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.

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.

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.

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.

Specific Populations

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 m2), moderate (eGFR 30 to <60 mL/min/1.73 m2), or severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment, or with end stage renal disease (eGFR <15 mL/min/1.73 m2), as compared to adult patients with normal (eGFR ≥90 mL/min/1.73 m2) 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) AUC0-INF and Cmax 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.

Mechanism of Action

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

Activity In Vitro

Bezlotoxumab binds to an epitope on toxin B that is conserved across reported strains of C. difficile, although amino acid sequence variation within the epitope does occur. In vitro studies in cell-based assays using Vero cells or Caco-2 cells, suggest that bezlotoxumab neutralizes the toxic effects of toxin B.