NEREUS Capsule Ref.[116150] Active ingredients: Tradipitant

5.1 Effects on the Ability to Drive or Operate Machinery

In placebo-controlled clinical trials, somnolence (6%, 12%) and fatigue (6%, 8%) were adverse reactions reported in subjects who took a single dose of 85 mg or 170 mg NEREUS, respectively [see Adverse Reactions (6.1)]. NEREUS may impair the mental and/or physical abilities required for driving a motor vehicle or operating heavy machinery. Concomitant use of other drugs that cause central nervous system depression and strong CYP3A4 inhibitors may increase this effect [see Drug Interactions (7.1)]. If concomitant use is unavoidable, warn patients against driving and other activities requiring complete mental alertness.

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 NEREUS was evaluated in adult subjects with a history of motion sickness in two randomized, double-blind, placebo-controlled trials, Study 1 and Study 2 [see Clinical Studies (14)]. Additional safety data for the 170 mg dose of NEREUS 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 NEREUS 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 NEREUS:

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

7.1 Effects of Other Drugs on NEREUS

Strong CYP3A4 Inhibitors

Tradipitant is a CYP3A4 substrate. Strong CYP3A4 inhibitors may increase tradipitant exposure, which may increase the risk of adverse reactions to NEREUS.

Risk Summary

Available data from clinical trials with NEREUS 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.

Data

Animal Data

In a combined fertility and embryo-fetal development study in pregnant rats, tradipitant was administered at oral doses of 10, 100, or 1000 mg/kg (approximately 1.4, 1.9, and 2.2 times the exposure to tradipitant at the MRHD) during the periods of mating and organogenesis, through gestation day 17. No adverse effects on maternal performance or embryo-fetal development were observed at any tested dose.

In an embryo-fetal development study in pregnant rabbits, tradipitant was administered at oral doses 30, 175, or 1000 mg/kg/day (approximately 0.2, 0.4, and 1.4 times the exposure to tradipitant at the MRHD) during the period of organogenesis, from gestation day 7 to 19. No adverse effects on maternal performance or embryo-fetal development were observed at any tested dose.

In a pre- and post-natal development study in pregnant rats, tradipitant was administered at oral doses of 100, 300, or 1000 mg/kg/day (approximately 2.3, 2.4, and 3.3 times the exposure to tradipitant at the MRHD) from gestation day 6 through lactation day 20. No maternal toxicity or developmental effects on the offspring were observed at any tested dose.

Risk Summary

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 (see Data). 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 NEREUS and any potential adverse effects on the breastfed child from NEREUS or the underlying maternal condition.

Data

Tradipitant was excreted in milk of lactating rats that received tradipitant at 100, 300, or 1000 mg/kg (2.3, 2.4, and 3.3 times the exposure to tradipitant at the MRHD) during pregnancy from gestation day 6 through lactation day 20. Serum concentrations of tradipitant and its major metabolites in pups were approximately 1% to 3% of maternal serum concentrations on lactation day 4 and up to 1% of those in the dams on lactation day 11.

The safety and effectiveness of NEREUS have not been established in pediatric patients.

Of the total number of NEREUS-treated subjects in controlled clinical studies for vomiting induced by motion, 69 (13%) were 65 years of age and older, while 4 (0.8%) were 75 years of age and older [see Adverse Reactions (6.1) and Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger adult subjects, and other reported clinical experience has not identified differences in responses between geriatric and younger adult subjects, but greater sensitivity of some older individuals cannot be ruled out.

The recommended dosage of NEREUS in patients with mild and moderate renal impairment (estimated glomerular filtration rate (eGFR) of at least 30 mL/minute/1.73m²) is the same as in patients with normal renal function. Tradipitant has not been studied in subjects with severe renal impairment (eGFR ≤29 mL/min/1.73m²) [see Clinical Pharmacology (12.3)]. Avoid use of NEREUS in patients with severe renal impairment.

Tradipitant has not been studied in patients with any degree of hepatic impairment (Child-Pugh Class A to C). Avoid NEREUS in patients with mild, moderate, or severe hepatic impairment.