabletb 75 mg RIM 75 mg: 19.2 RIM 75 mg: 56.0 Meeting American vs. placebo PLA: 14.2 PLA: 45.7 Headache Society75 Rimegepant tablet (non- RIM 75 mg: 19.6 RIM 75 mg: 58.1 Phase III (Lipton 2019)76 ODT)b 75 mg vs. placebo PLA: 12.0 PLA: 42.8 Rimegepant ODT 75 mg RIM 75 mg: 21.2 RIM 75 mg: 59.3 Phase III (Croop 2019)73 vs. placebo PLA: 10.9 PLA: 43.3

Table 12. Randomized Controlled Trials of Lasmiditan, Rimegepant, and Ubrogepant Compared to Placebo Pain freedom at Pain relief at 2 h Agent RCT Design (author, year) Intervention 2 h (% of patients) (% of patients) Ubrogepant (unspecified UBR 100 mg: 25.5 UBR 100 mg: 58.8 formulation) 1 mg, 10 g, Phase II77 (Voss 2016) UBR 50 mg: 21.0 UBR 50 mg: 57.1 25 mg, 50 mg, 100 mg vs. PLA: 8.9 PLA: 44.6 placebo Ubrogepant Ubrogepant tablet UBR 100 mg: 21.2 UBR 100 mg: 61.4 Phase III (Dodick 2019)71 100 mg or 50 mg vs. UBR 50 mg: 19.2 UBR 50 mg: 60.7 placebo PLA: 11.8 PLA: 49.1 Ubrogepant tablet 25 mg UBR 50 mg: 21.8 UBR 50 mg: 62.7 Phase III (Lipton 2019)72 or 50 mg vs. placebo PLA: 14.3 PLA: 48.2 Abbreviations: h, hours; FDA, U.S. Food and Drug Administration; LAS, lasmiditan; ODT, orally disintegrating tablet; PLA, placebo; RCT, randomized controlled trial; RIM, rimegepant; SUM, sumatriptan; UBR, ubrogepant a The RCT by Marcus et al (2014) was not powered to detect differences between rimegepant and sumatriptan b Non-FDA approved formulations

- Network Meta-Analyses Comparing Lasmiditan, Rimegepant, and Ubrogepant A 2020 evidence report for acute treatments of migraine from the Institute for Clinical and Economic Review (ICER) conducted network meta-analyses (NMAs) regarding the comparative efficacy and safety of lasmiditan, rimegepant, and ubrogepant in acute treatment of migraine.39 In the absence of head-to- head comparisons among these agents, results from these NMAs are provided as background information. Well-conducted head-to-head studies are needed to differentiate the effect of these drugs in patients with migraine. Authors of the ICER review identified 3 RCTs for lasmiditan, 4 RCTs for rimegepant, 3 RCTs for ubrogepant, and 23 RCTs for oral sumatriptan and oral eletriptan.39 All trials were considered comparable to include in NMAs, based on demographic characteristics.39 Three out of 4 trials with rimegepant and 1 out of 3 trials with lasmiditan included non-FDA approved formulations. NMAs included agents at FDA-approved doses (ubrogepant 50/100 mg, rimegepant 75 mg, lasmiditan 100/200 mg, eletriptan 40 mg, and sumatriptan 50/100 mg). Endpoints that were measured in NMAs include pain freedom at 2 hours after treatment, pain relief at 2 hours after treatment, sustained pain freedom from 2 to 24 hours, freedom from most bothersome symptoms (eg, photophobia), functional disability, and safety outcomes. Overall, lasmiditan, rimegepant, and ubrogepant were similar or inferior to triptans (sumatriptan and eletriptan) in terms of net health benefits (ie, balance between clinical benefits and risks), in adults with migraine who had an inadequate response to non-prescription medicines (but were eligible for triptan therapy). In this population, rimegepant and ubrogepant appeared to have a lower efficacy but similar incidence of short-term adverse reactions compared to triptans. Lasmiditan appeared to have a lower efficacy compared to triptans (sumatriptan and eletriptan), comparable efficacy to sumatriptan, and higher incidence of adverse reactions in comparison to triptans.39 For all adults with migraine episodes, results from NMAs suggested that rimegepant and ubrogepant had a comparable net health benefit. Lasmiditan appeared to be marginally more efficacious or had similar efficacy compared to rimegepant and ubrogepant. A higher incidence in adverse events and more discontinuations were observed with patients receiving lasmiditan compared to rimegepant and ubrogepant. Overall, authors of the ICER

review considered evidence regarding lasmiditan compared to rimegepant or ubrogepant to be “comparable or inferior.”39

2. Comparative Evidence for Celecoxib Oral Solution in the Acute Treatment of Migraine There are currently no head-to-head efficacy comparisons between celecoxib oral solution and other acute treatments of migraine. Celecoxib oral solution has shown efficacy in terms of freedom from pain and freedom from the most bothersome symptoms (MBS) at 2 hours post dose compared to placebo in 2 phase III RCTs including patients with moderate to severe migraine attacks.34

Table 13. Randomized Controlled Trials of Celecoxib Oral Solution Compared to Placebo Pain freedom at 2 h MBS free at 2 h Agent RCT Design (author, year) Intervention (% of patients) (% of patients) CEL: 32.4 CEL: 58.0 Phase III (Study 1 - PLA: 25.3 PLA: 44.4 NCT03009019)34 Celecoxib Celecoxib (p=0.076; NSS)a (p=0.003) 120 mg/4.8 mL vs. Oral Solution CEL: 35.1 CEL: 56.8 Phase III (Study 2 – Lipton placebo PLA: 21.0 PLA: 43.9 2020)78 (p<0.001) (p=0.006) Abbreviations: CEL, celecoxib; MBS, most bothersome symptom; NSS, non-statistically significant; PLA, placebo; RCT, randomized controlled trial a The difference between celexcoxib oral solution and placebo is not statistically significant

3. Comparative Evidence Among Triptans for Acute Treatment of Migraine

Xu et al (2016) conducted an SR and network meta-analysis (NMA) of RCTs that included conventional pair-wise MAs comparing triptans versus triptans or triptans versus NSAIDs for acute migraine treatment.37 Twenty head-to-head RCTs including almotriptan, diclofenac potassium, eletriptan, naratriptan, sumatriptan, rizatriptan, zolmitriptan, and sumatriptan/naproxen were relevant for this report. Frovatriptan was not included in this network meta-analysis. Direct MAs combined RCTs evaluating different doses and formulations (ie, tablet, nasal spray, and injection) per triptan, although the majority of trials assessed triptans tablets. Trials examined the following efficacy and safety outcomes: 1 hour-pain-free, 2 hour-pain-free, 1 hour-pain-free, 2 hour-pain-free, rescue medication, recurrence, all-adverse event, nausea, and 2 hour-nausea-absence.37 Based on pairwise MAs of RCTs:

- Oral rizatriptan was significantly better compared to oral sumatriptan regarding pain freedom at 1 and 2 hours after treatment. Furthermore, rizatriptan (tablet) was significantly more effective than naratriptan (tablet) concerning pain freedom at 1 or 2 hours post dose, and pain relief at 2 hours post dose; however, recurrence rate of migraine episodes was significantly lower with naratriptan compared to rizatriptan.

- Patients receiving eletriptan therapy showed better outcome compared to those receiving oral sumatriptan or zolmitriptan (tablet) regarding pain relief at 1 hour post dose and pain freedom at 2 hours post dose. In addition, eletriptan was significantly greater in reducing the use of rescue medication compared to oral sumatriptan.

- Almotriptan, naratriptan, and zolmitriptan (tablet) were not statistically different compared to sumatriptan (oral or SQ) regarding pain relief or pain freedom at different time points, use of rescue medication, recurrence of migraine attacks, and incidence of nausea.

- Diclofenac potassium (tablet) was similar to sumatriptan (tablet) concerning 1 hour-pain-free, recurrence of attacks, nausea, and 2 hour-nausea absence.

- No significant differences were reported between oral zolmitriptan and rizatriptan or almotriptan for the main efficacy endpoints (eg, 1 hour-pain-free, 1 hour-pain relief, 2 hour- pain-free, 2 hour-pain-relief, recurrence of migraine attacks, and use of rescue medication).

- Sumatriptan/naproxen (tablet) was significantly more efficacious than sumatriptan monotherapy regarding pain freedom and pain relief at 2 hours after treatment, use of rescue medication, and recurrence rate of migraine attacks.

- Regarding safety outcomes, agents performed similarly with no significant differences in terms of incidence of all adverse events.37

Cameron et al (2015) performed an SR and NMA of RCTs including direct pairwise comparisons between the 7 different triptan agents (almotriptan, eletriptan, frovatriptan, naratriptan, sumatriptan, rizatriptan, and zolmitriptan).79 The NMA included a total of 133 RCTs comparing triptan tablets at standard doses with placebo or active comparators, although it is unclear how many of these RCTs were used for the pairwise comparisons between triptans or how the estimates were calculated. Triptan doses were classified as low dose (half), standard dose (common), and high dose (double). The main efficacy outcomes reported were headache relief at 2 hours, pain freedom at 2 hours, sustained headache relief at 24 hours, sustained pain freedom at 24 hours, and use of rescue medications.79 Authors reported the following results among triptan tablets at standard doses:

- Eletriptan (40 mg tablet) performed more favorably compared to almotriptan 12.5 mg (tablet), naratriptan (2.5 mg tablet), sumatriptan (50 mg tablet), and zolmitriptan (2.5 mg tablet) on all 5 efficacy outcomes.

- Eletriptan (40 mg tablet) performed more favorably compared to frovatriptan (2.5 mg tablet) in terms of headache relief at 2 hours and compared to rizatriptan (10 mg tablet) in terms of headache relief at 24 hours, pain freedom at 24 hours, and use of rescue medications.

- Rizatriptan (10 mg tablet) was significantly better compared to all other triptan tablets except eletriptan 40 mg in terms of headache relief at 2 hours and compared to all other triptan tablets except eletriptan 40 mg and frovatriptan 2.5 mg in terms of pain freedom at 2 hours.

- Naratriptan (2.5 mg tablet) performed more poorly compared to all other triptan tablets except almotriptan (12.5 mg tablet) in terms of pain freedom at 2 hours.79

Worthington et al (2013) developed the Canadian Headache Society (CHS) guideline that included SRs, MAs, and RCTs evaluating agents for the acute treatment of migraine.52 There were no RCTs comparing all triptans with each other. Most head-to-head RCTs evaluated oral sumatriptan versus another oral triptan and used pain-free and/or headache relief at 2 hours as primary efficacy endpoints. Authors concluded that there were small differences among triptans. Head-to-head RCTs showed the presence of some distinctions:52

- Rizatriptan 10 mg (tablet) seems to provide an earlier onset of pain relief in comparison with other triptan tablets and greater relief of nausea compared to sumatriptan (tablet)

- Eletriptan 40 mg (tablet) seems to provide a greater sustained improvement over 24 hours compared to sumatriptan (tablet). This may be caused by the low incidence of headache recurrence with eletriptan

- The occurrence of adverse events seems to be lower with almotriptan 12.5 mg (tablet) compared to zolmitriptan and sumatriptan (tablets)

- Naratriptan and frovatriptan (tablets) have slower onset on action; however, head-to-head trials showed that frovatriptan was similarly efficacious at 2 hours to other triptans. Studies were small with inadequate statistical power to identify differences, and results should be interpreted carefully52

- Trials showed significantly better results in terms of headache relief at 2 hours and sustained pain relief over 24 hours with the oral fixed-dose combination of sumatriptan plus naproxen compared to sumatriptan or naproxen monotherapy52

Menshawy et al (2018) and Derry et al (2012) included 1 RCTs that compared sumatriptan 20 mg nasal spray to rizatriptan 10 mg orally disintegrating tablet (ODT) [SUM40031].80,81 Results from the SUM40031 study were available at the manufacturer’s website. Authors from the Cochrane review (Derry 2012) reported that the percentage of patients with headache relief at 2 hours and relief of migraine-associated symptoms including nausea, photophobia, and phonophobia was numerically higher with rizatriptan compared to sumatriptan (p-value not reported). There were no differences in other outcomes (eg, safety outcomes) between the 2 treatment groups.81

Bird et al (2014) conducted a Cochrane review that included 2 RCTs of oral zolmitriptan 2.5 mg or 5 mg vs. oral sumatriptan 50 mg. A MA of these 2 RCTs showed no significant differences between groups in terms of headache relief at 2 hours post dose and safety outcomes (any adverse events within 24 hours and withdrawals due to adverse events).82 Similar results were reported by the SR from Xu 2016, which included one additional RCT.82

Derry et al (2012) conducted a Cochrane review including 1 RCTs that compared SQ sumatriptan 6 mg vs. several doses of SQ naratriptan (Dahlof 1998) in adult patients with migraine.83 No statistical significance was reported for each comparison. Overall, authors concluded that no sound conclusions on comparative efficacy can be drawn due to limited data.83

Derry et al (2012) conducted a Cochrane review including 17 RCTs that evaluated oral sumatriptan versus other oral triptans in patients with migraine, as specified by IHS diagnostic criteria.84 Cochrane review authors stated that there was enough data for rizatriptan 5 mg, zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg and 80 mg, and almotriptan 12.5 mg to be statistically analyzed for a specific outcome.84 There is extensive evidence of the short-term efficacy of sumatriptan for headache relief; however, data regarding long-term efficacy (sustained headache relief for 24 and 48 hours), relief of headache-associated symptoms, functional disability, and safety outcomes is limited.84 Main clinical outcomes among oral triptans are reported below:

- Rizatriptan 5 mg was superior to sumatriptan 25 mg in terms of pain freedom and headache relief at 2 hours; however, no significant differences between treatment groups were reported for headache relief at 1 hour. These 2 triptan doses are not frequently used

- Rizatriptan 5 mg was similar to sumatriptan 50 mg regarding all reported efficacy outcomes (pain freedom at 2 hours and headache relief at 1 hour and 2 hours)

- Rizatriptan 10 mg was superior to sumatriptan 25 mg, 50 mg, 100 mg regarding all reported efficacy outcomes (eg, pain freedom at 2 hours and headache relief at 1 and 2 hours)

- Zolmitriptan 2.5 mg and 5 mg performed similarly compared to sumatriptan 50 mg in terms of headache relief at 1 or 2 hours

- Almotriptan 12.5 mg was similar to sumatriptan 100 mg in terms of pain freedom at 2 hours and sustained freedom from pain over 24 hours after treatment

- Eletriptan 40 mg and 80 mg were superior to sumatriptan 50 mg and 100 mg regarding most outcomes reported (eg, pain freedom at 2 hours, headache relief at 1 and 2 hours, functional disability); however, sumatriptan 50 mg performed similar to eletriptan 40 mg in terms of headache relief at 1 hour, and sumatriptan 100 mg performed similar to eletriptan 40 mg in terms of pain freedom at 1 hour

- Regarding safety outcomes (eg, any adverse events within 24 hours or specific individual adverse events such as nausea/vomiting and photophobia), there were generally no significant differences between sumatriptan and active comparators

Tepper et al (2015) conducted an RCT (COMPASS trial) to compare sumatriptan 22 mg nasal powder (Onzetra) vs. oral sumatriptan 100 mg in adults with migraine. A significantly higher reduction of migraine pain intensity within the first 30 minutes was reported with sumatriptan nasal powder vs. oral sumatriptan, but pain relief or pain freedom at 2 hours and sustained pain relief or pain freedom from 2 to 24 and 48 hours were comparable between treatment groups. Unpleasant taste and nasal discomfort was numerically higher with nasal powder compared to oral tablets. Incidence of atypical sensations (ie, tingling and tightness of chest, jaw, or neck) was significantly lower with sumatriptan nasal powder. These results suggest an earlier onset of efficacy with the nasal powder formulation, which may be attributed to its pharmacokinetic profile.85

4. Comparative Evidence of Triptans Versus Ergot Derivatives for Acute Treatment of Migraine

Worthington et al (2013),52 2 Cochrane reviews (Derry et al [2012]81 and Derry et al [2012]83), and Menshawy 201880 identified a few RCTs that compared triptans with ergot derivatives in patients with migraine. Overall, comparative trials suggest that triptans are more efficacious than ergot derivatives (DHE and ergotamine/caffeine). Canadian guideline authors considered those RCTs of poor quality.52

- Intranasal or SQ sumatriptan vs. intranasal or SQ DHE:

o Worthington et al reported an RCT (Boureau 2000) showing significantly better efficacy in terms of headache relief at 1 hour with intranasal sumatriptan 20 mg (single dose in 1 nostril) compared to intranasal DHE 1 mg (plus optional 1 mg after 30 minutes).52,86 On the other hand, the Cochrane review by Derry et al (2012) stated that efficacy data comparing sumatriptan and DHE was not usable.81 The incidence of adverse events within 24 hours of treatment and withdrawal rate due to adverse events were numerically similar between sumatriptan and DHE.80,81

o Another RCT (Touchon 1996) reported significantly greater efficacy with SQ sumatriptan 6 mg vs. intranasal DHE 1 mg (plus optional 1 mg after 30 minutes) regarding headache relief at all time intervals (15 minutes to 2 hours) and sustained headache relief over 24 hours. Nevertheless, more patients receiving sumatriptan had headache recurrences than those receiving DHE (31% vs. 17%; no p-value was reported).52,87

Note that the FDA approved dosage for intranasal DHE (ie, DHE 1 mg plus optional 1 mg after 15 minutes) is slightly different than the dosage used in Boureau 2000 and Touchon 1996 (ie, DHE 1 mg plus optional 1 mg after 30 minutes).15

o When SQ sumatriptan 6 mg was compared with SQ DHE 1 mg, no significant differences in headache relief by 4 hours were reported in 1 RCT (Winner 1996); however, patients on DHE had significantly less headache recurrences compared to sumatriptan group.52,88

Derry et al stated in their Cochrane review that a numerically greater percentage of patients achieved efficacy responses with SQ sumatriptan 6 mg compared to SQ or intranasal DHE; however, no sound conclusions can be drawn due to limited data. The percentage of patients experiencing adverse events (eg, nausea and vomiting) was numerically greater with SQ or intranasal DHE compared with sumatriptan.83

- Triptans vs. oral ergotamine/caffeine (Cafergot):

o An RCT showed oral ergotamine/caffeine (2 mg/200 mg) was inferior to oral sumatriptan 100 mg dispersible tablet for headache relief and pain freedom at 2 hours after treatment (p<0.001 for both outcomes); however, the percentage of patients experiencing headache recurrences within 48 hours was significantly higher in the sumatriptan group compared to ergotamine/caffeine group

o A second study demonstrated inferiority of oral ergotamine/caffeine (2 mg/200 mg) compared to oral eletriptan (40 mg and 80 mg) in terms of headache relief and pain freedom at 2 hours (p<0.001 for both outcomes)

o A third RCT reported a significantly higher number of patients achieving headache relief and freedom from pain at 2 hours post-dose with almotriptan vs. oral ergotamine/caffeine

o An MA showed oral ergotamine/caffeine was significantly less efficacious compared to oral sumatriptan.52,84

5. Comparative Evidence of Sumatriptan Versus Diclofenac Potassium for Acute Treatment of Migraine

Worthington et al (2013) identified an RCT that compared oral sumatriptan with oral diclofenac potassium (tablets) in migraine. Overall, sumatriptan was similarly efficacious at relieving headache pain compared to diclofenac potassium.52

- Oral sumatriptan vs. oral diclofenac potassium (tablets):

o A Cochrane review (Derry et al 2012) included an RCT (DKSMSG 1999) that evaluated a single oral dose of sumatriptan 100 mg versus single oral doses of diclofenac potassium

(50 mg and 100 mg) for migraine attacks with or without aura in adults.89 No significant difference was reported between diclofenac potassium (any dose) and sumatriptan for the primary endpoint of headache pain relief at 2 hours post-dose. Diclofenac potassium (any dose) was significantly better than sumatriptan in terms of nausea relief at 2 hours.52,89,90 Note that this trial used a standard tablet formulation of diclofenac potassium without a migraine-specific indication. The FDA-approved diclofenac potassium for acute treatment of migraine (Cambia) is available as a powder for oral solution, which has different pharmacokinetics.10,91

o Derry et al (2013) was a Cochrane review to update the previously reported Cochrane review (Derry et al 2012). The same head-to-head RCT (DKSMSG 1999) was reported.91

6. Comparative Evidence of Butorphanol Versus Butalbital-Containing Products for Acute Treatment of Migraine

Worthington et al (2013) identified an RCT that compared butorphanol with a combination of butalbital/caffeine/aspirin/codeine (Fiorinal with codeine). Overall, butorphanol was more efficacious than the butalbital-containing product at reducing pain intensity in adults with migraine.52

- Butorphanol nasal spray vs. butalbital/caffeine/aspirin/codeine:

An RCT (Goldstein 1998) showed butorphanol 1 mg nasal spray (plus an additional 1-mg dose, if needed) produced a greater reduction in headache pain intensity at 2 hours post-dose (primary efficacy endpoint) compared to butalbital 50 mg/caffeine 40 mg/aspirin 325 mg/codeine 30 mg in adults with moderate to severe migraine. However, there were more adverse events with butorphanol than butalbital-containing product.52,92

7. Comparative Evidence of Sumatriptan/Naproxen Versus Butalbital-Containing Products for Acute Treatment of Migraine

Worthington et al (2013) identified an RCT that compared sumatriptan/naproxen with butalbital/APAP/caffeine showing that the butalbital-containing product may be efficacious for migraine; however, it is not superior to sumatriptan/naproxen.

- Butalbital/APAP/caffeine vs. sumatriptan/naproxen:

Sumatriptan 85 mg/naproxen 500 mg was statistically superior to butalbital 50 mg/ APAP 325 mg/caffeine 40 mg for most secondary endpoints (eg, pain-free, pain relief, associated symptoms) in an RCT (Derosier 2012) including patients with moderate to severe migraine who were previously treated with a butalbital medication. However, there were no significant differences between products for the primary efficacy endpoint of sustained freedom from pain from 2 to 24 hours.52,93 Overall, the study showed that “butalbital-containing analgesics may have efficacy in the treatment of migraine attacks, but are not superior to an NSAID-triptan combination.”52 A limitation highlighted by Canadian guideline authors is that the “study population may have been biased”52 favoring patients who respond to butalbital-containing product.52 Derosier et al emphasize that use of butalbital-containing products for migraine is challenging because these products are associated with risk of dependence, abuse, withdrawal syndrome, and development of chronic daily headache.93

8. Comparative Evidence Between Diclofenac Potassium Powder for Oral Solution and Tablets for Acute Treatment of Migraine

An RCT (Diener 2006) comparing diclofenac potassium 50 mg powder for oral solution and diclofenac potassium 50 mg tablets in patients with moderate to severe migraine showed significantly better results in achieving pain freedom at 2 hours post dose with the oral solution compared to tablets (24.7% vs. 18.5%; p=0.0035).62 In addition, the oral solution was significantly better than tablets for the endpoints of headache intensity reduction at 4 hours post dose, sustained headache response within 24 hours, and sustained pain freedom within 24 hours.61,62

Safety CGRP-Receptor Antagonists The most common side effects of oral ubrogepant were nausea and somnolence, occurring in at least 2% of patients receiving the medication in phase 3 studies and greater than the occurrence in the placebo arm.6 A meta-analysis of the phase 3 studies showed that treatment-related adverse events between ubrogepant and placebo were similar.38 In a long-term follow-up safety study (open-label extension up to 1 year), 2.5% of patients withdrew from ubrogepant because of an adverse event, most commonly due to nausea.6 Prescribing information of ubrogepant does not describe any specific warning or precaution aside from a contraindication with concomitant use of strong CYP3A4 inhibitors.6 For rimegepant, prescribing information states that the most common adverse reaction in the pivotal study was nausea, occurring in 2% of patients receiving the drug compared to 0.4% of patients in the placebo arm.7 Meta-analyses of RCTs in the acute treatment of migraine did not show a significant increase in adverse events with rimegepant compared to placebo.36 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. Rimegepant is contraindicated in patients with a hypersensitivity to the active drug or any components of the product.7 Drug interactions Both rimegepant and ubrogepant are primarily metabolized by CYP3A4. Concomitant administration with strong CYP3A4 inhibitors and strong CYP3A4 inducers should be avoided with these CGRP-receptor antagonists. 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 also depends on potential drug-drug interactions.6,7

Lasmiditan The most commonly reported adverse events with lasmiditan were dizziness, fatigue, paresthesia, and sedation, occurring in at least 5% of patients receiving the medication in phase 3 studies and greater than the occurrence in the placebo arm.4 In a long-term safety study (up to 12 months), 14% of patients receiving lasmiditan 200 mg and 11% of patients receiving lasmiditan 100 mg withdrew from the trial due to an adverse reaction, most commonly due to dizziness.4

Lasmiditan is a Schedule V controlled substance with abuse potential. It has a labeled restriction regarding driving due to its potential to cause CNS depression (ie, dizziness, sedation, reduced metal alertness). 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 central nervous system (CNS) depressants. Clinical trials reported reactions compatible with serotonin syndrome in patients receiving lasmiditan who did not take other agents associated with serotonin syndrome. This syndrome may also occur with lasmiditan in combination with serotonergic drugs.4 Drug Interactions Concomitant use of lasmiditan with alcohol and other CNS depressants can increase the risk for CNS depression. Lasmiditan may decrease heart rate and increase blood pressure. Combination of lasmiditan with heart rate lowering drugs can further decrease heart rate. Patients should be cautious and monitor heart rate when taking lasmiditan and heart rate lowering drugs. Lasmiditan inhibits P-gp and Breast Cancer Resistant Protein (BCRP). Avoid using lasmiditan with P-gp and BCRP substrates. Since lasmiditan acts on the serotonergic system, there is a theoretical risk of serotonin syndrome, particularly when patients are receiving concomitant selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors (MAOIs).4 Triptans and Ergot Derivatives Common adverse reactions reported with the use of triptans include malaise/fatigue, dizziness, somnolence, nausea, dry mouth, numbness, tingling, throat symptoms, hot or cold sensation, pain/pressure sensation, and chest and neck tightness. With nasal spray formulations, unusual taste may occur. With subcutaneous injections, injection-site reactions may occur.1-3,5,8,17,18,28-30 Ergot derivatives are associated with paresthesia, numbness, application site reactions, dizziness, nausea, and vomiting, according to clinical trial data with DHE and ergotamine.9,15 Serious cardiac events (eg, coronary artery vasospasm, myocardial infarction), that were life-threatening but rare, have been reported with the use of injectable DHE.14 A complete list of warnings is included in Table 14 and Table 15. Ischemic Conditions

Both triptans and ergotamines induce cerebral vasoconstriction via stimulation of 5-HT1 receptors. Ergotamines also bind to 5-HT2 receptors and alpha adrenergic receptors. 5-HT2 receptors (and 5-HT1 receptors to a lesser extent) are also present in the coronary and peripheral vasculature.94-96 Vasoconstriction in these areas contributes to the classic constellation of chest, throat, or jaw sensations of tightness, pressure, and/or pain associated with these agents. More seriously, vasoconstriction can increase risk for ischemic or vasospastic coronary artery events (eg, myocardial infarction, coronary artery vasospasm [Prinzmetal's angina]) and life-threatening arrhytmias.1-3,5,8,9,11,12,14-18,28-30,96 With ergotamines, peripheral ischemia can progress to gangrene and tissue death.9,11,12,14,15 Triptans and ergotamines are contraindicated for patients with a history of ischemic coronary artery disease (CAD), coronary artery vasospasm, stroke, transient ischemic attack (TIA), peripheral vascular disease (PVD), ischemic bowel disease, uncontrolled hypertension, and hemiplegic or basilar migraine. A

thorough cardiac workup should be performed prior to initiating these agents, especially for patients with multiple risk factors for CAD such as hypertension, hyperlipidemia, diabetes, obesity, smoking, or a strong family history of CAD.1-3,5,8,9,11,12,14-18,28-30 Cerebrovascular Events Vasoconstriction of the cerebral arteries may increase risk for cerebrovascular events such as cerebral hemorrhage, subarachnoid hemorrhage, and stroke. However, it is possible that in some patients, a cerebrovascular event occurred first and was mistaken for a migraine, and patients subsequently took a triptan or ergotamine. It is important to rule out other serious neurological conditions when treating patients for migraine. Patients with migraines may also be at an elevated baseline risk for cerebrovascular events (eg, stroke) compared to patients without migraines.1-3,5,8,9,11,12,14-18,28-30 Fibrosis There have been reports of pleural, retroperitoneal, and rarely, cardiac valvular fibrosis with chronic daily use of ergotamines. While these events have most commonly been reported with injectable dihydroergotamine and ergotamine/caffeine formulations, fibrosis is listed as a warning for all ergotamine products. These agents should not be used in a chronic daily manner, and all dosing guidelines should be followed.9,11,12,14,15 Drug Interactions Several important drug interactions exist with triptans and ergotamines. As these medications act on the serotonergic system, there is a theoretical risk of serotonin syndrome, particularly when patients are receiving concomitant SSRIs, SNRIs, TCAs, or MAOIs. Patients should be monitored for signs and symptoms of serotonin syndrome, including altered mental status, confusion, agitation, hyperreflexia, muscle rigidity or tremor, severe nausea/vomiting/diarrhea, or labile autonomics, if they are taking any of these serotonergic medications.1-3,5,8,9,11,12,14-18,28-30 Ergotamines are substrates of the CYP3A4 enzyme pathway. As such, CYP3A4 inhibitors increase ergotamine plasma levels and increase the risk of serious adverse events. There have been reports of life-threatening peripheral and cerebral ischemia after concomitant use of ergotamines and CYP3A4 inhibitors. The use of strong CYP3A4 inhibitors is contraindicated with ergotamines, which carry a black box warning for this drug interaction.9,11,12,14,15 There may be synergistic elevation of blood pressure with ergotamines and peripheral vasoconstrictors, such as epinephrine, norepinephrine, ephedrine, pseudoephedrine, phenylephrine, and midodrine.15 Propranolol may block the vasodilatory effects of epinephrine, resulting in unopposed vasoconstriction. Nicotine may cause additional vasoconstriction, potentiating peripheral ischemia. All of these agents should be avoided or used with great caution when taking ergotamines.9,11,12,14,15 Considerations for Sumatriptan Plus Naproxen Treximet (sumatriptan/naproxen) carries additional warnings as a result of the naproxen component. Sumatriptan/naproxen has a black box warning for increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke; increased risk of gastrointestinal (GI) bleeding, ulceration, and perforation; and a contraindication against use in the setting of CABG surgery.16 These warnings apply to all NSAIDs.10,34 Other NSAID-specific warnings include renal and hepatotoxicity; edema and heart failure exacerbation; premature closure of the ductus arteriosus in pregnant women in the

third trimester; exacerbation of asthma and bronchospasm in the setting of aspirin sensitivity; masking of inflammation, fever, and signs of infection; and serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).10,16,34 These additional warnings should be taken into account when using sumatriptan/naproxen. Nonsteroidal Anti-inflammatory Drugs The most common adverse event reported with celecoxib (Elyxyb) was dysgeusia.34 With diclofenac potassium (Cambia), the most common adverse events were nausea and dizziness.10 Like other NSAIDs, diclofenac potassium and celecoxib carry a black box warning related to the risk of serious cardiovascular thrombotic events and serious gastrointestinal events.10,34 A complete list of NSAID- specific warnings was described above for sumatriptan/naproxen and is included in Table 16. Opioids and Barbiturates Use of opioids is limited by adverse effects such as respiratory and CNS depression, and risk of addiction, abuse, and misuse.13 The most common adverse effects reported in clinical trials with butorphanol nasal spray were somnolence (49%), dizziness (23%), and nausea/vomiting (8%). Butorphanol is a schedule IV controlled substance with abuse potential.13 The black box warning (BBW) for butorphanol includes the risk of addiction, abuse, and misuse; the requirement of an opioid analgesic risk evaluation and mitigation strategy (REMS); the potential for life-threatening respiratory depression, accidental exposure (especially by children), and neonatal opioid withdrawal syndrome; and the potential occurrence of adverse events with concomitant use of butorphanol with CYP3A4 inhibitors, benzodiazepines, or CNS depressants.13 Butalbital is available as part of fixed-dose combinations that may include APAP or aspirin, caffeine, and codeine. Codeine is a schedule III controlled substance with abuse potential. In addition, butalbital is associated with risk of dependence, abuse, and withdrawal syndrome.19-27 Combinations of butalbital with codeine carry an opioid-related BBW as a result of the codeine component.24,25 This BBW also includes the risk of life-threatening respiratory depression and death in children who are ultra-rapid metabolizers of codeine.24,25 Combinations of butalbital with APAP carry a black box warning associated with hepatotoxicity due to the APAP component.19-23 Due to the risk of abuse and dependence associated with opioids, butorphanol and combinations of butalbital with codeine are reserved for use when alternative treatments (eg, non-opioid analgesics) are inadequately effective or not tolerated.13,24,25 Medication Overuse Headache The frequent use (> 9 days per month) of traditional acute treatments for migraine (eg, triptans, NSAIDs, ergotamines, opioids, or combination of these agents) is not recommended. Overuse of these agents may exacerbate headaches, increase the frequency of headaches or migraine attacks, and lead to the development of chronic migraine. Triptans, lasmiditan, ergotamines, opioids, and NSAIDs should not be taken more frequently than 9 days per month.16,174,5,10,16,34 Patients can reverse medication overuse headache by discontinuing the causal agents.16,174,5,10,16,34 Medication overuse headache does not appear to be an issue with the CGRP agents thus far. The underlying mechanism is useful for prevention of migraine as there are several CGRP antagonist on the market that are effective for migraine prevention as the patient is under continuous CGRP antagonist

exposure. Additionally, scheduled dosing of rimegepant 75 mg every-other-day has preliminary positive results for migraine prevention (ie, reducing the frequency of migraine with frequent use, as opposed to increasing the frequency). Table 14, Table 15, and Table 16 summarize warnings and precautions for the acute treatments of migraine. Table 14. Warnings and Precautions for Triptans and Lasmiditan Warning/Precaution ALM ELE FRO LAS NAR RIZ SUM ZOL SUM/NAP Risk of myocardial ischemia, myocardial infarction, and X X X X X X X Xa,b coronary artery vasospasm (Prinzmetal’s angina) Risk of life-threatening cardiac arrhythmias, including X X X X X X X ventricular tachycardia and ventricular fibrillation Risk of cerebrovascular events X X X X X X X Xa,b and fatalities Risk of non-coronary vasospasm, including peripheral vascular ischemia, X X X X X X X X GI vascular ischemia, splenic ischemia, and Raynaud’s syndrome Contraindicated in the setting Xa,c of CABG surgery Increased risk of GI bleeding, Xa,c ulceration, and perforation Sensations of pain, tightness, or pressure in the chest, X X X X X X X X throat, neck, or jaw Potential development of medication overuse X X X X X X X X X headaches if used > 9 days per month Risk of serotonin syndrome, particularly with SSRIs, SNRIs, X X X X X X X X X TCAs, or MAOIs Increase in blood pressure X X X X X X X X Use with caution in patients with seizure disorders or X X conditions that lower seizure threshold Anaphylaxis and X X X X X hypersensitivity reactions Long-term development of X corneal opacities Use with caution in patients with renal or hepatic X impairment

Table 14. Warnings and Precautions for Triptans and Lasmiditan Warning/Precaution ALM ELE FRO LAS NAR RIZ SUM ZOL SUM/NAP Exercise caution with known hypersensitivity to X sulfonamides Potentially severe local Xd irritation Potential harm for patients Xe with phenylketonuria Elevated liver tests and Xc hepatotoxicity Renal toxicity and Xc hyperkalemia Heart failure exacerbation and Xc edema Hematologic toxicity and Xc anemia Premature closure of the Xc ductus arteriosus in pregnant women Exacerbation of asthma and Xc bronchospasm with aspirin sensitivity Masking of inflammation, Xc fever, and signs of infection Serious skin reactions, Xc including SJS and TEN Periodic laboratory monitoring Xc recommended for GI bleeding, hepatoxicity, and renal impairment Driving Impairment/ warning X against machinery operation CNS depression (eg, dizziness, X sedation) Abbreviations: ALM, almotriptan; CABG, coronary artery bypass graft; CNS, central nervous system; ELE, eletriptan; FRO, frovatriptan; GI, gastrointestinal; LAS, lasmiditan; MAOIs, monoamine oxidase inhibitors; NAR, naratriptan; RIZ, rizatriptan; SJS, Stevens-Johnson syndrome; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; SUM, sumatriptan; SUM/NAP, sumatriptan/naproxen; TCAs, tricyclic antidepressants; TEN, toxic epidermal necrolysis; ZOL, zolmitriptan a Boxes outlined in black indicate a black box warning b Sumatriptan/naproxen carries a black box warning for increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be life-threatening c Attributed to the naproxen component of the formulation d Only applies to the nasal spray formulation of sumatriptan e Only applies to the orally disintegrating tablet formulation of zolmitriptan as this product contains phenylalanine

Table 15. Warnings and Precautions for Ergot Derivatives8,9,13,14 Warning/Precaution DHE ERG ERG/CAF Severe or life-threatening cerebral or peripheral ischemia with concomitant use of Xa Xa Xa CYP3A4 inhibitors Risk of myocardial ischemia, myocardial X infarction, and coronary artery vasospasm Risk of life-threatening cardiac arrhythmias X Risk of cerebrovascular events and fatalities X Risk of ergotism, non-coronary vasospasm, and peripheral ischemia that may progress to X X X gangrene or death Increase in blood pressure X Pleural, retroperitoneal, or cardiac valvular X X X fibrosis with chronic daily useb Local irritation Xc Avoid use while pregnant or breastfeeding X X X Safety and efficacy have not been established X X X for pediatric use Safety and efficacy have not been established Xc for geriatric use Significant drug interactions exist with other vasoconstrictors, sumatriptan, propranolol, X X X nicotine, and potentially SSRIs Provide and discuss important patient information, directions for use, and serious X X X adverse events with all patients Do not exceed dosing guidelines; not for X X X chronic daily use Abbreviations: CYP, cytochrome P 450; DHE, dihydroergotamine mesylate; ERG, ergotamine; ERG/CAF, ergotamine/caffeine; SSRIs, selective serotonin reuptake inhibitors a Boxes outlined in black indicate a black box warning b Fibrosis has most commonly been reported with injectable dihydroergotamine or ergotamine/caffeine formulations c Only applies to the nasal spray formulation of dihydroergotamine

Table 16. Warnings and Precautions for Nonsteroidal Anti-inflammatory Drugs Warning/Precaution DIC CEL Risk of serious CV and GI Events X X Hepatotoxicity X X Hypertension X X Heart failure and edema X X Renal toxicity X X Anaphylactic Reactions X X Exacerbation of Asthma Related to Aspirin Sensitivity X X Serious Skin Reactions X X Medication overuse headache X X Hematologic toxicity X X Premature closure of fetal ductus arteriosus X X Abbreviations: CEL, celecoxib; CV, cardiovascular; DIC, diclofenac; GI, gastrointestinal

Summary Regarding preference of acute treatments for migraine in the Utah Medicaid PDL, the P&T Committee may consider the following suggestions:

- Consider at least 2 triptans as preferred agents, with at least 1 of them being a non-traditional oral formulation (eg, ODT) or a non-oral formulation (eg, intranasal or injectable formulation) that can be taken in the event of nausea/vomiting or with swallowing difficulty.

o The AHS recommends migraine-specific agents (triptans or DHE) for moderate to severe migraine attacks and mild to moderate migraine attacks that respond inadequately to non- opioid analgesics (eg, NSAIDs). Triptans are usually preferred over DHE. There is evidence suggesting that eletriptan and/or rizatriptan have better efficacy than other oral triptans at relieving headache or achieving pain freedom in patients with migraine; however, clinical practice guidelines do not state a preference for 1 triptan over another. In addition, the AHS states that non-oral formulations (eg, subcutaneous injection, nasal spray) and agents available as orally disintegrating or rapid melting tablets can be offered for patients with migraine accompanied by severe nausea or vomiting, for patients who have swallowing difficulties, and for patients with inadequate response to traditional oral formulations.

- Consider butalbital-containing products and butorphanol as non-preferred products since the AHS highlights that these products are generally not recommended for regular use in patients with migraine due to the availability of more effective migraine-specific agents and the risk of dependence, abuse, and medication overuse headache.

Other points to consider are included below:

- Considerations for CGRP-receptor antagonists (rimegepant, ubrogepant) and lasmiditan:

o CGRP-receptor antagonists are efficacious in the treatment of moderate to severe migraine attacks with a favorable safety profile. Common adverse events include nausea (with ubrogepant and rimegepant) and somnolence (with ubrogepant). Rimegepant can cause hypersensitivity reactions (eg, dyspnea and rash) and prescribing information for ubrogepant does not specify any warnings aside from a contraindication with concomitant use of strong CYP3A4 inhibitors. CGRP-receptor antagonists do not appear to be associated with medication overuse headache. Lasmiditan is also efficacious for patients with moderate to severe migraine but seems to have more safety concerns than the CGRP-receptor antagonists. Common adverse events with lasmiditan include dizziness, fatigue, paresthesia, and sedation. Lasmiditan is a schedule V controlled substance and prescribing information warns about the potential for development of medication overuse headache, risk of serotonin syndrome, CNS depression such as dizziness and sedation, and driving impairment. As there are no head-to-head RCTs comparing lasmiditan, ubrogepant, and rimegepnat versus each other or versus other acute treatments of migraine, it is unclear whether there are differences in efficacy and safety among them. The AHS states that ubrogepant, rimegepant, and lasmiditan should be offered when triptans are contraindicated or when at least 2 oral triptans are inadequately effective or not tolerated.

Potential inclusion of at least 1 CGRP-receptor antagonist (rimegepant or ubrogepant) as preferred in the PDL may be considered since these agents can be used in some populations with contraindications to triptans and appear to have fewer safety concerns than lasmiditan.

o Prior authorization criteria are currently in place for the 2 CGRP-receptor antagonists requiring failure of at least 1 preferred agent from 2 or 3 drug classes (triptans, NSAIDs, APAP) before accessing a CGRP-receptor antagonist.

- Considerations for acute treatments of migraine in pediatric patients:

o The 2019 American Academy of Neurology (AAN) guideline for acute treatment of migraine in pediatric patients recommends ibuprofen 10 mg/kg oral solution as initial therapy in children and adolescents. For adolescents, several other medications including sumatriptan/naproxen oral tablets, sumatriptan nasal spray, zolmitriptan nasal spray, rizatriptan ODT, or almotriptan oral tablets have evidence supporting their use in reducing migraine pain and should be offered in this population.

o Ibuprofen is listed as a preferred agent in the PDL under the NSAID category. Among the triptans recommended by the 2019 AAN guideline, rizatriptan (tablet and ODT) is listed as preferred under the Migraine Agents, Abortive Therapy category.

- Considerations for oral NSAID solutions with a migraine-specific indication in adults (ie, diclofenac potassium powder for oral solution or celecoxib oral solution):

o The AHS recommends non-opioid analgesics such as NSAIDs, APAP, or caffeinated combinations for acute treatment of mild to moderate migraine attacks. The 2015 AHS expert review on migraine pharmacotherapies in adults states that NSAIDs (eg, diclofenac 50 and 100 mg, ibuprofen 200 and 400 mg, and naproxen 500 and 550 mg) are established as effective (Level A evidence) for the acute treatment of migraine in adults.

o No head-to-head comparisons of diclofenac potassium or celecoxib oral solutions versus each other or versus other acute treatments of migraine were identified. These 2 oral solutions are more rapidly absorbed and show a shorter time to peak concentration compared to the capsule or tablet counterpart, which are not specifically approved for migraine. In addition, an RCT showed diclofenac potassium oral solution outperformed the tablet in terms of migraine-related pain freedom at 2 hours after treatment.

o Several NSAIDs without a migraine-specific indication are listed as preferred in the PDL under the NSAID category (eg, generic diclofenac potassium, ibuprofen, and naproxen tablet, and Zipsor [diclofenac potassium capsule]). Thus patients have access to oral NSAID options for migraine treatment, and if needing an oral solution, patients can use ibuprofen which is available in a generic oral suspension at 200 mg-400 mg, the effective dose for migraine per the 2015 AHS guideline.

References

1. Maxalt and Maxalt-MLT (rizatriptan) [package insert]. Whitehouse station, NJ: Merck Sharp & Dohme Corp.; revised October 2019. 2. Relpax (eletriptan) [package insert]. New York, NY: Pfizer Inc; revised March 2020. 3. Almotriptan [package insert]. Bridgewater, NJ: Ajanta Pharma Limited; revised November 2019. 4. Reyvow (lasmiditan) [package insert]. Indianapolis, IN: Lilly USA, LLC; revised January 2020. 5. Naratriptan [package insert]. Princeton, NJ: OrchidPharma, Inc.; revised December 2019. 6. Ubrelvy (ubrogepant) [package insert]. Madison, NJ: Allergan USA, Inc.; revised December 2019. 7. Nurtec ODT (rimegepant) [package insert]. New Haven, CT: Biohaven Pharmaceuticals Inc.; revised February 2020. 8. Frovatriptan [package insert]. Mahwah, NJ: Glenmark Pharmaceuticals Inc.; revised December 2019. 9. Ergomar (ergotamine tartrate) [package insert]. Lake Forest, IL: TerSera Therapeutics LLC; revised May 2018. 10. Cambia (diclofenac potassium) [package insert]. Newark, CA: Depomed, Inc.; revised March 2017. 11. Cafergot (ergotamine tartrate and caffeine) [package insert]. Princeton, NJ: Sandoz Inc.; revised December 2019. 12. Migergot (ergotamine tartrate and caffeine) [package insert]. South Plainfield, NJ: Cosette Pharmaceuticals , Inc.; revised August 2019. 13. Butorphanol nasal spray [package insert]. Morgantown, WV: Mylan Pharmaceuticals Inc.; revised August 2019. 14. D.H.E. 45 (dihydroergotamine mesylate) [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; revised November 2017. 15. Migranal (dihydroergotamine mesylate) [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; revised August 2019. 16. Treximet (sumatriptan and naproxen sodium) [package insert]. Morristown, NJ: Pernix Therapeutics; revised July 2019. 17. Zomig (zolmitriptan) nasal spray [package insert]. Bridgewater, NJ: Amneal Pharmaceuticals LLC; revised May 2019. 18. Zomig and Zomig-ZMT (zolmitriptan) [package insert]. Hayward, CA: Impax Laboratories; revised December 2018. 19. Butalbital and acetaminophen capsule [package insert]. Chantilly, VA: Granules Pharmaceuticals Inc.; revised December 2019. 20. Butalbital and acetaminophen tablet [package insert]. Pine Brook, NJ: Alvogen, Inc.; revised January 2020. 21. Butalbital, acetaminophen, and caffeine capsule [package insert]. Philadelphia, PA: Lannett Company, Inc.; revised April 2019. 22. Butalbital, acetaminophen, and caffeine tablet [package insert]. Chestnut Ridge, NY: Par Pharmaceutical; revised October 2019. 23. Butalbital, acetaminophen, and caffeine syrup [package insert]. Atlanta, GA: Mikart, Inc.; revised April 2019. 24. Fioricet with codeine (butalbital, acetaminophen, caffeine, and codeine) capsule [package insert]. Parsippany, NJ: Actavis Pharma, Inc.; revised February 2020. 25. Fiorinal with codeine (butalbital, aspirin, caffeine, and codeine) capsule [package insert]. Madison, NJ: Allergan USA, Inc.; revised October 2019.

26. Fiorinal (butalbital, aspirin, and caffeine) capsule [package insert]. Madison, NJ: Allergan USA, Inc.; revised June 2018. 27. Butalbital, aspirin, and caffeine tablet [package insert]. Yardley, PA: Vensun Pharmaceuticals, Inc.; revised July 2016. 28. Imitrex (sumatriptan succinate) injection [package insert]. Research Triangle Park, NC: GlaxoSmithKline; revised July 2018. 29. Imitrex (sumatriptan succinate) nasal spray [package insert]. Research Triangle Park, NC: GlaxoSmithKline; revised December 2017. 30. Imitrex (sumatriptan succinate) tablet [package insert]. Research Triangle Park, NC: GlaxoSmithKline; revised December 2017. 31. Onzetra Xsail (sumatriptan) [package insert]. Morristown, NJ: Currax Pharmaceuticals LLC; revised December 2019. 32. Tosymra (sumatriptan) [package insert]. Princeton, NJ: Promius Pharma, LLC.; revised January 2019. 33. Zembrace SymTouch (sumatriptan succinate) [package insert]. Princeton, NJ: Promius Pharma, LLC.; revised June 2019. 34. Elyxyb (celecoxib) [package insert]. Telangana, India: Dr. Reddy’s Laboratories Limited; revised May 2020. 35. Biohaven Achieves Positive Results in Pivotal Trial of Oral Nurtec, Dosed Every Other Day, for the Preventive Treatment of Migraine [news release]. Biohaven Pharmaceutical’s website. https://www.biohavenpharma.com/investors/news-events/press-releases/03-30-2020. Accessed May 20, 2020. 36. Gao B, Yang Y, Wang Z, et al. Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine: Evidence From Randomized Controlled Trials. Frontiers in pharmacology. 2019;10(101548923):1577. 37. Xu H, Han W, Wang J, Li M. Network meta-analysis of migraine disorder treatment by NSAIDs and triptans. The journal of headache and pain. 2016;17(1):113. 38. Yang Y, Chen M, Sun Y, Gao B, Chen Z, Wang Z. Safety and Efficacy of Ubrogepant for the Acute Treatment of Episodic Migraine: A Meta-Analysis of Randomized Clinical Trials. CNS Drugs. 2020;34(5):463-471. 39. Atlas S, Touchette D, Agboola F, Lee T, Chapman R, Pearson S D, Rind D M. Acute Treatments for Migraine: Effectiveness and Value. Institute for Clinical and Economic Review, January 8,2020. http://icer-review.org/material/acute-migraine-evidence-report/. 40. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. 41. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. 42. The American Headache Society Position Statement On Integrating New Migraine Treatments Into Clinical Practice. Headache. 2019;59(1):1-18. 43. Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA. Migraine and the trigeminovascular system-40 years and counting. Lancet Neurol. 2019;18(8):795-804. 44. Henson B, Hollingsworth H, Nevois E, Herndon C. Calcitonin Gene-Related Peptide (CGRP) Antagonists and Their Use in Migraines. J Pain Palliat Care Pharmacother. 2020;34(1):22-31. 45. Kelman L. The triggers or precipitants of the acute migraine attack. Cephalalgia. 2007;27(5):394- 402. 46. Oskoui M, Pringsheim T, Holler-Managan Y, et al. Practice guideline update summary: Acute treatment of migraine in children and adolescents: Report of the Guideline Development,

Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society. Headache. 2019;59(8):1158-1173. 47. National Center for Health Statistics. National Health Interview Survey, 2018. Table A-5. Migraines and pain in neck, lower back, face, or jaw among adults aged 18 and over, by selected characteristics: United States, 2018. Centers for Disease Control and Prevention. Available at: https://ftp.cdc.gov/pub/Health_Statistics/NCHS/NHIS/SHS/2018_SHS_Table_A-5.pdf. Accessed May 11, 2020. 48. Abu-Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies. Dev Med Child Neurol. 2010;52(12):1088-1097. 49. Laurell K, Artto V, Bendtsen L, et al. Premonitory symptoms in migraine: A cross-sectional study in 2714 persons. Cephalalgia. 2016;36(10):951-959. 50. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. Headache. 2015;55(1):3-20. 51. Pringsheim T, Davenport WJ, Marmura MJ, Schwedt TJ, Silberstein S. How to Apply the AHS Evidence Assessment of the Acute Treatment of Migraine in Adults to your Patient with Migraine. Headache. 2016;56(7):1194-1200. 52. Worthington I, Pringsheim T, Gawel MJ, et al. Canadian Headache Society Guideline: acute drug therapy for migraine headache. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques. 2013;40(5 Suppl 3):S1-S80. 53. Moreno-Ajona D, Chan C, Villar-Martinez MD, Goadsby PJ. Targeting CGRP and 5-HT1F Receptors for the Acute Therapy of Migraine: A Literature Review. Headache. 2019;59 Suppl 2(2985091r, g1n):3-19. 54. Choosing Wisely. American Board of Internal Medicine (ABIM) Initiative Foundation of behalf of American Academy of Neurology. Don’t use opioid or butalbital treatment for migraine except as a last resort. (Released February 21, 2013). ABIM Foundation: Philadelphia, PA. https://www.choosingwisely.org/clinician-lists/american-academy-neurology-opioid-or- butalbital-treatment-for-migraine/. Accessed May 11, 2020. 55. Loder E, Weizenbaum E, Frishberg B, Silberstein S. Choosing wisely in headache medicine: the American Headache Society's list of five things physicians and patients should question. Headache. 2013;53(10):1651-1659. 56. Robbins MS, Starling AJ, Pringsheim TM, Becker WJ, Schwedt TJ. Treatment of Cluster Headache: The American Headache Society Evidence-Based Guidelines. Headache. 2016;56(7):1093-1106. 57. National Institute for Health and Care Excellence (NICE). Headaches in over 12s: diagnosis and management. Clinical guideline [CG150]. Published date: 19 September 2012. Last updated: 25 November 2015. https://www.nice.org.uk/guidance/cg150. Accessed April 27, 2020. 58. Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J. EFNS guideline on the treatment of tension-type headache - Report of an EFNS task force. European Journal of Neurology. 2010;17(11):1318-1325. 59. Ashina M, Vasudeva R, Jin L, et al. Onset of Efficacy Following Oral Treatment With Lasmiditan for the Acute Treatment of Migraine: Integrated Results From 2 Randomized Double-Blind Placebo-Controlled Phase 3 Clinical Studies. Headache. 2019;59(10):1788-1801. 60. Peck J, Urits I, Zeien J, et al. A Comprehensive Review of Over-the-counter Treatment for Chronic Migraine Headaches. Current Pain and Headache Reports. 2020;24(5). 61. Joshi S, Rapoport AM. Diclofenac potassium for oral solution (CAMBIA(®)) in the acute management of a migraine attack: clinical evidence and practical experience. Ther Adv Neurol Disord. 2017;10(4):217-226.

62. Diener HC, Montagna P, Gács G, et al. Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo. Cephalalgia. 2006;26(5):537-547. 63. Pal A, Shenoy S, Gautam A, et al. Pharmacokinetics of DFN-15, a Novel Oral Solution of Celecoxib, Versus Celecoxib 400-mg Capsules: A Randomized Crossover Study in Fasting Healthy Volunteers. Clin Drug Investig. 2017;37(10):937-946. 64. Lexi-Drugs, Drug Monographs. Lexicomp Online 2020. In: Wolters Kluwer. Accessed May 5, 2020. 65. Micromedex (electronic version). Truven Health Analytics; 2020. http://www.micromedexsolutions.com/. Accessed May 5, 2020. 66. Burch R. Epidemiology and Treatment of Menstrual Migraine and Migraine During Pregnancy and Lactation: A Narrative Review. Headache. 2020;60(1):200-216. 67. Xu F, Sun W. Network Meta-Analysis of Calcitonin Gene-Related Peptide Receptor Antagonists for the Acute Treatment of Migraine. Frontiers in pharmacology. 2019;10(101548923):795. 68. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34(2):114-125. 69. Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double- blind study of lasmiditan for acute treatment of migraine. Brain. 2019;142(7):1894-1904. 70. Kuca B, Silberstein SD, Wietecha L, Berg PH, Dozier G, Lipton RB. Lasmiditan is an effective acute treatment for migraine: A phase 3 randomized study. Neurology. 2018;91(24):e2222-e2232. 71. Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the Treatment of Migraine. N Engl J Med. 2019;381(23):2230-2241. 72. Lipton RB, Dodick DW, Ailani J, et al. Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. Jama. 2019;322(19):1887-1898. 73. Croop R, Goadsby PJ, Stock DA, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019;394(10200):737-745. 74. Farkkila M, Diener HC, Geraud G, et al. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo- controlled, parallel-group, dose-ranging study. Lancet Neurol. 2012;11(5):405-413. 75. 60th Annual Scientific Meeting American Headache Society® June 28–July 1, 2018 Marriott Marquis San Francisco San Francisco, CA. Headache: The Journal of Head and Face Pain. 2018;58(8):1287-1337. 76. Lipton RB, Croop R, Stock EG, et al. Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med. 2019;381(2):142-149. 77. Voss T, Lipton RB, Dodick DW, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016;36(9):887-898. 78. Lipton RB, Munjal S, Brand-Schieber E, Tepper SJ, Dodick DW. Efficacy, Tolerability, and Safety of DFN-15 (Celecoxib Oral Solution, 25 mg/mL) in the Acute Treatment of Episodic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study. Headache. 2020;60(1):58-70. 79. Cameron C, Kelly S, Hsieh S-C, et al. Triptans in the Acute Treatment of Migraine: A Systematic Review and Network Meta-Analysis. Headache. 2015;55 Suppl 4(2985091r, g1n):221-235. 80. Menshawy A, Ahmed H, Ismail A, et al. Intranasal sumatriptan for acute migraine attacks: a systematic review and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;39(1):31-44.

81. Derry CJ, Derry S, Moore RA. Sumatriptan (intranasal route of administration) for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2012(2):CD009663. 82. Bird S, Derry S, Moore RA. Zolmitriptan for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2014(5):CD008616. 83. Derry CJ, Derry S, Moore RA. Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2012(2):CD009665. 84. Derry CJ, Derry S, Moore RA. Sumatriptan (oral route of administration) for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2012(2):CD008615. 85. Tepper SJ, Cady RK, Silberstein S, et al. AVP-825 breath-powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg oral sumatriptan in the acute treatment of migraines (The COMPASS study): a comparative randomized clinical trial across multiple attacks. Headache. 2015;55(5):621-635. 86. Boureau F, Kappos L, Schoenen J, Esperanca P, Ashford E. A clinical comparison of sumatriptan nasal spray and dihydroergotamine nasal spray in the acute treatment of migraine. Int J Clin Pract. 2000;54(5):281-286. 87. Touchon J, Bertin L, Pilgrim AJ, Ashford E, Bès A. A comparison of subcutaneous sumatriptan and dihydroergotamine nasal spray in the acute treatment of migraine. Neurology. 1996;47(2):361- 365. 88. Winner P, Ricalde O, Le Force B, Saper J, Margul B. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol. 1996;53(2):180-184. 89. Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. The Cochrane database of systematic reviews. 2012(2):CD008783. 90. Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac-potassium, in comparison to oral sumatriptan and placebo. The Diclofenac- K/Sumatriptan Migraine Study Group. Cephalalgia. 1999;19(4):232-240. 91. Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. The Cochrane database of systematic reviews. 2013(4):CD008783. 92. Goldstein J, Gawel MJ, Winner P, et al. Comparison of butorphanol nasal spray and fiorinal with codeine in the treatment of migraine. Headache. 1998;38(7):516-522. 93. Derosier F, Sheftell F, Silberstein S, et al. Sumatriptan-naproxen and butalbital: a double-blind, placebo-controlled crossover study. Headache. 2012;52(4):530-543. 94. Neeb L, Meents J, Reuter U. 5-HT(1F) Receptor agonists: a new treatment option for migraine attacks? Neurotherapeutics. 2010;7(2):176-182. 95. MacIntyre PD, Bhargava B, Hogg KJ, Gemmill JD, Hillis WS. Effect of subcutaneous sumatriptan, a selective 5HT1 agonist, on the systemic, pulmonary, and coronary circulation. Circulation. 1993;87(2):401-405. 96. MaassenVanDenBrink A, Reekers M, Bax WA, Ferrari MD, Saxena PR. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation. 1998;98(1):25-30. 97. Gallagher RM, Dennish G, Spierings EL, Chitra R. A comparative trial of zolmitriptan and sumatriptan for the acute oral treatment of migraine. Headache. 2000;40(2):119-128. 98. Gruffyd-Jones K, Kies B, Middleton A, Mulder LJ, Rosjo O, Millson DS. Zolmitriptan versus sumatriptan for the acute oral treatment of migraine: a randomized, double-blind, international study. Eur J Neurol. 2001;8(3):237-245. 99. Geraud G, Olesen J, Pfaffenrath V, et al. Comparison of the efficacy of zolmitriptan and sumatriptan: issues in migraine trial design. Cephalalgia. 2000;20(1):30-38.

100. Spierings EL, Gomez-Mancilla B, Grosz DE, Rowland CR, Whaley FS, Jirgens KJ. Oral almotriptan vs. oral sumatriptan in the abortive treatment of migraine: a double-blind, randomized, parallel- group, optimum-dose comparison. Arch Neurol. 2001;58(6):944-950. 101. Dodick DW. Almotriptan increases sustained pain-free outcomes in acute migraine: results from three controlled clinical trials. Headache. 2002;42(1):21-27. 102. Dowson AJ, Massiou H, Lainez JM, Cabarrocas X. Almotriptan improves response rates when treatment is within 1 hour of migraine onset. Headache. 2004;44(4):318-322. 103. Göbel H, Winter P, Boswell D, et al. Comparison of naratriptan and sumatriptan in recurrence- prone migraine patients. Naratriptan International Recurrence Study Group. Clin Ther. 2000;22(8):981-989. 104. Dahlof C, Hogenhuis L, Olesen J, et al. Early clinical experience with subcutaneous naratriptan in the acute treatment of migraine: a dose-ranging study. Eur J Neurol. 1998;5(5):469-477. 105. Havanka H, Dahlöf C, Pop PH, et al. Efficacy of naratriptan tablets in the acute treatment of migraine: a dose-ranging study. Naratriptan S2WB2004 Study Group. Clin Ther. 2000;22(8):970- 980. 106. Dahlof C, Winter P, Whitehouse H, Hassani H. Randomized, double-blind, placebo-controlled comparison of oral naratriptan and oral sumatriptan in the acute treatment of migraine [abstract]. Neurology. 1997;48(3):A85-A6. 107. Goldstein J, Ryan R, Jiang K, et al. Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 mg and 50 mg in migraine. Rizatriptan Protocol 046 Study Group. Headache. 1998;38(10):737-747. 108. Kolodny A, Polis A, Battisti WP, Johnson-Pratt L, Skobieranda F. Comparison of rizatriptan 5 mg and 10 mg tablets and sumatriptan 25 mg and 50 mg tablets. Cephalalgia. 2004;24(7):540-546. 109. Tfelt-Hansen P, Teall J, Rodriguez F, et al. Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group. Headache. 1998;38(10):748-755. 110. Visser WH, Terwindt GM, Reines SA, Jiang K, Lines CR, Ferrari MD. Rizatriptan vs sumatriptan in the acute treatment of migraine. A placebo-controlled, dose-ranging study. Dutch/US Rizatriptan Study Group. Arch Neurol. 1996;53(11):1132-1137. 111. A randomised double-blind, double-dummy, single-attack, parallel group study to compare the speed of onset of sumatriptan nasal spray (20 mg) with rizatriptan wafer (10 mg) in he acute treatment of migraine. www.gskclinicalstudyregister.com/. 112. Lines CR, Vandormael K, Malbecq W. A comparison of visual analog scale and categorical ratings of headache pain in a randomized controlled clinical trial with migraine patients. Pain. 2001;93(2):185-190. 113. Mathew NT, Schoenen J, Winner P, Muirhead N, Sikes CR. Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg. Headache. 2003;43(3):214-222. 114. Goadsby PJ, Ferrari MD, Olesen J, et al. Eletriptan in acute migraine: a double-blind, placebo- controlled comparison to sumatriptan. Eletriptan Steering Committee. Neurology. 2000;54(1):156-163. 115. Sandrini G, Färkkilä M, Burgess G, Forster E, Haughie S. Eletriptan vs sumatriptan: a double- blind, placebo-controlled, multiple migraine attack study. Neurology. 2002;59(8):1210-1217. 116. A multicentre, double-blind, placebo controlled, parallel group study of two dose levels of oral eletriptan and two dose levels of oral sumatriptan given for the acute treatment of migraine. Pfizer clinical trial report 1998 (unpublished data). 117. Goadsby PJ, Massiou H, Pascual J, et al. Almotriptan and zolmitriptan in the acute treatment of migraine. Acta Neurol Scand. 2007;115(1):34-40.

118. Pascual J, Vega P, Diener HC, Allen C, Vrijens F, Patel K. Comparison of rizatriptan 10 mg vs. zolmitriptan 2.5 mg in the acute treatment of migraine. Rizatriptan-Zolmitriptan Study Group. Cephalalgia. 2000;20(5):455-461. 119. Steiner TJ, Diener HC, MacGregor EA, Schoenen J, Muirheads N, Sikes CR. Comparative efficacy of eletriptan and zolmitriptan in the acute treatment of migraine. Cephalalgia. 2003;23(10):942- 952. 120. Bomhof M, Paz J, Legg N, Allen C, Vandormael K, Patel K. Comparison of rizatriptan 10 mg vs. naratriptan 2.5 mg in migraine. Eur Neurol. 1999;42(3):173-179. 121. Bartolini M, Giamberardino MA, Lisotto C, et al. A double-blind, randomized, multicenter, Italian study of frovatriptan versus almotriptan for the acute treatment of migraine. J Headache Pain. 2011;12(3):361-368. 122. Bartolini M, Giamberardino MA, Lisotto C, et al. Frovatriptan versus almotriptan for acute treatment of menstrual migraine: analysis of a double-blind, randomized, cross-over, multicenter, Italian, comparative study. J Headache Pain. 2012;13(5):401-406. 123. Savi L, Omboni S, Lisotto C, et al. A double-blind, randomized, multicenter, Italian study of frovatriptan versus rizatriptan for the acute treatment of migraine. J Headache Pain. 2011;12(2):219-226. 124. Tullo V, Allais G, Ferrari MD, et al. Frovatriptan versus zolmitriptan for the acute treatment of migraine: a double-blind, randomized, multicenter, Italian study. Neurol Sci. 2010;31 Suppl 1(Suppl 1):S51-54. 125. Tullo V, Allais G, Curone M, et al. Frovatriptan versus zolmitriptan for the acute treatment of migraine with aura: a subgroup analysis of a double-blind, randomized, multicenter, Italian study. Neurol Sci. 2012;33 Suppl 1(Suppl 1):S61-64. 126. Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. Jama. 2007;297(13):1443-1454. 127. Smith TR, Sunshine A, Stark SR, Littlefield DE, Spruill SE, Alexander WJ. Sumatriptan and naproxen sodium for the acute treatment of migraine. Headache. 2005;45(8):983-991. 128. A randomized, double-blind comparison of sumatriptan and Cafergot in the acute treatment of migraine. The Multinational Oral Sumatriptan and Cafergot Comparative Study Group. Eur Neurol. 1991;31(5):314-322. 129. Diener HC, Jansen JP, Reches A, Pascual J, Pitei D, Steiner TJ. Efficacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: a multicentre, randomised, double-blind, placebo-controlled comparison. Eur Neurol. 2002;47(2):99-107. 130. Láinez MJ, Galván J, Heras J, Vila C. Crossover, double-blind clinical trial comparing almotriptan and ergotamine plus caffeine for acute migraine therapy. Eur J Neurol. 2007;14(3):269-275.

Appendix A – Additional Product Information

Table 1. Comparison Table for Agents Indicated for the Acute Treatment of Migraine and Other Primary Headaches Generic Name Preparations Brand Name (Availability of Labeled Indication(s) Recommended Dosage (Approval date) Generic) Selective Serotonin Agonists Almotriptan1 Tablets: 6.25 mg Acute treatment of migraine attacks Recommended dose: 6.25 mg or and 12.5 mg in adults with a history of migraine 12.5 mg single dose. Dose may Axert (Generic Only) with or without aura be repeated after 2 hours if (2001 – Brand DSC) headache returns Acute treatment of migraine headache pain in adolescents 12 to Maximum daily dose: 25 mg 17 years with a history of migraine attacks with or without aura usually Reduce dose in hepatic and lasting 4 hours or more (when renal impairment untreated)

Not indicated for the prophylactic therapy of migraine, for the management of hemiplegic or basilar migraine, and for treatment of cluster headache Eletriptan2 Tablets: 20 mg Acute treatment of migraine with or Recommended dose: 20 mg or and 40 mg without aura in adults 40 mg single dose. Dose may be Relpax (Generic repeated after 2 hours if (2002) available) Not indicated for the prophylactic headache returns therapy of migraine and for treatment of cluster headache Maximum daily dose: 80 mg Frovatriptan3 Tablets: 2.5 mg Acute treatment of migraine with or Recommended dose: 2.5 mg (Generic without aura in adults single dose. Dose may be Frova available) repeated after 2 hours if (2001) Not indicated for the prophylactic headache returns therapy of migraine and for treatment of cluster headache Maximum daily dose: 7.5 mg Lasmiditan5 Tablets: 50 mg, Acute treatment of migraine with or Recommended dose: 50 mg, 100 mg without aura in adults 100 mg, or 200 mg as needed. Reyvow

(2019) Not indicated for the preventive No more than 1 dose per day treatment of migraine Naratriptan6 Tablets: 1 mg Acute treatment of migraine with or Recommended dose: 1 mg or and 2.5 mg without aura in adults 2.5 mg. Dose may be repeated Amerge (Generic after 4 hours if headache (1998) available) Not indicated for the prophylactic returns therapy of migraine and for treatment of cluster headache Maximum daily dose: 5 mg

Reduce dose in hepatic and renal impairment

Table 1. Comparison Table for Agents Indicated for the Acute Treatment of Migraine and Other Primary Headaches Generic Name Preparations Brand Name (Availability of Labeled Indication(s) Recommended Dosage (Approval date) Generic) Rizatriptan4 Tablets: 5 mg Acute treatment of migraine with or Adults: 5 or 10 mg single dose. and 10 mg without aura in adults and Dose may be repeated after Maxalt and Maxalt- (Maxalt) adolescents 6-17 years of age 2 hours if headache returns. MLT (Generic (1998) available) Not indicated for the prophylactic Maximum daily dose: 30 mg therapy of migraine and for ODT (Maxalt- treatment of cluster headache Children 6-17 years of age: MLT): 5 mg and <40 kg: 5 mg single dose 10 mg ≥40 kg: 10 mg single dose (Generic available) Sumatriptan SQ injection: - Acute treatment of migraine Recommended dose: - SD prefilled with or without aura in SQ injection: Imitrex28-30 adults syringe - Acute treatment of cluster • Single dose of 1 mg to 6 mg (1992) (4 mg and headache in adults (ONLY for for acute treatment of Alsuma, Sumavel 6 mg); use SQ injection) migraine (for cluster Dosepro, and with Imitrex headache: single dose of Not indicated for the prophylactic Zecuity (Brand DSC) STATdose 6 mg). An additional dose therapy of migraine (for all pen (auto- should be repeated after ≥ sumatriptan formulations) injector) 1 hour if there was some

- SD vial response to the first dose Not indicated for the treatment of (6 mg) cluster headache (ONLY for tablets • Maximum daily dose: 12 mg (2 injections of 6 mg Tablets: 25 mg, and nasal spray) separated by 1 hour) 50 mg, 100 mg Not indicated for the prophylactic Tablets: therapy of cluster headache attacks Nasal spray: • (ONLY for SQ injection) Single dose of 25 mg, 5 mg/actuation, 50 mg, or 100 mg. An 20 mg/actuation additional dose may be (Generic repeated after ≥ 2 hours if available for all there was some response to formulations) the first dose • Maximum daily dose: 200 mg • Safety of treating > 4 headaches in 30 days has not been established

Nasal spray: • Single dose of 5 mg, 10 mg, or 20 mg. If initial dose was partially effective or headache recurs, may repeat dose after ≥ 2 hours • Maximum daily dose: 40 mg

Table 1. Comparison Table for Agents Indicated for the Acute Treatment of Migraine and Other Primary Headaches Generic Name Preparations Brand Name (Availability of Labeled Indication(s) Recommended Dosage (Approval date) Generic) • Safety of treating > 4 headaches in 30 days has not been established Sumatriptan Nasal powder: Acute treatment of migraine with or Recommended dose: 22 mg 11 mg per without aura in adults (11 mg insufflated in each Onzetra Xsail31 nosepiece (use nostril); if initial dose was (2016) with Xsail breath- Not indicated for the preventive partially effective or headache powdered treatment of migraine or treatment recurs, may repeat dose after ≥ delivery device of cluster headache 2 hours only) Maximum daily dose: 2 doses of Onzetra (44 mg/ 4 nosepieces) or 1 dose of Onzetra and 1 dose of another sumatriptan product, separated by at least 2 hours Sumatriptan Nasal spray: Acute treatment of migraine with or Recommended dose: single 10 mg/actuation without aura in adults dose of 10 mg in 1 nostril Tosymra32

(2019) Not indicated for the preventive Maximum daily dose: 30 mg; treatment of migraine or treatment doses separated by at least 1 of cluster headache hour Sumatriptan SQ injection: Acute treatment of migraine with or Recommended dose: single - Prefilled SD without aura in adults dose of 3 mg Zembrace auto-injector SymTouch33 (3 mg) Not indicated for the preventive Maximum daily dose: 12 mg; (2016) treatment of migraine doses separated by at least 1 hour. Zembrace may be administered after 1 dose of another sumatriptan product Zolmitriptan Tablets (Zomig): Acute treatment of migraine with or Recommended daily dose: 2.5 mg (scored) without aura in adults 1.25 mg or 2.5 mg Zomig17,18 and 5 mg (not Zomig-ZMT18 scored) Not indicated for the preventive Maximum daily dose: 10 mg; treatment of migraine or treatment doses separated by at least (1997) ODT (Zomig- of cluster headache 2 hours ZMT): 2.5 mg and 5 mg Zomig-ZMT is not recommended in Safety of Zomig/Zomig-ZMT in moderate to severe hepatic the treatment of > 3 migraines impairment because ODTs cannot in 30 days have not been be broken in half established Nasal spray Acute treatment of migraine with or Recommended dose: 2.5 mg (Zomig): without aura in adults and children 2.5 mg/spray and ≥ 12 years of age Maximum daily dose: 10 mg; 5 mg/spray doses separated by at least Not indicated for the preventive 2 hours treatment of migraine or treatment of cluster headache. Not recommended in moderate to severe hepatic impairment

Table 1. Comparison Table for Agents Indicated for the Acute Treatment of Migraine and Other Primary Headaches Generic Name Preparations Brand Name (Availability of Labeled Indication(s) Recommended Dosage (Approval date) Generic) Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant7 Tablets: 50 mg Acute treatment of migraine with or Recommended dose: 50 mg or and 100 mg without aura in adults 100 mg as needed. A second Ubrelvy dose may be taken after (2019) Not indicated for the preventive 2 hours. treatment of migraine Maximum daily dose: 200 mg

Reduce dose in hepatic and renal impairment

Safety of treating > 8 migraines in 30 days has not been established Rimegepant8 ODT: 75 mg Acute treatment of migraine with or Recommended dose: 75 mg as without aura in adults needed Nurtec ODT

(2020) Not indicated for the preventive Maximum daily dose: 75 mg treatment of migraine Safety of treating > 15 migraines in 30 days has not been established Ergot derivatives Dihydroergotamine Ampules - Acute treatment of migraine Recommended dose: 1 mL. mesylate (1 mg/mL) for IV, headaches with or without aura Repeat dose as needed, IM, or SQ separated by 1 hour D.H.E. 4514 - Acute treatment of cluster injection headache episodes (1946) (Generic Maximum daily dose: 3 mL (for available) IM or SQ administration); 2 mL (for IV administration); maximum weekly dose: 6 mL

Should not be used for chronic daily administration Dihydroergotamine Nasal spray Acute treatment of migraine Recommended dose: 2 mg (4 mesylate containing 4 mg headaches with or without aura sprays). Administer 0.5 mg (1 of DHE spray) in each nostril and an Migranal15 (0.5 mg/spray) Not indicated for the preventive additional 0.5 mg dose in each (1997) (Generic treatment of migraine or the nostril 15 minutes later available) management of hemiplegic or basilar migraine There is no additional benefit from daily doses > 2 mg. The safety of daily doses > 3 mg and weekly doses > 4 mg has not been established

Should not be used for chronic daily administration

Table 1. Comparison Table for Agents Indicated for the Acute Treatment of Migraine and Other Primary Headaches Generic Name Preparations Brand Name (Availability of Labeled Indication(s) Recommended Dosage (Approval date) Generic) Ergotamine9 SL tablets: 2 mg To abort or prevent vascular Recommended dose: 1 tablet of headache, eg, migraine, migraine 2 mg at or after onset of attack; Ergomar variants, or so-called "histaminic add 1 tablet 30 minutes later, if (1992) cephalalgia" needed

Maximum daily dosage: 3 tablets (6 mg) Maximum weekly dosage: 5 tablets (10 mg) NSAIDs Diclofenac10 Powder for oral Acute treatment of migraine attacks One packet of 50 mg. Safety and solution: 50 mg with or without aura in adults 18 effectiveness of an additional Cambia years of age or older dose have not been established (2009) Not indicated for the preventive treatment of migraine. Safety and effectiveness not established for cluster headache Celecoxib34 Oral solution: Acute treatment of migraine with or Recommended dose: 120 mg; 120 mg/4.8 mL without aura in adults maximum daily dose: 120 mg. Elyxyb (25 mg/mL) Safety and effectiveness of an (2020) Not indicated for the preventive additional dose within 24 hours treatment of migraine. have not been established Other Miscellaneous and Combinations Butalbital/APAP19,20 Tablets and For the relief of the symptom 1 or 2 tablets every 4 hours. capsules: complex of tension (or muscle Allzital 50 mg/300 mg contraction) headache Maximum daily dosage: (2015) 6 tablets (Generic Efficacy and safety in the treatment Butapap available) of multiple recurrent headaches Extended and repeated use is (1992) have not been established not recommended due to physical dependence potential Butalbital/APAP/ Tablets: For the relief of the symptom 1 or 2 tablets/capsules/ caffeine21-23 50 mg/325 mg/ complex of tension (or muscle tablespoons every 4 hours, as 40 mg contraction) headache needed.

Capsules: Efficacy and safety in the treatment Maximum daily dosage: 50 mg/325 mg/ of multiple recurrent headaches 6 tablets/capsules/tablespoons 40 mg have not been established 50 mg/300 mg/ Extended and repeated use is 40 mg not recommended due to physical dependence potential Oral solution: 50 mg/325 mg/ 40 mg per 15 mL (Generic only)

Table 1. Comparison Table for Agents Indicated for the Acute Treatment of Migraine and Other Primary Headaches Generic Name Preparations Brand Name (Availability of Labeled Indication(s) Recommended Dosage (Approval date) Generic) Butalbital/APAP/ Capsules: For the management of the 1 or 2 capsules every 4 hours caffeine/codeine 50 mg/300 mg/ symptom complex of tension (or 40 mg/30 mg muscle contraction) headache, Maximum daily dosage: Fioricet with when other non-opioid analgesic 6 capsules codeine24 50 mg/325 mg/ and alternative treatments are 40 mg/30 mg inadequate (Generic available) Butalbital/aspirin/ Capsules and For the relief of the symptom 1 or 2 tablets/capsules every 4 caffeine25,27 tablets: complex of tension (or muscle hours. 50 mg/325 mg/ contraction) headache Fiorinal25 40 mg Maximum daily dosage: (Generic Efficacy and safety in the treatment 6 tablets/capsules available) of multiple recurrent headaches have not been established Extended and repeated use is not recommended due to physical dependence potential Butalbital/aspirin/ Capsules: For the management of the 1 or 2 capsules every 4 hours caffeine/codeine 50 mg/325 mg/ symptom complex of tension (or 40 mg/30 mg muscle contraction) headache, Maximum daily dosage: Fiorinal with (Generic when other non-opioid analgesics 6 capsules codeine26 available) and alternative treatments are inadequate Butorphanol13 Nasal spray Management of pain severe enough Usual dose: 1 mg (1 spray in one (10 mg/ml; to require an opioid analgesic and nostril); add another 1 mg dose Stadol (Brand DSC) 2.5 ml) for which alternative treatments are 60 to 90 minutes later, if (Generic only) inadequate (clinical trials in patients needed. The initial dose with migraine headache pain) sequence may be repeated 3-4 hours later.

Reduce the dose to 1 mg in elderly patients and patients with renal or hepatic impairment Ergotamine/ Tablets: To abort or prevent vascular Recommended dose for adults: caffeine 1 mg/100 mg headache, eg, migraine, migraine 2 tablets at onset of attack; add (Generic variants, or so-called "histaminic 1 tablet 30 minutes later, if Cafergot11 available) cephalalgia" needed (1976) Rectal 1 suppository at onset of attack; Migergot12 suppositories: add 1 suppository after 1 hour, (1983) 2 mg/100 mg if needed

Maximum adult dosage: 6 tablets/attack, 10 tablets/week 2 suppositories/attack 5 suppositories/week

Table 1. Comparison Table for Agents Indicated for the Acute Treatment of Migraine and Other Primary Headaches Generic Name Preparations Brand Name (Availability of Labeled Indication(s) Recommended Dosage (Approval date) Generic) Sumatriptan/ Tablets: 85 mg Acute treatment of migraine with or Adults: Naproxen sumatriptan/ without aura in adults and children Recommended dose: 1 tablet 500 mg naproxen ≥ 12 years of age 85/500 mg Treximet16 sodium Maximum daily dose: 2 tablets (2008) of 85/500 mg; doses separated 10 mg by at least 2 hours sumatriptan/ 60 mg naproxen Pediatric Patients 12-17 years of sodium age: (Generic Recommended dose: 1 tablet available) 10/60 mg Maximum daily dose: 1 tablet of 85/500 mg

Mild to moderate hepatic impairment: 1 tablet of 10/60 mg Abbreviations: APAP, acetaminophen; DHE, dihydroergotamine; DSC, discontinued; IM, intramuscular; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; ODT, orally disintegrating tablet; SD, single-dose; SL, sublingual; SQ, subcutaneous

Table 2. Special Population Considerations Hepatic and Renal Agent Pregnancy and Lactation Pediatrics Impairment Selective Serotonin Agonists Pregnancy: no adequate data is available in pregnant women. Animal studies showed developmental toxicity (eg, increased fetal mortality and decreased Dosage reduction in FDA approved for weight) with almotriptan use at doses patients with hepatic Almotriptan3 patients ≥12 higher than those used clinically or severe renal years impairment Lactation: unknown if almotriptan is excreted in human milk. It is present in rat milk. Use with caution Pregnancy: available data in pregnant women is limited to determine harms No dosage adjustments and risk of major birth defect and are provided in the miscarriage. Animal studies showed Efficacy and manufacturer’s developmental toxicity (decreased fetal safety not labeling for both Eletriptan2 weight and viability and increased fetal established in hepatic and renal abnormalities) with oral eletriptan at patients <18 impairment. clinically-relevant doses years Eletriptan has not been

studied in patients with Lactation : eletriptan is present in human severe hepatic milk but there are no data on the clinical

Table 2. Special Population Considerations Hepatic and Renal Agent Pregnancy and Lactation Pediatrics Impairment effects of eletriptan for a breastfeeding impairment and is not infant. Benefits of breastfeeding, recommended mother´s clinical need for eletriptan, and potential adverse effects on infants should be considered Pregnancy: available data in pregnant women regarding developmental risk is No dosage adjustments inadequate. Animal studies showed are provided in the developmental toxicity (decreased fetal manufacturer’s growth, increased fetal mortality and Efficacy and labeling for both renal abnormalities) with frovatriptan use at safety not impairment and mild to doses higher than those used clinically. established in moderate hepatic Frovatriptan8 patients <18 impairment. Lactation: unknown if frovatriptan is years (not Frovatriptan has not excreted in human milk. Frovatriptan recommended in been studied in and/or its metabolites were excreted in this age group) patients with severe rat milk. Benefits of breastfeeding, hepatic impairment mother´s clinical need for frovatriptan, and should be used and potential adverse effects on infants with caution should be considered. Pregnancy: available data in pregnant women regarding developmental risk is No dosage adjustments inadequate. Animal studies showed are provided in the developmental toxicity with lasmiditan at manufacturer’s labeling for both renal doses lower or higher than those used impairment and mild to clinically Efficacy and moderate hepatic safety not Lasmiditan4 impairment. Lactation: unknown if lasmiditan is established in Lasmiditan has not excreted in human milk. Lasmiditan pediatric patients been studied in and/or its metabolites were excreted in patients with severe rat milk. Benefits of breastfeeding, hepatic impairment mother´s clinical need for lasmiditan, and is not and potential adverse effects on infants recommended should be considered. Pregnancy: available data in pregnant women regarding developmental risk is inadequate. Animal studies showed developmental toxicity with naratriptan Contraindicated with Efficacy and at plasma concentrations higher than severe renal and safety not that in humans receiving the maximum hepatic impairment. established in recommended daily dose Dosage adjustments Naratriptan5 patients <18 are recommended for years (not Lactation: unknown if naratriptan is mild to moderate renal recommended in excreted in human milk. It is present in and hepatic this age group) rat milk. Benefits of breastfeeding, impairment mother´s clinical need for naratriptan, and potential adverse effects on infants should be considered.

Table 2. Special Population Considerations Hepatic and Renal Agent Pregnancy and Lactation Pediatrics Impairment No dosage adjustments are provided in the manufacturer’s Pregnancy: available data in pregnant labeling for both women is limited to determine harms hepatic and renal and risk of major birth defect. Animal impairment data showed rizatriptan decreases fetal FDA approved for Patient on weight, increases fetal mortality and children and Rizatriptan1 hemodialysis, neurobehavioral impairment in rats adolescents age rizatriptan AUC can exposed to doses higher than the 6-17 years therapeutic doses in humans. increase 40% Lactation: no data is available to show Rizatriptan plasma if rizatriptan is present in breast milk concentration increases by 30% in patients with moderate hepatic impairment

Pregnancy: data suggest no increased risk of major birth defects in humans; doses 2-3 times the maximum Manufacturer recommended daily dose increased risk labeling does not Contraindicated with for embryolethality and birth defects in recommend use severe hepatic animal studies; contraindicated for patients less impairment; dose sumatriptan/naproxen combination than 18 years of reduction required for products during the third trimester of age; data are orally administered pregnancy mixed regarding sumatriptan with mild the efficacy of to moderate hepatic Sumatriptan16,28-33 Lactation: sumatriptan is present in sumatriptan in impairment small amounts in breast milk but oral pediatric

Sumatriptan/naproxen16 bioavailability is poor in breastfeeding patients; infants, limiting exposure; there are no guidelines from No dose adjustments data on the clinical effects of the AAN are provided for renal sumatriptan for a breastfeeding infant; recommends impairment (has not risk is likely low, but women can sumatriptan nasal been studied, but renal consider avoiding breastfeeding for 12 spray 20 mg as a impairment is not hours after the administration of treatment option expected to affect sumatriptan. Benefits of breastfeeding, for adolescents pharmacokinetics) mother´s clinical need for sumatriptan, with migraine46 and potential adverse effects on infants should be considered

Pregnancy: available data on Nasal spray: FDA Nasal spray: Use not developmental risks is inadequate in approved for recommended in pregnant women. Reproductive toxicity patients ≥12 moderate to severe studies in animals showed years hepatic impairment Zolmitriptan17,18 embryolethality and fetal abnormalities due to an increase in at clinically relevant exposures Tablets: not zolmitriptan plasma recommended in levels and blood Lactation: no data is available regarding patients <18 pressure (in some the presence of zolmitriptan in breast years patients) milk. Benefits of breastfeeding,

Table 2. Special Population Considerations Hepatic and Renal Agent Pregnancy and Lactation Pediatrics Impairment mother´s clinical need for zolmitriptan, ODT: Use not and potential adverse effects on infants recommended in should be considered moderate to severe hepatic impairment because ODT cannot be split in half Tablets: Dosage reduction in patients with moderate to severe hepatic impairment CGRP Receptor Antagonists Pregnancy: no adequate data is available in pregnant women. Animal studies showed adverse effects during organogenesis (increased incidence of fetal variations and decreased fetal body weight) with rimegepant at doses higher Efficacy and Avoid use in patients than those used clinically, which also safety not with severe hepatic Rimegepant7 caused maternal toxicity established in impairment and end- pediatric patients stage renal disease Lactation: unknown if rimegepant is excreted in human milk. Benefits of breastfeeding, mother´s clinical need for rimegepant, and potential adverse effects on infants should be considered Pregnancy: no adequate data is available in pregnant women. Animal studies showed embryofetal developmental adverse effects (increased mortality and decreased fetal body weight) with ubrogepant at doses higher than those Efficacy and Dosage adjustment in used clinically safety not patients with severe Ubrogepant6 established in hepatic and renal Lactation: unknown if ubrogepant is pediatric patients impairment excreted in human milk. It is present in rat milk. Benefits of breastfeeding, mother´s clinical need for ubrogepant, and potential adverse effects on infants should be considered. Ergot Derivatives Pregnancy: contraindicated during pregnancy due to its oxytocic properties. Contraindicated in Efficacy and safety Animal studies showed developmental patients with severe Dihydroergotamine14,15 not established in toxicity (decreased fetal body weight and hepatic or renal pediatric patients delayed skeletal ossification) impairment

Table 2. Special Population Considerations Hepatic and Renal Agent Pregnancy and Lactation Pediatrics Impairment Lactation: contraindicated during lactation. Ergot drugs inhibit prolactin. Unknown if DHE is excreted in human milk, but ergotamine is present in human milk and may induce vomiting, diarrhea, weak pulse, and unstable blood pressure in breastfed infants Pregnancy: contraindicated during pregnancy due to its oxytocic properties

Lactation: ergot drugs inhibit prolactin. Efficacy and safety Contraindicated in Ergotamine9 Ergotamine is present in human milk and not established in hepatic or renal may induce vomiting, diarrhea, weak pediatric patients impairment pulse, and unstable blood pressure in breastfed infants. Breastfeeding or drug discontinuation should be considered Pregnancy: contraindicated during pregnancy

Efficacy and safety Contraindicated in Lactation: ergotamine and caffeine are Ergotamine/caffeine11,12 not established in hepatic or renal both excreted in human milk and may pediatric patients impairment cause adverse events in breastfed infants. Breastfeeding or drug discontinuation should be considered NSAIDs

Pregnancy: starting at week 30, diclofenac should be avoided because premature closure of the ductus Not recommended arteriosus in the fetus may occur. Prior to Efficacy and safety in advanced renal Diclofenac powder for week 30, potential benefits should be not established in disease unless oral solution10 outweighed against the potential risks pediatric patients benefits outweigh

the risks Lactation: unknown if diclofenac is excreted in human milk. Breastfeeding or drug discontinuation may be considered

Pregnancy: starting at week 30, celecoxib should be avoided because premature Not recommended closure of the ductus arteriosus in the in severe hepatic fetus may occur. Celecoxib oral Efficacy and safety and renal

solution34 not established in impairment. Dosage Lactation: celecoxib is excreted in human pediatric patients adjustment required milk. Benefits of breastfeeding, mother´s in moderate hepatic clinical need for celecoxib, and potential impairment adverse effects on infants should be considered.

Table 2. Special Population Considerations Hepatic and Renal Agent Pregnancy and Lactation Pediatrics Impairment Other Miscellaneous Pregnancy: no animal studies were conducted with the combination. Weigh No dosage potential benefits and risks Efficacy and safety adjustment required. Butalbital combinations not established in Caution in severe without codeine19-23,26,27 Lactation: drug is present in human milk. pediatric patients hepatic and renal Breastfeeding or drug discontinuation impairment should be considered Pregnancy: BBW related to the risk of neonatal opioid withdrawal syndrome after birth due to long-term use of opioids during pregnancy. Not No dosage recommended during labor and delivery adjustment required. because opioids may cause respiratory Caution in hepatic Efficacy and safety Butalbital combinations depression in neonates. The drug may and renal not established in with codeine24,25 cause fetal harm (animal studies showed impairment and pediatric patients adverse effects) based on the individual monitor the patient agents of the combination. Weigh carefully for adverse potential benefits and risks events

Lactation: drug is present in human milk. Breastfeeding not recommended Pregnancy: BBW related to the risk of neonatal opioid withdrawal syndrome after birth due to long-term use of opioids during pregnancy. Not recommended during labor and delivery Dosage because opioids may cause respiratory Efficacy and safety modifications in Butorphanol13 depression in neonates. The drug may not established in hepatic and renal cause fetal harm (animal studies showed pediatric patients impairment adverse effects). Weigh potential benefits and risks

Lactation: drug is present in human milk. Weigh potential benefits and risks Abbreviations: AAN, American Academy of Neurology; AUC, area under the curve; BBW, black box warning; CGRP, calcitonin gene-related peptide; DHE, dihydroergotamine; FDA, U.S. Food and Drug Administration; NSAID, nonsteroidal anti-inflammatory drug; ODT, orally disintegrating tablet

Appendix B – Literature Search Strategies

- Search for Celecoxib Oral Solution (Elyxyb)

Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to May 21, 2020 Search Strategy (date of search: May 22, 2020)

# Searches Results

1 exp Celecoxib/ or celecoxib.ti,ab,kw,kw. 6898

2 exp Headache Disorders/ or exp Migraine Disorders/ or migraine*.ti,ab,kw,kf. 45327

3 1 and 2 19

- Literature Searches for Systematic Reviews

Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to February 28, 2020 Search Strategy (date of search: March 2, 2020)

# Searches Results

1 exp Migraine Disorders/ or migraine*.ti,ab,kw,kf. 38765

2 exp Headache Disorders/ 33813

Serotonin Receptor Agonists/ or Serotonin 5-HT1 Receptor Agonists/ or (triptan* or ((5 HT* or 5HT* 3 18601 or serotonin) adj5 agonist*)).ti,ab,kw,kf.

Sumatriptan/ or (almotriptan or eletriptan or frovatriptan or naratriptan or rizatriptan or sumatriptan or 4 4072 zolmitriptan or lasmiditan).ti,ab,kw,kf.

((anti-migraine or antimigraine or abortive or acute) adj2 (medication* or drug* or agent* or 5 74980 pharmaco* or treatment* or therap*)).ti,ab,kw,kf.

Calcitonin Gene-Related Peptide Receptor Antagonists/ or (((CGRP or "Calcitonin Gene-Related 6 1514 Peptide") adj2 (antagonist* or inhibitor* or blocker*)) or CGRP-RA or gepant*).ti,ab,kw,kf.

7 (ubrogepant or rimegepant).ti,ab,kw,kf. 48

Ergotamines/ or dihydroergotamine/ or ergotamine/ or diclofenac/ or butorphanol/ or barbiturates/ or 8 37690 (ergot* or dihydroergotamine* or diclofenac or butorphanol or butalbital or isometheptene).ti,ab,kw,kf.

meta-analysis/ or (metaanaly$ or meta-analy$).ti,ab,kw,kf. or "Systematic Review"/ or ((systematic* 9 adj3 review*) or (systematic* adj2 search*) or cochrane$ or (overview adj4 review)).ti,ab,kw,kf. or 328512 (cochrane$ or systematic review?).jw.

10 (MEDLINE or systematic review).tw. or meta analysis.pt. 265943

11 1 or 2 44747

12 3 or 4 or 5 or 6 or 7 or 8 130430

13 9 or 10 360171

14 11 and 12 and 13 364

15 limit 14 to yr="2010 -Current" 190

Embase Session Results (date of search: April 27, 2020) No. Query Results 272 #13 #9 AND #10 AND #11 AND [2010-2020]/py 554 #12 #9 AND #10 AND #11 89,865 #11 'migraine'/exp/mj OR 'headache'/exp/mj OR 'primary headache'/exp/mj OR 'tension headache'/exp/mj OR 'trigeminal autonomic cephalalgia'/exp/mj OR 'vascular headache'/exp/mj OR migraine*:ti,ab,kw OR headache*:ti 190,736 #10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 352,532 #9 (cochrane*:jt OR 'systematic review*':jt OR 'meta analysis'/exp OR 'network meta-analysis'/exp OR 'systematic review'/exp OR ((systematic* NEAR/3 review*):ti,ab,kw) OR ((systematic* NEAR/2 search*):ti,ab,kw) OR 'meta analys*':ti,ab,kw OR metaanalys*:ti,ab,kw OR ((overview NEAR/4 (review OR reviews)):ti)) NOT ('conference abstract'/it OR 'conference review'/it) AND [english]/lim 28,621 #8 ergot*:ti,ab,kw OR dihydroergotamine*:ti,ab,kw OR diclofenac:ti,ab,kw OR butorphanol:ti,ab,kw OR butalbital:ti,ab,kw 51,422 #7 'ergotamine derivative'/exp OR 'ergotamine'/exp OR 'dihydroergotamine'/exp OR 'diclofenac'/exp OR 'butorphanol tartrate'/exp OR 'butalbital'/exp OR 'butalbital plus paracetamol'/exp OR 'butalbital plus caffeine plus paracetamol'/exp OR 'butalbital plus caffeine plus codeine phosphate plus paracetamol'/exp OR 'acetylsalicylic acid plus butalbital'/exp OR 'acetylsalicylic acid plus butalbital plus caffeine'/exp OR 'acetylsalicylic acid plus butalbital plus caffeine plus codeine phosphate'/exp 224 #6

'ubrogepant'/exp OR 'rimegepant'/exp OR ubrogepant:ti,ab,kw OR rimegepant:ti,ab,kw 2,178 #5 'calcitonin gene related peptide receptor antagonist'/de OR (((cgrp OR 'calcitonin gene-related peptide') NEAR/2 (antagonist* OR inhibitor* OR blocker*)):ti,ab,kw) OR 'cgrp-ra':ti,ab,kw OR gepant*:ti,ab,kw 11,640 #4 'sumatriptan'/exp OR 'almotriptan'/exp OR 'eletriptan'/exp OR 'frovatriptan'/exp OR 'naratriptan'/exp OR 'rizatriptan'/exp OR 'zolmitriptan'/exp OR 'lasmiditan'/exp OR almotriptan:ti,ab,kw OR eletriptan:ti,ab,kw OR frovatriptan:ti,ab,kw OR naratriptan:ti,ab,kw OR rizatriptan:ti,ab,kw OR sumatriptan:ti,ab,kw OR zolmitriptan:ti,ab,kw OR lasmiditan:ti,ab,kw 107,262 #3 'antimigraine agent'/mj OR ((('anti migraine' OR antimigraine OR abortive OR acute) NEAR/2 (medication* OR drug* OR agent* OR pharmaco* OR treatment* OR therap*)):ti,ab,kw) 17,020 #2 triptan*:ti,ab,kw OR (((5ht* OR '5 ht*' OR serotonin) NEXT/5 agonist*):ti,ab,kw) 10,060 #1 'serotonin agonist'/de OR 'triptan derivative'/exp OR 'triptan'/exp

- Literature Searches for Randomized Controlled Trials

Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to May 13, 2020 Search Strategy (date of search: May 14, 2020)

# Searches Results

1 exp Migraine Disorders/ or migraine*.ti,ab,kw,kf. 39239

2 exp Headache Disorders/ 34095

Sumatriptan/ or (almotriptan or eletriptan or frovatriptan or naratriptan or rizatriptan or sumatriptan or 3 4042 zolmitriptan).ti,ab,kw,kf.

4 (ubrogepant or rimegepant or lasmiditan).ti,ab,kw,kf. 111

dihydroergotamine/ or ergotamine/ or diclofenac/ or butorphanol/ or (ergot* or dihydroergotamine* or 5 24487 diclofenac or butorphanol or butalbital).ti,ab,kw,kf.

((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or 6 1183966 clinical trials as topic.sh. or randomly.ab. or trial.ti.) not (exp animals/ not humans.sh.)

7 1 or 2 45274

8 4 and 6 and 7 56

9 limit 8 to yr="2019 -Current" 34

10 3 or 5 28047

11 6 and 7 and 10 1215

12 limit 11 to yr="2016 -Current" 84

13 9 or 12 116 Embase Session Results (search for CGRP receptor antagonists and lasmiditan; date of search: May 14, 2020) No. Query Results 127 #9 #6 NOT #7 AND [2019-2020]/py 213 #8 #6 NOT #7 7,517,303 #7 #4 OR #5 217 #6 #1 AND #2 AND #3 2,825,895 #5 animal*:ti OR beaver*:ti OR beef:ti OR bovine:ti OR breeding:ti OR canine:ti OR castoris:ti OR cat:ti OR cattle:ti OR cats:ti OR chicken*:ti OR cow:ti OR dog:ti OR dogs:ti OR equine:ti OR foal:ti OR foals:ti OR fish:ti OR insect*:ti OR livestock:ti OR mice:ti OR mouse:ti OR murine:ti OR plant:ti OR plants:ti OR pork:ti OR porcine:ti OR protozoa*:ti OR purebred:ti OR rabbit*:ti OR rat:ti OR rats:ti OR rodent*:ti OR sheep:ti OR thoroughbred:ti OR veterinar*:ti,ab,de 7,018,355 #4 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human cell'/de)) 2,376,008 #3 ('crossover procedure':de OR 'double-blind procedure':de OR 'randomized controlled trial':de OR 'single-blind procedure':de OR random*:de,ab,ti OR factorial*:de,ab,ti OR crossover*:de,ab,ti OR ((cross NEXT/1 over*):de,ab,ti) OR placebo*:de,ab,ti OR ((doubl* NEAR/1 blind*):de,ab,ti) OR ((singl* NEAR/1 blind*):de,ab,ti) OR assign*:de,ab,ti OR allocat*:de,ab,ti OR volunteer*:de,ab,ti) AND [english]/lim

367 #2 'ubrogepant'/exp OR 'rimegepant'/exp OR 'lasmiditan'/exp OR ubrogepant:ti,ab,kw OR rimegepant:ti,ab,kw OR lasmiditan:ti,ab,kw 90,078 #1 'migraine'/exp/mj OR 'headache'/exp/mj OR 'primary headache'/exp/mj OR 'tension headache'/exp/mj OR 'trigeminal autonomic cephalalgia'/exp/mj OR 'vascular headache'/exp/mj OR migraine*:ti,ab,kw OR headache*:ti

Embase Session Results (Search for triptans, ergot derivatives, and miscellaneous; date of search: May 14, 2020) No. Query Results 277 #12 #10 NOT #9 AND [2016-2020]/py 1,903 #11 #10 NOT #9 1,929 #10 #1 AND #5 AND #8 7,517,303 #9 #6 OR #7 68,999 #8 #2 OR #3 OR #4 2,825,895 #7 animal*:ti OR beaver*:ti OR beef:ti OR bovine:ti OR breeding:ti OR canine:ti OR castoris:ti OR cat:ti OR cattle:ti OR cats:ti OR chicken*:ti OR cow:ti OR dog:ti OR dogs:ti OR equine:ti OR foal:ti OR foals:ti OR fish:ti OR insect*:ti OR livestock:ti OR mice:ti OR mouse:ti OR murine:ti OR plant:ti OR plants:ti OR pork:ti OR porcine:ti OR protozoa*:ti OR purebred:ti OR rabbit*:ti OR rat:ti OR rats:ti OR rodent*:ti OR sheep:ti OR thoroughbred:ti OR veterinar*:ti,ab,de 7,018,355 #6 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human cell'/de)) 1,299,025

#5 ('clinical study'/mj OR 'clinical trial'/mj OR 'controlled clinical trial'/mj OR 'major clinical study'/mj OR 'randomized controlled trial'/exp OR 'randomized controlled trial (topic)'/exp OR 'control group'/mj OR (((clinical OR randomi* OR controlled OR 'double-blind') NEAR/3 (study OR trial)):ti,ab) OR placebo:ab,ti OR 'head to head':ti,ab) AND [english]/lim 28,677 #4 ergot*:ti,ab,kw OR dihydroergotamine*:ti,ab,kw OR diclofenac:ti,ab,kw OR butorphanol:ti,ab,kw OR butalbital:ti,ab,kw 51,121 #3 'ergotamine'/exp OR 'dihydroergotamine'/exp OR 'diclofenac'/exp OR 'butorphanol tartrate'/exp OR 'butalbital'/exp OR 'butalbital plus paracetamol'/exp OR 'butalbital plus caffeine plus paracetamol'/exp OR 'butalbital plus caffeine plus codeine phosphate plus paracetamol'/exp OR 'acetylsalicylic acid plus butalbital'/exp OR 'acetylsalicylic acid plus butalbital plus caffeine'/exp OR 'acetylsalicylic acid plus butalbital plus caffeine plus codeine phosphate'/exp 11,552 #2 'sumatriptan'/exp OR 'almotriptan'/exp OR 'eletriptan'/exp OR 'frovatriptan'/exp OR 'naratriptan'/exp OR 'rizatriptan'/exp OR 'zolmitriptan'/exp OR almotriptan:ti,ab,kw OR eletriptan:ti,ab,kw OR frovatriptan:ti,ab,kw OR naratriptan:ti,ab,kw OR rizatriptan:ti,ab,kw OR sumatriptan:ti,ab,kw OR zolmitriptan:ti,ab,kw 90,078 #1 'migraine'/exp/mj OR 'headache'/exp/mj OR 'primary headache'/exp/mj OR 'tension headache'/exp/mj OR 'trigeminal autonomic cephalalgia'/exp/mj OR 'vascular headache'/exp/mj OR migraine*:ti,ab,kw OR headache*:ti

Appendix C – Included and Excluded References

List of Included References

1. Bird S, Derry S, Moore RA. Zolmitriptan for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2014(5):CD008616. 2. Cameron C, Kelly S, Hsieh S-C, et al. Triptans in the Acute Treatment of Migraine: A Systematic Review and Network Meta-Analysis. Headache. 2015;55 Suppl 4(2985091r, g1n):221-235. 3. Derry CJ, Derry S, Moore RA. Sumatriptan (oral route of administration) for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2012(2):CD008615. 4. Derry CJ, Derry S, Moore RA. Sumatriptan (intranasal route of administration) for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2012(2):CD009663. 5. Derry CJ, Derry S, Moore RA. Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2012(2):CD009665. 6. Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. The Cochrane database of systematic reviews. 2013(4):CD008783. 7. Menshawy A, Ahmed H, Ismail A, et al. Intranasal sumatriptan for acute migraine attacks: a systematic review and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;39(1):31-44. 8. Tepper SJ, Cady RK, Silberstein S, et al. AVP-825 breath-powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg oral sumatriptan in the acute treatment of migraines (The COMPASS study): a comparative randomized clinical trial across multiple attacks. Headache. 2015;55(5):621-635. 9. Worthington I, Pringsheim T, Gawel MJ, et al. Canadian Headache Society Guideline: acute drug therapy for migraine headache. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques. 2013;40(5 Suppl 3):S1-S80. 10. Xu H, Han W, Wang J, Li M. Network meta-analysis of migraine disorder treatment by NSAIDs and triptans. The journal of headache and pain. 2016;17(1):113.

List of Excluded References

Wrong Study Design 1. Allais G, Benedetto C. Spotlight on frovatriptan: a review of its efficacy in the treatment of migraine. Drug design, development and therapy. 2016;10(101475745):3225-3236. 2. Allais G, Chiarle G, Sinigaglia S, Benedetto C. Menstrual migraine: a review of current and developing pharmacotherapies for women. Expert opinion on pharmacotherapy. 2018;19(2):123-136. 3. Becker WJ. Acute Migraine Treatment. Continuum (Minneapolis, Minn). 2015;21(4 Headache):953-972. 4. Brasure M, Nelson VA, Scheiner S, et al. 2019. 5. Evers S, Savi L, Omboni S, Lisotto C, Zanchin G, Pinessi L. Efficacy of frovatriptan as compared to other triptans in migraine with aura. The journal of headache and pain. 2015;16(100940562):514. 6. Hong P, Liu Y. Calcitonin gene-related peptide antagonism for acute treatment of migraine: a meta-analysis. The International journal of neuroscience. 2017;127(1):20-27. 7. Joshi S, Rapoport AM. Diclofenac potassium for oral solution (CAMBIA R) in the acute management of a migraine attack: clinical evidence and practical experience. Therapeutic advances in neurological disorders. 2017;10(4):217-226. 8. Knowles S, Oh P, Gomes T. Triptans for Acute Migraine: Drug Class Review to Help Inform Policy Decisions. Headache. 2015;55(S4):191-198. 9. Lipton RB, McGinley JS, Shulman KJ, Wirth RJ, Buse DC. Faster Improvement in Migraine Pain Intensity and Migraine-Related Disability at Early Time Points with AVP-825 (Sumatriptan Nasal Powder Delivery System) versus Oral Sumatriptan: A Comparative Randomized Clinical Trial Across Multiple Attacks from the CO. Headache. 2017;57(10):1570-1582.

10. Maasumi K, Tepper SJ, Kriegler JS. Menstrual Migraine and Treatment Options: Review. Headache. 2017;57(2):194-208. 11. McGinley JS, Buse DC, Shulman KJ, Wirth RJ, Hugentobler E, Lipton RB. Evaluating Mean Level and Within- Person Consistency in Migraine Pain Intensity and Migraine-Related Disability for AVP-825 vs Oral Sumatriptan: Results from the COMPASS Study, A Randomized Trial. Headache. 2019;59(7):1002-1013. 12. Moreno-Ajona D, Chan C, Villar-Martinez MD, Goadsby PJ. Targeting CGRP and 5-HT1F Receptors for the Acute Therapy of Migraine: A Literature Review. Headache. 2019;59 Suppl 2(2985091r, g1n):3-19. 13. Pascual J, Vila C. Almotriptan: a review of 20 years' clinical experience. Expert review of neurotherapeutics. 2019;19(8):759-768. 14. Peck J, Urits I, Zeien J, et al. A Comprehensive Review of Over-the-counter Treatment for Chronic Migraine Headaches. Current Pain and Headache Reports. 2020;24(5). 15. Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (DHE) - Then and Now: A Narrative Review. Headache. 2020;60(1):40-57. 16. Silberstein S, Winner PK, McAllister PJ, et al. Early Onset of Efficacy and Consistency of Response Across Multiple Migraine Attacks From the Randomized COMPASS Study: AVP-825 Breath Powered® Exhalation Delivery System (Sumatriptan Nasal Powder) vs Oral Sumatriptan. Headache. 2017;57(6):862-876. 17. Thorlund K, Toor K, Wu P, et al. Comparative tolerability of treatments for acute migraine: A network meta- analysis. Cephalalgia : an international journal of headache. 2017;37(10):965-978. 18. Vecsei L, Lukacs M, Tajti J, Fulop F, Toldi J, Edvinsson L. The Therapeutic Impact of New Migraine Discoveries. Current medicinal chemistry. 2019;26(34):6261-6281. 19. Vollono C, Vigevano F, Tarantino S, Valeriani M. Triptans other than sumatriptan in child and adolescent migraine: literature review. Expert review of neurotherapeutics. 2011;11(3):395-401. 20. Xu F, Sun W. Network Meta-Analysis of Calcitonin Gene-Related Peptide Receptor Antagonists for the Acute Treatment of Migraine. Frontiers in pharmacology. 2019;10(101548923):795.

Wrong Comparator 21. Barnes NP. Migraine headache in children. BMJ clinical evidence. 2011;2011(101294314). 22. Barnes NP. Migraine headache in children. BMJ clinical evidence. 2015;2015(101294314). 23. Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J. EFNS guideline on the treatment of tension-type headache - Report of an EFNS task force. European Journal of Neurology. 2010;17(11):1318- 1325. 24. Bonfert M, Straube A, Schroeder A, Reilich P, Ebinger F, Heinen F. Primary headache in children and adolescents: Udate on pharmacotherapy of migraine and tension-type headache. Neuropediatrics. 2013;44(1):3-19. 25. Derry CJ, Derry S, Moore RA. Sumatriptan (rectal route of administration) for acute migraine attacks in adults. The Cochrane database of systematic reviews. 2012(2):CD009664. 26. Derry CJ, Derry S, Moore RA. Sumatriptan (all routes of administration) for acute migraine attacks in adults - overview of Cochrane reviews. The Cochrane database of systematic reviews. 2014(5):CD009108. 27. Evers S. The efficacy of triptans in childhood and adolescence migraine. Current Pain and Headache Reports. 2013;17(7). 28. Faber AJ, Lagman-Bartolome AM, Rajapakse T. Drugs for the acute treatment of migraine in children and adolescents. Paediatrics and Child Health (Canada). 2017;22(8):454-458. 29. Francis GJ, Becker WJ, Pringsheim TM. Acute and preventive pharmacologic treatment of cluster headache. Neurology. 2010;75(5):463-473. 30. Gao B, Yang Y, Wang Z, et al. Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine: Evidence From Randomized Controlled Trials. Frontiers in pharmacology. 2019;10(101548923):1577. 31. Law S, Derry S, Moore RA. Sumatriptan plus naproxen for the treatment of acute migraine attacks in adults. The Cochrane database of systematic reviews. 2016;4(100909747):CD008541. 32. Matharu M. Cluster headache. BMJ clinical evidence. 2010;2010(101294314). 33. Oskoui M, Pringsheim T, Holler-Managan Y, et al. Practice guideline update summary: Acute treatment of migraine in children and adolescents: Report of the Guideline Development, Dissemination, and

Implementation Subcommittee of the American Academy of Neurology and the American Headache Society. Headache. 2019;59(8):1158-1173. 34. Robbins MS, Starling AJ, Pringsheim TM, Becker WJ, Schwedt TJ. Treatment of Cluster Headache: The American Headache Society Evidence-Based Guidelines. Headache. 2016;56(7):1093-1106.

Wrong Outcomes 35. Garcia-Azorin D, Yamani N, Messina LM, et al. A PRISMA-compliant systematic review of the endpoints employed to evaluate symptomatic treatments for primary headaches. The journal of headache and pain. 2018;19(1):90.

Wrong Intervention 36. Huang IH, Wu PC, Lin EY, Chen CY, Kang YN. Effects of anti-calcitonin gene-related peptide for migraines: A systematic review with meta-analysis of randomized clinical trials. International Journal of Molecular Sciences. 2019;20(14).

A More Recent Systematic Review is Available 37. Cortelli P, Allais G, Tullo V, et al. Frovatriptan versus other triptans in the acute treatment of migraine: pooled analysis of three double-blind, randomized, cross-over, multicenter, Italian studies. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2011;32 Suppl 1(drb, 100959175):S95-98. 38. Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. The Cochrane database of systematic reviews. 2012(2):CD008783. 39. Gobel H. Efficacy and tolerability of rizatriptan 10 mg compared with sumatriptan 100 mg: an evidence-based analysis. Expert review of neurotherapeutics. 2010;10(4):499-506. 40. Thorlund K, Mills EJ, Wu P, et al. Comparative efficacy of triptans for the abortive treatment of migraine: a multiple treatment comparison meta-analysis. Cephalalgia : an international journal of headache. 2014;34(4):258-267.

Wrong Indication 41. Nierenburg HDC, Ailani J, Malloy M, Siavoshi S, Hu NN, Yusuf N. Systematic Review of Preventive and Acute Treatment of Menstrual Migraine. Headache. 2015;55(8):1052-1071.

Unavailable 42. Caroline Sunitha K, Arvind M. Pharmacological interventions in the treatment of trigeminal neuralgia (TN), glossopharyngeal neuralgia (GN) and trigeminal autonomic cephalalgias (TAC) - a systematic review. International Journal of Pharma and Bio Sciences. 2014;5(3):P329-P335.

Non-English Article 43. Schytz HW, Bendtsen L. [Sumatriptan plus naproxen for acute migraine attacks in adults]. Ugeskrift for laeger. 2014;176(32).

Duplicate 44. Bonfert M, Straube A, Schroeder AS, Reilich P, Ebinger F, Heinen F. Primary headache in children and adolescents: update on pharmacotherapy of migraine and tension-type headache. Neuropediatrics. 2013;44(1):3-19. 45. Silberstein S, Winner PK, McAllister PJ, et al. Early Onset of Efficacy and Consistency of Response Across Multiple Migraine Attacks From the Randomized COMPASS Study: AVP-825 Breath Powered® Exhalation Delivery System (Sumatriptan Nasal Powder) vs Oral Sumatriptan. Headache. 2017;57(6):862-876.

Appendix D – Evidence Tables

Sumatriptan vs - No significant difference between the 2 agents sumatriptan- regarding 1 hour-pain-free, 1 hour-pain-relief, naproxen nausea, and 2 hour-nausea-absence ELE vs. SUM Sumatriptan vs. - 1 hour-pain-relief: (OR: 1.29, CI: 1.05-1.58) eletriptan - 2 hour-pain-free: (OR: 1.35, CI: 1.10-1.65)

- Rescue medication: (OR: 0.74, CI: 0.59-0.93) Sumatriptan vs - No data available on nausea diclofenac potassium - No significant difference between the 2 agents regarding 1 hour-pain-free, 2 hour-pain-relief, 2

Table 1. Characteristics and Results of Included Systematic Reviews First author, Population Intervention of Number of head- Literature Efficacy and safety endpoints/results year, study Interest head trials of search design interest databases identified by SR (search dates) RIZ vs. ZOL - No data available on rescue medication and nausea - No significant difference between 2 agents regarding 1 hour-pain-free, 1 hour-pain relief, 2 hour-pain-free, 2 hour-pain-relief, recurrence, 2 hour-nausea absence, and all-adverse-event Menshawy Patients Sumatriptan 2 RCTs PubMed, Boureau 200086: 201880 diagnosed with intranasal vs. SCOPUS, SUM 20 mg NS vs. DHE 1 mg NS (plus optional 1 mg after episodic migraine, dihydroergotamine Embase, and 30 minutes): SR and MA with intranasal Cochrane or without aura, CENTRAL - NSS for all AEs within 24 h and withdrawal due to according to the Sumatriptan AEs IHS criteria intranasal vs. (search date: SUM40031 (information published in the manufacturer (second edition) rizatriptan oral through August website): wafer 2016) SUM 20 mg NS vs. RIZ oral wafer 10 mg: - Pain relief at 1 hour: SUM (16%) vs. RIZ (15%) (p value not reported) Cameron Adults with Triptans vs. active Unclear CENTRAL, Conventional pairwise comparisons among the standard 79 2015 migraine specified comparators (133 RCTs Cochrane dose (SD) triptan tablets (reported as odd ratio [OR] and by the HIS (other triptans, comparing Database of 95% confidence interval [CI]): SR and NMA (patients with Systematic Eletriptan vs. triptans with of RCTs with cluster, tension or Reviews, ELE SD (40 mg) tablet vs. SUM SD (50 mg) tablet sumatriptan placebo or o pairwise other headaches, active treatment Emabse, Ovid HA relief at 2 hours: OR 0.65 (0.53 – 0.80), favors the Eletriptan vs. comparisons chronic or but unclear how MEDLINE, Ovid drug in the column (ELE) recurrent rizatriptan many RCTs were MEDLINE In migraines who Process & HA relief at 24 hours: OR 0.55 (0.45 – 0.67), favors ELE Eletriptan vs. used for direct are not Other Non- frovatriptan pairwise Freedom from pain at 2 hours: OR 0.59 (0.45 – 0.78), experiencing an comparisons) Indexed favors ELE Citations,

Table 1. Characteristics and Results of Included Systematic Reviews First author, Population Intervention of Number of head- Literature Efficacy and safety endpoints/results year, study Interest head trials of search design interest databases identified by SR (search dates) acute episode Eletriptan vs. Google Scholar, Freedom from pain at 24 hours: OR 0.60 (0.44 – 0.82), were excluded) almotriptan clinical trial favors ELE sites listed in Eletriptan vs. Use of rescue medications: OR 1.91 (1.47 – 2.49), favors CADTH’s Grey zolmitriptan SUM (use of rescue medication is higher with SUM) Matters ELE SD (40 mg) tablet vs. RIZ SD (10 mg) tablet Eletriptan vs. (search date: o naratriptan from inception HA relief at 2 hours: NSS to October 6, HA relief at 24 hours: OR 0.46 (0.32 – 0.66), favors ELE 2013) Sumatriptan vs. Freedom from pain at 2 hours: NSS rizatriptan Freedom from pain at 24 hours: OR 0.64 (0.43 – 0.95), Sumatriptan vs. favors ELE frovatriptan Use of rescue medications: OR 1.61 (1.19 – 2.17), favors Sumatriptan vs. RIZ (higher use of rescue medication with RIZ) almotriptan o ELE SD (40 mg) tablet vs. FRO SD (2.5 mg) tablet Sumatriptan vs. HA relief at 2 hours: OR 0.48 (0.34 – 0.67), favors ELE zolmitriptan Freedom from pain at 2 hours: NSS Sumatriptan vs. Use of rescue medications: NSS naratriptan ELE SD (40 mg) tablet vs. ALM SD (12.5 mg) tablet o HA relief at 2 hours: 0.61 (0.46 – 0.82), favors ELE Rizatriptan vs. frovatriptan HA relief at 24 hours: OR 0.62 (0.44 – 0.87), favors ELE Freedom from pain at 2 hours: OR 0.50 (0.36 – 0.71), Rizatriptan vs. favors ELE almotriptan Freedom from pain at 24 hours: OR 0.53 (0.36 – 0.82), Rizatriptan vs. favors ELE zolmitriptan Use of rescue medications: OR 1.76 (1.24 – 2.50), favors Rizatriptan vs. ALM (higher use with ALM) naratriptan

o SUM SD (50 mg) tablet vs. RIZ SD (10 mg) tablet HA relief at 2 hours: OR 1.35 (1.07 – 1.71), favors RIZ HA relief at 24 hours: NSS Freedom from pain at 2 hours: OR 1.51 (1.15 – 1.99), favors RIZ Freedom from pain at 24 hours: NSS Use of rescue medications: NSS

o SUM SD (50 mg) tablet vs. ALM SD (12.5 mg) tablet HA relief at 2 hours: NSS HA relief at 24 hours: NSS Freedom from pain at 2 hours: NSS Freedom from pain at 24 hours: NSS Use of rescue medications: NSS

o SUM SD (50 mg) tablet vs. ZOL SD (2.5 mg) tablet HA relief at 2 hours: NSS HA relief at 24 hours: NSS Freedom from pain at 2 hours: NSS Freedom from pain at 24 hours: NSS Use of rescue medications: NSS

o SUM SD (50 mg) tablet vs. NAR SD (2.5 mg) tablet HA relief at 2 hours: NSS HA relief at 24 hours: NSS Freedom from pain at 2 hours: OR 0.55 (0.34 – 0.90), favors SUM Freedom from pain at 24 hours: NSS Use of rescue medications: NSS

o RIZ SD (10 mg) tablet vs. FRO SD (2.5 mg) tablet

o RIZ SD (10 mg) tablet vs. ALM SD (12.5 mg) tablet HA relief at 2 hours: OR 0.70 (0.52 – 0.95), favors RIZ HA relief at 24 hours: NSS Freedom from pain at 2 hours: OR 0.56 (0.40 – 0.79), favors RIZ Freedom from pain at 24 hours: NSS Use of rescue medications: NSS

o RIZ SD (10 mg) tablet vs. ZOL SD (2.5 mg) tablet HA relief at 2 hours: OR 0.75 (0.58 – 0.97), favors RIZ HA relief at 24 hours: OR 1.46 (1.02 – 2.10), favors ZOL Freedom from pain at 2 hours: OR 0.65 (0.47 – 0.88), favors RIZ Freedom from pain at 24 hours: NSS Use of rescue medications: NSS

o RIZ SD (10 mg) tablet vs. NAR SD (2.5 mg) tablet HA relief at 2 hours: OR 0.60 (0.40 – 0.89), favors RIZ HA relief at 24 hours: NSS Freedom from pain at 2 hours: OR 0.37 (0.23 – 0.59), favors RIZ Freedom from pain at 24 hours: NSS

o FRO SD (2.5 mg) tablet vs. ALM SD (12.5 mg) tablet HA relief at 2 hours: NSS Freedom from pain at 2 hours: NSS Use of rescue medications: NSS

o FRO SD (2.5 mg) tablet vs. ZOL SD (2.5 mg) tablet HA relief at 2 hours: NSS Freedom from pain at 2 hours: NSS Use of rescue medications: NSS

o FRO SD (2.5 mg) tablet vs. NAR SD (2.5 mg) tablet HA relief at 2 hours: NSS Freedom from pain at 2 hours: OR 0.40 (0.20 – 0.77), favors FRO Use of rescue medications: NSS

o ALM SD (12.5 mg) tablet vs. ZOL (2.5 mg) SD tablet HA relief at 2 hours: NSS HA relief at 24 hours: NSS Freedom from pain at 2 hours: NSS Freedom from pain at 24 hours: NSS Use of rescue medications: NSS

o ALM SD (12.5 mg) tablet vs. NAR SD (2.5 mg) tablet HA relief at 2 hours: NSS HA relief at 24 hours: NSS Freedom from pain at 2 hours: NSS

o ZOL SD (2.5 mg) tablet vs. NAR SD (2.5 mg) tablet HA relief at 2 hours: NSS HA relief at 24 hours: NSS Freedom from pain at 2 hours: OR 0.57 (0.34 – 0.95), favors ZOL Freedom from pain at 24 hours: NSS Use of rescue medications: NSS Bird 201482 Adults with Zolmitriptan 2 RCTs CENTRAL, ZOL 2.5 mg or 5 mg vs. SUM 50 mg episodic migraine 2.5 mg or 5 mg MEDLINE, MA of 2 RCTs: Gallagher 200097 and Gruffyd-Jones 200198 Cochrane SR with or without oral tablet vs. EMBASE, and Primary outcomes of RCTs aura, according to sumatriptan 50 mg the Oxford Pain - Headache relief at 2 hours without the use of rescue IHS. Patients oral tablets Relief medication: NSS difference between groups could take stable Database, Secondary outcomes prophylactic together with - Any AEs during the 24 hours postdose: NSS difference therapy three online between groups databases Other outcomes: (www.astrazen - Withdrawals due to AEs: NSS difference between ecaclinicaltrials. groups com, Note: These 2 RCTs included in Bird 2014 are also included www.clinicaltria in Xu 2016 ls.gov, and ZOL vs. ALM (1 RCT: Goadsby 2007b) (reported in Xu 2016) apps.who.int/ ZOL vs. RIZ (Pascual 2000) (reported in Xu 2016) trialsearch) ZOL vs. ELE (Steiner 2003) (reported in Xu 2016) (Search up to ZOL vs. FRO (Tullo 2010) (reported in Cameron 2015) March 12, 2014)

Table 1. Characteristics and Results of Included Systematic Reviews First author, Population Intervention of Number of head- Literature Efficacy and safety endpoints/results year, study Interest head trials of search design interest databases identified by SR (search dates) Worthington Adults with acute Triptans, Medline, Comparative evidence among triptans (as oral tablets): 201352 migraine attacks ergotamine, DHE, Embase, the - RIZ 10 mg seems to provide an earlier onset of pain analgesics, NSAIDs, Cochrane relief in comparison with other triptans and greater Canadian and antiemetics collaboration, relief of nausea compared to SUM Headache versus placebo or (search in May - ELE 40 mg seems to provide a greater sustained Society active comparator 2012) improvement over 24 hours compared to SUM Guideline - The incidence of AEs seems to be lower with ALM (includes SRs, 12.5 mg compared with ZOL and SUM MAs, and - NAR and FRO have slower onset on action; however, RCTs) head-to-head trials showed that FRO was similarly efficacious at 2 hours to other triptans - SUM/NAP was significantly better than SUM or NAP monotherapy regarding headache relief at 2 hours and sustained pain relief over 24 hours Comparative evidence between triptans and ergot derivatives: - Intranasal SUM 20 mg vs. intranasal DHE 1 mg (plus optional 1 mg after 30 minutes): More headache relief at 1 hour with SUM compared to DHE (53% vs. 41%; p<0.001). - SQ SUM 6 mg vs. intranasal DHE 1 mg (plus optional 1 mg after 30 minutes): SUM had earlier onset of action and significantly better efficacy in terms of headache relief and headache freedom from 15 minutes to 2 hours than DHE - SQ SUM 6 mg vs. SQ DHE 1 mg: NSS in headache relief at 4 hours - Oral SUM 100 mg (dispersible tablet) vs. ERG/CAF (Cafergot) o Headache relief at 2 hours: (48% vs. 66%; p<0.001), in favor of SUM

Table 1. Characteristics and Results of Included Systematic Reviews First author, Population Intervention of Number of head- Literature Efficacy and safety endpoints/results year, study Interest head trials of search design interest databases identified by SR (search dates) Derry 201391 Adults with Oral diclofenac 1 RCT CENTRAL,MEDL Oral DIC-K 50 mg or 100 mg (single dose) vs. oral SUM migraine attacks potassium 50 mg INE, Embase, (single dose) [1 RCT – DK/SMSG 199990] Cochrane SR with or without vs. oral the Oxford Pain Primary efficacy endpoint: of RCTs aura, as specified sumatriptan Relief - Migraine headache pain at 2 h after dosing in the IHS. 100 mg Database, DIC 50 mg or DIC 100 mg vs. SUM 100 mg: NSS Patients we ClinicalTrials.go difference between groups allowed to take v (up to Secondary efficacy endpoints: stable February, 15 - Pain at other time points up to 8 h: NSS difference prophylactic 2013) between groups at any time point (DIC had a faster therapy onset of action than SUM) - Presence of accompanying symptoms (nausea, vomiting, photophobia, phonophobia) 2 hours after dosing: o DIC was significantly better than SUM in terms of reducing the incidence of nausea and vomiting. o For photophobia, phonophobia, there were NSS differences between groups but a trend in favor of DIC vs. SUM Safety - Patients receiving DIC reported fewer AEs than with SUM (no p-value reported) - Patient’s overall evaluation of tolerability: DIC was significantly better than SUM regarding the number of patients evaluating tolerability as good or excellent Derry 201281 Adults with Sumatriptan 2 RCTs CENTRAL, • Intranasal SUM 20 mg vs. DHE 1 mg (plus optional 1 mg migraine intranasal vs. DHE EMBASE, after 30 minutes) (1 RCT - Boureau 200086): Cochrane SR intranasal MEDLINE, Patients experiencing any AEs within 24 hours: of RCTs Oxford Pain SUM 10% vs. DHE 10% Sumatriptan Relief o intranasal vs. Database, Withdrawal due to AEs: rizatriptan ODT online o SUM 0% vs. DHE 0.52%

o SUM 65% vs. RIZ 71% Freedom from pain at 1 hour:

o SUM 16% vs. RIZ 15% Freedom from pain at 2 hours:

o SUM 37% vs. RIZ 40% Use of rescue medications within 24 hours:

o SUM 28% vs. RIZ 22% Relief of nausea at 2 hours:

o SUM 54% vs. RIZ 73% Relief of photophobia at 2 hours:

o SUM 56% vs. RIZ 64% Relief of phonophobia at 2 hours:

o SUM 55% vs. RIZ 60% Serious adverse events:

o SUM 0.48% vs. RIZ 0% Derry 201283 Adults with acute Sumatriptan SQ vs. 3 RCTs CENTRAL, No p-values were reported for the following comparisons migraine attacks, naratriptan SQ MEDLINE, and outcomes Cochrane SR per IHS. Patients EMBASE, online SQ SUM 6 mg vs. SQ NAR 0.5, 1, 2.5, 5, and 10 mg (Dahlof of RCTs we allowed to databases, and 1998 – trial already included in Xu 2016) take stable reference lists - Pain-free at 2 hours:

SQ SUM 6 mg vs. DHE nasal spray 1 mg (Touchon 1996) - Pain-free at 2 hours: SUM (66%) vs. DHE (31%) - Pain-free at 1 hour: SUM (47%) vs. DHE (13%) - Headache relief at 1 hour after treatment: SUM (71%) vs. DHE (34%) - Headache relief at 2 hour after treatment: SUM (81%) vs. DHE (52%) - Relief of nausea by 2 hours SUM (76%) vs. DHE (54%) - Relief of functional disability (% of patients improving from mild to no functional disability) SUM (82%) vs. DHE (61%) - % patients experiencing AEs within 24 hours: SUM (43%) vs. DHE (22%) - Withdrawal due to AEs 91

SQ SUM 6 mg vs. SQ DHE 1 mg (Winner 1996) - Headache relief at 1 hour after treatment: SUM (78%) vs. DHE (57%) - Headache relief at 2 hour after treatment: SUM (85%) vs. DHE (73%) - Relief of nausea by 1 hour SUM (71%) vs. DHE (50%) - Incidence of AEs within 24 hours after treatment: SUM (6%, 4%, and 6% for nausea, vomiting, and chest pain, respectively) vs. DHE (16%, 7%, and 1% for nausea, vomiting, and chest pain, respectively) - Withdrawal due to AEs SUM (0%) vs. DHE (1.3%) Derry 201284 Adults with acute Sumatriptan oral 17 RCTs CENTRAL, Head-to-head comparisons among triptans using risk ratio migraine attacks, vs. other oral MEDLINE, (M-H, fixed, 95% CI): Cochrane SR per IHS. Patients triptans EMBASE, online - SUM (25 mg, 50 mg, 100 mg) vs. ZOL (2.5 mg, 5 mg) of RCTs we allowed to databases, and (Gallagher 2000, Gruffyd-Jones 2001, Geraud 2000) take stable reference lists prophylactic (through 13 SUM 50 mg vs. ZOL 2.5 mg or ZOL 5 mg therapy October 2011) o Headache relief at 1 hour, headache relief at 2 hours, and any AE within 24 hours (2 RCTs): NSS difference between groups - SUM (25 mg, 50 mg, 100 mg) vs. RIZ (5 mg, 10 mg, 20 mg, 40mg) (Goldstein 1998, Kolodny 2004, Lines 2001, Tfelt-Hansen 1998, Visser 1996)

SUM 25 mg vs. RIZ 5 mg: o Pain-free at 2 hours (2 RCTs): RR 0.84 [0.74, 0.95], in favor of RIZ o Headache relief at 2 hours (2 RCTs): RR 0.90 [0.84, 0.95], in favor of RIZ 92

SUM 25 mg vs. RIZ 10 mg: o Pain-free at 2 hours (2 RCTs): RR 0.70 [0.62, 0.79], in favor of RIZ o Headache relief at 1 hour (2 RCTs): RR 0.82 [0.74, 0.91], in favor of RIZ o Headache relief at 2 hours (2 RCTs): RR 0.86 [0.80, 0.91], in favor of RIZ o Incidence of vertigo/dizziness: RR 0.5 [0.33,0.77], in favor of SUM o Incidence of somnolence: RR 0.6 [0.38,0.97], in favor of SUM o Other outcomes (use of rescue medication, and safety outcomes such as any AE, paraesthesia, chest symptoms, nausea/vomiting, dry mouth, fatigue): NSS differences between SUM and RIZ

SUM 50 mg vs. RIZ 5 mg: o Pain-free at 2 hours, headache relief at 1 hour, headache relief at 2 hours: NSS difference between groups o Use of rescue medication (2 RCTs): RR 0.78 [0.65, 0.93], favors SUM o Incidence of any AE within 24 hours (2 RCTs): RR 1.17 [1.03, 1.33], favors RIZ

SUM 100 mg vs. RIZ 10 mg: o Pain-free at 2 hours (2 RCTs): RR 0.82 [0.69, 0.98], favors RIZ o Headache relief at 1 hour (2 RCTs): RR 0.76 [0.62, 0.92], favors RIZ o Any AE within 24 hours (2 RCTs): NSS difference between SUM and RIZ

- SUM (25 mg, 50 mg, 100 mg) vs. ELE (20 mg, 40 mg, 80 mg) (160-104, Sandrini 2002, Goadsby 2000, Mathew 2003)

SUM 50 mg vs. ELE 40 mg o Pain-free at 2 hours (2 RCTs): RR 0.74 [0.55, 0.98], favors ELE o Headache relief at 2 hours (2 RCTs): RR 0.85 [0.75, 0.97], favors ELE o Relief of nausea at 2 hours (2 RCTs): RR 0.76 [0.60, 0.95], favors ELE o Relief of functional disability at 2 hours (2 RCTs): RR 0.83 [0.72, 0.96], favors ELE o Other outcomes (ie, headache relief at 1 hour, relief of photophobia at 2 hours, and relief of

SUM 50 mg vs. ELE 80 mg: o Pain-free at 2 hours (2 RCTs): RR 0.58 [0.44, 0.76], favors ELE o Headache relief at 1 hour (2 RCTs): RR 0.72 [0.57, 0.91], favors ELE o Headache relief at 2 hours (2 RCTs): RR 0.78 [0.69, 0.89], favors ELE o Relief of photophobia at 2 hours: RR 0.72 [0.60, 0.86], favors ELE o Relief of functional disability at 2 hours (2 RCTs): RR 0.84 [0.73, 0.97], favors ELE o Relief of nausea at 2 hours: NSS difference between SUM and ELE

SUM 100 mg vs. ELE 40 mg: o Pain-free at 2 hours (3 RCTs): RR 0.74 [0.65, 0.85], favors ELE o Pain-free at 1 hour (3 RCTs): NSS difference between SUM and ELE o Headache relief at 1 hour (3 RCTs): RR 0.77 [0.67, 0.88], favors ELE o Headache relief at 2 hours (3 RCTs): RR 0.88 [0.82, 0.95], favors ELE o 24 h sustained headache relief (2 RCTs): RR 0.79 [0.70, 0.88], favors ELE o Use of rescue medication (2 RCTs): RR 1.29 [1.10, 1.51], favors ELE o Relief of nausea at 2 hours (3 RCTs): RR 0.87 [0.79, 0.96], favors ELE

SUM 100 mg vs. ELE 80 mg: o Pain-free at 2 hours (2 RCTs): RR 0.54 [0.41, 0.72], favors ELE o Pain-free at 1 hour (2 RCTs): RR 0.48 [0.29, 0.82], favors ELE o Headache relief at 1 hour (2 RCTs): RR 0.65 [0.50, 0.84], favors ELE o Headache relief at 2 hours (2 RCTs): RR 0.78 [0.68, 0.89], favors ELE o Relief of nausea at 2 hours (2 RCTs): RR 0.83 [0.69, 0.99], favors ELE o Relief of photophobia at 2 hours (2 RCTs): RR 0.76 [0.64, 0.89], favors ELE o Relief of functional disability at 2 hours (2 RCTs): RR 0.77 [0.67, 0.90], favors ELE

- SUM (50 mg, 100 mg) vs. ALM (12.5 mg, 25 mg) (Spierings 2001, Dodick 2002, Dowson 2002) SUM 100 mg vs. ALM 12.5 mg o Pain-free at 2 hours (2 RCTs) and 24 hour sustained pain-free (2 RCTs): NSS difference between SUM and ALM

- SUM 100 mg vs. NAR (1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg) (Havanka 2000): Results not reported, but trial included in Xu 2016

Head-to-head comparisons of triptans vs. diclofenac: - SUM 100 mg vs. DIC-K (50 mg and 100 mg) (DKSMSG 1999): Results not reported, but summarized by Worthington 2013 and Xu 2016

Head-to-head comparisons of triptans vs. Cafergot: - SUM vs. ERG/CAF (Latere 1991): Results not reported, but summarized by Worthington 2013 Abbreviations: AE, adverse event; ALM, almotriptan; BUTOR, butorphanol; BUT/CAF/ASA/COD; butalbital/caffeine/aspirin/codeine; BUT/APAP/CAF, butalbital/acetaminophen/caffeine; CENTRAL, Cochrane Central Register of Controlled Trials; CI, confidence interval; DHE, dihydroergotamine; DIC-K, diclofenac potassium; ELE, eletriptan; ERG/CAF, ergotamine/caffeine; FRO, frovatriptan; HA, headache; ICHD, International Classification of Headache Disorders; IHS, International Headache Society; MA, meta-analysis; NAR, naratriptan; NMA, network meta-analysis; NS, nasal spray; NSS, non-statistically significant; OR, odds ratio; RCT, randomized controlled trial; RIZ, rizatriptan; RR, risk ratio; SR, systematic review; SD, standard dose; SUM, sumatriptan; SUM/NAP, sumatriptan/naproxen; SQ, subcutaneous; ZOL, zolmitriptan

Table 2. Head-to-Head Randomized Controlled Trials Included in Systematic Reviews for the Acute Treatment of Migraine SR/MA Formulations RCTs Doses Tested in RCTs Xu Cameron Menshawy Bird Worthington Derry Derry Derry Derry Tested in RCTs 201637 201579 201880 201482 201352 201391 201281 201283 201284 SUM vs. ZOL SUM 25 or 50 mg vs. Gallagher 200097 Tablet √ √ √ √ √ ZOL 2.5 or 5 mg Gruffyd-Jones SUM 50 mg vs. ZOL 2.5 Tablet √ √ √ √ √ 200198 or 5 mg SUM 100 mg vs. ZOL Geraud 200099 Tablet √ √ √ 5 mg SUM vs. ALM SUM 50 mg vs. ALM Spierings 2001100 Tablet √ √ √ √ 12.5 mg SUM 100 mg vs. ALM Dodick 2002101 Oral √ √ √ 12.5 mg Dowson 2004102 SUM 100 mg vs. ALM (post-hoc analysis Oral √ √ √ 12.5 mg or 25 mg from an RCT) SUM vs. NAR SUM 100 mg vs. NAR Gobel 2000103 Tablet √ √ 2.5 mg SUM 6 mg vs. NAR 0.5- Dahlof 1998104 SQ injectiona √ √ 10 mg SUM 100 mg vs. NAR Havanka 2000105 Tablet √ √ 1, 2.5, 5, 7.5, 10 mg Dahlof 1997 Oral Not found √ (abstract only)106 SUM vs. RIZ Oral (not SUM 25 mg or 50 mg Goldstein 1998107 reported if √ √ √ √ vs. RIZ 5 mg or 10 mg tablets or ODT) SUM 25 mg or 50 mg Kolodny 2004108 Tablet √ √ √ √ vs. RIZ 5 mg or 10 mg Tfelt-Hansen SUM 100 mg vs. RIZ √ Tablet √ √ √ 1998109 5 mg and 10 mg

Table 2. Head-to-Head Randomized Controlled Trials Included in Systematic Reviews for the Acute Treatment of Migraine SR/MA Formulations RCTs Doses Tested in RCTs Xu Cameron Menshawy Bird Worthington Derry Derry Derry Derry Tested in RCTs 201637 201579 201880 201482 201352 201391 201281 201283 201284 Oral (not SUM 100 mg vs. RIZ Visser 1996110 reported if √ √ √ 10, 20, 40 mg tablets or ODT) SUM40031 (from SUM 20 mg intranasal manufacturer Intranasal/oral vs. RIZ 10 mg oral √ √ website)111 wafer Oral (not SUM 50 mg vs. RIZ Lines 2001112 reported if √ √ 5 mg tablets or ODT) SUM vs. ELE SUM 100 mg capsule Mathew 2003113 Tablet/capsule √ √ √ √ vs. ELE 40 mg tablet SUM 100 mg vs. Goadsby 2000114 Tablet √ √ ELE 20, 40, 80 mg SUM 50, 100 mg vs. Sandrini 2002115 Tablet √ √ ELE 40, 80 mg 160-104 (unpublished Oral Not found √ data)116 ZOL vs. ALM ZOL 2.5 mg vs. ALM Goadsby 2007117 Oral √ √ √ √ 12.5 mg ZOL vs. RIZ ZOL 2.5 mg vs. RIZ Pascual 2000118 Tablet √ √ √ 10 mg ZOL vs. ELE ZOL 2.5 mg capsule vs. Steiner 2003119 Tablet ELE 40 mg or 80 mg √ √ √ √ tablet RIZ vs. NAR RIZ 10 mg vs. NAR 120 Bomhof 1999 Tablet 2.5 mg √ √ √

Table 2. Head-to-Head Randomized Controlled Trials Included in Systematic Reviews for the Acute Treatment of Migraine SR/MA Formulations RCTs Doses Tested in RCTs Xu Cameron Menshawy Bird Worthington Derry Derry Derry Derry Tested in RCTs 201637 201579 201880 201482 201352 201391 201281 201283 201284 FRO vs. ALM Not reported but agents only FRO 2.5 mg vs. ALM Bartolini 2011121 √ √ available as 12.5 mg tablets Bartolini 2012122 FRO 2.5 mg vs. ALM (menstrual Tablet √ 12.5 mg migraine) FRO vs. RIZ FRO 2.5 mg vs. RIZ Savi 2011123 Tablet √ √ 10 mg FRO vs. ZOL Not reported in RCT but Bird FRO 2.5 mg vs. ZOL Tullo 2010124 √ √ √ 2014 state ZOL 2.5 mg tablet tablet FRO 2.5 mg vs. ZOL Tullo 2012125 Tablet √ 2.5 mg SUM/NAP vs. SUM or NAP SUM/NAP 85/500 mg Brandes 2007126 Tablet vs. SUM 85 mg or NAP √ √ √ 500 mg SUM/NAP 50/500 mg Smith 2005127 Tablet vs. SUM 50 mg or NAP √ √ √ 500 mg SUM vs. DIC K SUM 100 mg vs. DIC-K DK/SMSG 199990 Tablet √ √ √ √ 50 or 100 mg SUM vs. DHE SUM 20 mg vs. DHE Boureau 200086 Nasal spray 1 mg plus optional √ √ √ 1 mg

100

Table 2. Head-to-Head Randomized Controlled Trials Included in Systematic Reviews for the Acute Treatment of Migraine SR/MA Formulations RCTs Doses Tested in RCTs Xu Cameron Menshawy Bird Worthington Derry Derry Derry Derry Tested in RCTs 201637 201579 201880 201482 201352 201391 201281 201283 201284 SUM vs. DHE SUM 6 mg SQ vs. DHE Touchon 199687 SQ/intranasal nasal spray 1 mg plus √ √ optional 1 mg SUM 6 mg vs. DHE Winner 199688 SQ injection √ √ 1 mg SUM vs. ERG/CAF SUM 100 mg Anonymous Oral dispersible tablet vs. √ 1991128 ERG/CAF 2/200 mg ELE vs. ERG/CAF ELE 40 or 80 mg vs. Diener 2002129 Tablet Cafergot √ (recommended dose) ALM vs. ERG/CAF ALM 12.5 mg vs. Lainez 2007130 Oral √ ERG/CAF 2/200 mg BUT vs. BUT/CAF/ASA/COD (Fiorinal with Codeine) BUTOR nasal spray Nasal spray/ 1 mg vs. Goldstein 199892 √ capsule BUT/CAF/ASA/COD 50/40/325/30 mg SUM/NAP vs. BUT/APAP/CAF (Fioricet) SUM/NAP 85/500 mg Derosier 201293 Tablet vs. BUT/APAP/CAF √ 50/325/40 mg Abbreviations: ALM, almotriptan; BUTOR, butorphanol; BUT/CAF/ASA/COD; butalbital/caffeine/aspirin/codeine; BUT/APAP/CAF, butalbital/acetaminophen/caffeine; DHE, dihydroergotamine; DIC-K, diclofenac potassium; ELE, eletriptan; ERG/CAF, ergotamine/caffeine; FRO, frovatriptan; NAR, naratriptan; RCT, randomized controlled trial; RIZ, rizatriptan; SR/MA, systematic review/meta-analysis; SUM, sumatriptan; SUM/NAP, sumatriptan/naproxen; SQ, subcutaneous; ZOL, zolmitriptan a Naratriptan SQ injection is not FDA approved

101