Bezlotoxumab is a human monoclonal antibody that binds to Clostridioides difficile toxin B. It is used to reduce recurrence of C. difficile infection (CDI) in adults and pediatric patients 1 year and older who are receiving antibacterial treatment of CDI and are at a high risk for CDI recurrence. Bezlotoxumab is not an antibacterial drug; it is only for use in conjunction with appropriate antibacterial agents.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Administer by intravenous infusion.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Dilution
-Do not shake the vial(s).
-Withdraw the required volume from the vial(s) based on the patient's weight and transfer into an intravenous bag containing either 0.9% Sodium Chloride Injection or 5% Dextrose Injection to prepare a diluted solution with a final concentration from 1 to 10 mg/mL.
-Mix the diluted solution by gentle inversion. Do not shake.
-Storage: The diluted solution may be stored at room temperature for 16 hours or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours. If refrigerated, allow the infusion solution to come to room temperature prior to use. Storage time limits include infusion duration. Do not freeze.
Intravenous (IV) Infusion
-Infuse the diluted solution IV over 60 minutes using a sterile, non-pyrogenic, low-protein binding 0.2 to 5 micron in-line or add-on filter.
-Administer via a central line or a peripheral catheter.
-Do not administer as IV push or bolus.
-Do not co-administer other drugs simultaneously through the same infusion line.
The adverse reactions observed in pediatric patients were comparable to those observed in adult patients. Five of 107 pediatric patients receiving bezlotoxumab (5%) and 1 of 36 pediatric patients receiving placebo (3%) died in the clinical trial (n = 143).
Heart failure was reported in 2.3% of bezlotoxumab-treated patients and occurred more often in patients with underlying congestive heart failure (CHF) in adult clinical trials. In patients with a history of CHF, reserve bezlotoxumab for use when the benefits outweigh the risks. In patients with a history of CHF, 12.7% of bezlotoxumab-treated patients and 4.8% of placebo-treated patients experienced heart failure during the 12-week study period. Additionally, in patients with a history of CHF, deaths occurred more frequently in bezlotoxumab-treated patients (19.5%) than in placebo-treated patients (12.5%). Causes of death included infections, cardiac failure, and respiratory failure. One patient discontinued bezlotoxumab due to ventricular tachycardia (tachyarrhythmia) that occurred 30 minutes after the start of the infusion.
Nausea was reported in 7% of bezlotoxumab-treated patients within 4 weeks of administration during adult clinical trials. In 3% of bezlotoxumab-treated patients, nausea occurred on the day of, or the day after, the infusion. In these patients, reactions usually resolved within 24 hours after onset.
Fever (pyrexia) was reported in 5% of bezlotoxumab-treated patients within 4 weeks of administration during adult clinical trials. In 1% of bezlotoxumab-treated patients, pyrexia occurred on the day of or the day after the infusion. In these patients, reactions usually resolved within 24 hours after onset. Fever was reported in 18% of pediatric patients treated with bezlotoxumab (n = 107) during a randomized, double-blind, placebo-controlled, multi-center trial.
Headache was reported in 4% of bezlotoxumab-treated patients within 4 weeks of administration during adult clinical trials. In 2% of bezlotoxumab-treated patients, headache occurred on the day of, or the day after, the infusion. In these patients, reactions usually resolved within 24 hours after onset. Headache was reported in 14% of pediatric patients treated with bezlotoxumab (n = 107) during a randomized, double-blind, placebo-controlled, multi-center trial.
Infusion-related reactions were reported in 10% of bezlotoxumab-treated patients during adult clinical trials. These events occurred on the day of, or the day after, the infusion and were mainly mild-to-moderate in severity. In addition to nausea, headache, and pyrexia, infusion-specific events included fatigue (1%), dizziness (1%), dyspnea (1%), and hypertension (1%). These reactions usually resolved within 24 hours after onset. One bezlotoxumab-treated pediatric patient (1%) experienced an infusion-related adverse reaction in a randomized, double-blind, placebo-controlled, multi-center trial.
As with all therapeutic proteins, there is a potential for immunogenicity after administration of bezlotoxumab. In adult clinical trials, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies (ADA); however, in the pediatric trial, 2 of the 100 evaluable patients developed ADA through 12 weeks post-treatment. The incidence of antibody formation is highly dependent on assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease; therefore the comparison of incidence of antibodies to bezlotoxumab with the incidence to other products may be misleading.
In patients with a history of congestive heart failure (CHF), reserve bezlotoxumab for use when the benefits outweigh the risks. Heart failure was reported more commonly with bezlotoxumab compared to placebo in adult clinical trials and occurred primarily in patients with underlying CHF. In patients with a history of CHF, 12.7%) of bezlotoxumab-treated patients and 4.8% of placebo-treated patients experienced heart failure during the 12-week study period. Additionally, in patients with a history of CHF, deaths occurred more frequently in the bezlotoxumab-treated patients (19.5%) than in the placebo-treated patients (12.5%). Causes of death included infections, cardiac failure, and respiratory failure.
There are no adequate and well controlled studies with bezlotoxumab in human pregnancy. No animal reproductive and developmental studies have been conducted.
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. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for bezlotoxumab and any potential adverse effects on the breast-fed child from bezlotoxumab or the underlying maternal condition.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Clostridioides difficile
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of pseudomembranous colitis as adjunct therapy to reduce recurrence of C. difficile infection (CDI) in persons who are receiving CDI-directed antibacterial therapy and are at a high risk for CDI recurrence:
Intravenous dosage:
Adults: 10 mg/kg IV as a single dose as adjunct therapy. Bezlotoxumab is not an antibacterial drug; therefore, use only in combination with antibacterial CDI treatment.
Children and Adolescents: 10 mg/kg IV as a single dose as adjunct therapy. Bezlotoxumab is not an antibacterial drug; therefore, use only in combination with antibacterial CDI treatment.
Maximum Dosage Limits:
-Adults
10 mg/kg IV once.
-Geriatric
10 mg/kg IV once.
-Adolescents
10 mg/kg IV once.
-Children
10 mg/kg IV once.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Bezlotoxumab products.
Bezlotoxumab is a human monoclonal antibody that binds to C. difficile toxin B, thereby inhibiting the binding of toxin B and neutralizing its effects. It does not bind C. difficile toxin A. Bezlotoxumab is not an antibiotic and is used in conjunction with appropriate antibacterial agents. There are several factors associated with the virulence of C. difficile, which include toxin production. Toxin B is one of the protein toxins secreted by C. difficile. A rise in C. difficile-associated disease (CDAD) has been associated with the emergence of more virulent strains categorized as North American pulsotype 1/PCR-ribotype 027 (NAP1/027). This increased virulence is due in part to a higher production of toxin A and toxin B as well a more cytopathic form of toxin B. Toxins damage the colonic epithelium by causing cell death and disrupting cell-cell junctions, which may lead to increased epithelial permeability and lumenal fluid accumulation. These toxins also induce the secretion of cytokines, which may be involved in the recruitment and activation of neutrophils that are present in high amounts at sites of C. difficile-associated inflammation. Anti-toxin antibodies are naturally produced; however, mechanisms that control this production are not understood. Lower endogenous anti-toxin antibodies may be a risk factor for recurrent disease.
Bezlotoxumab is administered intravenously. Based on a population pharmacokinetic analysis, the geometric mean (%CV) clearance is 0.317 L/day (41%), with a mean volume of distribution of 7.33 L (16%). The clearance of bezlotoxumab is increased with increasing body weight. Bezlotoxumab is eliminated by catabolism, and the elimination half-life is approximately 19 days.
Affected cytochrome P450 isoenzymes: none
No drug-drug interactions are expected due to the catabolic clearance of bezlotoxumab.
-Route-Specific Pharmacokinetics
Intravenous Route
After a single intravenous dose of bezlotoxumab 10 mg/kg, the geometric mean AUC was 53,000 mcg x hour/mL and the Cmax was 185 mcg/mL.
-Special Populations
Hepatic Impairment
No clinically meaningful differences in the exposure of bezlotoxumab were found between patients with hepatic impairment (defined as having 2 or more of the following: albumin 3.1 g/dL or less; ALT at least 2 times the upper limit of normal (ULN); total bilirubin at least 1.3 times the ULN; or mild, moderate, or severe liver disease as reported by the Charlson Co-morbidity Index) and patients with normal hepatic function.
Renal Impairment
No clinically meaningful differences in the exposure of bezlotoxumab were found between patients with renal impairment and patients with normal renal function. The effect of renal impairment on bezlotoxumab pharmacokinetics was studied in patients with mild impairment (eGFR 60 to less than 90 mL/minute/1.73 m2), moderate impairment (eGFR 30 to less than 60 mL/minute/1.73 m2), severe impairment (eGFR 15 to less than 30 mL/minute/1.73 m2), and in patients with end stage renal disease (eGFR less than 15 mL/minute/1.73 m2).
Pediatrics
After a single intravenous dose of bezlotoxumab 10 mg/kg in pediatric patients 1 to 17 years of age (n = 90), the geometric mean AUC and Cmax were 47,900 mcg x hour/mL and 139 mcg/mL, respectively. There is no clinically meaningful relationship between bezlotoxumab exposure and body weight following weight-based dosing in pediatric patients.
Geriatric
No clinically meaningful differences in the exposure of bezlotoxumab were found between patients 65 years and older and those under 65 years of age. The effect of age on bezlotoxumab pharmacokinetics was studied in patients 18 to 100 years.
Gender Differences
Gender had no clinically meaningful effect on the exposure of bezlotoxumab.
Ethnic Differences
Race had no clinically meaningful effect on the exposure of bezlotoxumab.
Other
Co-morbid Conditions
Co-morbid conditions had no clinically meaningful effect on the exposure of bezlotoxumab.