ZAVZPRET™ Warnings and Precautions

2.1 Dosing Information

The recommended dose of ZAVZPRET is 10 mg given as a single spray in one nostril, as needed.

The maximum dose that may be given in a 24-hour period is 10 mg (one spray). The safety of treating more than 8 migraines in a 30-day period has not been established.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including facial swelling and urticaria, have occurred in patients treated with ZAVZPRET in clinical studies. If a hypersensitivity reaction occurs, discontinue ZAVZPRET and initiate appropriate therapy [see Contraindications (4) and Adverse Reactions (6.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of ZAVZPRET for the acute treatment of migraine in adults has been evaluated in two randomized, double-blind, placebo-controlled trials (Study 1 and Study 2) in patients with migraine who received one 10 mg dose of ZAVZPRET nasal spray (N=1023) or placebo (N=1056) [see Clinical Studies (14)]. Approximately 83% were female, 81% were White, 20% were Hispanic or Latino, and 15% were Black. The mean age at study entry was 41 years (range 18-79 years of age).

Adverse reactions in Study 1 and 2 are shown in Table 1.

Table 1: Adverse Reactions Occurring in At Least 2% of Patients Treated with ZAVZPRET and at a Frequency Greater than Placebo in Study 1 and 2

Hypersensitivity, including facial swelling and urticaria, occurred in less than 1% of patients treated with ZAVZPRET [see Contraindications (4) and Warnings and Precautions (5.1)].

Long-term safety was assessed in an open-label extension study. That study evaluated 603 patients, dosing intermittently for up to one year, including 360 patients who were exposed to ZAVZPRET 10 mg for at least 6 months, and 298 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month.

7.1 OATP1B3 or NTCP Inhibitors

Concomitant administration of ZAVZPRET with inhibitors of the organic anion transporting polypeptide 1B3 (OATP1B3) or sodium taurocholate co-transporting polypeptide (NTCP) transporters may result in a significant increase in zavegepant exposure. Avoid concomitant administration of ZAVZPRET with drugs that inhibit OATP1B3 or NTCP transporters [see Clinical Pharmacology (12.3)].

7.2 OATP1B3 or NTCP Inducers

Concomitant administration of ZAVZPRET with inducers of OATP1B3 or NTCP transporters may result in a decrease in zavegepant exposure. Avoid concomitant administration of ZAVZPRET with drugs that induce OATP1B3 or NTCP transporters [see Clinical Pharmacology (12.3)].

7.3 Intranasal Decongestants

Concomitant administration of ZAVZPRET with intranasal decongestants may decrease the absorption of zavegepant. Avoid concomitant administration of intranasal decongestants with ZAVZPRET. When concomitant use is unavoidable, intranasal decongestants should be administered at least 1 hour after ZAVZPRET administration [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of ZAVZPRET in pregnant women. 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 (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated rate of major birth defects (2.2 to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.

Data

Animal Data

Subcutaneous administration of zavegepant to pregnant rats (0, 10, 20, or 40 mg/kg/day) or rabbits (0, 20, 40, or 60 mg/kg/day) during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposures (AUC) at the highest doses tested were approximately 4000 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day.

Subcutaneous administration of zavegepant (0, 5, 10, or 20 mg/kg/day) to rats throughout pregnancy and lactation resulted in no adverse effects on pre- and postnatal development. Plasma exposure (AUC) at the highest dose tested was approximately 2500 times that in humans at the MRHD.

8.2 Lactation

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of ZAVZPRET did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

In a limited number of patients 65 years of age and older, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects.

8.6 Hepatic Impairment

No dosage adjustment of ZAVZPRET is necessary in patients with mild hepatic impairment (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B). ZAVZPRET has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of ZAVZPRET in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dosage adjustment of ZAVZPRET is necessary in patients with estimated creatine clearance (CLcr) 30 mL/min or greater. Avoid use of ZAVZPRET in patients with CLcr less than 30 mL/min [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

The relationship between pharmacodynamic activity and the mechanism by which zavegepant exerts its clinical effects is unknown.

No clinically relevant differences in resting blood pressure were observed when zavegepant was concomitantly administered with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) compared with sumatriptan alone to healthy volunteers.

Cardiac Electrophysiology

At a dose up to 4 times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

Peak plasma concentration of zavegepant was observed at approximately 30 minutes after a single 10 mg dose of the nasal spray. After nasal spray administration of zavegepant, the absolute bioavailability is approximately 5%.

Zavegepant given as a single dose of the nasal spray displays slightly less than dose-proportional pharmacokinetics up to 40 mg (approximately 4 times the recommended dosage of 10 mg).

Following once daily dosing of ZAVZPRET for 14 days there was no evidence of zavegepant accumulation.

Distribution

The mean apparent volume of distribution of intranasal zavegepant is approximately 1774 L. Plasma protein binding of zavegepant is approximately 90%.

Elimination

Metabolism

Zavegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6, in vitro. After single IV dose of 5 mg [14C]-zavegepant, unchanged zavegepant was the most prevalent (approximately 90%) circulating component in the human plasma. No major metabolites (i.e., greater than 10%) of zavegepant were detected in plasma.

Excretion

The effective half-life of zavegepant following a 10 mg dose of the nasal spray is 6.55 hours. The mean apparent clearance of intranasal zavegepant is 266 L/h. Zavegepant is excreted mostly via the biliary/fecal route, while the renal route is a minor route of elimination. Following a single intravenous dose of 5 mg [14C]-zavegepant to healthy male subjects, approximately 80% and 11% of the dose was recovered as unchanged zavegepant in feces and urine, respectively.

Specific Populations

Patients with Hepatic Impairment

In a dedicated clinical study comparing the pharmacokinetics of zavegepant in subjects with moderate hepatic impairment (Child-Pugh B) to that of normal subjects (matched healthy controls), zavegepant Cmax was 16% higher and AUC was 1.9-fold higher in patients with moderate hepatic impairment. These changes in exposures are not expected to be clinically significant, based on clinical safety experience and minimal accumulation of drug exposures. The impact of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of zavegepant was not studied [see Use in Specific Populations (8.6)].

Patients with Renal Impairment

The renal route plays a minor role in the clearance of zavegepant. No clinically significant effect on the pharmacokinetics of zavegepant is expected in subjects with estimated creatinine clearance (CLcr) 30 mL/min or greater. In patients with CLcr 15 to 29 mL/min, accumulation of uremic solutes can cause an increase in zavegepant exposures by inhibiting OATP transporters. Zavegepant has not been studied in patients with CLcr less than 15 mL/min [see Use in Specific Populations (8.7)].

Other Specific Populations

Age, sex, race, ethnicity, and body weight did not show clinically significant effects on the pharmacokinetics of zavegepant.

Drug Interaction Studies

In Vitro Studies

Enzymes

Zavegepant is a substrate of CYP3A4 and to a lesser extent CYP2D6. Zavegepant is not an inducer of CYP1A2, 2B6, or 3A4, or an inhibitor of CYP1A2, CYP2C9, 2C19, 2B6, 2D6, 2C8, and 3A4 at clinically relevant concentrations.

Transporters

Zavegepant is a substrate for OATP1B3 and NTCP (see In Vivo studies).

Zavegepant is also a substrate for the transporters P-gp, MATE1, and MATE2-K. Considering the minor contribution of the renal pathway in the clearance of zavegepant, coadministration of zavegepant with inhibitors of P-gp, MATE1, and MATE2-K inhibitors is not expected to result in a clinically significant effect on zavegepant pharmacokinetics.

Zavegepant is not a substrate for BCRP, OATP1B1, OAT1, OAT3, OCT2, BSEP, MRP2, MRP3, and MRP4.

Zavegepant is an inhibitor of OCT2, MATE1, and MATE2-K, but drug interactions for ZAVZPRET are not expected at clinically relevant concentrations. Zavegepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, OATP1B1, and OATP1B3.

In Vivo Studies

CYP3A4 Inhibitors

Concomitant administration of a single dose of 10 mg ZAVZPRET with itraconazole (a strong CYP3A4 and P-gp inhibitor), at steady state did not result in a clinically relevant effect on the exposures of zavegepant.

OATP1B3 or NTCP Inhibitors

Concomitant administration of a single oral dose of 100 mg zavegepant with rifampin (an OATP1B3, NTCP inhibitor and a strong CYP3A inducer), at steady state resulted in increased zavegepant exposure (AUC by 2.3-fold and Cmax by 2.2-fold). The observed change in zavegepant exposures is a composite effect of inhibition of OATP1B3 and NTCP transporters as well as induction of CYP3A enzymes. Concomitant administration of ZAVZPRET with inhibitors of OATP1B3 or NTCP transporters may result in a significant increase in zavegepant exposure [see Drug Interactions (7.1)].

OATP1B3 or NTCP Inducers

Concomitant administration of ZAVZPRET with inducers of OATP1B3 or NTCP transporters has not been studied. However, since zavegepant is a substrate of OATP1B3 and NTCP, concomitant administration with inducers of these transporters may result in decreased zavegepant exposure [see Drug Interactions (7.2)].

Intranasal Decongestants

The effect of concomitant intranasal decongestants on the pharmacokinetics of zavegepant nasal spray has not been evaluated. Concomitant administration of intranasal decongestants may decrease the systemic exposure of zavegepant and potentially the efficacy of zavegepant [see Drug Interactions (7.3)].

Other Drugs

No significant pharmacokinetic interactions were observed when zavegepant was concomitantly administered with oral contraceptives (ethinyl estradiol) or sumatriptan [see Clinical Pharmacology (12.2)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Intranasal administration of zavegepant (0, 0.3, 0.8, or 2.5 mg/day) to Tg.rasH2 mice for 26 weeks resulted in no evidence of drug-related tumors.

Intranasal administration of zavegepant (0, 2, 9, or 18.8 mg/kg/day) to rats for up to 96 weeks resulted in no evidence of drug-related tumors. Plasma exposure (AUC) at the highest dose tested was approximately 140 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day.

Mutagenesis

Zavegepant was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (rat micronucleus) assays.

Impairment of Fertility

Subcutaneous administration of zavegepant (0, 5, 15, or 25 mg/kg/day) to male and female rats prior to and during mating and continuing in females to gestation day 7 resulted in no adverse effects on fertility or reproductive performance. Plasma exposures (AUC) at the highest dose tested were approximately 2800 times that in humans at MRHD.

16.1 How Supplied

ZAVZPRET nasal spray (NDC 0069-3500-01) contains 10 mg zavegepant and is supplied as a ready-to-use, unit-dose disposable device.

Each carton contains 6 units (NDC 0069-3500-02) and a Patient Information and Instructions for Use leaflet.

16.2 Storage and Handling

Store ZAVZPRET at controlled room temperature, 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Do not freeze. Do not test spray, prime, or press the plunger before use.