Etripamil

There are no available data on the use of etripamil during pregnancy to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Reproductive studies conducted with intravenous administration of etripamil in pregnant rats and rabbits during organogenesis did not show any evidence of fetal harm or malformations in rats at exposures up to approximately 3x the maximum concentration (C_max) and 0.4x the AUC at the maximum recommended human dose (MRHD) and in rabbits at exposures approximately equivalent to the C_max and 10x the AUC at the MRHD, at which maternal toxicities were observed.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

There are no data on the presence of etripamil in human milk or animal milk. However, the structurally related compound, verapamil, is known to be present in human milk. There are no data on the effects of etripamil on the breastfed infant or on milk production. Because the presence of etripamil in breastmilk has not been characterized, and there is a potential for adverse reactions in the breastfed infant including hypotension and bradycardia, lactating women should interrupt breastfeeding and pump and discard milk for 12 hours (approximately 5 terminal half-lives) after treatment with etripamil.

Carcinogenesis

Long term carcinogenicity studies in rodents have not been conducted with etripamil.

Mutagenesis

Etripamil was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, and an in vivo micronucleus study in rats (IV administration).

Impairment of Fertility

In a male and female fertility study, rats were dosed once daily via intravenous administration at etripamil doses of 0.05 to 0.374 mg/kg/day. Male rats were dosed for 28 days prior to mating, and female rats were dosed for 14 days prior to mating and continuing up to day 7 of pregnancy. There was no effect on fertility of male and female rats at doses up to 0.374 mg/kg/day, approximately 3× the C_max and 0.4× the AUC at the MRHD.

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 practice.

The safety of etripamil was evaluated using pooled data from double-blind, randomized, placebo-controlled trials including NODE-1, NODE-301 Part 1, RAPID, and RAPID Extension. A total of 321 patients were treated with etripamil in randomized controlled studies.

In the RAPID and RAPID Extension studies, in which patients had the option of self-administering a second dose of etripamil for a perceived episode of PSVT, the majority of patients (65%) self-administered a second dose of etripamil (2x70mg).

In NODE-301 Part 1, RAPID, and RAPID Extension, to assess tolerability, a test dose(s) was given prior to randomization. A small percentage of patients failed the test dose due to hypotension (0.4%).

The majority of treatment-related adverse reactions reported in clinical studies with etripamil have been related to local reactions to, at, or near the nasal administration site, including the nose, throat, and eyes. These local reactions included nasal discomfort, nasal congestion, throat irritation, oropharyngeal pain, lacrimation, rhinorrhea, bleeding from the nose, upper-airway cough syndrome, and sneezing.

Most frequent (≥5.0%) Adverse Reactions¹ Observed in Randomized Controlled Studies:

¹ Adverse reactions that occurred within 24 hours of study drug administration (TEAE24h) for perceived PSVT in the double-blind, placebo-controlled studies, NODE-1, NODE-301 Part 1, RAPID and RAPID Extension that had an overall incidence of 5% or greater and where the incidence is at least 1% greater than the placebo group.
² 2x70 mg: first administration of etripamil 70 mg followed by a second dose of etripamil 70 mg 10 minutes later if symptoms persisted.