Zavegepant Hydrochloride (Monograph)

Brand name: Zavzpret
Drug class: Calcitonin Gene-related Peptide (CGRP) Antagonists

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

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Introduction

Antimigraine agent; small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (gepant).

Uses for Zavegepant Hydrochloride

Acute Treatment of Migraine

Used for acute treatment of migraine with or without aura in adults.

Not indicated for preventive treatment of migraine.

Guideline from the American Headache Society generally recommends 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.

Zavegepant Hydrochloride Dosage and Administration

General

Patient Monitoring

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

Administration

Administer intranasally. Do not test spray, prime, or press the plunger prior to use.

Dosage

Adults

Acute Treatment of Migraine With or Without Aura

Intranasal

10 mg (1 spray) as a single dose, as needed. Maximum dose in a 24-hour period is 10 mg (1 spray). Safety of treating >8 migraines in a 30-day period not established.

Special Populations

Hepatic Impairment

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary.

Severe hepatic impairment (Child-Pugh class C): Not studied; avoid use.

Renal Impairment

Cl_cr ≥30 mL/minute: Dosage adjustment not necessary.

Cl_cr <30 mL/minute: Avoid use.

Geriatric Patients

No specific dosage recommendations.

Related/similar drugs

Ubrelvy, acetaminophen, ibuprofen, amitriptyline, naproxen, diclofenac, propranolol

Cautions for Zavegepant Hydrochloride

Contraindications

• Hypersensitivity to zavegepant or any component in the formulation.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including facial swelling and urticaria, reported.

If a hypersensitivity reaction occurs, discontinue drug and initiate appropriate therapy.

Specific Populations

Pregnancy

No adequate data on developmental risk associated with use in pregnant women. No adverse developmental effects observed when administered to pregnant animals at doses associated with plasma exposures higher than used clinically.

Lactation

Not known whether distributed into human milk. Effects on the breast-fed infant and on milk production also unknown. Consider developmental and health benefits of breast-feeding, mother's clinical need for zavegepant, and potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether such patients respond differently than younger adults. Clinically important pharmacokinetic differences not observed between patients ≥65 years and younger individuals.

Hepatic Impairment

Maximum serum concentrations and exposure increased in patients with moderate hepatic impairment (Child-Pugh class B); not expected to be clinically significant. Not studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Renal route plays a minor role in zavegepant clearance; no clinically significant effect on pharmacokinetics expected in patients with Cr_cl ≥30 mL/minute. Possible increased exposure in patients with Cr_cl15–29 mL/minute. Not studied in patients with Cr_cl<15 mL/minute.

Common Adverse Effects

Most common adverse reactions (≥2%): taste disorders, nausea, nasal discomfort, vomiting.

Drug Interactions

Metabolized primarily by CYP3A4 and to a lesser extent by CYP2D6; in vitro studies indicate zavegepant is a substrate of these isoenzymes. Does not inhibit CYP1A2, 2C9, 2C19, 2B6, 2D6, 2C8, or 3A4; does not induce CYP1A2, 2B6, or 3A4.

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. Does not inhibit P-glycoprotein (P-gp), BCRP, OAT1, OAT3, OATP1B1, or OATP1B3.

Substrate of OATP1B3 and sodium taurocholate cotransporting polypeptide (NTCP). Also a substrate of P-gp, multidrug and toxic compound extrusion (MATE) 1, and MATE2-K; however, coadministration not expected to have clinically important effects. Inhibitor of OCT2, MATE1, and MATE2-K; inhibition potential not expected to be clinically important.

Drugs Affecting or Affected by Transport Systems

OATP1B3 or NTCP inhibitors: concomitant use may result in significantly increased systemic exposure to zavegepant. Avoid concomitant use with OATP1B3 or NTCP inhibitors.

OATP1B3 or NTCP inducers: concomitant use not studied; however, may result in decreased systemic exposure to zavegepant. Avoid concomitant use with OATP1B3 or NTCP inducers.

Specific Drugs

Zavegepant Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Exhibits slightly less than dose-proportional pharmacokinetics at doses up to 4 times the recommended dosage.

Peak plasma concentrations occur approximately 30 minutes following a single dose.

Bioavailability: ~5%.

Special Populations

Moderate hepatic impairment (Child-Pugh class B): maximum serum concentration increased by 16%; exposure increased 1.9-fold. These changes not expected to be clinically significant.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Mild or moderate renal impairment (Cl_cr≥30 mL/minute): Pharmacokinetics not substantially affected.

Severe renal impairment (Cl_cr15–29 mL/minute): Accumulation of uremic solutes can increase exposure to zavegepant by inhibiting organic anion transporting polypeptide transporters.

End-stage renal disease (Cl_cr <15 mL/minute): Not studied.

Pharmacokinetics not substantially affected by age, sex, race, ethnicity, or body weight.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

~90%.

Elimination

Metabolism

Eliminated mainly through metabolism, primarily by CYP3A4 and to a lesser extent by CYP2D6. Parent compound is the most prevalent circulating component in human plasma; no major metabolites have been detected.

Elimination Route

Excreted mainly by the biliary/fecal route; renal route is a minor route of elimination. Following a single oral dose, eliminated in feces (80%) and urine (11%) as unchanged drug.

Half-Life

6.55 hours.

Stability

Storage

Intranasal

Solution

20–25°C (excursions permitted between 15–30°C). Do not freeze.

Actions

• Small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (gepant); binds to CGRP receptors with high affinity, blocking the binding of CGRP to the receptor and preventing subsequent receptor activation.

• CGRP is a potent vasodilator and pain-signaling neuropeptide that has been associated with migraine pathophysiology. 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.

• Increased serum CGRP concentrations observed in individuals during acute migraine attacks; these return to normal after resolution of the migraine. IV infusion of CGRP induces migraines in patients with a history of migraines.

• Unlike 5-HT₁ receptor agonists (triptans) and ergot alkaloids, zavegepant does not appear to cause vasoconstriction. Also does not appear to prolong the QT interval in dosages up to 4 times the maximum recommended daily dosage.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• Inform patients about the signs and symptoms of hypersensitivity reactions after administration of zavegepant. Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur.

• 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. Inform patients that if they need to use an intranasal decongestant it should be administered at least 1 hour after zavegepant administration.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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