Zoliflodacin

Based on findings from animal studies, zoliflodacin may cause fetal malformations or increased embryo-fetal loss when administered to a pregnant female. In pregnant mice, repeat oral administration of zoliflodacin during organogenesis was associated with fetal malformations (exencephaly) and increased embryo-fetal loss at AUC exposures 1.6-fold the MRHD and decreased fetal weights at 2.9-fold the MRHD. In pregnant rats, zoliflodacin administration resulting in AUC exposures 8.5-fold the MRHD increased embryo-fetal loss, and exposures 3.2- fold the MRHD decreased fetal weights. There was no effect on embryo-fetal survival at exposures 5.5-fold the MRHD to zoliflodacin in pregnant rats. When zoliflodacin was administered to rats throughout pregnancy, parturition, and lactation, no effects on pup survival, birth weight, or growth were observed at maternal exposures up to 2.4-fold the MRHD.

There are no human data on zoliflodacin use in pregnancy to evaluate the drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Advise pregnant females about the potential risk to the fetus with maternal exposure to zoliflodacin.

A postmarketing descriptive pregnancy safety study is available for zoliflodacin. If exposure occurs during pregnancy, pregnant females or their healthcare providers should report the pregnancy to Entasis Therapeutics at 1-800-651-3861.

The background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defects, 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 zoliflodacin in either human or animal milk, effects on the breastfed infant, or effects on milk production. If zoliflodacin is present in breast milk, intestinal flora alteration in the breastfed infant could occur. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for zoliflodacin and any potential adverse effects on the breastfed infant from zoliflodacin or from the underlying maternal condition.

Carcinogenesis

Carcinogenicity studies have not been conducted with zoliflodacin.

Mutagenesis

Zoliflodacin was not genotoxic in the mouse lymphoma assay (MLA) and rat in vivo micronucleus assay. In the Ames bacterial reverse mutation assay, zoliflodacin was mutagenic in the TA102 strain, consistent with its pharmacologic action as a bacterial topoisomerase II inhibitor.

Impairment of Fertility

Male Fertility

In male rats, once daily oral administration of zoliflodacin for 4 weeks resulted in dose-related effects on fertility. At 1000 mg/kg/day (exposures 8-fold the MRHD based on AUC), males were completely infertile. At 500 mg/kg/day (exposures 4-fold the MRHD) fertility was reduced by 31%, with decreased pregnancy rates and increased pre- and post-implantation loss. After a 29-day recovery period, full recovery of fertility was observed; however, minimal to mild testicular tubular degeneration persisted after a 57-days recovery period. No zoliflodacin-related effects on fertility or testicular histopathology were observed at 200 mg/kg/day (exposures 2.4-fold the MRHD).

In a non-GLP study in rats, minimal exfoliation of germinal epithelial cells/immature sperm was observed in the testes at 1000 mg/kg/day and in the epididymides at 500 and 1000 mg/kg/day following 14 days of dosing (exposures greater than or equal to 2.8-fold the MRHD). Similar minimal epididymal findings occurred after 2-days of dosing at 1000 and 2000 mg/kg/day (exposures at and above 4-fold the MRHD).

After 4 weeks of daily zoliflodacin administration in rats, minimal to mild testicular degeneration and cellular debris in the epididymides were observed at or above 500 mg/kg/day (exposures 7.2-fold the MRHD). The microscopic findings, at a dose equivalent to exposures 10.7-fold the MRHD, were partially reversed after a 3-month recovery period. No adverse effects were reported at 200 mg/kg/day (exposures 3.3-fold the MRHD).

In dogs, 4 weeks of daily zoliflodacin administration produced mild to moderate testicular degeneration and moderate epididymides cellular debris at and above 200 mg/kg/day (exposures 7.5-fold the MRHD). No adverse effects were reported at 100 mg/kg/day (exposures 2.3-fold the MRHD). Findings were not present after a 3-month recovery period, although minimal to mild decreased spermatogenesis persisted in 2 of 3 dogs administered 500 mg/kg/day (exposures 8.1-fold the MRHD).

Female Fertility

In female rats, oral administration of zoliflodacin at 1000 mg/kg/day (exposures 12.7-fold the MRHD, extrapolated from nonpregnant rats) for 2 weeks prior to mating reduced pregnancy rates. No effects on pregnancy rates or embryo-fetal survival were observed at 500 mg/kg/day (7.9-fold the MRHD).

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.

A total of 782 patients received a 3 g dose of zoliflodacin across all phases of clinical trials.

The safety of zoliflodacin was evaluated in a phase 3, randomized, open-label, active-controlled, multicenter, multinational trial (NCT03959527) (Trial 1). In total, 927 patients with suspected uncomplicated gonorrhea due to N. gonorrhoeae were randomized (2:1) and treated with either a single oral 3 g dose of zoliflodacin (N=619) or a combination of a single 500 mg intramuscular dose of ceftriaxone and a single 1 g oral dose of azithromycin (N=308). Patients were eligible for enrollment if they were ≥12 years old and ≥35 kg. The majority (98%) of patients were adults (≥18 years); 14 patients were 15 to 18 years old: 12/619 (1.9%) in the zoliflodacin arm and 2/308 (0.6%) in the ceftriaxone and azithromycin arm. South Africa had the highest proportion of enrolled patients (46%), followed by Thailand (29%), the United States (17%), and the European Union (8%). The majority of patients treated with zoliflodacin were male (88%). Patients identified as Black or African American (56%), Asian (31%), White (11%), American Indian or Alaska Native (1%), or Other (1%). A total of 3% of patients treated with zoliflodacin identified as Hispanic or Latino and 22% were living with Human Immunodeficiency Virus (HIV).

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

There were no serious adverse reactions or adverse reactions leading to treatment discontinuation or death.

Common Adverse Reactions

Table 1 lists adverse reactions occurring in ≥2% of patients receiving zoliflodacin in Trial 1.

Table 1. Adverse Reactions in ≥2% of Patients with Suspected Uncomplicated Gonorrhea Infection Treated with Zoliflodacin in Trial 1^a (Safety Population):

N, total number of patients in treatment arm; n, number of patients meeting criteria.
^a Trial 1 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the zoliflodacin and the ceftriaxone and azithromycin treatment groups. The safety population includes patients with urogenital gonorrhea as well as those with uncomplicated gonorrhea infections at other body sites not covered under the approved indication.
^b Headache includes tension headache and headache.

Headache

In Trial 1, headache was reported in 61/619 (10%) of patients receiving zoliflodacin; headache severity was mild in 8% of patients and moderate in 2%.

Laboratory Abnormalities

Laboratory abnormalities that occurred at a frequency of 2% or greater in Trial 1 are provided in Table 2.

Table 2. Laboratory Abnormalities in ≥2% of Patients with Suspected Uncomplicated Gonorrhea Infection Treated with zoliflodacin, with Normal Baseline Values in Trial 1^a (Safety Population):

N, total number of patients in treatment arm with normal baseline values; n, number of patients meeting criteria.
^a Trial 1 was not designed to evaluate meaningful comparisons of the incidence of laboratory changes in the zoliflodacin and the ceftriaxone and azithromycin treatment groups. The safety population includes patients with urogenital gonorrhea as well as those with uncomplicated gonorrhea infections at other body sites not covered under the approved indication.
^b Neutropenia is defined as neutrophil count less than 1500 cells/μL.
^c Leukopenia is defined as white blood cell count less than 3500 cells/μL.

Neutropenia

In Trial 1, 41/609 (7%) and 30/609 (5%) patients developed neutropenia from 4 to 8 days and from 27 to 33 days following zoliflodacin administration, respectively. Of these 71 patients, 25% were living with HIV and 8% had unknown HIV status. No patients required treatment for neutropenia.

Leukopenia

In Trial 1, 54/609 (9%) of patients developed leukopenia following zoliflodacin administration; 16% of these patients were living with HIV and 11% had unknown HIV status. No patients required treatment for leukopenia.

Other Adverse Reactions Associated with Zoliflodacin in Trial 1

Adverse reactions occurring in less than 2% of patients receiving zoliflodacin in Trial 1 (Safety Population), are presented below:

Blood and lymphatic system disorders: Thrombocytopenia, monocyte count decreased, hemoglobin decreased

Cardiac disorders: Palpitations

Gastrointestinal disorders: Vomiting, abdominal pain, constipation, abdominal distension, flatulence

General disorders: Asthenia, fatigue, malaise, pyrexia, chills, feeling hot, night sweats

Hepatobiliary disorders: Alanine aminotransferase increased, blood bilirubin increased

Infections and infestations: Tinea infections, candidal infections

Musculoskeletal and connective tissue disorders: Musculoskeletal pain

Nervous system disorders: Somnolence, hypersomnia, hypoesthesia

Psychiatric disorders: Insomnia

Renal and urinary disorders: Hematuria, blood creatinine increased, glomerular filtration rate decreased

Respiratory, thoracic, and mediastinal disorders: Cough

Skin and subcutaneous tissue disorders: Rash, pruritus, alopecia, eyelid swelling

Vascular disorders: Hot flush