4.1. Therapeutic indications

Recarbrio is indicated for:

• Treatment of hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP), in adults (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, in adults.

• Treatment of infections due to aerobic Gram-negative organisms in adults 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.

4.2. Posology and method of administration

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

Posology

Table 1 shows the recommended intravenous dose for patients with a creatinine clearance (CrCl) ≥ 90 mL/min (see sections 4.4 and 5.1).

Table 1: Recommended intravenous dose for patients with a creatinine clearance (CrCl) ≥ 90 mL/min1,2

Type of infection

Dose of Recarbrio

(imipenem/cilastatin/ relebactam)

Frequency

Infusion time

Duration of treatment

Hospital-acquired pneumonia, including ventilator associated pneumonia2,3

500 mg/500 mg/250 mg

Every 6 hours

30 mins

7 to 14 days

Infections due to aerobic Gram-negative organisms in patients with limited treatment options2

500 mg/500 mg/250 mg

Every 6 hours

30 mins

Duration in accordance with the site of infection4

1As calculated using the Cockcroft-Gault formula.

2For HAP or VAP patients with CrCl ˃ 250 mL/min, and for patients with complicated intra-abdominal infections (cIAI) or complicated urinary tract infections (cUTI), including pyelonephritis with CrCl ˃ 150 mL/min, the recommended dose of Recarbrio may not be sufficient (see section 4.4).

3Includes bacteraemia, in association with, or suspected to be associated with, HAP or VAP.

4e.g., for cIAI and cUTI the recommended treatment duration is 5 to 10 days; treatment may continue up to 14 days.

Special populations

Renal impairment

Patients who have a CrCl less than 90 mL/min require dosage reduction of Recarbrio as indicated in Table 2. For patients with fluctuating renal function, CrCl should be monitored.

Table 2: Recommended intravenous doses for patients with a CrCl < 90 mL/min

Estimated Creatinine Clearance (mL/min)*

Recommended dosage 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.

†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.

Recarbrio is provided as a single vial in a fixed-dose combination; the dose for each component will be adjusted equally during preparation (see section 6.6).

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

Hepatic impairment

No dose adjustment is required in patients with impaired hepatic function (see section 5.2).

Elderly population

No dose adjustment is required for elderly patients (see section 5.2).

Paediatric population

The safety and efficacy of imipenem/cilastatin/relebactam in children and adolescents below 18 years of age have not yet been established. No data are available.

Method of administration

Intravenous use.

Recarbrio is administered by intravenous infusion over 30 minutes.

Recarbrio must be reconstituted (see sections 6.2, 6.3, and 6.6) prior to intravenous infusion.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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, pharmacokinetic-pharmacodynamic 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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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

System Organ Class

Common

Uncommon

Rare

Very rare

Unknown

Infections and infestations

Pseudomembranous colitis*

Candidiasis*

Gastro-enteritis*

Blood and lymphatic system disorders

Eosinophilia*

Pancytopenia*

Neutropenia*

Leukopenia*

Thrombocytopenia*

Thrombocytosis*

Agranulocytosis*

Haemolytic anaemia*

Bone marrow depression*

Immune system disorders

Anaphylactic reactions*

Nervous system disorders

Seizures*

Hallucinations*

Confusional states*

Myoclonic activity*

Dizziness*

Somnolence*

Encephalopathy*

Paraesthesia*

Focal tremor*

Taste perversion*

Aggravation of myasthenia gravis*

Headache*

Agitation*

Dyskinesia*

Ear and labyrinth disorders

Hearing loss*

Vertigo*

Tinnitus*

Cardiac disorders

Cyanosis*

Tachycardia*

Palpitations*

Vascular disorders

Thrombophlebitis*

Hypotension*

Flushing*

Respiratory, thoracic and mediastinal disorders

Dyspnoea*

Hyperventilation*

Pharyngeal pain*

Gastrointestinal disorders

Diarrhoea†*

Nausea†*

Vomiting†*

Staining of teeth and/or tongue*

Haemorrhagic colitis*

Abdominal pain*

Heartburn*

Glossitis*

Tongue papilla hypertrophy*

Increased salivation*

Hepatobiliary disorders

Alanine aminotransferase increased†*

Aspartate aminotransferase increased†*

Hepatic failure*

Hepatitis*

Fulminant hepatitis*

Jaundice*

Skin and subcutaneous tissue disorders

Rash (e.g., exanthematous)*

Urticaria*

Pruritus*

Toxic epidermal necrolysis*

Angioedema*

Stevens-Johnson syndrome*

Erythema multiforme*

Exfoliative dermatitis*

Hyperhidrosis*

Skin texture changes*

Musculoskeletal and connective tissue disorders

Polyarthralgia*

Thoracic spine pain*

Renal and urinary disorders

Elevations in serum creatinine*

Acute renal failure*

Oliguria/anuria*

Polyuria*

Urine discoloration (harmless and should not be confused with haematuria)*

Reproductive system and breast disorders

Pruritus vulvae*

General disorders and administration site conditions

Fever*

Local pain and induration at the injection site*

Chest discomfort*

Asthenia/weakness*

Investigations

Increases in serum alkaline phosphatase*

Coombs test positive*

Prolonged prothrombin time*

Decreased haemoglobin*

Increases in serum bilirubin*

Elevations in blood urea nitrogen*

Blood lactate dehydrogenase increased*

*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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the event of overdose, discontinue Recarbrio, treat based on symptoms, and institute general supportive treatment. Imipenem, cilastatin, and relebactam can be removed by haemodialysis. No clinical information is available on the use of haemodialysis to treat overdosage.