ZINPLAVA Concentrate for solution for infusion Ref.[6508] Active ingredients: Bezlotoxumab

ZINPLAVA is not a treatment for CDI and has no effect on the current CDI episode. ZINPLAVA should be administered during the course of antibacterial therapy for CDI. There is no data regarding the efficacy of ZINPLAVA if given after the initial 10- to 14-days of antibacterial therapy for CDI.

ZINPLAVA should not be administered as an intravenous push or bolus.

There is no experience with repeat administration of ZINPLAVA in patients with CDI. In clinical trials, patients with CDI were only administered a single dose of ZINPLAVA (see section 5.1).

No formal interactions studies with other medicinal products were conducted. Therapeutic monoclonal antibodies do not typically have significant drug-drug interaction potential, as they do not directly affect cytochrome P450 enzymes and are not substrates of hepatic or renal transporters.

Bezlotoxumab-mediated drug-drug interactions are unlikely as the target of bezlotoxumab is an exogenous toxin.

Concomitant oral standard of care (SoC) antibacterial therapy for CDI was given together with ZINPLAVA.

Pregnancy

There are limited data from the use of bezlotoxumab in pregnant women. Animal studies do not indicate reproductive toxicity (see section 5.3). ZINPLAVA should not be used during pregnancy unless the clinical condition of the woman requires treatment with bezlotoxumab.

Breast-feeding

It is unknown whether bezlotoxumab is secreted in human milk. Because monoclonal antibodies may be excreted in human milk, a decision should be made whether to discontinue breast-feeding or to not administer ZINPLAVA, taking into account the importance of ZINPLAVA to the mother.

Fertility

No clinical data are available on the possible effects of bezlotoxumab on fertility. Fertility studies have not been conducted in animals. There was no binding of bezlotoxumab to reproductive tissue in tissue cross reactivity studies, and no notable effects in the male and female reproductive organs in repeat dose toxicity studies in mice (see section 5.3).

Bezlotoxumab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The safety profile of ZINPLAVA was assessed in two Phase 3 clinical studies. The most common adverse reactions following treatment with ZINPLAVA (reported in ≥4% of patients within the first 4 weeks of infusion) were nausea, diarrhoea, pyrexia and headache. These adverse reactions were reported at a similar frequency in placebo treated patients compared with ZINPLAVA treated patients.

Tabulated list of adverse reactions

Table 1 presents the adverse reactions reported within 4 weeks of infusion in ZINPLAVA-treated patients and listed by System Organ Class. The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing frequency.

Table 1. Adverse Reactions with ZINPLAVA:

Nervous system disorders

Common: Headache

Gastrointestinal disorders

Common: Nausea, diarrhoea

General disorders and administration site conditions

Common: Pyrexia

Injury, poisoning and procedural complications

Common: Infusion related reactions†

^† See Description of selected adverse reactions below.

Description of selected adverse reactions

Serious adverse reactions

In clinical studies, serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of ZINPLAVA-treated patients and 33% in patients receiving placebo.

Infusion related reactions

Overall, 10% of subjects in the ZINPLAVA group experienced one or more infusion specific adverse reactions on the day of, or the day after, the infusion compared to 8% in the placebo group. Infusion specific adverse reactions reported in ≥0.5% of 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 national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.