DRUG INTERACTIONS-(summary)

 • Avoid use with drugs that inhibit OATP1B3 or NTCP transporters.

 • Avoid use with drugs that induce OATP1B3 or NTCP transporters.

 • Avoid use of intranasal decongestants; if unavoidable, administer intranasal decongestants at least 1 hour after ZAVZPRET administration

BRIEF SUMMARY-

ZAVEGEPANT- (Mar 203)

Indcn- To  treat migraine 

Dosage- Nasal spray: 10 mg, • The recommended dose is 10 mg given as a single spray in one nostril, as needed.

ADR-  Most common adverse reactions  were taste disorders, nausea, nasal discomfort, and vomiting.

CI-    Patients with a history of hypersensitivity reaction to zavegepant

WARNINGS - Hypersensitivity Reactions:   If a serious hypersensitivity reaction occurs, discontinue and initiate appropriate therapy.

Pat inform- Hypersensitivity Reactions-    Inform patients about the signs and symptoms of hypersensitivity reactions after adimn. Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur.

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 9

Name-        ZAVPRET 

Acive  Ingredient -  Zavegepant

 Pharmacological clssificiation-        To  treat migraine                                                                                                                                                                                                   Date of Approval-         3/9/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                              ZAVZPRET safely and effectively.                                                                                  See full prescribing information for ZAVZPRET. ZAVZPRET™ (zavegepant) nasal spray

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

 ZAVZPRET is a calcitonin gene-related peptide receptor antagonist 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.

ADVERSE REACTIONS-

 Most common adverse reactions (at least 2% of patients treated with ZAVZPRET and greater than placebo) were taste disorders, nausea, nasal discomfort, and vomiting.

CONTRAINDICATIONS-

 Patients with a history of hypersensitivity reaction to zavegepant or to any of the components of ZAVZPRET. 

WARNINGS AND PRECAUTIONS-

 Hypersensitivity Reactions:                                                                                           If a serious hypersensitivity reaction occurs, discontinue ZAVZPRET and initiate appropriate therapy. Hypersensitivity Reactions including facial swelling and urticaria have occurred with ZAVZPRET.

DOSAGE AND ADMINISTRATION-

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

 • The maximum dose 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.

DOSAGE FORMS AND STRENGTHS-

 Nasal spray: 10 mg

PATIENT COUNSELING INFORMATION-

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

Hypersensitivity Reactions-                                                                                    Inform patients about the signs and symptoms of hypersensitivity reactions after administration of ZAVZPRET.

Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur.

Drug Interactions-                                                                                                     Advise patients to speak with their healthcare provider about any prescription or over-thecounter medications or herbal supplements that they take or plan to take.

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

ZAVZPRET-This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-1544-0.7

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                 Zavegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist.

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.

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.

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.

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.

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.

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 .

Other Drugs- No significant pharmacokinetic interactions were observed when zavegepant was concomitantly administered with oral contraceptives (ethinyl estradiol) or sumatriptan.

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USE IN SPECIFIC POPULATIONS

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.

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.

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.

3. Pediatric Use- Safety and effectiveness in pediatric patients have not been stablished.

4. Geriatric Use-                                                                                                      Clinical studies of ZAVZPRET did not include sufficient numbers of atients 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.

5.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

6. Renal Impairment- No dosage adjustment of ZAVZPRET is necessary in patients with estimated creatine clearance (CLcr) 30 mL/min or greater.