NUZOLVENCE Oral suspension Ref.[116102] Active ingredients: Zoliflodacin

5.1 Embryo-Fetal Toxicity: Potential Risk for Pregnant Females

Based on data from animal studies, NUZOLVENCE may cause fetal harm when administered to a pregnant female at clinically relevant doses. Reproductive and developmental toxicity studies at AUC exposures 1.6-fold (mice) and 8.5-fold (rats) the maximum recommended human dose (MRHD) of zoliflodacin administered to pregnant rodents during organogenesis resulted in fetal malformations (exencephaly) and increased embryo-fetal loss [see Use in Specific Populations (8.1)].

Advise pregnant females about the potential risk to the fetus with maternal exposure to NUZOLVENCE. Avoid use of NUZOLVENCE during pregnancy. Obtain a pregnancy test prior to initiation of treatment with NUZOLVENCE in females of reproductive potential [see Dosage and Administration (2.1) and Use in Specific Populations (8.1, 8.3)].

5.2 Embryo-Fetal Toxicity: Potential Risk Related to Males with Female Partners of Reproductive Potential

Based on data from an animal toxicity study, the risk of early pregnancy loss may be increased in female partners of males treated with NUZOLVENCE. A reduced number of live embryos and increased number of embryonic losses were observed in untreated female rats mated with male rats administered zoliflodacin at exposures approximately 3.9-times the clinical exposure at the MRHD for 4 weeks.

Advise males with female partners of reproductive potential to use effective contraception for at least 3 months after administration of NUZOLVENCE. [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

5.3 Testicular Toxicity and Risks to Male Fertility

Based on findings from animal studies, NUZOLVENCE may cause testicular toxicity and impair male fertility. In repeat-dose toxicity studies, rats and dogs administered zoliflodacin for durations of 2 days to 4 weeks at AUC exposures 3- to 11-times the MRHD experienced minimal to moderate decreased spermatogenesis and testicular histopathological changes. In rats, loss of male rat fertility was no longer observed 4 weeks after the last dose; however, testicular histopathological changes in rats and dogs were only partially reversible after 2 to 3 months [see Nonclinical Toxicology (13.1)]. An evaluation of spermatogenesis has not been conducted in humans.

Advise males that NUZOLVENCE may cause testicular toxicity and impair male fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

5.4 Hypersensitivity Reactions

Hypersensitivity reactions, including rash and pruritus, have been reported in patients receiving NUZOLVENCE [see Adverse Reactions (6.1)]. NUZOLVENCE is contraindicated in patients with a known history of hypersensitivity to NUZOLVENCE [see Contraindications (4)]. Before therapy with NUZOLVENCE is instituted, carefully inquire about previous hypersensitivity reactions to NUZOLVENCE.

If an allergic reaction to NUZOLVENCE occurs, institute appropriate supportive measures.

5.5 Clostridioides difficile Infection

Clostridioides difficile infection (CDI) has been reported with use of nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDI. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDI must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDI has been reported to occur over two months after the administration of antibacterial agents.

If CDI is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.6 Development of Drug-Resistant Bacteria

Prescribing NUZOLVENCE in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.2)].

The following clinically significant adverse reactions are discussed in the Warnings and Precautions section of the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

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 NUZOLVENCE 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 NUZOLVENCE (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) [see Clinical Studies (14)]. 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 NUZOLVENCE 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 NUZOLVENCE 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 NUZOLVENCE 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 2 lists adverse reactions occurring in ≥2% of patients receiving NUZOLVENCE in Trial 1.

Table 2. Adverse Reactions in ≥2% of Patients with Suspected Uncomplicated Gonorrhea Infection Treated with NUZOLVENCE 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 NUZOLVENCE 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 NUZOLVENCE; 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 3.

Table 3. Laboratory Abnormalities in ≥2% of Patients with Suspected Uncomplicated Gonorrhea Infection Treated with NUZOLVENCE, 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 NUZOLVENCE 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 NUZOLVENCE 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 NUZOLVENCE 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 NUZOLVENCE in Trial 1

Adverse reactions occurring in less than 2% of patients receiving NUZOLVENCE 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

7.1 Effect of Other Drugs on NUZOLVENCE

Moderate and Strong CYP3A4 Inducers

Concomitant use of moderate or strong inducers of CYP3A4 with NUZOLVENCE is contraindicated [see Contraindications (4)]. Zoliflodacin is a CYP3A4 substrate. Moderate and strong CYP3A4 inducers are predicted to result in decreased plasma concentrations of zoliflodacin and may reduce NUZOLVENCE efficacy [see Clinical Pharmacology (12.3)].

Risk Summary

Based on findings from animal studies, NUZOLVENCE 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 (see Data).

There are no human data on NUZOLVENCE 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 NUZOLVENCE [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].

A postmarketing descriptive pregnancy safety study is available for NUZOLVENCE. 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.

Data

Animal Data

In pregnant mice, repeat oral administration of zoliflodacin at 250, 500, and 1000 mg/kg/day during organogenesis (gestation days [GD] 5-16) was associated with fetal exencephaly at and above doses of 500 mg/kg/day (AUC exposures equal to or greater than 1.6-fold the MRHD). Increased implant losses occurred at 500 mg/kg/day, and decreased fetal weights occurred at 1000 mg/kg/day (AUC exposures 2.9-fold the MRHD). No adverse embryo-fetal effects were observed at 250 mg/kg/day (AUC exposure 0.6-fold the MRHD).

In female rats, repeat oral administration of zoliflodacin at 200, 500, or 1000 mg/kg/day from at least 2 weeks prior to mating through organogenesis (GD 16), decreased pregnancy rates and reduced embryo-fetal survival occurred at 1000 mg/kg/day (AUC exposures 8.5-fold the MRHD), without fetal malformations. No effect on embryo-fetal survival occurred at 500 mg/kg/day (AUC exposures 5.5-fold the MRHD). Across all dose levels, decreased fetal weights and delayed skeletal ossification were observed.

In pregnant rats, repeat oral administration of zoliflodacin from GD 6 through lactation Day 20 at doses up to 200 mg/kg/day (maternal AUC exposures 2.4-fold the MRHD at the end of gestation), resulted in no maternal toxicity or adverse effects on prenatal or postnatal offspring survival or growth. In offspring evaluated at 8-9 weeks, increased motor activity occurred in males and females at 200 mg/kg/day and in females at 100 mg/kg/day (maternal AUC exposures 1.4-fold MRHD at the end of gestation). At both dose levels, maternal AUC exposures were below clinical exposures at the end of lactation. Results of learning and memory assessments were indeterminate due to limitations of the study design.

Risk Summary

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 NUZOLVENCE 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 NUZOLVENCE and any potential adverse effects on the breastfed infant from NUZOLVENCE or from the underlying maternal condition.

Based on animal studies, NUZOLVENCE may cause fetal malformations when administered to a pregnant female at clinically relevant doses. Additionally, based on data from an animal study, the risk of early pregnancy loss may be increased in partners of males treated with NUZOLVENCE [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

Pregnancy Testing

Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with NUZOLVENCE [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)].

Contraception

Males

Advise males with female partners of reproductive potential to use effective contraception for at least 3 months after their single-dose treatment of NUZOLVENCE [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)].

Infertility

Males

Based on data from repeat-dose animal toxicity and fertility studies, NUZOLVENCE may cause testicular toxicity and impair male fertility [see Warnings and Precautions (5.3) and Nonclinical Toxicology (13.1)].

The safety and effectiveness of NUZOLVENCE for the treatment of uncomplicated urogenital gonorrhea have been established in pediatric patients 12 years of age and older, weighing at least 35 kg [see Indications and Usage (1.1]. Use of NUZOLVENCE in this pediatric population is supported by clinical, microbiological and safety data from an adequate and well-controlled trial (Trial 1) in adults and pediatric patients with uncomplicated urogenital gonorrhea and additional pharmacokinetic data in adult patients. In Trial 1, 12 patients aged 16 to <18 years, weighing 46 to 76.2 kg, received a single 3 g dose of NUZOLVENCE [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

The safety and effectiveness of NUZOLVENCE in pediatric patients younger than 12 years of age or weighing less than 35 kg have not been established.

Clinical studies of NUZOLVENCE did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients.