Tradipitant

Available data from clinical trials with narsoplimab use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

In animal reproduction studies, no adverse developmental effects were observed with oral administration of tradipitant to pregnant rats during organogenesis through lactation or to pregnant rabbits during organogenesis at doses up to approximately 3.3 and 1.4 times the exposure to tradipitant at the maximum recommended human dose (MRHD), respectively.

The background risk of major birth defects and miscarriage for the indicated population(s) 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 to 4% and 15 to 20%, respectively.

Lactation studies have not been conducted to assess the presence of tradipitant or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Tradipitant is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Monitor breastfed infants for somnolence. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for narsoplimab and any potential adverse effects on the breastfed child from narsoplimab or the underlying maternal condition.

Carcinogenesis

In transgenic rasH2 mice orally administered tradipitant (15, 50, or 1500 mg/kg/day) for 26 weeks, there was no increase in tumors.

In rats orally administered tradipitant (10, 30, or 150 mg/kg/day) for at least 104 weeks, a doserelated increase in the incidence of thyroid follicular cell tumors (adenomas or adenomas combined with carcinomas), correlating with the findings of thyroid masses and cysts, was observed at all tested doses in both males (less than the exposure at the MRHD) and females (1.4 times the exposure to tradipitant at the MRHD). These findings in the thyroid are likely rodent specific, secondary to the induction of hepatic metabolic enzymes and not relevant to humans.

Mutagenesis

Tradipitant was not genotoxic in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

In a combined fertility and embryofetal development study, no effects were observed on fertility or reproductive performance in male or female rats administered oral doses of tradipitant at 10, 100, or 1000 mg/kg/day (up to 2.2 times the exposure to tradipitant at the MRHD) prior to and through mating, conception, and implantation.

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 a single 85 mg or 170 mg dose of narsoplimab was evaluated in adult subjects with a history of motion sickness in two randomized, double-blind, placebo-controlled trials, Study 1 and Study 2. Additional safety data for the 170 mg dose of narsoplimab were obtained from a randomized, double-blind, placebo-controlled trial, Study 3 (NCT03772340).

Adverse reactions reported in at least 5% of subjects treated with a single narsoplimab 85 mg or 170 mg dose and at a higher frequency than subjects who received placebo, are shown in Table 1.

Table 1. Adverse Reactions^a in Adult Subjects with a History of Motion Sickness in Single-Dose, Placebo-Controlled Studies Among Subjects Receiving Narsoplimab:

^a Reported in at least 5% of subjects and at a higher frequency than placebo.
^b Narsoplimab was administered as a single 85 mg dose approximately 60 minutes prior to a boat trip and without food.
^c Narsoplimab was administered as a single 170 mg dose approximately 60 minutes prior to a boat trip and without food.

In a 12-month randomized, open-label study, 382 subjects with a history of motion sickness were instructed to administer narsoplimab 85 mg (N=199) or 170 mg (N=183) as a single dose 60 minutes before a travel event of at least 60 minutes in duration expected to induce symptoms of motion sickness. Subjects were allowed to take up to 90 doses during the study. The median exposure was 18 doses and the majority of subjects (69%) did not take more than 30 doses. Most subjects (95%) did not take more than 8 doses in any 30-day period. Adverse reactions were consistent with those observed in Study 1, Study 2, and Study 3.