Adverse reactions reported within 4 weeks of administration of ZINPLAVA or placebo
SoC = Standard of Care antibacterial drugs (metronidazole or vancomycin or fidaxomicin) for CDI
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.
Infusion Related Reactions
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.
As with all therapeutic proteins, there is a potential for immunogenicity following administration of ZINPLAVA. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bezlotoxumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
Following treatment with ZINPLAVA in Trial 1 and Trial 2, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies.
7 DRUG INTERACTIONS
Since ZINPLAVA is eliminated by catabolism, no metabolic drug-drug interactions are expected [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
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.
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
Safety and efficacy of ZINPLAVA in patients below 18 years of age have not been established.
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)].
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.
Bezlotoxumab is a human monoclonal antibody that binds to C. difficile toxin B and neutralizes its effects. Bezlotoxumab is an IgG1 immunoglobulin with an approximate molecular weight of 148.2 kDa.
ZINPLAVA (bezlotoxumab) Injection is a sterile, preservative-free, clear to moderately opalescent, colorless to pale yellow solution that requires dilution for intravenous infusion. The product is provided in a 50 mL vial that contains 1000 mg of bezlotoxumab in 40 mL of solution. Each mL of solution contains bezlotoxumab (25 mg), citric acid monohydrate (0.8 mg), diethylenetriaminepentaacetic acid (0.0078 mg), polysorbate 80 (0.25 mg), sodium chloride (8.77 mg), sodium citrate dihydrate (4.75 mg), and Water for Injection, USP. The vial may contain sodium hydroxide to adjust the pH to 6.0.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ZINPLAVA (bezlotoxumab) is a human monoclonal antibody that binds to C. difficile toxin B and neutralizes its effects [see Microbiology (12.4)].
The pharmacokinetics of bezlotoxumab were studied in 1515 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 bezlotoxumab, geometric mean AUC0-INF and Cmax were 53000 mcg∙h/mL and 185 mcg/mL, respectively, in the 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.
Gender, Race, Ethnicity, and Co-Morbid Conditions
The following factors had no clinically meaningful effect on the exposure of bezlotoxumab: 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 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 patients with normal (eGFR ≥90 mL/min/1.73 m2) renal function. No clinically meaningful differences in the exposure of bezlotoxumab were found between patients with renal impairment and patients with normal renal function.
Patients with Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of bezlotoxumab was evaluated in patients with hepatic impairment (defined as having two or more of the following:  albumin ≤3.1 g/dL;  ALT ≥2× ULN;  total bilirubin ≥1.3× ULN; or  mild, moderate or severe liver disease as reported by the Charlson Co-morbidity Index), as compared to patients with normal hepatic function. No clinically meaningful differences in the exposure of bezlotoxumab were found between patients with hepatic impairment and patients with normal hepatic function.
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.
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.
Fertility studies have not been conducted with bezlotoxumab.
14 CLINICAL STUDIES
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. The median age was 65 years, 85% were white, 57% were female, and 68% were inpatients. 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 ≥21). A hypervirulent strain (ribotypes 027, 078 or 244) was isolated in 22% of patients who had a positive baseline culture, of which 87% (189 of 217 strains) were ribotype 027.
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.
Table 2: Efficacy Results Through 12 Weeks After Infusion (Trial 1 and Trial 2, Full Analysis Set*)
SoC = Standard of Care antibacterial drugs (metronidazole or vancomycin or fidaxomicin) for CDI
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).
In Trial 1, the clinical cure rate of the presenting CDI episode was lower in the ZINPLAVA arm as compared to the placebo arm and in Trial 2, the clinical cure rate was lower in the placebo arm compared to the ZINPLAVA arm. 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.
1.Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45(3):302-7.
16 HOW SUPPLIED/STORAGE AND HANDLING
ZINPLAVA Injection: is a sterile, preservative-free, clear to moderately opalescent, colorless to pale yellow solution and is supplied in the following packaging configuration:
Carton (NDC 0006-3025-00) containing one (1) single-dose vial of ZINPLAVA 1,000 mg/40 mL (25 mg/mL).
Store in a refrigerator, 2ºC to 8ºC (36ºF to 46ºF) in original carton to protect from light. Do Not Freeze. Do Not Shake.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Concurrent Antibacterial Therapy
Inform patients that ZINPLAVA does not take the place of their antibacterial treatment for their CDI infection. They must continue their antibacterial treatment as directed [see Indications and Usage (1) and Dosage and Administration (2.1)].
简介： ZINPLAVA(bezlotoxumab)注射液为治疗：预防艰难梭菌感染复发近日,美国制药巨头默沙东单抗药物Zinplava（bezlotoxumab）获FDA批准联合标准的抗生素护理用于18岁及以上患者，预防艰难梭菌（C.difficile） ...