Gepotidacin

There are no available data on the use of gepotidacin in pregnant women to evaluate for a drug‑associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

In embryo‑fetal development studies in mice and rats, decreased fetal weights and increased fetal mortality (late resorptions) were observed at exposures about 0.8-to-1-times the maximum recommended human dose (MRHD). In a mouse pre- and postnatal development study, there were no adverse developmental effects at exposures of approximately 3-times the MRHD.

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

There are no data on the presence of gepotidacin in human milk, its effects on the breastfed child, or on milk production. Based on a study in lactating mice, gepotidacin is likely transferred into milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

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

Carcinogenesis

Long term carcinogenicity studies have not been conducted with gepotidacin.

Mutagenesis

Gepotidacin was positive in an in vitro micronucleus test in human peripheral blood lymphocytes and in an L5178Y mouse lymphoma assay, consistent with the known in vitro clastogenic effects of topoisomerase inhibitors in in vitro mammalian cell assays. Gepotidacin was negative in an in vivo micronucleus test or Comet assay in rat. Based on an overall weight of evidence, gepotidacin is unlikely to be genotoxic.

Impairment of Fertility

In animal studies with gepotidacin, there were no adverse effects on fertility in male and female rats treated for approximately 3 weeks at 4-times the exposure at the MRHD (AUC extrapolated from rats orally administered the same dose for up to 4 weeks). There were no effects on spermatogenesis in rats and dogs at 4 and 5 times the exposure at MRHD, respectively, when treated for up to 13 weeks.

6.1. 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of gepotidacin was evaluated in 2 double‑blind, active‑controlled, randomized trials in female adult and pediatric patients 12 years of age and older with uUTI (Trial 1 and Trial 2). A total of 1,570 patients were treated with gepotidacin and 1,558 patients were treated with nitrofurantoin (pooled safety populations for gepotidacin and nitrofurantoin, respectively). Patients received treatment for a median duration of 5 days.

In Trials 1 and 2 (pooled, intent-to-treat [ITT] population), the median age of patients treated with gepotidacin was 49 (range 13 to 89) years; <1% were <18 years, 77% of patients were 18 to 64 years, 14% were 65 to 74 years, and 8% were ≥75 years. Patients were female (100%) and White (83%), Black or African American (7%), Asian (5%), or American Indian or Alaskan Native (4%); for ethnicity, 33% identified as Hispanic/Latino and 67% as non-Hispanic/Latino. The majority of patients were enrolled from the U.S. (55%).

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In the pooled trials (Trials 1 and 2), serious adverse reactions occurred in 1/1,570 (<1%) patient treated with gepotidacin and 1/1,558 (<1%) patient treated with nitrofurantoin. The serious adverse reaction reported with gepotidacin was dysarthria. No adverse reaction led to death in either treatment group.

In the pooled trials, adverse reactions leading to discontinuation of treatment occurred in 79/1,570 (5%) of patients treated with gepotidacin and 30/1,558 (2%) of patients treated with nitrofurantoin. Adverse reactions occurring in >1% of patients leading to treatment discontinuation in patients treated with gepotidacin included diarrhea (3%) and nausea (1%).

Common Adverse Reactions

Table 1 lists the adverse reactions occurring in ≥1% of patients receiving gepotidacin in the pooled trials (Trials 1 and 2).

Table 1. Adverse Reactions Occurring in ≥1% of Uncomplicated Urinary Tract Infection Patients Treated with Gepotidacin (Trials 1 and 2 Pooled Data; Safety Population):

^a Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.

Diarrhea: In Trial 1 and 2, diarrhea was reported in 258/1,570 (16%) patients receiving gepotidacin; 11% mild, 5% moderate, and <1% severe. The diarrhea started within the first 2 days of treatment for the majority of patients and the median duration of diarrhea was 4 days.

Adverse Reactions Occurring in Less than 1% of Patients Receiving Gepotidacin in Trials 1 and 2 (pooled)

Gastrointestinal Disorders: Abdominal distension, dyspepsia (includes epigastric discomfort, eructation)

Nervous System Disorders: Presyncope, dysarthria

Infections and Infestations: Clostridioides difficile infection

Musculoskeletal and Connective Tissue Disorders: Muscle spasms

Vascular Disorders: Hot flush

Cardiac Disorders: Tachycardia

Eye Disorders: Blurred vision

Ear and Labyrinth Disorders: Vertigo

General Disorders and Administration Site Disorders: Fatigue

Investigations: Alanine aminotransferase/aspartate aminotransferase increased

Skin and Subcutaneous Tissue: Rash, hyperhidrosis

Immune System Disorders: Hypersensitivity reactions

Select Adverse Reactions Occurring in Patients Receiving Gepotidacin in Phase 1 and 2 Clinical Studies

Gastrointestinal Disorders: hypersalivation (with oral daily doses ranging from 100 mg to 6,000 mg, which includes not approved doses)