Revefenacin

Risk Summary

There are no adequate and well-controlled studies with revefenacin in pregnant women. Women should be advised to contact their physician if they become pregnant while taking revefenacin. In animal reproduction studies, subcutaneous administration of revefenacin to pregnant rats and rabbits during the period of organogenesis produced no evidence of fetal harm at respective exposures approximately 209 times the exposure at the maximum recommended human dose (MRHD) (on an area under the curve [AUC] basis) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

Data

Animal Data

In an embryo‑fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 17, revefenacin was not teratogenic and did not affect fetal survival at exposures up to 209 times the MRHD (based upon summed AUCs for revefenacin and its active metabolite at maternal subcutaneous doses up to 500 mcg/kg/day).

In an embryo‑fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7 to 19, revefenacin was not teratogenic and did not affect fetal survival at exposures up to 694 times the MRHD (based upon summed AUCs for revefenacin and its active metabolite at maternal subcutaneous doses up to 500 mcg/kg/day).

Placental transfer of revefenacin and its active metabolite was observed in pregnant rabbits.

In a pre- and postnatal development (PPND) study in pregnant rats dosed during the periods of organogenesis and lactation from gestation day 6 to lactation day 20, revefenacin had no adverse developmental effects on pups at exposures up to 196 times the MRHD (based upon summed AUCs for revefenacin and its active metabolite at maternal subcutaneous doses up to 500 mcg/kg/day).

Risk Summary

There is no information regarding the presence of revefenacin in human milk, the effects on the breastfed infant, or the effects on milk production. However, revefenacin was present in the milk of lactating rats following dosing during pregnancy and lactation (see Data).

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for revefenacin and any potential adverse effects on the breastfed infant from revefenacin or from the underlying maternal condition.

Data

Animal Data

In a PPND study [see Pregnancy], revefenacin and its active metabolite were present in milk of lactating rats on lactation day 22. Milk-to-plasma concentration ratios were up to 10 for revefenacin and its active metabolite.

Two-year inhalation studies in Sprague-Dawley rats and CD1 mice were conducted to assess the carcinogenic potential of revefenacin. No evidence of tumorigenicity was observed in male and female rats at inhaled doses up to 338 mcg/kg/day (approximately 35 times the MRHD based upon summed AUCs for revefenacin and its active metabolite). No evidence of tumorigenicity was observed in male and female mice at inhaled doses up to 326 mcg/kg/day (approximately 40 times the MRHD based on summed AUCs for revefenacin and its active metabolite).

Revefenacin and its active metabolite were negative for mutagenicity in the Ames test for bacterial gene mutation. Revefenacin was negative for genotoxicity in the in vitro mouse lymphoma assay and in vivo rat bone marrow micronucleus assay.

There were no effects on male or female fertility and reproductive performance in rats at subcutaneous revefenacin doses up to 500 mcg/kg/day (approximately 30 times the MRHD on an mg/m² basis for revefenacin).

• Paradoxical bronchospasm
• Worsening of narrow-angle glaucoma
• Worsening of urinary retention
• Immediate hypersensitivity reactions

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 practice.

The revefenacin safety database included 2,285 subjects with COPD in two 12-week efficacy studies and one 52-week long-term safety study. A total of 730 subjects received treatment with revefenacin 175 mcg once daily. The safety data described below are based on the two 12-week trials and the one 52-week trial.

12-Week Trials

Revefenacin was studied in two 12-week replicate placebo-controlled trials in patients with moderate to very severe COPD (Trials 1 and 2). In these trials, 395 patients were treated with revefenacin at the recommended dose of 175 mcg once daily.

The population had a mean age of 64 years (range from 41 to 88 years), with 50% males, 90% Caucasian, and had COPD with a mean post-bronchodilator forced expiratory volume in one second (FEV₁) percent predicted of 55%. Of subjects enrolled in the two 12-week trials, 37% were taking concurrent LABA or ICS/LABA therapy. Patients with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.

Table 1 shows the most common adverse reactions that occurred with a frequency of greater than or equal to 2% in the revefenacin group and higher than placebo in the two 12‑week placebo-controlled trials.

The proportion of subjects who discontinued treatment due to adverse reactions was 13% for the revefenacin-treated subjects and 19% for placebo-treated subjects.

Table 1. Adverse Events with Revefenacin ≥2% Incidence and Higher than Placebo:

Other adverse reactions defined as events with an incidence of ≥1.0%, less than 2.0%, and more common than with placebo included the following: hypertension, dizziness, oropharyngeal pain, and bronchitis.

52-Week Trial

Revefenacin was studied in one 52-week, open-label, active-control (tiotropium 18 mcg once daily) trial in 1,055 patients with COPD. In this trial, 335 patients were treated with revefenacin 175 mcg once daily and 356 patients with tiotropium. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled 12-week studies described, with the exception that concurrent LABA or LABA/ICS therapy was used in 50% of patients. The adverse reactions reported in the long-term safety trial for revefenacin were consistent with those observed in the placebo-controlled studies of 12-weeks.