Zavegepant hydrochloride (monograph)

Zavegepant hydrochloride (monograph)

Zavegepant hydrochloride (monograph)

introduction

antimigraine drugs; small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (Gepant).

Uses for Zavegepant Hydrochloride

Acute treatment of migraine

For the acute treatment of migraine with or without aura in adults.

Not suitable for the preventative treatment of migraines.

The American Headache Society guidelines generally recommend oral calcitonin gene-related peptide (CGRP) antagonists (gepants) as second-line agents for the acute treatment of migraine in patients with inadequate response to or contraindications to triptans.

Dosage and administration of zavegepant hydrochloride

Generally

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, bleed, or press the plunger before use.

dosage

Adult

Acute treatment of migraine with or without aura

Intranasally

10 mg (1 spray) as a single dose as needed. The maximum dose in 24 hours is 10 mg (1 spray). Safety of treatment of >8 migraines in a 30-day period has not been established.

Special populations

Liver dysfunction

Mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment: No dose adjustment is necessary.

Severe hepatic impairment (Child-Pugh Class C): Not studied; Avoid using.

Renal dysfunction

Clcr ≥30 ml/minute: No dose adjustment required.

Clcr <30 ml/minute: Avoid use.

Geriatric patients

No specific dosage recommendations.

Zavegepant hydrochloride precautions

Contraindications

• Hypersensitivity to zavegepant or any components of the formulation.

Warnings/Precautions

Hypersensitivity reactions

Hypersensitivity reactions, including facial swelling and urticaria, have been reported.

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

Specific populations

pregnancy

There are insufficient data on the developmental risk associated with use in pregnant women. No adverse developmental effects were observed when pregnant animals were administered doses associated with higher plasma exposure than those used clinically.

lactation

It is not known whether it passes into breast milk. Effects on the breastfed infant and on milk production are also not known. Consider the developmental and health benefits of breastfeeding, the mother's clinical need for zavegepant, and potential adverse effects of the drug or underlying maternal condition on the breastfed infant.

Pediatric use

Safety and effectiveness not proven.

Geriatric use

There is insufficient experience in patients ≥ 65 years of age to determine whether these patients respond differently than younger adults. Clinically significant pharmacokinetic differences between patients ≥ 65 years of age and younger subjects were not observed.

Liver dysfunction

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

Renal dysfunction

The renal route plays a minor role in zavegepant clearance; No clinically significant effect on pharmacokinetics is expected in patients with a Crcl ≥ 30 ml/minute. Possible increased exposure in patients with Crcl15-29 ml/minute. Not studied in patients with Crcl < 15 ml/minute.

Common side effects

Most common side effects (≥2%): taste disturbances, nausea, nasal discomfort, vomiting.

Interactions with other medications

Metabolized primarily by CYP3A4 and to a lesser extent by CYP2D6; In vitro studies suggest that 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.

No substrate for breast cancer resistance protein (BCRP), organic anion transport 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 cotransport polypeptide (NTCP). Also a substrate of P-gp, Multidrug and Toxic Compound Extrusion (MATE) 1 and MATE2-K; However, coadministration is not expected to have clinically relevant effects. inhibitor of OCT2, MATE1 and MATE2-K; The inhibitory potential is not expected to be clinically relevant.

Drugs that affect or are affected by transportation systems

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

OATP1B3 or NTCP inducers: concurrent use not studied; However, this may result in reduced systemic exposure to zavegepant. Avoid concurrent use with OATP1B3 or NTCP inducers.

Specific medications

Pharmacokinetics of zavegepant hydrochloride

absorption

Bioavailability

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

Maximum plasma concentrations are reached approximately 30 minutes after 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 are not expected to be clinically significant.

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

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

Schwere Nierenfunktionsstörung (Clcr15–29 ml/Minute): Die Ansammlung urämischer gelöster Stoffe kann die Exposition gegenüber Zavegepant erhöhen, indem sie organische Anionen transportierende Polypeptidtransporter hemmt.

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

Pharmacokinetics are not significantly affected by age, gender, race, ethnicity, or body weight.

distribution

extent

It is not known whether it passes into breast milk.

Plasma protein binding

~90%.

Elimination

metabolism

Eliminated primarily through metabolism, primarily by CYP3A4 and to a lesser extent by CYP2D6. The parent compound is the most abundant circulating component in human plasma; No major metabolites were detected.

Elimination route

Excreted primarily biliary/fecal; The renal route is a minor elimination route. After a single oral dose, the drug is excreted unchanged in feces (80%) and urine (11%).

Half-life

6.55 hours.

stability

storage

Intranasally

Solution

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

Actions

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

• CGRP is a potent vasodilator and pain signaling neuropeptide that has been implicated in the pathophysiology of migraine. CGRP and its receptors are located in sites relevant to migraine development, such as trigeminal neurons, and are also widely distributed in the central and peripheral nervous systems as well as in non-neuronal tissues throughout the body.

• Increased serum CGRP concentrations observed in subjects during acute migraine attacks; these return to normal after the migraine subsides. Intravenous infusion of CGRP induces migraine in patients with a history of migraine.

• In contrast to 5-HT1 receptor agonists (triptans) and ergot alkaloids, zavegepant does not appear to cause vasoconstriction. There also does not appear to be any prolongation of the QT interval at doses up to four times the maximum recommended daily dose.

Advice for patients

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

• Inform patients of the signs and symptoms of hypersensitivity reactions following administration of zavegepant. Advise patients to contact their healthcare provider immediately if any signs or symptoms of a hypersensitivity reaction occur.

• Instruct the patient to inform their physician of any existing or planned concomitant therapies, including prescription and over-the-counter medications and nutritional or herbal supplements, as well as any comorbidities. Inform patients that if they must use an intranasal decongestant, it should be administered at least 1 hour after administration of zavegepant.

• Advise women to inform their doctor if they are pregnant or planning to become pregnant or plan to breastfeed.

• Inform patients of other important precautionary information.

More information

The American Society of Health-System Pharmacists, Inc. certifies that the information provided in the accompanying monograph has been formulated with reasonable care and in accordance with professional standards in the field. Readers are cautioned that drug use decisions are complex medical decisions that require the independent, informed decision of an appropriate health care professional and that the information contained in the monograph is provided for informational purposes only. For more detailed information, the manufacturer's label should be consulted. 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 commercial drug preparations may have clinically significant effects in some individuals; Details can be found on the respective product labeling.

For information about shortages of one or more of these drugs, visit the ASHP Drug Shortages Resource Center.

Zavegepant hydrochloride

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