Imipenem, Cilastatin and Relebactam

Patients with pre-existing liver disorders should have liver function monitored during treatment with imipenem/cilastatin/relebactam. There is no dose adjustment necessary.

Patients who have a CrCl less than 90 mL/min require dosage reduction of imipenem/cilastatin/relebactam as indicated in the table below. For patients with fluctuating renal function, CrCl should be monitored.

Recommended intravenous doses for patients with a CrCl <90 mL/min:

^* CrCl calculated using the Cockcroft-Gault formula.
^† Administer intravenously over 30 minutes every 6 hours.
^‡ Administration should be timed to follow haemodialysis. Imipenem, cilastatin, and relebactam are cleared from the circulation during haemodialysis.

Patients with CrCl less than 15 mL/min should not receive imipenem/cilastatin/relebactam unless haemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of imipenem/cilastatin/relebactam for patients undergoing peritoneal dialysis.

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

The concomitant use of imipenem/cilastatin/relebactam 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 imipenem/cilastatin/relebactam is necessary, supplemental anti-convulsant therapy should be considered.

Based on pharmacokinetic-pharmacodynamic analyses, the dose of imipenem/cilastatin/relebactam 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.

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. The potential risk for humans is unknown. Animal studies with relebactam do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Imipenem/cilastatin/relebactam should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

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.

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue imipenem/cilastatin/relebactam 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.

Imipenem/cilastatin/relebactam combination 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. 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 imipenem/cilastatin/relebactam 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 (imipenem/cilastatin/relebactam including 266 patients) clinical trials and with imipenem/cilastatin in clinical studies or during post-marketing experience with imipenem/cilastatin (see table).

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).

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