Zinplava Drug Information

Generic name: BEZLOTOXUMAB

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Uses of Zinplava

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. 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.

Dosage & Administration of Zinplava

Important Administration Instructions Administer

ZINPLAVA during antibacterial drug treatment for CDI.

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.

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.

Side Effects of Zinplava

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. 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.

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 s 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. 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. The majority (94%) of patients had one or more risk factors for CDI recurrence.

The adverse reactions observed in pediatric patients were comparable to those observed in adult patients. There were no treatment discontinuations due to adverse reactions. One ZINPLAVA-treated pediatric patient (1%) experienced an infusion-related adverse reaction.

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%

Warnings & Cautions for Zinplava

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). 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.

Drug Interactions with Zinplava

Since ZINPLAVA is eliminated by catabolism, no metabolic drug-drug interactions are expected.

Pregnancy Safety for Zinplava

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.

Pediatric Use of Zinplava

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.

The safety and effectiveness of ZINPLAVA have not been established in pediatric patients younger than 1 year of age.

Overdosage Information for Zinplava

There is no clinical experience with overdosage of ZINPLAVA. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be instituted.

Clinical Studies of Zinplava

Clinical Trials in Adults The safety and efficacy of ZINPLAVA were investigated in two randomized, double-blind, placebo-controlled, multicenter, Phase 3 trials (Trial 1 and Trial 2) in patients receiving Standard of Care antibacterial drugs for treatment of CDI (SoC). Randomization was stratified by SoC (metronidazole, vancomycin, or fidaxomicin) and hospitalization status (inpatient vs. outpatient) at the time of study entry. Enrolled patients were 18 years of age or older and had a confirmed diagnosis of CDI, which was defined as diarrhea (passage of 3 or more loose bowel movements in 24 or fewer hours) and a positive stool test for toxigenic C. difficile from a stool sample collected no more than 7 days before study entry.

Patients were excluded if surgery for CDI was planned, or if they had uncontrolled chronic diarrheal illness. Patients received a 10- to 14-day course of oral SoC and a single infusion of ZINPLAVA or placebo was administered during the course of SoC. Patients on oral vancomycin or oral fidaxomicin could have also received intravenous metronidazole.

Choice of SoC was at the discretion of the health care provider. The day of the infusion of ZINPLAVA or placebo in relation to the start of SoC ranged from the day prior to the start of SoC to 14 days after the start of SoC with the median being day 3 of SoC. In Trial 1, 403 patients were randomized to receive ZINPLAVA and 404 patients were randomized to receive placebo.

In Trial 2, 407 subjects were randomized to receive ZINPLAVA and 399 patients were randomized to receive placebo. The Full Analysis Set (FAS) was a subset of all randomized subjects with exclusions for: (i) not receiving infusion of study medication; (ii) not having a positive local stool test for toxigenic C. difficile; (iii) not receiving protocol defined standard of care therapy within a 1 day window of the infusion. The baseline characteristics of the 1554 patients randomized to ZINPLAVA or placebo in the FAS were similar across treatment arms and in Trial 1 and Trial 2.

A similar proportion of patients received oral metronidazole (48%) or oral vancomycin (48%) and 4% of the patients received oral fidaxomicin as their SoC. The following risk factors associated with a high risk of CDI recurrence or CDI-related adverse outcomes were present in the study population: 51% were ≥65 years of age, 39% received one or more systemic antibacterial drugs (during the 12-week follow-up period), 28% had one or more episodes of CDI within the six months prior to the episode under treatment (15% had two or more episodes prior to the episode under treatment), 21% were immunocompromised and 16% presented at study entry with clinically severe CDI (as defined by a Zar score of ≥2 1 ). Patients were assessed for clinical cure of the presenting CDI episode, defined as no diarrhea for 2 consecutive days following the completion of a ≤14 day SoC regimen.

Patients who achieved clinical cure were then assessed for recurrence of CDI through 12 weeks following administration of the infusion of ZINPLAVA or placebo. CDI recurrence was defined as the development of a new episode of diarrhea associated with a positive stool test for toxigenic C. difficile following clinical cure of the presenting CDI episode. Sustained clinical response was defined as clinical cure of the presenting CDI episode and no CDI recurrence through 12 weeks after infusion.

Table 2 contains the results for Trial 1 and Trial 2. Patients in the ZINPLAVA and placebo arms who did not achieve clinical cure of the presenting CDI episode (no diarrhea for 2 consecutive days following the completion of a ≤14 day SoC regimen) received a mean of 18 to 19 days of SoC and had a mean of 4 additional days of diarrhea following completion of SoC. Additional analyses showed that by 3 weeks post study drug infusion the clinical cure rates of the presenting CDI episode were similar between treatment arms.

Efficacy results in patients at high risk for CDI recurrence (i.e., patients aged 65 years and older, with a history of CDI in the past 6 months, immunocompromised state, severe CDI at presentation, or C. difficile ribotype 027) were consistent with the efficacy results in the overall trial population in Trials 1 and 2.

Table 2: Efficacy Results Through 12 Weeks After Infusion (Trial 1 and Trial 2, Full Analysis Set Full Analysis Set = a subset of all randomized subjects with exclusions for: (i) did not receive infusion of study medication; (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol defined standard of care therapy within a 1 day window of the infusion )
Trial		ZINPLAVA with SoC SoC = Standard of Care antibacterial drugs (metronidazole or vancomycin or fidaxomicin) for CDI	Placebo with SoC	Adjusted Difference (95% CI) Adjusted difference of ZINPLAVA-placebo (95% confidence interval) based on Miettinen and Nurminen method stratified by SoC antibacterial drugs (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient).
		n (%)	n (%)
n (%) = Number (percentage) of subjects in the analysis population meeting the criteria for endpoint
N = Number of subjects included in the analysis population
1		N=386	N=395
	Sustained clinical response	232 (60.1)	218 (55.2)	4.8 (-2.1, 11.7)
	Reasons for failure to achieve sustained clinical response:
	Clinical failure	87 (22.5)	68 (17.2)
	Recurrence	67 (17.4)	109 (27.6)
2		N=395	N=378
	Sustained clinical response	264 (66.8)	197 (52.1)	14.6 (7.7, 21.4)
	Reasons for failure to achieve sustained clinical response:
	Clinical failure	69 (17.5)	84 (22.2)
	Recurrence	62 (15.7)	97 (25.7)

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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