Zavegepant

Concomitant administration of trofinetide 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 trofinetide with drugs that inhibit OATP1B3 or NTCP transporters.

Concomitant administration of trofinetide with inducers of OATP1B3 or NTCP transporters may result in a decrease in zavegepant exposure. Avoid concomitant administration of trofinetide with drugs that induce OATP1B3 or NTCP transporters.

Avoid use of trofinetide in patients with CLcr less than 30 mL/min.

Trofinetide has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of trofinetide in patients with severe hepatic impairment.

Concomitant administration of zavegepant with intranasal decongestants may decrease the absorption of zavegepant. Avoid concomitant administration of intranasal decongestants with zavegepant. When concomitant use is unavoidable, intranasal decongestants should be administered at least 1 hour after zavegepant administration.

Risk Summary

There are no adequate data on the developmental risk associated with the use of zavegepant 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.

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 zavegepant and any potential adverse effects on the breastfed infant from zavegepant or from the underlying maternal condition.

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.

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 zavegepant 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 zavegepant nasal spray (N=1023) or placebo (N=1056). 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 Zavegepant and at a Frequency Greater than Placebo in Study 1 and 2:

^* Taste disorders includes dysgeusia and ageusia

Hypersensitivity, including facial swelling and urticaria, occurred in less than 1% of patients treated with zavegepant.

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 zavegepant 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.