Bezlotoxumab

ZINPLAVA™ is indicated to reduce recurrence of Clostridioides difficile infection (CDI) in adults and pediatric patients 1 year of age and older who are receiving antibacterial drug treatment for CDI and are at a high risk for CDI recurrence. ZINPLAVA is a human monoclonal antibody that binds to Clostridioides difficile toxin B, indicated to reduce recurrence of Clostridioides difficile infection (CDI) in adults and pediatric patients 1 year of age and older who are receiving antibacterial drug treatment for CDI and are at a high risk for CDI recurrence. ( 1 ) Limitation of Use: ZINPLAVA is not indicated for the treatment of CDI. ZINPLAVA is not an antibacterial drug. ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI. ( 1 ) Limitation of Use: ZINPLAVA is not indicated for the treatment of CDI. ZINPLAVA is not an antibacterial drug. ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI. [See Dosage and Administration (2.1) .]

Injection: 1,000 mg/40 mL (25 mg/mL) clear to moderately opalescent, colorless to pale yellow solution in a single-dose vial. Injection : 1,000 mg/40 mL (25 mg/mL) solution in a single-dose vial. ( 3 )

None. None ( 4 )

Heart Failure : Was reported more commonly in ZINPLAVA-treated patients with a history of congestive heart failure (CHF) in Trial 1 and Trial 2. In patients with a history of CHF, ZINPLAVA should be reserved for use when the benefit outweighs the risk. ( 5.1 )

5.1 Heart Failure Heart failure was reported more commonly in Trial 1 and Trial 2 in ZINPLAVA-treated patients compared to placebo-treated patients. These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of ZINPLAVA-treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period [see Adverse Reactions (6.1) ] . Additionally, in patients with a history of CHF, there were more deaths in ZINPLAVA-treated patients, 19.5% (23/118) than in placebo-treated patients, 12.5% (13/104) during the 12-week study period. The causes of death varied and included cardiac failure, infections, and respiratory failure. In patients with a history of CHF, ZINPLAVA should be reserved for use when the benefit outweighs the risk.

Adult Patients : The most common adverse reactions (reported in ≥4% of adult patients) included nausea, pyrexia, and headache. ( 6.1 ) Pediatric Patients : The most common adverse reactions (reported in >10% of pediatric patients) were pyrexia and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults The safety of ZINPLAVA was evaluated in two placebo-controlled Phase 3 trials (Trial 1 n=390 and Trial 2 n=396). Patients received a single 10 mg/kg intravenous infusion of ZINPLAVA and concomitant standard of care (SoC) antibacterial drugs (metronidazole, vancomycin or fidaxomicin) for CDI. Adverse reactions reported within the first 4 weeks after ZINPLAVA was administered are described for the pooled Phase 3 trial population of 786 patients. The median age of patients receiving ZINPLAVA was 65 years (range 18 to 100), 50% were age 65 years or older, 56% were female, and 83% were white. Serious Adverse Reactions in Adults Serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of ZINPLAVA-treated patients and 33% of placebo-treated patients. Heart failure was reported as a serious adverse reaction in 2.3% of the ZINPLAVA-treated patients and 1.0% of the placebo-treated patients [see Warnings and Precautions (5.1) ] . One patient discontinued the ZINPLAVA infusion due to ventricular tachyarrhythmia that occurred 30 minutes after the start of the infusion. Mortality rates were 7.1% and 7.6% in ZINPLAVA-treated patients and placebo-treated patients, respectively, during the 12-week follow-up period. Most Common Adverse Reactions in Adults The most common adverse reactions following treatment with ZINPLAVA (reported in ≥4% of patients within the first 4 weeks of infusion and with a frequency greater than placebo) were nausea, pyrexia, and headache (see Table 1 ). Table 1: Adverse Reactions Reported in ≥4% of ZINPLAVA-Treated Patients with CDI and at a Frequency Greater than Placebo in Trial 1 and Trial 2 All patients as treated population, defined as all randomized patients who received a dose of study medication, by treatment received , Adverse reactions reported within 4 weeks of administration of ZINPLAVA or placebo Adverse Reaction ZINPLAVA with SoC SoC = Standard of Care antibacterial drugs (metronidazole or vancomycin or fidaxomicin) for CDI N=786 % Placebo with SoC N=781 % Gastrointestinal disorders Nausea 7% 5% General disorders and administration site conditions Pyrexia 5% 3% Nervous system disorders Headache 4% 3% Infusion Related Adverse Reactions in Adults Overall, 10% of ZINPLAVA-treated patients experienced one or more infusion specific adverse reactions on the day of, or the day after, the infusion compared to 8% of placebo-treated patients. Infusion specific adverse reactions reported in ≥0.5% of patients receiving ZINPLAVA and at a frequency greater than placebo were nausea (3%), fatigue (1%), pyrexia (1%), dizziness (1%), headache (2%), dyspnea (1%) and hypertension (1%). Of these patients, 78% and 20% of patients experienced mild and moderate adverse reactions, respectively. These reactions resolved within 24 hours following onset. Clinical Trial Experience in Pediatric Patients The safety and pharmacokinetics of ZINPLAVA in pediatric patients 1 year of age and older were evaluated in a randomized, double-blind, placebo-controlled, multi-center trial (Trial 3). Enrolled patients had a diagnosis of CDI and received SoC (vancomycin, metronidazole, or fidaxomicin) for the baseline CDI episode. In this trial, 143 patients were randomized and treated, of whom 107 received a single infusion of ZINPLAVA (10 mg/kg) and 36 received a placebo infusion. Of these randomized patients, 58% were 1 to <12 years of age, 52% were male, 80% were white, and 7% were multi-racial. The majority (94%) of patients had one or more risk factors for CDI recurrence. [See Clinical Pharmacology (12.3) .] The adverse reactions observed in pediatric patients were comparable to those observed in adult patients. Five of 107 pediatric patients (5%) receiving ZINPLAVA and one of 36 pediatric patients receiving placebo (3%) died in Trial 3. There were no treatment discontinuations due to adverse reactions. The most common adverse reactions occurring in greater than 10% of pediatric patients treated with ZINPLAVA were pyrexia (19 patients, 18%) and headache (15 patients, 14%). One ZINPLAVA-treated pediatric patient (1%) experienced an infusion-related adverse reaction.

Since ZINPLAVA is eliminated by catabolism, no metabolic drug-drug interactions are expected [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Adequate and well controlled studies with ZINPLAVA have not been conducted in pregnant women. No animal reproductive and developmental studies have been conducted with bezlotoxumab. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

8.2 Lactation Risk Summary There is no information regarding the presence of bezlotoxumab in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZINPLAVA and any potential adverse effects on the breastfed child from ZINPLAVA or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of ZINPLAVA to reduce recurrence of CDI have been established in pediatric patients 1 year of age and older. Use of ZINPLAVA in pediatric patients 1 year of age and older is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic and safety data in pediatric patients aged 1 year and older. The adverse reactions and the pharmacokinetics observed in pediatric patients were comparable to that observed in adult patients [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . The safety and effectiveness of ZINPLAVA have not been established in pediatric patients younger than 1 year of age.

8.5 Geriatric Use Of the 786 patients treated with ZINPLAVA, 50% were 65 years of age and over, and 27% were 75 years of age and over. No overall differences in safety and efficacy were observed between these subjects and younger subjects [see Clinical Studies (14) ] . No dose adjustment is necessary for patients ≥65 years of age [see Clinical Pharmacology (12.3) ] .

ZINPLAVA (bezlotoxumab) is a human monoclonal antibody that binds to C. difficile toxin B and neutralizes its effects [see Microbiology (12.4) ] .

Mechanism of Action Bezlotoxumab is a human monoclonal antibody that binds C. difficile toxin B with an equilibrium dissociation constant (K d ) of <1×10 -9 M. Bezlotoxumab inhibits the binding of toxin B and prevents its effects on mammalian cells. Bezlotoxumab does not bind to C. difficile toxin A.