PRINCIPAL DISPLAY PANEL – Nasal Spray Carton

NDC 0069-3500-02
Rx only

ZavzpretTM
(zavegepant)
nasal spray 10 mg

This box contains:
• 6 unit-dose nasal spray devices.
Each unit-dose nasal spray device
contains 10 mg of zavegepant.
• 1 Prescribing Information booklet.
• 1 Instructions for Use leaflet.

For Intranasal use only.
1 spray (10 mg dose) per unit.
Do not test spray, prime or
press the plunger before use.

4 CONTRAINDICATIONS

ZAVZPRET is contraindicated in patients with a history of hypersensitivity reaction to zavegepant or any of the components of ZAVZPRET. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, facial swelling, and urticaria, have occurred in patients treated with ZAVZPRET. If a hypersensitivity reaction occurs, discontinue ZAVZPRET and initiate appropriate therapy [see Contraindications (4) and Adverse Reactions (6.1, 6.2)].

5.2 Hypertension

Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists in the postmarketing setting.

Some of the patients receiving a CGRP antagonist who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalization. Hypertension may occur at any time during treatment, but was most frequently reported within 7 days of therapy initiation. The CGRP antagonist was discontinued in many of the reported cases.

Monitor patients treated with ZAVZPRET for new-onset hypertension or worsening of pre-existing hypertension, and consider whether discontinuation of ZAVZPRET is warranted if evaluation fails to establish an alternative etiology or blood pressure is inadequately controlled.

5.3 Raynaud’s Phenomenon

Development of Raynaud’s phenomenon and recurrence or worsening of pre- existing Raynaud’s phenomenon have been reported in the postmarketing setting following the use of CGRP antagonists.

In reported cases with small molecule CGRP antagonists, symptom onset occurred a median of 1.5 days following dosing. Many of the cases reported serious outcomes, including hospitalizations and disability, generally related to debilitating pain. In most reported cases, discontinuation of the CGRP antagonist resulted in resolution of symptoms.

ZAVZPRET should be discontinued if signs or symptoms of Raynaud’s phenomenon develop, and patients should be evaluated by a healthcare provider if symptoms do not resolve. Patients with a history of Raynaud’s phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.

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)]

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.

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)]

RECENT MAJOR CHANGES

14 CLINICAL STUDIES

The efficacy of ZAVZPRET for the acute treatment of migraine with or without aura in adults was demonstrated in two randomized, double-blind, placebo- controlled trials (Study 1 and Study 2). In both studies, patients were instructed to treat a migraine of moderate to severe headache pain intensity. Rescue medication (i.e., NSAIDs, acetaminophen, and/or an antiemetic) was allowed 2 hours after the initial treatment. Other forms of rescue medication such as triptans were not allowed within 48 hours of initial treatment. In Study 1 and Study 2, 13.4% and 13.6% of patients were taking preventive medications for migraine at baseline, respectively. None of the patients were on concomitant preventive medication that act on the CGRP pathway.

In Study 1 (NCT04571060), patients were randomized to receive a single dose of ZAVZPRET 10 mg (N=623) or placebo (N=646). Efficacy was demonstrated with ZAVZPRET 10 mg by an effect on the coprimary endpoints of pain freedom and most bothersome symptom (MBS) freedom at 2 hours after a single dose, compared to placebo. Pain freedom was defined as a reduction of moderate or severe headache pain to no headache pain, and MBS freedom was defined as the absence of the self-identified MBS (i.e., photophobia, phonophobia, or nausea). The most common MBS reported before dosing was photophobia (55%), followed by nausea (28%), and phonophobia (16%).

In Study 1, the percentage of patients achieving headache pain freedom and MBS freedom 2 hours after a single dose was statistically significantly greater in patients who received ZAVZPRET compared to those who received placebo (Table 2).

Table 2: Efficacy Endpoints in Study 1

Figures 1 and 2 present the percentage of patients achieving migraine pain freedom and MBS freedom within 2 hours following treatment in Study 1.

Figure 1: Percentage of Patients Achieving Pain Freedom within 2 Hours in Study 1

Figure 2: Percentage of Patients Achieving MBS Freedom within 2 Hours in Study 1

In Study 1, statistically significant effects of ZAVZPRET compared to placebo were demonstrated for the additional efficacy endpoints of pain relief at 2 hours post-dose, return to normal function at 2 hours post-dose, sustained pain freedom from 2 to 48 hours post-dose (Table 3), and phonophobia and photophobia freedom at 2 hours post-dose. Pain relief was defined as a reduction in migraine pain from moderate or severe severity to mild or none. The measurement of the percentage of patients reporting normal function at two hours after dosing was derived from a single item questionnaire, asking patients to select one response on a 4-point scale: normal function, mild impairment, severe impairment, or required bedrest.

Table 3: Additional Efficacy Endpoints in Study 1

The incidence of photophobia and phonophobia was reduced following administration of ZAVZPRET 10 mg as compared to placebo.

In Study 2 (NCT03872453), patients were randomized to receive a single dose of ZAVZPRET 10 mg (n=391) or placebo (n=401).

In Study 2, statistically significant efficacy was demonstrated with ZAVZPRET 10 mg by an effect on the coprimary endpoints of pain freedom and most bothersome symptom (MBS) freedom at 2 hours after a single dose, compared to placebo. Pain freedom was observed in 22.5% of patients receiving ZAVZPRET and 15.5% of patients receiving placebo (p-value = 0.011). MBS freedom was observed in 41.9% of patients receiving ZAVZPRET and 33.7% of patients receiving placebo (p-value = 0.016). The most common MBS reported before dosing was photophobia (53%), followed by nausea (31%), and phonophobia (15%).

Table 4: Efficacy Endpoints in Study 2

Figure 3: Percentage of Patients Achieving Pain Freedom within 2 Hours in Study 2

Figure 4: Percentage of Patients Achieving MBS Freedom within 2 Hours in Study 2

8 USE IN SPECIFIC POPULATIONS

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)].

Patient Package Insert

What is ZAVZPRET?

ZAVZPRET is a prescription medicine used in adults for the acute treatment of migraine attacks with or without aura.

ZAVZPRET is not used to prevent migraine attacks.

It is not known if ZAVZPRET is safe and effective in children.

Do not use ZAVZPRET if you are:

•

allergic to zavegepant, or any of the ingredients in ZAVZPRET.

See the end of this leaflet for a complete list of ingredients in ZAVZPRET.

Before you use ZAVZPRET, tell your healthcare provider about all of your medical conditions, including if you:

•

have high blood pressure.

•

have circulation problems in your fingers and toes.

•

have kidney problems.

•

have liver problems.

•

are pregnant or plan to become pregnant. It is not known if ZAVZPRET will harm your unborn baby.

•

are breastfeeding or plan to breastfeed. It is not known whether ZAVZPRET passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you use ZAVZPRET. 

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I use ZAVZPRET?

•

Use ZAVZPRET exactly how your healthcare provider tells you to use it.

•

See the Instructions for Use for complete information on how to use ZAVZPRET nasal spray.

•

ZAVZPRET is given in the nose (nasal) only.

•

Each ZAVZPRET only sprays 1 time and cannot be reused.**Do not** test or prime the nasal spray before use.

•

Each dose of ZAVZPRET is provided in an individual pack. Use all of the medicine in 1 pack for a complete dose.

•

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

•

Do not use more than 1 spray (10 mg) of ZAVZPRET nasal spray in a 24-hour period.

•

It is not known if it is safe to use more than 8 sprays (doses) of ZAVZPRET in 30 days.

•

Avoid using intranasal decongestants with ZAVZPRET. If you have to use an intranasal decongestant, use it at least 1 hour after using ZAVZPRET.

What are the possible side effects of ZAVZPRET?

ZAVZPRET may cause serious side effects including:

•

**Allergic reactions.** Allergic reactions, including trouble breathing, hives, and swelling of the face, can happen after you use ZAVZPRET. Call your healthcare provider or get emergency help right away if you have any of the following symptoms, which may be part of an allergic reaction:

o

swelling of the face, mouth, tongue, or throat

o

trouble breathing

o

rash

o

hives

•

**High blood pressure.** High blood pressure or worsening of high blood pressure can happen after you use ZAVZPRET. Contact your healthcare provider if you have an increase in blood pressure.

•

**Raynaud’s phenomenon.** A type of circulation problem can worsen or happen after you use ZAVZPRET. Raynaud’s phenomenon can lead to your fingers or toes feeling numb, cool, or painful, or changing color from pale, to blue, to red. Contact your healthcare provider if these symptoms occur.

The most common side effects of ZAVZPRET are:

•

unusual taste

•

nausea 

•

nasal discomfort

•

vomiting

These are not the only possible side effects of ZAVZPRET.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ZAVZPRET?

•

Store ZAVZPRET in the blister package that it comes in.

•

Store ZAVZPRET at room temperature between 68°F to 77°F (20°C to 25°C). 

•

Do not freeze.

Keep ZAVZPRET and all medicines out of the reach of children.

General information about the safe and effective use of ZAVZPRET:

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZAVZPRET for a condition for which it was not prescribed. Do not give ZAVZPRET to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ZAVZPRET that is written for health professionals.

What are the ingredients in ZAVZPRET?

Active ingredients in ZAVZPRET: zavegepant

Inactive ingredients in ZAVZPRET: dextrose, hydrochloric acid, sodium hydroxide, and succinic acid in water for injection.

For more information, go to www.zavzpret.com or call 1-800-438-1985.

LAB-1545-3.0

Instructions for Use

**For nasal use only** (spray into nose).

**Do not** spray in the eyes.

**Keep** ZAVZPRET and all medicines out of reach of children.

**Do not** use if the expiration (EXP) date has passed. Throw away the expired device in the trash if the expiration (EXP) date has passed.

**Do not** remove the device from its blister packaging until you are ready to use it.

**Do not** test spray, prime, or press the plunger before dosing. Each device is single use and can only be used 1 time. If you press the plunger before dosing, the spray will be lost, and the device will no longer function.

**Do not** try to spray (dose) into more than 1 nostril. A dose is 1 spray into 1 nostril. 

**Do not** use more than 1 dose in a 24-hour period. Only 1 dose can be used per day. 

**Do not** use more than 8 doses per month. A maximum of 8 doses can be used per month. 

**The device should be stored at room temperature** between 68°F to 77°F (20°C to 25°C).

**Do not** freeze.

**Keep** the device in the sealed blister package until time of use.

**Keep** ZAVZPRET and all medicines out of reach of children.

Used 1 device

Given 1 spray into 1 nostril

11 DESCRIPTION

ZAVZPRET (zavegepant) nasal spray contains zavegepant hydrochloride, a calcitonin gene-related peptide receptor antagonist. Zavegepant hydrochloride is described chemically as (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl) piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl) piperidine-1-carboxamide hydrochloride and its structural formula is:

Its molecular formula is C36H46N8O3․HCl, representing a molecular weight of 675.28 g/mol. Zavegepant free base has a molecular weight of 638.82 g/mol. Zavegepant hydrochloride is a white to off-white powder, freely soluble in water, and has pKa values of 4.8 and 8.8.

Each unit-dose ZAVZPRET device for nasal administration delivers 10 mg of zavegepant (equivalent to 10.6 mg of zavegepant hydrochloride) in a buffered aqueous solution containing dextrose, hydrochloric acid, sodium hydroxide, and succinic acid in water for injection. The solution has a pH of 5.3 to 6.7.

17 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, and that these reactions can occur after administration of ZAVZPRET. Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur [see Warnings and Precautions (5.1)].

Hypertension

Inform patients that hypertension can develop or pre-existing hypertension can worsen with ZAVZPRET, and that they should contact their healthcare provider if they experience elevation in their blood pressure [see Warnings and Precautions (5.2)].

Raynaud’s Phenomenon

Inform patients that Raynaud’s phenomenon can develop or worsen with ZAVZPRET. Advise patients to discontinue ZAVZPRET and contact their healthcare provider if they experience signs or symptoms of Raynaud’s phenomenon [see Warnings and Precautions (5.3)].

Drug Interactions

Advise patients to speak with their healthcare provider about any prescription or over-the-counter 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 [see Drug Interactions (7.3)].

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

LAB-1544-3.0