Secnidazole

Risk Summary

Limited available data with secnidazole use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies, there were no adverse developmental outcomes when secnidazole was administered orally to pregnant rats and rabbits during organogenesis at doses up to 4 times the clinical dose (see Data)

The estimated 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 miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In animal reproduction studies, pregnant rats were dosed orally with secnidazole during organogenesis (gestational days 6-17) at 100, 300 and 1000 mg/kg/day, up to 4 times the clinical dose based on AUC comparisons. Animals showed no evidence of adverse developmental outcomes, but maternal toxicity (including reduced body weight gain) was observed at and above 300 mg/kg/day. In rabbits, no evidence of adverse developmental outcomes was observed when oral doses of secnidazole were administered to dams during organogenesis (gestational days 7-20) at doses up to 100 mg/kg/day (about 0.1 times the clinical dose, based on AUC comparisons). Secnidazole was associated with maternal toxicity (reduced food consumption and markedly reduced body weight gain) in dams at 100 mg/kg/day.

In a peri- and post-natal development study in rats, secnidazole was administered at 30, 100 and 300 mg/kg/day from Day 6 of gestation through Day 20 of lactation. Secnidazole was not associated with any adverse effects on gestation, parturition, lactation or on subsequent development of first generation (F1) and second generation (F2) offspring at these doses, equivalent to up to 1.4 times the clinical dose based on AUC comparisons. Maternal toxicity (reduced gestational body weight gain) was evident at doses of 100 mg/kg and above (about 0.3 times the clinical dose based on AUC comparisons).

Risk Summary

There is no information on the presence of secnidazole in human milk, the effects on the breast- fed child, or the effects on milk production. Other nitroimidazole derivatives are present in human milk. Because of the potential for serious adverse reactions, including tumorigenicity, advise patients that breastfeeding is not recommended during treatment with secnidazole and for 96 hours (based on halflife) after administration of secnidazole.

Clinical Considerations

A nursing mother may choose to pump and discard her milk during treatment with secnidazole and for 96 hours after administration of secnidazole and feed her infant stored human milk or formula.

Nitroimidazoles, which have similar chemical structures to secnidazole, have been associated with tumors affecting the liver, lungs, mammary, and lymphatic tissues in animals after lifetime exposures. It is unclear if these positive tumor findings in lifetime rodent studies of these nitroimidazoles indicate a risk to patients taking a single dose of secnidazole to treat bacterial vaginosis.

Secnidazole was positive in the bacterial reverse mutation assay, but was negative for the rat micronucleus test and mouse lymphoma test.

In a rat fertility study, females were dosed for two weeks prior to mating until Day 7 of gestation with males that were dosed for a minimum of 28 days before cohabitation. No parental toxicity or adverse effects on mating performance, estrous cycles, fertility or conception was observed at doses of up to the maximum tolerated dose (300 mg/kg/day, approximately 1.4 times the recommended dose based on AUC comparisons).

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 safety data described below reflect exposure to 589 patients, of whom 518 received a 2 g dose of secnidazole. Secnidazole was evaluated in three clinical trials of patients diagnosed with bacterial vaginosis: two placebo-controlled trials (Trial 1 n=215, Trial 2 n=189) and one uncontrolled safety trial (Trial 3 n=321).

All patients received a single oral dose of study medication or placebo. Trial 1 evaluated a 1 g (this dose is not approved) dose (n=71) and a 2 g dose (n=72) of secnidazole. Trial 2 evaluated a 2 g dose (n=125). The population was female, aged 15 to 54 years. Patients in the placebo-controlled trials were primarily Black or African American (54%) or Caucasian (41%). There were no deaths in the trials. Two patients in Trial 3 discontinued due to vulvovaginal candidiasis in the secnidazole-treated arm.

Most Common Adverse Reactions

Among 197 patients treated with a single 2 g dose of secnidazole in the two placebo-controlled trials, Trial 1 and 2, adverse reactions were reported by approximately 29% of patients. Table 1 displays the most common adverse reactions (≥2% in secnidazole-treated patients) in these two trials.

Table 1. Advers e Reactions Occurring (≥2% secnidazole-Treated Patients) in the Pooled Placebo-Controlled Trials 1 and 2 in Adult Women with Bacterial Vaginosis:

Among the 321 patients in an uncontrolled trial, Trial 3, adverse reactions were reported in 30% of patients. Vulvovaginal candidiasis (8.4%), nausea (5.3%), vomiting (2.5%) and dysgeusia (3.4%) were the most common adverse reactions reported in this trial.