Bezlotoxumab

1 INDICATIONS AND USAGE 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) .]

2 DOSAGE AND ADMINISTRATION Administer ZINPLAVA during antibacterial drug treatment for CDI. ( 2.1 ) The recommended dose is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes. ( 2.2 ) Dilute prior to intravenous infusion. Administer via a low-protein binding 0.2 micron to 5 micron in-line or add-on filter. See Full Prescribing Information for dilution and administration instructions. ( 2.3 ) 2.1 Important Administration Instructions Administer ZINPLAVA during antibacterial drug treatment for CDI. 2.2 Dosing Recommendations in Adults and Pediatric Patients 1 year of age and older The recommended dose of ZINPLAVA is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes. The safety and efficacy of repeat administration of ZINPLAVA in patients with CDI have not been studied. 2.3 Preparation and Administration Preparation of Diluted Solution ZINPLAVA must be diluted prior to intravenous infusion. Prepare the diluted solution immediately after removal of the vial(s) from refrigerated storage, or the vial(s) may be stored at room temperature protected from light for up to 24 hours prior to preparation of the diluted solution. Inspect vial contents for discoloration and particulate matter prior to dilution. ZINPLAVA is a clear to moderately opalescent, colorless to pale yellow solution. Do not use the vial if the solution is discolored or contains visible particles. Do not shake the vial. Withdraw the required volume from the vial(s) based on the patient's weight (in kg) and transfer into an intravenous bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 10 mg/mL. Mix diluted solution by gentle inversion. Do not shake. Discard vial(s) and all unused contents. Storage of Diluted Solution The product does not contain preservative. The diluted solution of ZINPLAVA may be stored either at room temperature for up to 16 hours or under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 24 hours. If refrigerated, allow the intravenous bag to come to room temperature prior to use. These time limits include storage of the infusion solution in the intravenous bag through the duration of infusion. Do not freeze the diluted solution. Administration Administer the diluted solution as an intravenous infusion over 60 minutes using a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. The diluted solution can be infused via a central line or peripheral catheter. Do not administer ZINPLAVA as an intravenous push or bolus. Do not co-administer other drugs simultaneously through the same infusion line.

6 ADVERSE REACTIONS 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.

12.3 Pharmacokinetics The pharmacokinetics of bezlotoxumab were studied in 1515 adult CDI patients in two Phase 3 trials (Trial 1 and Trial 2). Based on a population PK analysis, the geometric mean (%CV) clearance of bezlotoxumab was 0.317 L/day (41%), with a mean volume of distribution of 7.33 L (16%), and elimination half-life (t½) of approximately 19 days (28%). After a single intravenous dose of 10 mg/kg ZINPLAVA, geometric mean AUC 0-INF and C max were 53000 mcg∙h/mL and 185 mcg/mL, respectively, in the adult patients with CDI. The clearance of bezlotoxumab increased with increasing body weight; the resulting exposure differences are adequately addressed by the administration of a weight-based dose. Bezlotoxumab is eliminated by catabolism. Specific Populations Gender, Race, Ethnicity, and Co-Morbid Conditions The following factors had no clinically meaningful effect on the exposure of bezlotoxumab in adults: gender, race, ethnicity, and presence of co-morbid conditions. Patients with Renal Impairment The effect of renal impairment on the pharmacokinetics of bezlotoxumab was evaluated in adult patients with mild (eGFR 60 to <90 mL/min/1.73 m 2 ), moderate (eGFR 30 to <60 mL/min/1.73 m 2 ), or severe (eGFR 15 to <30 mL/min/1.73 m 2 ) renal impairment, or with end stage renal disease (eGFR <15 mL/min/1.73 m 2 ), as compared to adult patients with normal (eGFR ≥90 mL/min/1.73 m 2 ) renal function. No clinically meaningful differences in the exposure of bezlotoxumab were found between adult patients with renal impairment and adult patients with normal renal function. Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of bezlotoxumab was evaluated in adult patients with hepatic impairment (defined as having two or more of the following: [1] albumin ≤3.1 g/dL; [2] ALT ≥2× ULN; [3] total bilirubin ≥1.3× ULN; or [4] mild, moderate or severe liver disease as reported by the Charlson Co-morbidity Index), as compared to adult patients with normal hepatic function. No clinically meaningful differences in the exposure of bezlotoxumab were found between adult patients with hepatic impairment and adult patients with normal hepatic function. Geriatric Patients The effect of age on the pharmacokinetics of bezlotoxumab was evaluated in patients ranging from 18 to 100 years of age. No clinically meaningful differences in the exposure of bezlotoxumab were found between patients 65 years and older and patients under 65 years of age. Pediatric Patients The pharmacokinetics of bezlotoxumab were studied in 90 pediatric patients (1 year to less than 18 years) and after a single intravenous dose of 10 mg/kg ZINPLAVA, geometric mean (%CV) AUC 0-INF and C max were 47,900 (35.9) mcg·h/mL and 139 (32.4) mcg/mL, respectively. There is no clinically meaningful relationship between bezlotoxumab exposure and body weight following weight-based dosing of ZINPLAVA in pediatric patients. Drug Interaction Studies Because bezlotoxumab is eliminated by catabolism, no metabolic drug-drug interactions are expected.