Zavegepant is an intranasal calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura. Zavegepant is not indicated for the preventive treatment of migraine. In 2 randomized, double-blind, placebo-controlled trials, significantly more subjects were pain free at 2 hours post-dose with zavegepant 10 mg (22.5% to 23.6%) compared to placebo (14.9% to 15.5%). Absence of the most bothersome migraine-associated symptom (i.e., phonophobia, photophobia, or nausea) at 2 hours post-dose was also significantly higher in subjects treated with zavegepant 10 mg (39.6% to 41.9%) compared to placebo (31.1% to 33.7%). The safety of treating more than 8 migraines in a 30-day period has not been established. Hypersensitivity reactions, including facial swelling and urticaria, have been reported with zavegepant use.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Inhalation Administration
Intranasal Administration
-Do not test spray, prime, or press the plunger before use.
-Administer as single spray in 1 nostril.
Nasal irritation was reported in 3% of subjects given zavegepant (n = 1,023) compared to 1% of subjects given placebo (n = 1,056) in clinical trials.
Ageusia and dysgeusia were reported in 18% of subjects given zavegepant (n = 1,023) compared to 4% of subjects given placebo (n = 1,056) in clinical trials.
Gastrointestinal adverse reactions reported in clinical trials with zavegepant (n = 1,023) vs. placebo (n = 1,056) include nausea (4% vs. 1%) and vomiting (2% vs. less than 1%).
Hypersensitivity reactions, including facial swelling and urticaria, were reported in less than 1% of subjects given zavegepant (n = 1,023) in clinical trials. If a hypersensitivity reaction occurs, discontinue zavegepant and institute appropriate therapy.
Zavegepant is contraindicated in persons with a history of hypersensitivity to zavegepant or any of its components. Hypersensitivity reactions occurred during clinical trials; if a hypersensitivity reaction occurs, discontinue zavegepant and institute appropriate therapy.
Avoid use of zavegepant in persons with severe hepatic disease (Child-Pugh class C). Zavegepant has not been studied in persons with severe hepatic impairment.
Avoid use of zavegepant in persons with CrCl less than 30 mL/minute (i.e., renal impairment, renal failure) due to risk for increased zavegepant exposure. Zavegepant has not been studied in persons with CrCl less than 15 mL/minute.
There are no adequate data on the developmental risk associated with zavegepant use during human pregnancy. Persons of childbearing potential with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. In animal studies, subcutaneous administration of zavegepant during the period of organogenesis or throughout pregnancy and lactation resulted in no adverse effects on embryo-fetal development or pre- and postnatal development at plasma exposures higher than those used clinically.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for zavegepant and any potential adverse effects on the breast-fed infant from zavegepant or the underlying maternal condition. There are no data on the presence of zavegepant or its metabolites in human milk, the effects on the breast-fed infant, or the effects on milk production.
Guideline indications for initiating acute treatment with calcitonin gene-related peptide (CGRP) receptor antagonists:
-Contraindications to or inability to tolerate serotonin-receptor agonists ("triptans") or
-Inadequate response to at least 2 oral triptans, as determined by either health care provider attestation or a validated acute treatment patient-reported outcome questionnaire (e.g., mTOQ, Migraine-ACT, PPMQ-R, FIS, PGIC).
Guideline criteria for continuation of acute treatment with CGRP receptor antagonists: -Continue coverage until at least 3 attacks are treated to assess efficacy and tolerability.
-Base treatment continuation decisions on the average monthly headache frequency and clinical assessment of improvement by a health care provider or response to a validated acute treatment patient-reported outcome questionnaire.
For the acute treatment of migraine with or without aura:
Intranasal dosage:
Adults: 10 mg into 1 nostril as a single dose. Max: 10 mg/day. The safety of treating more than 8 migraines in a 30-day period has not been established. Guidelines classify zavegepant as having established efficacy for the treatment of acute migraine.
Maximum Dosage Limits:
-Adults
10 mg/day intranasally.
-Geriatric
10 mg/day intranasally.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is needed in persons with mild or moderate hepatic impairment (Child-Pugh class A or B). Avoid zavegepant use in persons with severe hepatic disease (Child-Pugh class C).
Patients with Renal Impairment Dosing
No dosage adjustment is needed in persons with a CrCl of 30 mL/minute or more. Avoid zavegepant use in persons with a CrCl less than 30 mL/minute.
*non-FDA-approved indication
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Acetaminophen; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of zavegepant and clarithromycin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and clarithromycin is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Asciminib: (Major) Avoid concomitant use of zavegepant and asciminib. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and asciminib is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of zavegepant and cobicistat. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and cobicistat is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Brompheniramine; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Chlorpheniramine; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Clarithromycin: (Major) Avoid concomitant use of zavegepant and clarithromycin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and clarithromycin is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Cobicistat: (Major) Avoid concomitant use of zavegepant and cobicistat. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and cobicistat is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Codeine; Phenylephrine; Promethazine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Darolutamide: (Major) Avoid concomitant use of zavegepant and darolutamide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and darolutamide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Darunavir; Cobicistat: (Major) Avoid concomitant use of zavegepant and cobicistat. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and cobicistat is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of zavegepant and cobicistat. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and cobicistat is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Diphenhydramine; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Elexacaftor; tezacaftor; ivacaftor: (Major) Avoid concomitant use of zavegepant and elexacaftor. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and elexacaftor is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of zavegepant and cobicistat. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and cobicistat is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of zavegepant and cobicistat. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and cobicistat is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Enasidenib: (Major) Avoid concomitant use of zavegepant and enasidenib. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and enasidenib is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Encorafenib: (Major) Avoid concomitant use of zavegepant and encorafenib. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and encorafenib is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Epinephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Erythromycin: (Major) Avoid concomitant use of zavegepant and erythromycin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and erythromycin is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Fostemsavir: (Major) Avoid concomitant use of zavegepant and fostemsavir. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and fostemsavir is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Glecaprevir; Pibrentasvir: (Major) Avoid concomitant use of zavegepant and glecaprevir. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and glecaprevir is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold. (Major) Avoid concomitant use of zavegepant and pibrentasvir. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and pibrentasvir is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Guaifenesin; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of zavegepant and rifampin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is a NTCP and OATP1B3 substrate and rifampin is a NTCP and OATP1B3 inhibitor. Concomitant use with rifampin increased zavegepant overall exposure by 2.3-fold.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of zavegepant and rifampin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is a NTCP and OATP1B3 substrate and rifampin is a NTCP and OATP1B3 inhibitor. Concomitant use with rifampin increased zavegepant overall exposure by 2.3-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of zavegepant and clarithromycin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and clarithromycin is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Leflunomide: (Major) Avoid concomitant use of zavegepant and leflunomide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and leflunomide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Leniolisib: (Major) Avoid concomitant use of zavegepant and leniolisib. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and leniolisib is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Letermovir: (Major) Avoid concomitant use of zavegepant and letermovir. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and letermovir is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Lidocaine; Epinephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Oxymetazoline: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Pretomanid: (Major) Avoid concomitant use of zavegepant and pretomanid. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and pretomanid is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Promethazine; Phenylephrine: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Rifampin: (Major) Avoid concomitant use of zavegepant and rifampin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is a NTCP and OATP1B3 substrate and rifampin is a NTCP and OATP1B3 inhibitor. Concomitant use with rifampin increased zavegepant overall exposure by 2.3-fold.
Sofosbuvir; Velpatasvir: (Major) Avoid concomitant use of zavegepant and velpatasvir. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and velpatasvir is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of zavegepant and velpatasvir. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and velpatasvir is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold. (Major) Avoid concomitant use of zavegepant and voxilaprevir. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and voxilaprevir is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Teriflunomide: (Major) Avoid concomitant use of zavegepant and teriflunomide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and teriflunomide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Tetrahydrozoline: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Topical Nasal Decongestants: (Moderate) Administer intranasal decongestants at least 1 hour after zavegepant administration. Simultaneous coadministration may decrease zavegepant absorption which may reduce its efficacy.
Trofinetide: (Major) Avoid concomitant use of zavegepant and trofinetide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and trofinetide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of zavegepant and clarithromycin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and clarithromycin is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Zavegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist. CGRP is distributed throughout the nervous system, and it is concentrated at anatomical sites, such as the trigeminovascular system, which are involved in migraine pathophysiology. Centrally, CGRP is involved in nociceptive transmission through second and third-order neurons and pain modulation in the brainstem. Peripherally, CGRP mediates vasodilation through smooth muscle receptors. CGRP concentrations are elevated during acute migraine attacks and may be chronically elevated in chronic migraineurs.
Zavegepant is administered intranasally. Plasma protein binding of zavegepant is approximately 90%. The mean apparent Vd of zavegepant is 1,774 L. Zavegepant is metabolized primarily by CYP3A4 and to a lesser extent by CYP2D6, in vitro. Unchanged zavegepant was the most prevalent circulating component (approximately 90%) in human plasma after a single IV dose of radiolabeled zavegepant 5 mg. No major metabolites were detected in plasma. Zavegepant is excreted mostly via the biliary/fecal route, with minor elimination via the renal route. Approximately 80% and 11% of a single IV dose of radiolabeled zavegepant 5 mg was recovered as unchanged zavegepant in the feces and urine, respectively.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, MATE1, MATE2-K, NTCP, OATP1B3, OCT2, P-gp
Zavegepant is a substrate of CYP2D6, CYP3A4, MATE1, MATE2-K, NTCP, OATP1B3, and P-gp. Zavegepant is an inhibitor of MATE1, MATE2-K, and OCT2. Coadministration of zavegepant with CYP3A4, MATE1, MATE2-K, and P-gp inhibitors is not expected to have a clinically significant impact on zavegepant exposure. Clinically relevant drug interactions are not expected with MATE1, MATE2-K, and OCT2 substrates.
-Route-Specific Pharmacokinetics
Inhalation Route
Peak plasma concentration occurs approximately 30 minutes after a single 10 mg intranasal dose of zavegepant. After nasal spray administration, the absolute bioavailably is approximately 5%. Zavegepant given as a single intranasal dose displays slightly less than dose-proportional pharmacokinetics up to 40 mg. There was no evidence of zavegepant accumulation after once daily intranasal dosing for 14 days. Mean apparent clearance of intranasal zavegepant is 266 L/hour. The effective half-life of zavegepant after intranasal administration of zavegepant 10 mg is 6.55 hour.
-Special Populations
Hepatic Impairment
Zavegepant exposure and Cmax were approximately 1.9-fold and 16% higher, respectively, in subjects with moderate hepatic impairment (Child-Pugh class B) relative to subjects with normal hepatic function. These changes are not expected to be clinically meaningful. The effect of severe hepatic impairment (Child-Pugh class C) on the pharmacokinetics of zavegepant has not been studied.
Renal Impairment
No clinically significant effect on the pharmacokinetics of zavegepant is expected in subjects with a CrCl of 30 mL/minute or more. Accumulation of uremic solutes may increase zavegepant exposure through OATP transporter inhibition in subjects with a CrCl of 15 to 29 mL/minute. Zavegepant has not been studied in persons with a CrCl less than 15 mL/minute.
Geriatric
Age did not have a clinically significant effect on the pharmacokinetics of zavegepant.
Gender Differences
Sex did not have a clinically significant effect on the pharmacokinetics of zavegepant.
Ethnic Differences
Race and ethnicity did not have a clinically significant effect on the pharmacokinetics of zavegepant.
Obesity
Body weight did not have a clinically significant effect on the pharmacokinetics of zavegepant.