SOLOSEC Oral granules Ref.[10387] Active ingredients: Secnidazole

Secnidazole exposure-response relationships and the time course of pharmacodynamic response are unknown.

Cardiac Electrophysiology

The effect of secnidazole on the QTc interval was evaluated in a Phase 1 randomized, double blind, placebo- and positive-controlled four-period crossover thorough QTc study in 52 healthy adult subjects following single oral granule doses of 2 g and 6 g (3-times the recommended dose). Although there was a positive relationship of the QTc interval with secnidazole concentrations, there was no clinically relevant increase in the QTc interval following either dose.

A single oral dose of 2 g of SOLOSEC in healthy adult female subjects, following an overnight fast and admixed with (4 oz) of applesauce, resulted in a mean (SD) secnidazole peak plasma concentration (C_max) of 45.4 (7.64) mcg/mL and mean (SD) systemic exposure (AUC_0-inf) of 1331.6 (230.16) mcg•hr/mL. Median (range) time to peak concentration (T_max) was 4.0 (3.0-4.0) hours. Following administration of the 2 g dose, mean secnidazole plasma concentrations decreased to 22.1 mcg/mL at 24 hours, 9.2 mcg/mL at 48 hours, 3.8 mcg/mL at 72 hours, and 1.4 mcg/mL at 96 hours.

Absorption

Effect of Food

Administration of 2 g of SOLOSEC admixed with applesauce followed by ingestion of a high-fat meal (approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories) resulted in no significant change in the rate (C_max) and extent (AUC) of secnidazole exposure as compared to administration when admixed with applesauce and taken under fasted conditions. There was no effect of admixing SOLOSEC with pudding and yogurt as compared to admixing with applesauce (Table 2) [see Dosage and Administration (2.2)].

Table 2. Pharmacokinetic Parameters Following Single Dose Administration of SOLOSEC 2 g Given Orally:

^* Median (range)
^† Admixed with applesauce

Distribution

The apparent volume of distribution of secnidazole is approximately 42 L. The plasma protein binding of secnidazole is <5%.

Elimination

The total body clearance of secnidazole is approximately 25 mL/min. The renal clearance of secnidazole is approximately 3.9 mL/min.

The plasma elimination half-life for secnidazole is approximately 17 hours.

Metabolism

Secnidazole is metabolized in vitro via oxidation by human hepatic CYP450 enzyme system with ≤1% conversion to metabolites.

Excretion

Approximately 15% of a 2 g oral dose of SOLOSEC is excreted as unchanged secnidazole in the urine.

Drug Interactions

Oral Contraceptives

Concomitant administration of 2 g of SOLOSEC with the combination oral contraceptive (OC), ethinyl estradiol (EE) plus norethindrone (NE), to healthy adult female subjects resulted in a decrease in mean C_max of EE of 29%, and no significant effect on the mean AUC of EE. Administration of 2 g of SOLOSEC 1 day before combination OC administration resulted in no significant effect on mean C_max or AUC of EE.

Concomitant administration of 2 g of SOLOSEC with the combination OC resulted in no significant effect on mean C_max and AUC of NE (increases of 13% and 16%, respectively). Administration of 2 g of SOLOSEC 1 day before combination OC administration also resulted in no significant effect on mean C_max and AUC of NE [see Drug Interactions (7.1)].

Ethanol Metabolism

In vitro studies showed that secnidazole had no effect on aldehyde dehydrogenase activity.

Mechanism of Action

Secnidazole is a 5-nitroimidazole antimicrobial. 5-nitroimidazoles enter the bacterial cell as an inactive prodrug where the nitro group is reduced by bacterial enzymes to radical anions. It is believed that these radical anions interfere with bacterial DNA synthesis of susceptible isolates.

Resistance

The development of resistance to secnidazole by bacteria associated with bacterial vaginosis was not examined. Bacterial isolates exhibiting reduced in vitro susceptibility to metronidazole also show reduced susceptibility to secnidazole. The clinical significance of such an effect is unknown.

Antibacterial Activity

Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis [see Indications and Usage (1.2)]; standard methodology for the susceptibility testing of potential bacterial pathogens, Gardnerella vaginalis or Mobiluncus spp. has not been defined.

The following in vitro data are available but their clinical significance is unknown. Secnidazole is active in vitro against most isolates of the following organisms reported to be associated with bacterial vaginosis:

Bacteroides spp.
Gardnerella vaginalis
Prevotella spp.
Mobiluncus spp.
Megasphaera-like type I/II

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).

Two randomized placebo-controlled clinical trials (Trial 1 and Trial 2) with similar designs were conducted to evaluate the efficacy of SOLOSEC 2 gram for the treatment of bacterial vaginosis. A diagnosis of bacterial vaginosis was defined as all of (a) the presence of an off-white (milky or gray), thin, homogeneous vaginal discharge; (b) a vaginal pH ≥4.7; © the presence of Clue cells ≥20% of the total epithelial cells on a microscopic examination of the vaginal saline wet mount; (d) a positive “whiff” test (detection of amine odor on addition of 10% KOH solution to a sample of the vaginal discharge); and (e) a Nugent score ≥4.

Trial 1 enrolled 144 non-pregnant female patients aged 19 to 54 years and Trial 2 enrolled 189 non-pregnant females aged 18 to 54 years. Black or African American subjects in both trials were 54%. Efficacy was assessed by clinical outcome evaluated 21 to 30 days following a single dose of SOLOSEC. A clinical responder was defined as “normal” vaginal discharge, negative “whiff” test, and clue cells <20%. Additional endpoints included Nugent score cure (Nugent score of 0-3) and therapeutic outcome. A therapeutic responder was defined as a clinical responder with a Nugent score cure. In Trial 2, the endpoints were also assessed at Day 7-14.

In both trials, a statistically significantly greater percentage of patients experienced clinical response, Nugent score cure, and therapeutic response at 21 to 30 days following a single dose of SOLOSEC compared to placebo. Statistically significant results for the endpoints were also achieved at Day 7-14 in Trial 2.

The percentage of patients with clinical response was also consistently higher in both trials in the SOLOSEC arm compared to placebo among all subsets of patients: number of prior episodes of bacterial vaginosis (≤ 3 episodes and ≥ 4 episodes) in past 12 months, baseline Nugent score (score 4-6 and score 7-10), and race (Black/African American and White). Tables 3 and 4 describe the efficacy of SOLOSEC in the treatment of bacterial vaginosis.

Table 3. Efficacy of SOLOSEC for Treatment of Bacterial Vaginosis in Two Randomized, Double-Blind, Placebo-Controlled Trials in Modified-Intent-to-Treat Population at 21-30 Days:

^* N=number of patients in treatment group (modified intent-to-treat population defined as all patients randomized who had a baseline Nugent score ≥4 and were negative for other sexually transmitted infections at baseline).
^† Patients missing one or more of the clinical assessments were considered as non-responders/not cured.
^‡ Difference in response (SOLOSEC-placebo) and 95% confidence interval
^§ Patients with missing Nugent scores were considered Nugent score failures.

Table 4. Efficacy of SOLOSEC for Treatment of Bacterial Vaginosis in Trial 2 in Modified- Intent-to-Treat Population at 7-14 Days:

^* N=number of patients in treatment group (modified intent-to-treat population defined as all patients randomized who had a baseline Nugent score ≥4 and were negative for other sexually transmitted infections at baseline).
^† Patients missing one or more of the clinical assessments were considered as non-responders/not cured.
^‡ Difference in response (SOLOSEC-placebo) and 95% confidence interval
^§ Patients with missing Nugent scores were considered Nugent score failures.