By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first intranasal calcitonin gene-related peptide (CGRP) receptor antagonist to treat migraines. Zavegepant is distributed as Zavzpret.
INDICATION
Zavegepant can be prescribed to treat migraine, with or without aura, in adults.1
DOSAGE
The recommended dose is 10 mg as a single spray in one nostril, as needed.1 The maximum dose is one spray in a 24-hour period.1 Zavegepant is available as a ready-to-use, unit-dose disposable device. Each carton contains six units.
POTENTIAL ADVANTAGES
Zavegepant is the first CGRP antagonist designed to be delivered intranasally. Some patients may experience pain relief in 15 minutes.2 Because of its route of administration, zavegepant carries low potential for drug-drug interaction (e.g., involving CYP3A4) in contrast to other “gepants” (i.e., ubrogepant, rimegepant).
POTENTIAL DISADVANTAGES
Zavegepant is a substrate of organic anion transporting polypeptide 1B3 and sodium taurocholate co-transporting polypeptide transporters. Avoid using zavegepant with inhibitors and inducers of these transporters.1 Avoid intranasal decongestants, as these may reduce the absorption of zavegepant.1 The most frequently occurring adverse reactions (vs. placebo) are taste disorders (18% vs. 4%), nausea (4% vs. 1%), and nasal discomfort (3% vs. 1%).1
COMMENTS
The efficacy of zavegepant was shown in two randomized, double-blind, placebo-controlled trials (study 1 and study 2) that included adults with migraine, with or without aura.1-3 The co-primary endpoints were pain freedom and most bothersome symptom (MBS) freedom at two hours after a single dose of zavegepant or placebo. Pain freedom was defined as a reduction of moderate or severe headache pain to no headache pain. MBS freedom was defined as the absence of the self-identified MBS (photophobia, phonophobia, or nausea).
In study 1,623 subjects were randomized to zavegepant and 646 subjects were randomized to placebo. At two hours, 23.6% were pain-free vs. 14.9% for subjects who took placebo (difference from placebo = 8.8%). MBS response was 39.6% vs. 31.1% (difference from placebo = 8.7%).
In study 2, subject allocations were 391 for zavegepant and 401 for placebo. The percentage of subjects who were pain-free at two hours was 22.5% for zavegepant and 15.5% for placebo (difference from placebo = 7%). For MBS-free at two hours, the percentage for zavegepant was 41.9% vs. 33.7% for placebo (difference from placebo = 8.3%).
Secondary endpoints from study 1 showed 16% of subjects who took zavegepant reported pain relief at 15 minutes vs. 8% for placebo-treated subjects.2 However, there was no statistical difference in the subjects’ ability to function normally at 15 minutes (3% vs. 2%). The numbers improved to 11% vs. 6% and 20% vs. 16%, respectively, after 30 minutes and 60 minutes post-dose. Other secondary endpoints favored zavegepant, such as the ability to function normally at two hours (36% vs. 26%). There were no statistical differences in terms of freedom from nausea (52% vs. 52%) or in pain relapse (59% vs. 65%).
CLINICAL IMPLICATIONS
Migraine is a common neurological condition that affects about 1 billion people worldwide.4 Women are nearly twice as likely as men to experience severe headache or migraine.5 The American Headache Society Consensus Statement recommends nonsteroidal anti-inflammatory drugs, non-opioid analgesics, acetaminophen, or caffeinated analgesic combinations for mild-to-moderate attacks.6
Migraine-specific agents, such as triptans, dihydroergotamine, gepants, and selective serotonin (5-HT1F) receptor agonists (ditans), are recommended for moderate or severe attacks. Consider non-oral formulations for attacks associated with nausea or vomiting, difficulty swallowing, or for patients who do not respond well to oral administration.
Currently, there are two triptans available as nasal sprays (sumatriptan and zolmitriptan). About 30% of patients produce an insufficient response to a triptan.6 Zavegepant offers a CGRP antagonist with intranasal administration. Consider preventive tactics for patients with four or five headache days per month or three or more days with severe disability.6
There are no published comparative studies with triptans or gepants. The efficacy of zavegepant (pain free and MBS free at two hours, placebo-subtracted) is similar to those reported for ubrogepant and rimegepant.7,8 Zavegepant is expected to be available in July 2023.
REFERENCES
1. Pfizer. Zavzpret prescribing information. March 2023.
2. Lipton RB, Croop R, Stock DA, et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: A phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol 2023;22:209-217.
3. Croop R, Madonia J, Stock DA, et al. Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial. Headache 2022;62:1153-1163.
4. Amiri P, Kazeminasab S, Nejadghaderi SA, et al. Migraine: A review on its history, global epidemiology, risk factors, and comorbidities. Front Neurol 2022;12:800605.
5. QuickStats: Percentage of adults who had a severe headache or migraine in the past 3 months, by sex and age group — National Health Interview Survey, United States, 2018. MMWR Morb Mortal Wkly Rep 2020;69:359.
6. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache 2021;61:1021-1039.
7. Pfizer. Nurtec ODT prescribing Information. February 2023.
8. Allergan, Inc. Ubrelvy prescribing information. February 2023.
Zavegepant can be prescribed to treat migraine, with or without aura, in adults.
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