Zavzpret (Zavegepant) Nasal Spray for Migraine

ZAVZPRET is a medication that has been recently approved by the FDA for the acute treatment of migraine attacks.

Brand Name: ZAVZPRET

Medical Name: Zavegepant

Date of FDA Approval: 29th March 2023

Expected availability: July 2023

Marketed by: Pfizer Pharmaceutical

Class of Medicines: CGRP antagonist (calcitonin-gene-related peptide receptor antagonist)

ZAVZPRET FDA-Approved Indications:

ZAVZPRET  is indicated for managing the painful symptoms of migraine attacks, such as severe headaches, nausea, and sensitivity to light and sound.

It is not intended for use as a preventive treatment for migraines. While it can be very effective in treating acute migraine symptoms, it is not designed to prevent migraines from occurring in the first place.

ZAVZPRET  Dosing recommendations [Ref]:

The recommended dose of ZAVZPRET is 10 mg, which should be administered as a single spray into one nostril, as needed.

The maximum dose of ZAVZPRET that can be safely given in a 24-hour period is 10 mg or one spray.

Exceeding this dose can increase the risk of adverse effects and may not provide additional relief for the patient.

The safety of treating more than 8 migraines within a 30-day period with ZAVZPRET has not yet been established.

Dosage strength:

Zavegepant is available in a nasal spray form that contains 10 mg of the medication per device.

This means that each individual spray bottle or unit-dose nasal spray device delivers a single spray of the medication, with a standardized dosage of 10 mg of Zavegepant per spray.

Contraindications and precautions:

Some patients have experienced hypersensitivity reactions such as facial swelling and urticaria (hives). These types of reactions can be serious and potentially life-threatening if not promptly addressed.

Therefore, it is crucial to closely monitor patients who are receiving ZAVZPRET for any signs or symptoms of a hypersensitivity reaction.

If such a reaction does occur, it is essential to discontinue the use of ZAVZPRET immediately and initiate appropriate therapy to manage the symptoms and prevent the reaction from worsening.

Side effects of ZAVZPRET:

Side effects are uncommon. The most commonly reported adverse reaction among patients treated with ZAVZPRET was taste disorders, with 18% of patients experiencing this side effect. This was significantly higher than the placebo group, where only 4% of patients reported taste disorders.

Nausea was the second most commonly reported adverse reaction among patients treated with ZAVZPRET, with 4% of patients experiencing this side effect. This was higher than the placebo group, where only 1% of patients reported nausea.

Nasal discomfort and vomiting were also reported as adverse reactions, with 3% and 2% of patients respectively reporting these symptoms while on ZAVZPRET.

Drug interactions:

ZAVZPRET is a medication used to treat migraines, but it’s important to avoid potential drug interactions to ensure safe and effective use.

Concomitant administration of ZAVZPRET with drugs that inhibit or induce OATP1B3 or NTCP transporters or intranasal decongestants can affect the medication’s effectiveness.

ZAVZPRET  Use in pregnancy:

The use of ZAVZPRET in pregnant women has limited data on developmental risk. Animal studies showed no adverse effects on embryofetal development with subcutaneous administration of Zavegepant at doses higher than those used clinically.

However, there are no adequate data on the developmental risk associated with the use of ZAVZPRET in pregnant women.

Women with migraine may have an increased risk of preeclampsia and gestational hypertension during pregnancy.

The estimated rate of major birth defects and miscarriage among deliveries to women with migraine is similar to rates reported in women without migraine.

Use in Lactation:

The presence of Zavegepant or its metabolites in human milk and its effects on breastfed infants and milk production have not been studied.

The decision to breastfeed while using ZAVZPRET should be made after considering the benefits of breastfeeding and the mother’s need for the medication, as well as potential adverse effects on the breastfed infant from either the medication or the maternal condition being treated.

There is currently no data to inform whether ZAVZPRET is safe for use during breastfeeding, and caution should be exercised.

Use in Liver and renal disease:

The dosage adjustment of ZAVZPRET is not required in patients with mild to moderate hepatic impairment.

However, the drug has not been studied in patients with severe hepatic impairment and should be avoided in such cases.

For patients with renal impairment, no dosage adjustment is necessary if their estimated creatine clearance (CLcr) is 30 mL/min or more. ZAVZPRET should be avoided in patients with CLcr less than 30 mL/min.

ZAVZPRET  MOA (Mechanism of Action):

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

The CGRP receptor is involved in the pathogenesis of migraine, a neurovascular disorder characterized by recurrent episodes of headache often accompanied by photophobia, phonophobia, and nausea.

By blocking the CGRP receptor, Zavegepant can prevent the vasodilation, inflammation, and pain associated with migraine attacks.

Zavegepant represents a novel approach to the treatment of migraine, as it targets a specific component of the CGRP system, without affecting other neurotransmitters or receptors.

The development of CGRP receptor antagonists, including Zavegepant, has been a major advance in the field of migraine therapeutics, providing patients with a new option for the management of their condition.

Pharmacodynamics:

CGRP is a neuropeptide that is involved in the transmission and modulation of pain signals.

The drug has been tested in healthy volunteers and found to have no clinically relevant differences in resting blood pressure when administered alone or concomitantly with sumatriptan, a drug used to treat migraines.

Additionally, at a dose up to four times the recommended daily dose, Zavegepant has been found to have no significant effect on QT interval prolongation, which is an indicator of the risk of potentially fatal arrhythmias.

• Absorption:

Zavegepant, when administered as a single 10 mg dose of nasal spray, reaches peak plasma concentration in approximately 30 minutes, with an absolute bioavailability of approximately 5%. Zavegepant displays slightly less than dose-proportional pharmacokinetics up to 40 mg.

• Distribution:

The mean apparent volume of distribution of intranasal Zavegepant is approximately 1774 L, with plasma protein binding of approximately 90%.

• Elimination:

Zavegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6, and is excreted mostly via the biliary/fecal route, with the renal route being a minor route of elimination.

The effective half-life of Zavegepant following a 10 mg dose of the nasal spray is 6.55 hours, and Zavegepant does not accumulate after once-daily dosing for 14 days.

Efficacy of ZAVZPRET in the treatment of Acute Migraine:

The efficacy of ZAVZPRET was evaluated using two endpoints:

• pain freedom and
• MBS (most bothersome symptom) freedom,

both measured at 2 hours after dosing.

The study included a total of 1,269 adult patients with a history of moderate-to-severe migraine attacks, who were randomly assigned to receive either ZAVZPRET 10 mg or a placebo.

The results showed that a significantly higher proportion of patients in the ZAVZPRET group achieved pain freedom at 2 hours compared to the placebo group (23.6% vs 14.9%, respectively).

This corresponds to a difference of 8.8% between the two groups, which was statistically significant with a p-value of less than 0.001.

Similarly, a significantly higher proportion of patients in the ZAVZPRET group achieved MBS freedom at 2 hours compared to the placebo group (39.6% vs 31.1%, respectively).

This corresponds to a difference of 8.7% between the two groups, which was also statistically significant with a p-value of 0.001.

In addition to the primary efficacy endpoints, the study also evaluated additional efficacy endpoints for ZAVZPRET compared to the placebo.

The first endpoint was pain relief at 2 hours, which showed that 58.7% of patients who received ZAVZPRET reported pain relief compared to 49.7% of patients who received a placebo, with a statistically significant difference of 9.0%.

The second endpoint was the percentage of patients reporting normal function at 2 hours, which showed that 35.8% of patients who received ZAVZPRET reported normal function compared to 25.6% of patients who received placebo, with a statistically significant difference of 10.2%.

The third endpoint was sustained pain freedom from 2 to 48 hours, which showed that 12.4% of patients who received ZAVZPRET maintained pain freedom compared to 8.7% of patients who received a placebo, with a statistically significant difference of 3.7%.

Important Instructions for Using ZAVZPRET Nasal Spray

• Nasal Use:

Only ZAVZPRET is designed for nasal use only. Do not spray the medication in your eyes.

• Keep Out of Reach of Children:

Always store ZAVZPRET and all other medications out of reach of children.

• Check Expiration Date:

Do not use ZAVZPRET if the expiration date has passed. If the device has expired, dispose of it in the trash.

• Do Not Remove from Blister Packaging:

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

• Do Not Prime or Test Spray:

Do not prime, test spray, or press the plunger before dosing. The device is for single use only and can only be used one time. Pressing the plunger before dosing will cause the spray to be lost, and the device will no longer function.

• One Dose per Nostril:

A single dose is one spray into one nostril. Do not try to spray (dose) into more than one nostril.

• One-Dose per Day:

Do not use more than one dose in a 24-hour period.

• Maximum Doses per Month:

Do not use more than 8 doses per month.

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