Recarbrio · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-098767 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most frequently occurring adverse reaction (≥ 2 %) in adult patients receiving imipenem/cilastatin plus relebactam in pooled Phase 2 studies 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 study 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 studies and with imipenem/cilastatin in clinical studies or during post-marketing experience with imipenem/cilastatin (see Table 4). 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 4: Tabulated list of adverse reactions System Organ Common Uncommon Rare Very rare Unknown Class Pseudomembranous Infections and colitis* Gastro- infestations enteritis* Candidiasis* Pancytopenia* Neutropenia* Haemolytic Blood and anaemia* lymphatic system Eosinophilia* Leukopenia* Agranulocytosis* disorders Bone marrow Thrombocytopenia* depression* Thrombocytosis* Immune system Anaphylactic disorders reactions*

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HOS-098763 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Hypersensitivity to any other carbapenem antibacterial agent. Severe hypersensitivity (e.g., anaphylactic reaction, severe skin reaction) to any other type of beta- lactam antibacterial agent (e.g., penicillins, cephalosporins or monobactams) (see section 4.4).

HOS-098762 · has-indication-information · PDF-Seite 2

Recarbrio is indicated in adult and paediatric patients from birth for: • Treatment of hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP) (see sections 4.4 and 5.1). • Treatment of bacteraemia that occurs in association with, or is suspected to be associated with HAP or VAP. • Treatment of infections due to aerobic Gram-negative organisms with limited treatment options (see sections 4.2, 4.4, and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-098765 · has-interaction-information · PDF-Seite 7

Ganciclovir 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. Valproic acid Case reports in the literature have shown that co-administration of carbapenems, including imipenem/cilastatin, 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 imipenem/cilastatin/relebactam 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 imipenem/cilastatin/relebactam 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, this medicine may be administered concomitantly with OAT inhibitors.

HOS-098766 · has-pregnancy-information · PDF-Seite 7

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). 7 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).

HOS-098764 · has-warning-information · PDF-Seite 4

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). 4 These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before initiating therapy with imipenem/cilastatin/relebactam, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams, and other allergens. If an allergic reaction to imipenem/cilastatin/relebactam occurs, treatment must be discontinued immediately. Serious anaphylactic reactions require immediate emergency treatment. Hepatic function Hepatic function should be closely monitored during treatment with imipenem/cilastatin/relebactam 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 imipenem/cilastatin/relebactam. 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, especially when recommended doses 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. Special awareness should be made to neurological symptoms or convulsions in children with known risk factors for seizures, or on concomitant treatment with medicinal products lowering the seizures threshold. Increased seizure potential due to interaction with valproic acid 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 this medicine 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 imipenem/cilastatin/relebactam. CDAD may

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