RECABRIO

It is recommended that Recarbrio should be used to treat infections due to aerobic Gram-negative organisms in patients with limited treatment options only after consultation with a physician with appropriate experience in the management of infectious diseases.

1).

Table 1:

Recommended doses for adult patients with a CrCl ≥ 90 mL/min*† Type of infection Dose of Recarbrio (imipenem/cilastatin/ relebactam) Frequency Infusion time (minutes) Duration of treatment Hospital-acquired pneumonia, including ventilator associated pneumonia†‡ 500 mg/500 mg/250 mg Every 6 hours 30 7 to 14 days Infections due to aerobic Gram-negative organisms in patients with limited treatment options† 500 mg/500 mg/250 mg Every 6 hours 30 Duration in accordance with the site of infection§ *As calculated using the Cockcroft-Gault formula.

4). ‡Includes bacteraemia, in association with, or suspected to be associated with, HAP or VAP. , for cIAI and cUTI the recommended treatment duration is 5 to 10 days; treatment may continue up to 14 days. 5 mg/kg) Every 8 hours 60 *As measured by estimated glomerular filtration rate (eGFR) calculated using the bedside Schwartz formula.

The recommended treatment duration for paediatric patients with HAP/VAP is the same as for adults. For treatment of infections due to aerobic Gram-negative organisms in paediatric patients with limited treatment options, duration of treatment should be based on prescriber discretion.

1. Special populations Renal impairment Adult patients who have a CrCl less than 90 mL/min require dose reduction of imipenem/cilastatin/relebactam as indicated in Table 3. For patients with fluctuating renal function, CrCl should be monitored.

73 m2 require a dose reduction of imipenem/cilastatin/relebactam as indicated in Table 3. Imipenem/cilastatin/relebactam is not recommended in paediatric patients weighing less than 30 kg with renal impairment. 73 m2]†) Recommended dose of Recarbrio (imipenem/cilastatin/relebactam) (mg)‡ Less than 90 to greater than or equal to 60 400/400/200 Less than 60 to greater than or equal to 30 300/300/150 Less than 30 to greater than or equal to 15 200/200/100 End stage renal disease (ESRD) on haemodialysis§ 200/200/100 *CrCl calculated using the Cockcroft-Gault formula for adult patients.

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). 1). Eighty-five participants were enrolled and treated in the imipenem/cilastatin/relebactam arm out of whom there were 10 adolescents, 31 children aged 6 to less than 12 years, 21 from 2 years to less than 6 years, 15 from 3 months to less than 2 years, and 8 from birth (full-term) to less than 3 months.

Based on this data, adverse reactions were generally comparable to those observed in adults. 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.

8). 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. 8). Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with imipenem/cilastatin/relebactam.

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.

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.

5). Clostridioides difficile-Associated Diarrhoea (CDAD) Clostridioides difficile-associated diarrhoea (CDAD) has been reported with imipenem/cilastatin/relebactam. CDAD may range in severity from mild diarrhoea to fatal colitis. 8). Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

1. Hypersensitivity to any other carbapenem antibacterial agent. 4).