f subjects receiving ZINPLAVA and at a frequency greater than placebo were nausea (3 %), fatigue (1 %), pyrexia (1 %), dizziness (1 %), headache (2 %), dyspnoea (1 %) and hypertension (1 %). Of the patients who experienced an infusion specific adverse reaction, the majority reported a reaction with a maximum intensity of mild (78 %) or moderate (20 %), and the majority of reactions resolved within 24 hours following onset.
Immune-related adverse reactions
In a Phase 1 clinical trial, healthy subjects received two consecutive doses of 10 mg/kg of bezlotoxumab separated by 12 weeks. The adverse reactions after the second dose were not markedly different from those observed after the first dose, and are consistent with adverse reactions observed in the two Phase 3 trials (MODIFY I and MODIFY II; see section 5.1) in which all patients received a single dose.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
There is no clinical experience with overdosage of ZINPLAVA. In clinical trials, healthy subjects received up to 20 mg/kg, which was generally well tolerated. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be instituted.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiinfectives for systemic use, specific immunoglobulins. ATC code: J06BB21
Mechanism of action
Bezlotoxumab is a human monoclonal antitoxin antibody that binds with high affinity to C. difficile toxin B and neutralizes its activity. Bezlotoxumab prevents CDI recurrence by providing passive immunity against toxin produced by the outgrowth of persistent or newly-acquired C. difficile spores.
Pharmacodynamic effects
Microbiology
Activity in vitro and in vivo
The toxin B epitope to which bezlotoxumab binds is conserved, though not identical, across all known toxin sequences.
Clinical trials
The efficacy of ZINPLAVA (bezlotoxumab) was investigated in two randomised, double-blind, placebo-controlled, multicentre, Phase 3 studies (MODIFY I and MODIFY II) where 810 patients were randomised to bezlotoxumab and 803 to placebo. The number of patients completing the studies and included in the full analysis set (FAS) was 781 in the ZINPLAVA group versus 773 in the placebo group. All patients received concomitant standard of care antibacterial therapy for CDI. Randomisation was stratified by the antibacterial agent and hospitalisation status (inpatient vs. outpatient) at the time of study entry. Adult patients had a confirmed diagnosis of CDI, which was defined as diarrhoea (passage of 3 or more loose bowel movements as defined in the Bristol stool chart as types 5 through 7 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 received a 10- to 14-day course of oral antibacterial therapy for CDI (metronidazole, vancomycin or fidaxomicin, chosen by the investigator). Patients on oral vancomycin or oral fidaxomicin could have also receiv |
