AHFS Class:

• Calcitonin Gene-related Peptide (CGRP) Antagonists 28:32.12

Generic Name(s):

• Zavegepant Hydrochloride

Zavegepant hydrochloride is a calcitonin gene-related peptide (CGRP) receptor antagonist.1

Acute Migraine Treatment

Zavegepant is used for the acute treatment of migraine with or without aura in adults.1

Zavegepant is not indicated for the preventive treatment of migraine.1

Guidelines from the American Headache Society generally recommend oral calcitonin gene-related peptide (CGRP) antagonists (gepants) as second-line agents for acute treatment of migraine in patients with inadequate responses to or contraindications to triptans.2,21

Clinical Experience

The current indication for zavegepant is based principally on the results of 2 randomized, double-blind, clinical trials.1 In study 1, eligible patients were adults with a ≥1 year history of migraines and 2 to 8 moderate to severe migraine attacks per month.2 Patients were randomized at a 1:1 ratio to treatment with a single dose of either zavegepant 10 mg (n=623) or placebo (n=646), and were instructed to treat migraine headaches of moderate to severe intensity.1,2 A rescue medication (nonsteroidal anti-inflammatory agents, acetaminophen, and/or antiemetics) was allowed 2 hours after the initial treatment.1 The coprimary outcomes assessed were freedom from pain (defined as pain intensity of 0) and freedom from the most bothersome migraine symptoms (photophobia, phonophobia, or nausea) at 2 hours after the first dose.1,2 Additional outcomes included pain relief at 2 hours post-dose, normal functioning at 2 hours post-dose, and sustained freedom from pain from 2 to 48 hours post-dose.1,2

Enrolled patients were a mean age of 40.8 years, 83% were white, and 83% were female, with a mean of 4.7 moderate to severe migraine attacks per month.2 At 2 hours after treatment, 23.6 or 14.9% of patients given zavegepant or placebo were responders based on freedom from pain.1,2 For freedom from the most bothersome symptoms, 39.6 or 31.1% of patients given zavegepant or placebo were responders.1 For pain relief at 2 hours, 58.7 or 49.7% of patients given zavegepant or placebo were responders, respectively.1,2 Normal functioning at 2 hours was reported by 35.8 or 25.6% of patients given zavegepant or placebo, respectively.1,2 Sustained freedom from pain was reported by 12.4 or 8.7% of patients given zavegepant or placebo, respectively.1

Study 2 was a phase 2/3 double-blind, placebo-controlled, dose-ranging trial, enrolling patients with a history of migraine onset prior to 50 years of age, with ≤8 migraine attacks of moderate to severe intensity per month and a migraine duration of 4-72 hours untreated.1,3 Patients were randomized to treatment with intranasal zavegepant 5, 10, or 20 mg or placebo.3 The coprimary outcomes assessed were freedom from pain (defined as pain intensity of 0) and freedom from the most bothersome migraine symptoms (photophobia, phonophobia, or nausea) at 2 hours after the dose.1,3 Secondary outcomes included pain relief at 2 hours post-dose, return to normal functioning at 2 hours post-dose, and sustained freedom from pain at 2 to 24 hours post-dose.3 For all enrolled patients, the mean age was 40.8 years; 85.5% were female, 78.3% were white, and 16.3% were Black.3

Among patients randomized to 10 mg zavegepant, 22.5% were pain free at 2 hours, compared to 15.5% of placebo patients.1 For freedom from most bothersome symptoms, 41.9 or 33.7% of patients given zavegepant 10 mg or placebo were responders, respectively.1,3 Results in favor of zavegepant 10 mg over placebo were also seen for secondary outcomes including pain relief at 2 hours (60.6 or 53.6% for zavegepant or placebo, respectively), return to normal functioning at 2 hours (34.5 or 27.4%, respectively), and sustained freedom from pain at 2 to 24 hours (15.1 or 9%, respectively).3

Clinical Perspective

The American Headache Society (AHS) guideline includes the oral CGRP antagonists (gepants) as one of several drugs with established efficacy in the acute treatment of migraine.2,21 Unlike 5-HT₁ receptor agonists (triptans) and ergot alkaloids, CGRP antagonists do not cause constriction of blood vessels, and therefore may have a role in patients with cardiovascular contraindications to triptans.2,21 Because of the relatively high cost of CGRP antagonists compared with oral triptans in the acute treatment of migraine, AHS recommends that oral CGRP antagonists be considered for use only in patients who have contraindications to the use of triptans and/or who have an inadequate response or intolerance to at least 2 oral triptans.2,21

General

Patient Monitoring

• Monitor for signs of hypersensitivity during treatment; if hypersensitivity reactions occur, discontinue zavegepant and initiate appropriate treatment.1

Administration

Zavegepant hydrochloride is administered intranasally as a single spray in one nostril, as needed.1 Do not test spray, prime, or press the plunger prior to use.1

Store zavegepant nasal spray between 20-25°C (excursions permitted between 15-30°C).1 Do not freeze.1

Dosage

Adults

For the acute treatment of migraine with or without aura, the recommended dose is 10 mg of zavegepant given as a single spray in one nostril, as needed.1

The maximum dose in a 24-hour period is 10 mg (one spray).1

The safety of treating more than 8 migraines in a 30-day period has not been established.1

Special Populations

Hepatic Impairment

Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Use of zavegepant has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should be avoided.1

Renal Impairment

Dosage adjustment is not necessary in patients with an estimated creatinine clearance of ≥30 mL/minute.1 Avoid use of zavegepant in patients with a creatinine clearance <30 mL/minute.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• History of hypersensitivity reaction to zavegepant or any component in the formulation.1

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including facial swelling and urticaria, have occurred in patients treated with zavegepant in clinical trials.1 If a hypersensitivity reaction occurs during treatment, discontinue the drug and initiate appropriate treatment.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of zavegepant in pregnant women.1 No adverse developmental effects were observed following subcutaneous administration of zavegepant to pregnant animals at doses associated with plasma exposures higher than those used clinically.1

Lactation

There are no data on the presence of zavegepant or its metabolites in human milk, the effects on the breast-fed infant, or on milk production.1 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for zavegepant and any potential adverse effects on the breastfed infant from zavegepant or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness of zavegepant use in pediatric patients have not been established.1

Geriatric Use

Clinical studies of zavegepant did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger adult patients.1 In a limited number of patients ≥65 years of age who received treatment with zavegepant, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects.1

Hepatic Impairment

In a clinical study comparing pharmacokinetics of zavegepant in patients with moderate hepatic impairment (Child-Pugh class B) to healthy controls, maximum serum concentrations were 16% higher and exposure to zavegepant was 1.9-fold higher in patients with moderate hepatic impairment.1 These changes are not expected to be clinically significant, based on clinical safety experience and minimal accumulation of drug exposures.1 The pharmacokinetics of zavegepant have not been studied in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

The renal route plays a minor role in zavegepant clearance; no clinically significant impact on zavegepant pharmacokinetics is expected in patients with an estimated creatinine clearance of ≥30 mL/minute.1 In patients with a creatinine clearance of 15-29 mL/minute, accumulation of uremic solutes can increase exposure to zavegepant by inhibiting organic anion transporting polypeptide transporters.1 The pharmacokinetics of zavegepant have not been studied in patients with a creatinine clearance <15 mL/minute.1

Common Adverse Effects

The most common adverse reactions observed in patients treated with zavegepant in clinical trials (≥2% of patients treated with zavegepant and greater than placebo) were taste disorders, nausea, nasal discomfort, and vomiting.1

Zavegepant is metabolized principally by cytochrome P-450 (CYP) 3A4 and to a lesser extent by CYP2D6.1 In vitro studies indicate that zavegepant is a substrate of CYP3A4 and CYP2D6 (to a lesser extent).1 Zavegepant does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2B6, 2D6, 2C8, or 3A4 and does not induce CYP isoenzymes 1A2, 2B6, or 3A4 at clinically relevant concentrations.1

In vitro, the drug is not a substrate for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, organic anion transporter (OAT) 1 and OAT3, organic cation transporter (OCT) 2, bile salt export pump (BSEP), multidrug resistance protein (MRP) 2 and MRP4.1 Zavegepant also does not inhibit P-glycoprotein (P-gp), BCRP, OAT1, OAT3, OATP1B1, or OATP1B3 at clinically relevant concentrations.1

In vitro studies indicate that zavegepant is a substrate of OATP1B3, and sodium taurocholate cotransporting polypeptide (NTCP).1 Zavegepant is also a substrate of P-gp, multidrug and toxic compound extrusion (MATE) 1, and MATE2-K; however, coadministration of zavegepant with inhibitors of these transporters is not expected to be clinically important since the drug is minimally cleared by the renal pathway.1 The drug is an inhibitor of OCT2, MATE1, and MATE2-K; however, this inhibition potential is not expected to be clinically important.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP Inhibitors

Concomitant administration of a single 10 mg dose of zavegepant and itraconazole (a strong CYP3A4 and P-gp inhibitor) at steady state did not result in a clinically relevant change in exposure to zavegepant.1

Drugs Affecting or Affected by Transport Systems

OATP1B3 or NTCP Inhibitors

Concomitant use of zavegepant and inhibitors of OATP1B3 or NTCP transporters may result in significantly increased systemic exposure to zavegepant.1 When rifampin (an OATP1B3 inhibitor, NTCP inhibitor, and strong CYP3A inducer) and zavegepant were administered concomitantly at steady state, exposure and peak plasma concentrations of zavegepant were increased 2.3-fold and 2.2-fold, respectively.1 This change is a composite effect of OATP1B3 and NTCP inhibition and CYP3A induction.1

Avoid concomitant administration of zavegepant with inhibitors of OATP1B3 or NTCP.1

OATP1B3 or NTCP Inducers

Concomitant use of zavegepant and inducers of OATP1B3 or NTCP transporters has not been studied.1 However, concomitant use of zavegepant and inducers of OATP1B3 or NTCP transporters may result in decreased systemic exposure to zavegepant, since zavegepant is a substrate of OATP1B3 and NTCP.1

Avoid concomitant administration of zavegepant with inducers of OATP1B3 or NTCP.1

Intranasal Decongestants

The pharmacokinetic effects of concomitant use of zavegepant nasal spray and intranasal decongestants have not been evaluated.1 Concomitant use of zavegepant nasal spray and intranasal decongestants may decrease the absorpotion of zavegepant, potentially resulting in decreased systemic exposure and decreased efficacy of zavegepant.1

Avoid concomitant administration of intranasal decongestants with zavegepant.1 If concomitant use is not avoidable, administer intransasal decongestants at least 1 hour after zavegepant.1

Oral Contraceptives

No significant pharmacokinetic interactions were observed when zavegepant and oral contraceptives (ethinyl estradiol) were administered concomitantly.1

Sumatriptan

No significant pharmacokinetic interactions were observed when zavegepant and sumatriptan were administered concomitantly.1

Description

Zavegepant is a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (sometimes referred to as a gepant).1,4 CGRP is a potent vasodilator and pain-signaling neuropeptide that has been associated with migraine pathophysiology.4 CGRP and its receptors are located at sites that are relevant to migraine development such as the trigeminal neurons and are also widely distributed throughout the central and peripheral nervous systems as well as in nonneuronal tissues throughout the body.4 Serum CGRP concentrations are increased during acute migraine attacks and return to normal after resolution of the migraine.4 Furthermore, IV infusion of CGRP has been shown to induce migraines in patients with a history of migraines.4

Zavegepant and other small molecule CGRP receptor antagonists bind to CGRP receptors with high affinity, blocking the binding of CGRP to the receptor and preventing subsequent receptor activation.4 Unlike 5-HT₁ receptor agonists (triptans), CGRP receptor antagonists do not appear to cause vasoconstriction.2,21 Zavegepant does not appear to prolong the QT interval in dosages up to 4 times the maximum recommended daily dosage.1

Zavegepant exhibits slightly less than dose-proportional pharmacokinetics at doses up to 4 times the recommended dosage.1 Peak plasma concentrations of zavegepant occur approximately 30 minutes after a single dose; the absolute bioavailability of zavegepant is about 5%.1 The drug is approximately 90% bound to plasma proteins.1 Zavegepant is mainly eliminated through metabolism, primarily by cytochrome P-450 (CYP) 3A4 and to a lesser extent by CYP2D6.1 The parent compound is the most prevalent circulating component in human plasma; no major metabolites of zavegepant have been detected in plasma.1 Zavegepant is excreted mostly by the biliary/fecal route; the renal route is a minor route of elimination.1 Following oral administration of a single, radiolabeled dose of zavegepant, 80 and 11% of the dose was recovered as unchanged zavegepant in feces and urine, respectively.1 The elimination half-life of the drug is 6.55 hours.1 Population pharmacokinetic analysis indicates that the pharmacokinetics of zavegepant are not substantially affected by age, sex, race, ethnicity, or body weight.1

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).1
• Inform patients about the signs and symptoms of hypersensitivity reactions after administration of zavegepant.1 Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur.1
• Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 Inform patients that if they need to use an intranasal decongestant it should be administered at least 1 hour after zavegepant administration.1
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

1. Pfizer Laboratories Div Pfizer Inc. ZAVZPRET® (zavegepant) NASAL prescribing information. 2023 Mar. [Web]

2. Lipton R, Croop R, Stock D, 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 D, 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. Wattiez AS, Sowers LP, Russo AF. Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting. Expert Opin Ther Targets. 2020;24(2):91-100.

12. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache . 2019; 59:1-18.

21. Ailani J, Burch RC, Robbins MS et al. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache . 2021; 61:1021-1039.