Zavegepant

1 INDICATIONS AND USAGE ZAVZPRET is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use ZAVZPRET is not indicated for the preventive treatment of migraine. ZAVZPRET is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. ( 1 ) Limitations of Use ZAVZPRET is not indicated for the preventive treatment of migraine. ( 1 )

2 DOSAGE AND ADMINISTRATION • The recommended dose is 10 mg given as a single spray in one nostril, as needed. ( 2.1 ) • The maximum dose in a 24-hour period is 10 mg (one spray). ( 2.1 ) • The safety of treating more than 8 migraines in a 30-day period has not been established. ( 2.1 ) 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] • Hypertension [see Warnings and Precautions (5.2) ] • Raynaud’s Phenomenon [see Warnings and Precautions (5.3) ] Most common adverse reactions (at least 2% of patients treated with ZAVZPRET and greater than placebo) were taste disorders, nausea, nasal discomfort, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 Adverse Reaction ZAVZPRET N=1023 % Placebo N=1056 % Taste Disorders Taste disorders includes dysgeusia and ageusia 18 4 Nausea 4 1 Nasal Discomfort 3 1 Vomiting 2 <1 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZAVZPRET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Hypersensitivity (e.g., anaphylaxis) [see Contraindications (4) and Warnings and Precautions (5.1) ] Vascular Disorders : Hypertension [see Warnings and Precautions (5.2) ] , Raynaud’s phenomenon [see Warnings and Precautions (5.3) ]

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 [ 14 C]-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 [ 14 C]-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 C max 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 C max 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) ] .