NUZOLVENCE- zoliflodacin for suspension
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]
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Overview
NUZOLVENCE- zoliflodacin for suspension is a spiropyrimidinetrione bacterial type II topoisomerase inhibitor that is FDA approved for the treatment of uncomplicated urogenital gonorrhea due to Neisseria gonorrhoeae in adults and pediatric patients 12 years of age and older, weighing at least 35 kg.. Common adverse reactions include neutropenia, headache, leukopenia, dizziness, nausea, and diarrhea..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Uncomplicated Urogenital Gonorrhea
- NUZOLVENCE is indicated for the treatment of uncomplicated urogenital gonorrhea due to Neisseria gonorrhoeae in adults and pediatric patients 12 years of age and older, weighing at least 35 kg
Usage to Reduce Development of Drug-Resistant Bacteria
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of NUZOLVENCE and other antibacterial drugs, NUZOLVENCE should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
Dosing Information
Pregnancy Testing in Females of Reproductive Potential
- Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with NUZOLVENCE
Important Administration Instructions
- NUZOLVENCE must be mixed with water before administering.
- Do not mix NUZOLVENCE with other liquids or sprinkle on food.
- Do not take NUZOLVENCE in the dry form.
- Administer the entire dose within 15 minutes of mixing.
Recommended Dosage in Adults and Pediatric Patients 12 Years of Age and Older Weighing at Least 35 Kg
- The recommended dose of NUZOLVENCE in adults and pediatric patients 12 years of age and older weighing at least 35 kg is 3 grams (g) (one packet) administered as a single dose orally.
Administration of NUZOLVENCE With or Without Food Based on Weight
| Dose | Body Weight | Administration |
|---|---|---|
| 3 g single oral dose | 35 kg to <50 kg | Take on an empty stomach, 1 hour before or 2 hours after food |
| ≥50 kg | Take with food |
Preparation and Administration Instructions for NUZOLVENCE for Oral Suspension
- NUZOLVENCE must be mixed with water before administering.
- Do not mix NUZOLVENCE with other liquids or sprinkle on food.
- Accurately measure 60 mL of water into the provided mixing container.
- Add the entire contents of one unit-dose packet of NUZOLVENCE to the mixing container and immediately secure the provided lid onto the mixing container. Shake vigorously for at least 60 seconds.
- Once NUZOLVENCE is mixed to achieve a uniform suspension, administer the entire contents of the mixing container immediately.
- To ensure the full dose of NUZOLVENCE is consumed, add an additional 60 mL of water to the same mixing container, shake, and administer the entire additional 60 mL of water.
- Administer the entire dose within 15 minutes of mixing. If the dose is not administered within 15 minutes of mixing, a new dose of NUZOLVENCE must be prepared.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of NUZOLVENCE- zoliflodacin for suspension in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of NUZOLVENCE- zoliflodacin for suspension in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Uncomplicated Urogenital Gonorrhea
- NUZOLVENCE is indicated for the treatment of uncomplicated urogenital gonorrhea due to Neisseria gonorrhoeae in adults and pediatric patients 12 years of age and older, weighing at least 35 kg
- 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.
- 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.
- 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.
Dosing Information
Recommended Dosage in Adults and Pediatric Patients 12 Years of Age and Older Weighing at Least 35 Kg
- The recommended dose of NUZOLVENCE in adults and pediatric patients 12 years of age and older weighing at least 35 kg is 3 grams (g) (one packet) administered as a single dose orally.
Administration of NUZOLVENCE With or Without Food Based on Weight
| Dose | Body Weight | Administration |
|---|---|---|
| 3 g single oral dose | 35 kg to <50 kg | Take on an empty stomach, 1 hour before or 2 hours after food |
| ≥50 kg | Take with food |
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of NUZOLVENCE- zoliflodacin for suspension in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of NUZOLVENCE- zoliflodacin for suspension in pediatric patients.
Contraindications
NUZOLVENCE is contraindicated in:
- patients with a known history of hypersensitivity to NUZOLVENCE
- patients who use concomitant moderate or strong CYP3A4 inducers because concomitant use is predicted to result in decreased plasma concentrations of zoliflodacin and may reduce the efficacy of NUZOLVENCE
Warnings
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.
- Advise pregnant females about the potential risk to the fetus with maternal exposure to NUZOLVENCE.
- Avoid use of NUZOLVENCE during pregnancy.
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.
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.
- Advise males that NUZOLVENCE may cause testicular toxicity and impair male fertility.
Hypersensitivity Reactions
- Hypersensitivity reactions, including rash and pruritus, have been reported in patients receiving NUZOLVENCE.
- NUZOLVENCE is contraindicated in patients with a known history of hypersensitivity to NUZOLVENCE.
- If an allergic reaction to NUZOLVENCE occurs, institute appropriate supportive measures.
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.
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.
Adverse Reactions
Clinical Trials Experience
The following clinically significant adverse reactions are discussed in the Warnings and Precautions section of the labeling:
- Hypersensitivity Reactions
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.
- 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).
- 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 Reaction | NUZOLVENCE N = 619 n (%) | Ceftriaxone and Azithromycin N = 308 n (%) |
|---|---|---|
| Headache† | 61 (10) | 15 (5) |
| Dizziness | 21 (3) | 5 (2) |
| Nausea | 16 (3) | 12 (4) |
| Diarrhea | 15 (2) | 22 (7) |
†Headache includes tension headache and headache.
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.
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 the Table below.
| Laboratory Parameters | NUZOLVENCE N = 609 n (%) | Ceftriaxone and Azithromycin N = 304 n (%) |
|---|---|---|
| Neutropenia† | 71 (12) | 43 (14) |
| <1500 to 1000 cells/µL | 56 (9) | 31 (10) |
| <1000 to 500 cells/µL | 14 (2) | 12 (4) |
| <500 cells/µL | 1 (0.2) | 0 |
| Leukopenia‡ | 54 (9) | 33 (11) |
| <3500 to 3000 cells/µL | 34 (6) | 20 (7) |
| <3000 to 1000 cells/µL | 20 (3) | 13 (4) |
| <1000 cells/µL | 0 | 0 |
†Neutropenia is defined as neutrophil count less than 1500 cells/µL.
‡Leukopenia is defined as white blood cell count less than 3500 cells/µL.
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.
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.
Postmarketing Experience
There is limited information regarding NUZOLVENCE- zoliflodacin for suspension Postmarketing Experience in the drug label.
Drug Interactions
Effect of Other Drugs on NUZOLVENCE
Moderate and Strong CYP3A4 Inducers
- Concomitant use of moderate or strong inducers of CYP3A4 with NUZOLVENCE is contraindicated.
- 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.
Use in Specific Populations
Pregnancy
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 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.
Clinical Considerations
- Advise pregnant females about the potential risk to the fetus with maternal exposure to NUZOLVENCE.
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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of NUZOLVENCE- zoliflodacin for suspension in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of NUZOLVENCE- zoliflodacin for suspension during labor and delivery.
Nursing Mothers
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.
Pediatric Use
- 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.
- 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.
- 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.
Geriatic Use
There is no FDA guidance on the use of NUZOLVENCE- zoliflodacin for suspension in geriatric settings.
Gender
There is no FDA guidance on the use of NUZOLVENCE- zoliflodacin for suspension with respect to specific gender populations.
Race
There is no FDA guidance on the use of NUZOLVENCE- zoliflodacin for suspension with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of NUZOLVENCE- zoliflodacin for suspension in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of NUZOLVENCE- zoliflodacin for suspension in patients with hepatic impairment.
Females of Reproductive Potential and Males
- 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.
Pregnancy Testing
- Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with NUZOLVENCE.
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.
Infertility
Males
- Based on data from repeat-dose animal toxicity and fertility studies, NUZOLVENCE may cause testicular toxicity and impair male fertility.
Immunocompromised Patients
There is no FDA guidance one the use of NUZOLVENCE- zoliflodacin for suspension in patients who are immunocompromised.
Administration and Monitoring
Administration
Important Administration Instructions
- NUZOLVENCE must be mixed with water before administering.
- Do not mix NUZOLVENCE with other liquids or sprinkle on food.
- Do not take NUZOLVENCE in the dry form.
- Administer the entire dose within 15 minutes of mixing.
Recommended Dosage in Adults and Pediatric Patients 12 Years of Age and Older Weighing at Least 35 Kg
- The recommended dose of NUZOLVENCE in adults and pediatric patients 12 years of age and older weighing at least 35 kg is 3 grams (g) (one packet) administered as a single dose orally.
Administration of NUZOLVENCE With or Without Food Based on Weight
| Dose | Body Weight | Administration |
|---|---|---|
| 3 g single oral dose | 35 kg to <50 kg | Take on an empty stomach, 1 hour before or 2 hours after food |
| ≥50 kg | Take with food |
Preparation and Administration Instructions for NUZOLVENCE for Oral Suspension
- NUZOLVENCE must be mixed with water before administering.
- Do not mix NUZOLVENCE with other liquids or sprinkle on food.
- Accurately measure 60 mL of water into the provided mixing container.
- Add the entire contents of one unit-dose packet of NUZOLVENCE to the mixing container and immediately secure the provided lid onto the mixing container. Shake vigorously for at least 60 seconds.
- Once NUZOLVENCE is mixed to achieve a uniform suspension, administer the entire contents of the mixing container immediately.
- To ensure the full dose of NUZOLVENCE is consumed, add an additional 60 mL of water to the same mixing container, shake, and administer the entire additional 60 mL of water.
- Administer the entire dose within 15 minutes of mixing. If the dose is not administered within 15 minutes of mixing, a new dose of NUZOLVENCE must be prepared.
Monitoring
Pregnancy Testing in Females of Reproductive Potential
- Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with NUZOLVENCE
Hypersensitivity Reactions
- If an allergic reaction to NUZOLVENCE occurs, institute appropriate supportive measures.
Clostridioides difficile Infection
- CDI must be considered in all patients who present with diarrhea following antibacterial drug use.
IV Compatibility
There is limited information regarding the compatibility of NUZOLVENCE- zoliflodacin for suspension and IV administrations.
Overdosage
There is limited information regarding NUZOLVENCE- zoliflodacin for suspension overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding NUZOLVENCE- zoliflodacin for suspension Pharmacology in the drug label.
Mechanism of Action
NUZOLVENCE is an antibacterial drug.
Microbiology
Mechanism of Action
- Zoliflodacin is a spiropyrimidinetrione inhibitor of the bacterial type II topoisomerases (DNA gyrase and topoisomerase IV), which are required for DNA synthesis.
- Zoliflodacin binds within the cleaved DNA–gyrase complex, blocking re-ligation, and interacts with conserved amino acids in the gyrase B subunit.
Resistance
- Resistance to spiropyrimidinetriones is associated with mutations in the bacterial type II topoisomerases (DNA gyrase and DNA topoisomerase IV) and efflux pumps.
- Zoliflodacin primarily targets DNA gyrase B in N. gonorrhoeae.
- Additionally, zoliflodacin shows reduced in vitro activity due to the up-regulation of efflux pumps such as MtrCDE, MacAB, and NorM.
- Resistance to zoliflodacin due to spontaneous mutations occurs at mutation frequencies of <5.2 × 10-9 to <1.7 × 10-8 at 8 times the MIC.
Cross-resistance
- Cross-resistance has not been identified with other classes of antimicrobials, including penicillins, cephalosporins, aminoglycosides, macrolides, fluoroquinolones and tetracyclines.
Antimicrobial Activity
- Zoliflodacin has been shown to be active against the following microorganisms both in vitro and in clinical infections:
Gram-negative bacteria
- Neisseria gonorrhoeae
Susceptibility Test Methods
- For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC.
Structure
- NUZOLVENCE for oral suspension contains zoliflodacin, an oral spiropyrimidinetrione bacterial type II topoisomerase inhibitor.
- The chemical name of zoliflodacin is (2R,4S,4aS)-11-Fluoro-1,2,4,4a-tetrahydro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-3-oxazolidinyl]spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5(6H),5'(2'H)-pyrimidine]-2',4',6'(1'H,3'H)-trione.
Add structure image
- Its molecular formula is C22H22FN5O7 and molecular mass is 487.4 g/mol.
- Its chemical structure is depicted below.
- Each unit dose packet of NUZOLVENCE for oral suspension contains 3 g of zoliflodacin and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, talc, and xanthan gum.
Dosage Forms and Strengths
- For Oral Suspension: 3 g of zoliflodacin as white to off-white granules in each unit-dose packet of NUZOLVENCE.
Pharmacodynamics
- The ratio of the unbound plasma zoliflodacin area under the concentration-time curve from time of dosing extrapolated to infinity to the zoliflodacin MIC (fAUC0-inf/MIC) is the best predictor of efficacy based on in vitro models of infection.
Cardiac Electrophysiology
- A thorough QTc study of single oral doses of zoliflodacin 2 g and 4 g (not approved doses of NUZOLVENCE) was conducted in 72 healthy subjects aged 18 to 45 years.
- A concentration-dependent increase in QTc interval was observed in the thorough QTc study.
- Based on the observed relationship, clinically significant QTc interval prolongation is not expected at the maximum recommended single dose of NUZOLVENCE.
Pharmacokinetics
- Zoliflodacin, as single doses, generally displayed dose-proportional increases in exposure up to 800 mg (0.27 times the recommended dosage).
- Increases above 800 mg led to slightly less than dose-proportional increases in exposure up to 4 g (1.3 times the recommended dosage).
Pharmacokinetic Properties of Zoliflodacin in Healthy Subjects
| Parameter | Fasted | Fed |
|---|---|---|
| Absorption | ||
| Tmax (h), median (minimum to maximum) | 2.5 (1.0 to 4.0) | 4.0 (3.0 to 5.5) |
| Distribution | ||
| % bound to human plasma proteins | 83% | |
| Blood-to-plasma ratio | 0.69 | |
| Vz/F (L), geometric mean (%GCV) | 177 (26.6) | 98.7 (24.1) |
| Elimination | ||
| Major route of elimination | Fecal | |
| T1/2 (h), geometric mean (%GCV) | 6.4 (20.4) | 5.5 (14.0) |
| CL/F (L/h), geometric mean (%GCV) | 19.1 (28.8) | 12.5 (27.8) |
| Metabolism | ||
| Metabolic pathways | The primary clearance mechanism is metabolism through both CYP-mediated and non-CYP-mediated pathways. CYP-mediated metabolism is predominantly via CYP 3A4/5 enzymes, with lesser contributions from CYP1A2, CYP2C9, CYP2C8, and CYP2C19. | |
| Excretion | ||
| % drug-related material in feces | 79.6% | |
| % of dose excreted unchanged in feces | 1.5% | |
| % drug-related material in urine | 18.2% | |
| % of dose excreted unchanged in urine | 2.5% | |
Zoliflodacin Exposures in Patients with Uncomplicated Urogenital Gonorrhea
| Pharmacokinetic Parameter | Geometric Mean (%GCV) |
|---|---|
| Cmax (mcg/mL) | 28.5 (21.6%) |
| AUC0-inf (h*mcg/mL) | 353 (24.1%) |
Effect of Food
- At the 3 g dose, Cmax was increased by approximately 1.5-fold and AUC was increased by approximately 1.5 to 2-fold when given with a moderate or high fat meal vs fasted conditions.
Specific Populations
- No clinically significant differences in the pharmacokinetics of zoliflodacin were observed based on age (18 to 55 years old), sex, and race (White 61%, Black 28%, Asian 8%).
Body Weight
- There is an inverse relationship between body weight and zoliflodacin exposure.
Pediatric Patients
- There are no pharmacokinetic data in pediatric patients.
- Using modeling and simulation, the recommended dosage with administration based on weight is expected to result in comparable plasma exposures of zoliflodacin in pediatric patients 12 years of age and older and weighing at least 35 kg as observed in healthy adults
Drug Interaction Studies
Clinical Studies and Model Informed Approaches
- In a clinical drug-drug interaction study in 18 healthy subjects, the strong CYP3A4 inhibitor (and P-gp inhibitor) itraconazole, administered as a 400 mg loading dose followed by 200 mg once daily for 6 days, increased zoliflodacin systemic exposure (AUC0-inf) by approximately 1.4-fold with minimal changes in peak concentrations (Cmax) of zoliflodacin, when zoliflodacin was administered under fasted conditions.
- Co-administration of zoliflodacin with CYP3A4 inducers, rifampin and efavirenz, is predicted to reduce the geometric mean zoliflodacin exposure (AUC0-inf) by approximately 56 and 41%, respectively
In Vitro Studies
- Clearance of zoliflodacin via metabolism by CYP- and non-CYP-mediated pathways is the major clearance mechanism for zoliflodacin.
- CYP phenotyping studies indicated that CYP-mediated metabolism of zoliflodacin is via CYP3A4 (68%), with lesser contributions from CYP1A2 (14%), CYP2C9 (10%), CYP2C8 (5%), and CYP2C19 (2.7%).
- Zoliflodacin inhibited CYP2C8, CYP2C9, and CYP2C19 at IC50 values that were approximately 14- to 28-fold higher than the anticipated unbound therapeutic plasma concentrations.
- Zoliflodacin is a substrate for P-gp and BCRP and possible substrate for OATP1B1/3.
- Zoliflodacin is not an inhibitor for OCT2, MATE1, MATE2K at clinically relevant concentrations.
- Zoliflodacin is an inhibitor of P-gp, BCRP, OAT1, OAT3, OATP1B1, and OATP1B3.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
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).
Clinical Studies
- A total of 930 patients with suspected uncomplicated gonorrhea due to Neisseria gonorrhoeae were randomized in an open-label, active-controlled, multicenter, multinational trial (NCT03959527; Trial 1).
- Patients were randomized 2:1 to receive a single, oral, 3 g dose of NUZOLVENCE or a combination of a single intramuscular 500 mg dose of ceftriaxone and a single 1 g oral dose of azithromycin.
- Patients were eligible for enrollment if they were ≥12 years old and ≥35 kg.
- Patients with confirmed or suspected complicated or disseminated gonorrhea were excluded from the study.
- The primary analysis population was the microbiologic intent-to-treat (micro-ITT) urogenital population, which included patients who had N. gonorrhoeae isolated at baseline from the urethra or cervix and who were not infected with a strain that showed resistance to both ceftriaxone and azithromycin at baseline.
- The micro-ITT urogenital population consisted of 744 patients (506 for NUZOLVENCE and 238 for ceftriaxone and azithromycin).
- The demographic and baseline characteristics in the micro-ITT urogenital population were comparable between treatment groups.
- In total, 91% were male; 55% Black, 31% Asian, 13% White, and 4% Hispanic or Latino; the mean age was 30 years (range: 16 to 73) and the mean weight was 70 kg (range: 37 to 139 kg).
- The primary efficacy endpoint was microbiological cure as determined by confirmed bacterial eradication of N. gonorrhoeae at the urogenital body site at the test of cure (TOC) visit (Day 4 to 8) and was assessed in the micro-ITT urogenital population.
- Table 6 shows the primary endpoint of microbiological cure rates at the urogenital site at TOC in the micro-ITT urogenital population.
- Trial 1 demonstrated non-inferiority of NUZOLVENCE to the combination of ceftriaxone and azithromycin.
| NUZOLVENCE n/N (%) | Ceftriaxone and Azithromycin n/N (%) | Difference (95% CI)* | |
|---|---|---|---|
| Microbiological Cure† | 460/506 (90.9) | 229/238 (96.2) | -5.3 (-8.7, -1.4) |
| Failure | 46/506 (9.1) | 9/238 (3.8) | |
| Bacterial Persistence by Culture | 15/506 (3.0) | 0 | |
| Nonassessable‡ | 31/506 (6.1) | 9/238 (3.8) |
TOC = Test of Cure; micro-ITT = microbiological Intent to Treat; CI=confidence interval; n = number of patients in a subcategory; N = number of patients in the specified population.
*Calculated with the Newcombe score method for the NUZOLVENCE – (ceftriaxone and azithromycin) treatment difference
†Microbiological cure is defined as negative or indeterminate Neisseria gonorrhoeae (NG) culture at the urogenital site at the TOC visit. There were no indeterminate NG cultures at the urogenital site at TOC.
‡Nonassessable outcomes were due to missed TOC visits, unobtainable specimens, or TOC visits out of window.
How Supplied
How Supplied
- NUZOLVENCE (zoliflodacin) for oral suspension is supplied as a kit.
NUZOLVENCE Kit Configuration
| Kit Configuration | Strength | NDC Code |
|---|---|---|
| Carton containing: 1 unit-dose packet of white to off-white granules containing zoliflodacin One 120 mL mixing container with lid Instructions for Use Medication Guide | 3 g | 68547-915-10 |
Storage
- NUZOLVENCE should be stored in the original packaging at room temperature 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F). [See USP Controlled Room Temperature].
- Do not freeze.
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Patient Counseling Information
Advise the patient to read the FDA-approved labeling (Medication Guide and Instructions for Use).
Embryo-Fetal Toxicity: Potential Risk for Pregnant Females
- Advise pregnant females about the potential risk to the fetus with maternal exposure to NUZOLVENCE.
- Advise females who take NUZOLVENCE during pregnancy that a pregnancy safety study is available to monitor pregnancy outcomes and encourage them to report their pregnancy to Entasis Therapeutics at 1-800-651-3861.
Embryo-Fetal Toxicity Related to Males with Female Partners of Reproductive Potential
- Advise males who receive NUZOLVENCE and have female partners of reproductive potential to use effective contraception for at least 3 months after receiving NUZOLVENCE.
Testicular Toxicity and Risks to Male Fertility
- Advise males that NUZOLVENCE may cause testicular toxicity and impair male fertility.
Important Preparation Instructions Prior to Administration
- Advise patients that NUZOLVENCE are granules for oral suspension and must be mixed with water before administration.
- Instruct patients not to take the granules in the dry form.
Important Administration Instructions Regarding the Ingestion of Food
- Advise patients weighing 35 kg (77 pounds) to less than 50 kg (110 pounds) to take NUZOLVENCE on an empty stomach, 1 hour before or 2 hours after food.
- Advise patients weighing 50 kg (110 pounds) or more to take NUZOLVENCE with food.
Diarrhea
- Advise the patient, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including NUZOLVENCE.
- Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection.
- If severe watery or bloody diarrhea develops, tell them to contact their healthcare provider.
Antibacterial Resistance
- Patients should be counseled that antibacterial drugs including NUZOLVENCE should only be used to treat bacterial infections.
- They do not treat viral infections (e.g., the common cold).
- When NUZOLVENCE is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.
- Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NUZOLVENCE or other antibacterial drugs in the future.
Precautions with Alcohol
Alcohol-NUZOLVENCE- zoliflodacin for suspension interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Look-Alike Drug Names
There is limited information regarding NUZOLVENCE- zoliflodacin for suspension Look-Alike Drug Names in the drug label.
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References
The contents of this FDA label are provided by the National Library of Medicine.