RECARBRIO Powder for solution for infusion Ref.[10656] Active ingredients: Cilastatin Imipemide Imipenem, Cilastatin and Relebactam

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams (see sections 4.3 and 4.8).

These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before initiating therapy with Recarbrio, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams, and other allergens.

If an allergic reaction to Recarbrio occurs, treatment with Recarbrio must be discontinued immediately. Serious anaphylactic reactions require immediate emergency treatment.

Hepatic function

Hepatic function should be closely monitored during treatment with Recarbrio due to the risk of hepatic toxicity (such as increase in transaminases, hepatic failure, and fulminant hepatitis) (see section 4.8).

Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with Recarbrio. There is no dose adjustment necessary (see section 4.2).

Central nervous system (CNS)

CNS adverse reactions, such as seizures, confusional states, and myoclonic activity have been reported during treatment with imipenem/cilastatin, components of Recarbrio, especially when recommended dosages of imipenem were exceeded. These reactions have been reported most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function.

Increased seizure potential due to interaction with valproic acid

The concomitant use of Recarbrio and valproic acid/divalproex sodium is not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium. If administration of Recarbrio is necessary, supplemental anti-convulsant therapy should be considered (see section 4.5).

Clostridioides difficile-Associated Diarrhoea (CDAD)

Clostridioides difficile-associated diarrhoea (CDAD) has been reported with Recarbrio. CDAD may range in severity from mild diarrhoea to fatal colitis. CDAD must be considered in all patients who present with diarrhoea during or following the administration of Recarbrio (see section 4.8). Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, discontinuation of therapy with Recarbrio, and the administration of specific treatment for C. difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Patients with CrCl ≥150 mL/min

Based on pharmacokinetic-pharmacodynamic analyses, the dose of Recarbrio that is recommended for patients with CrCl of ≥90 mL/min may not be sufficient to treat patients with HAP or VAP and CrCl >250 mL/min, or patients with cIAI or cUTI and CrCl >150 mL/min. Consideration should be given to using alternative therapies for these patients.

Renal impairment

Dose adjustment is recommended in patients with renal impairment (see section 4.2). There is inadequate information to recommend usage of Recarbrio for patients undergoing peritoneal dialysis.

Limitations of the clinical data

Patients who were immunocompromised, including those with neutropenia, were excluded from clinical trials.

Hospital-acquired pneumonia, including ventilator-associated pneumonia

In a single study of hospital-acquired pneumonia, including ventilator-associated pneumonia, 6.2% (33/535) of patients had bacteraemia at baseline.

Patients with limited treatment options

The use of Recarbrio to treat patients with infections due to aerobic Gram-negative organisms who have limited treatment options is based on experience with imipenem/cilastatin, pharmacokineticpharmacodynamic analysis for imipenem/cilastatin/relebactam, and on limited data from a randomised clinical study in which 21 evaluable patients were treated with Recarbrio and 10 evaluable patients were treated with colistin and imipenem/cilastatin for infections caused by imipenem-non-susceptible organisms.

Limitations of the spectrum of antibacterial activity

Imipenem does not have activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) or against Enterococcus faecium. Alternative or additional antibacterial agents should be used when these pathogens are known or suspected to be contributing to the infectious process.

The inhibitory spectrum of relebactam includes class A beta-lactamases (such as ESBLs and KPC) and Class C beta-lactamases including PDC. Relebactam does not inhibit class D carbapenemases such as OXA-48 or class B metallo-beta-lactamases such as NDM and VIM (see section 5.1).

Non-susceptible organisms

The use of imipenem/cilastatin/relebactam may result in the overgrowth of non-susceptible organisms, which may require interruption of treatment or other appropriate measures.

Antiglobulin test (Coombs test) seroconversion

A positive direct or indirect Coombs test may develop during treatment with imipenem/cilastatin/relebactam (see section 4.8).

Controlled sodium diet

Each vial contains a total of 37.5 mg of sodium (1.6 mmol), equivalent to 1.9% of the WHO (World Health Organization) recommended maximum daily intake of 2 g sodium for an adult. This should be considered when administering Recarbrio to patients who are on a controlled sodium diet.

Ganciclovir

Generalised seizures have been reported in patients who received ganciclovir concomitantly with imipenem/cilastatin, components of Recarbrio. Ganciclovir should not be used concomitantly with Recarbrio unless the potential benefits outweigh the risks.

Valproic acid

Case reports in the literature have shown that co-administration of carbapenems, including imipenem/cilastatin (components of Recarbrio), to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. The concomitant use of Recarbrio and valproic acid/divalproex sodium is not recommended (see section 4.4).

Oral anti-coagulants

Simultaneous administration of antibacterial agents with warfarin may augment its anticoagulant effects. It is recommended that the INR should be monitored as appropriate during and shortly after co-administration of antibiotics with oral anti-coagulant medicinal products.

Clinical drug interaction studies

A clinical drug-drug interaction study demonstrated that imipenem and relebactam exposures do not increase by a clinically significant extent when Recarbrio is co-administered with the prototypical OAT-inhibitor probenecid, indicating a lack of clinically meaningful OAT-mediated drug-drug interactions. Concomitant administration of imipenem/cilastatin and probenecid increased the plasma level and half-life of cilastatin, though not to a clinically meaningful extent. Therefore, Recarbrio may be administered concomitantly with OAT inhibitors.

Pregnancy

There are no adequate and well-controlled studies for the use of imipenem, cilastatin, or relebactam in pregnant women.

Animal studies with imipenem/cilastatin have shown reproductive toxicity in monkeys (see section 5.3). The potential risk for humans is unknown. Animal studies with relebactam do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Recarbrio should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breastfeeding

Imipenem and cilastatin are excreted into the mother’s milk in small quantities.

It is unknown whether relebactam is excreted in human milk. Available data in animals have shown excretion of relebactam in the milk of rats (for details see section 5.3).

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Recarbrio therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no human data available regarding potential effects of imipenem/cilastatin or relebactam treatment on male or female fertility. Animal studies do not indicate harmful effects of imipenem/cilastatin or relebactam on fertility (see section 5.3).

Recarbrio has moderate influence on the ability to drive and use machines. CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, components of Recarbrio, especially when recommended dosages of imipenem were exceeded (see section 4.4). Therefore, caution should be exercised when driving or using machines.

Summary of the safety profile

The most frequently occurring adverse reaction (≥2%) in patients receiving imipenem/cilastatin plus relebactam in pooled Phase 2 trials of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI), including pyelonephritis (N=431) was diarrhoea. The most frequently occurring adverse reactions (≥2%) in patients receiving Recarbrio in a Phase 3 trial of HAP or VAP (N=266) were diarrhoea, alanine aminotransferase increased, and aspartate aminotransferase increased.

Tabulated summary of adverse reactions

The following adverse reactions have been reported during Phase 2 (imipenem/cilastatin plus relebactam including 431 patients) and Phase 3 (Recarbrio including 266 patients) clinical trials and with imipenem/cilastatin in clinical studies or during post-marketing experience with imipenem/cilastatin (see Table 3).

Adverse reactions are classified according to MedDRA System Organ Class and frequency. Frequency categories are derived according to the following conventions: 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), and not known (cannot be estimated from the available data).

Table 3. Frequency of adverse reactions by system organ class:

^* reported with imipenem/cilastatin in clinical studies or during post-marketing experience with imipenem/cilastatin
^† reported with imipenem/cilastatin plus relebactam in Phase 2 (N=431) and in Phase 3 (N=266) studies

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.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.