RECARBRIO 500 MG / 500 MG / 250 MG POWDER FOR SOLUTION FOR INFUSION - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Recarbrio 500 mg/500 mg/250 mg powder for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains imipenem monohydrate equivalent to 500 mg imipenem, cilastatin sodium equivalent to 500 mg cilastatin, and relebactam monohydrate equivalent to 250 mg relebactam.

Excipient(s) with known effect

The total amount of sodium in each vial is 37.5 mg (1.6 mmol).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for infusion.

A white to light yellow powder.

4 CLINICAL PARTICULARS

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

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

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 Gramnegative 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

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems, ATC code: J01DH56

Mechanism of action

The bactericidal activity of imipenem results from the inhibition of penicillin binding proteins (PBPs) leading to inhibition of peptidoglycan cell wall synthesis.

Cilastatin limits the renal metabolism of imipenem and does not have antibacterial activity.

Relebactam is a non-beta lactam inhibitor of Ambler class A and class C betalactamases, including class A Klebsiella pneumoniae carbapenemase (KPC) and extended-spectrum beta-lactamases (ESBLs), and class C (AmpC-type) beta-lactamases including Pseudomonas-Derived Cephalosporinase (PDC). Relebactam does not inhibit class B enzymes (metallo-beta-lactamases) or class D carbapenemases. Relebactam has no antibacterial activity.

Resistance

Mechanisms of resistance in Gram-negative bacteria that are known to affect imipenem/relebactam include the production of metallo-beta-lactamases or oxacillinases with carbapenemase activity.

Expression of certain alleles of the class A beta-lactamase Guiana extended-spectrum beta-lactamase (GES) and overexpression of PDC coupled with loss of imipenem entry porin OprD may confer resistance to imipenem/relebactam in P. aeruginosa. The expression of efflux pumps in P. aeruginosa does not affect activity of either imipenem or relebactam. Mechanisms of bacterial resistance that could decrease the antibacterial activity of imipenem/relebactam in Enterobacterales include porin mutations affecting outer membrane permeability.

Antibacterial activity in combination with other antibacterial a­gents

In vitro studies have demonstrated no antagonism between imipenem/relebactam and amikacin, azithromycin, aztreonam, colistin, gentamicin, levofloxacin, linezolid, tigecycline, tobramycin, or vancomycin.

Susceptibility testing breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Pharmacokinetic/phar­macodynamic relationship

Time that unbound plasma concentrations of imipenem exceed the imipenem/relebactam minimum inhibitory concentration (% fT > MIC) has been shown to best correlate with efficacy. The ratio of the 24 – hour unbound plasma relebactam AUC to imipenem/relebactam MIC (fAUC / MIC) has been determined to be the index that best predicts activity of relebactam.

Clinical efficacy against specific pathogens

Efficacy has been demonstrated in clinical studies against the pathogens listed under each indication that were susceptible to imipenem and relebactam in vitro:

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Pseudomonas aeruginosa

Serratia marcescens

In vitro studies suggest that the following pathogens would be susceptible to imipenem and relebactam in the absence of acquired mechanisms of resistance:

Gram-negative aerobic micro-organisms

Acinetobacter calcoaceticus-baumannii complex

Citrobacter spp. (including C. freundii and C. koseri)

Enterobacter spp. (including E. asburiae and E. cloacae)

Escherichia coli

Klebsiella spp. (including K. aerogenes, K. oxytoca and K. pneumoniae)

Pseudomonas aeruginosa

Serratia marcescens

Gram-negative anaerobic micro-organisms

Bacteroides spp. (including B. fragilis)

Fusobacterium spp. (including F. nucleatum and F. necrophorum)

Prevotella spp. (including P. melaninogenica, P. bivia, and P. buccae)

Gram-positive aerobic micro-organisms

Enterococcus faecalis

Staphylococcus aureus (methicillin susceptible isolates only)

Viridans group streptococci (including S. anginosus and S. constellatus)

In vitro studies indicate that the following species are not susceptible to imipenem and relebactam:

Gram-negative aerobic micro-organisms

Legionella spp.

Stenotrophomonas maltophilia

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Recarbrio in one or more subsets of the paediatric population in the treatment of Gram-negative bacterial infections (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

General introduction

The steady-state pharmacokinetic parameters of imipenem, cilastatin, and relebactam in healthy adults with normal renal function (CrCl 90 mL/min or greater), after multiple 30-minute intravenous infusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam administered every 6 hours are summarised in Table 4. The steady-state pharmacokinetic parameters of imipenem and relebactam in patients with cIAI or cUTI and HAP or VAP with normal renal function (90 mL/min < CrCl < 150 mL/min) after multiple 30-minute intravenous infusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam administered every 6 hours are summarised in Tables 5 and 6, respectively. Pharmacokinetic parameters were similar for single- and multiple-dose administration due to minimal accumulation.

The C max and AUC of imipenem, cilastatin, and relebactam increase in proportion to dose. The elimination half-lives (t %) of imipenem, cilastatin, and relebactam are independent of dose.

Table 4: Steady-state geometric mean (% geometric co-efficient of variation) plasma pharmacokinetic parameters of imipenem, cilastatin, and relebactam after multiple intravenous 30-minute infusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam every 6 hours in healthy adults

Table 5: Population pharmacokinetic model based steady-state geometric mean (% geometric co-efficient of variation) plasma pharmacokinetic parameters of imipenem and relebactam after multiple intravenous 30-minute infusions of Recarbrio (500 mg imipenem/500 mg cilastatin/250 mg relebactam) every 6 hours in cIAI or cUTI patients with CrCl 90 mL/min or greater

Table 6: Population pharmacokinetic model based steady-state geometric mean (% geometric co-efficient of variation) plasma pharmacokinetic parameters of imipenem and relebactam after multiple intravenous 30-minute infusions of Recarbrio (500 mg imipenem/500 mg cilastatin + 250 mg relebactam) every 6 hours in HAP or VAP patients with CrCl 90 mL/min or greater

Distribution

The binding of imipenem and cilastatin to human plasma proteins is approximately 20 % and 40 %, respectively. The binding of relebactam to human plasma proteins is approximately 22 % and is independent of concentration.

The steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and 19.0 L, respectively, in subjects following multiple doses infused over 30 minutes every 6 hours.

The penetration into pulmonary epithelial lining fluid (ELF) expressed as the total ELF-to-unbound plasma exposure ratio was 55 % and 54 % for imipenem and relebactam, respectively.

Biotransformation

Imipenem, when administered alone, is metabolised in the kidneys by dehydropeptidase-I, resulting in low levels of imipenem (average of 15–20 % of the dose) recovered in human urine. Cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism so that when imipenem and cilastatin are given concomitantly, adequate levels of imipenem (approximately 70 % of the dose) are achieved in the urine to enable antibacterial activity.

Cilastatin is mainly eliminated in the urine as unchanged parent drug (approximately 70 –80 % of the dose), with 10 % of the dose recovered as an N-acetyl metabolite, which has inhibitory activity against dehydropeptidase-I comparable to the parent medicinal product.

Relebactam is cleared primarily via renal excretion as unchanged parent drug (greater than 90 % of the dose) and is minimally metabolised. Unchanged relebactam was the only drug-related component detected in human plasma.

Elimination

Imipenem, cilastatin, and relebactam are mainly excreted by the kidneys.

Following multiple-dose administration of 500 mg imipenem, 500 mg cilastatin, and 250 mg relebactam to healthy male subjects, approximately 63 % of the administered imipenem dose, and 77 % of the administered cilastatin dose are recovered as unchanged parent in the urine. The renal excretion of imipenem and cilastatin involves both glomerular filtration and active tubular secretion. Greater than 90 % of the administered relebactam dose was excreted unchanged in human urine. The mean renal clearance for relebactam is 135 mL/min, close to the plasma clearance (148 mL/min), indicating nearly complete elimination of relebactam by the renal route. The unbound renal clearance of relebactam is greater than the glomerular filtration rate, suggesting that in addition to glomerular filtration, active tubular secretion is involved in the renal elimination, accounting for ~ 30 % of the total clearance.

Linearity/non-linearity

The pharmacokinetics of relebactam are linear across the 25 mg to 1150 mg dose range studied for a single intravenous administration, and 50 mg to 625 mg dose range studied for multiple intravenous administration every 6 hours up to 7 days. Minimal accumulation of imipenem, cilastatin or relebactam was observed following multiple 30-minute intravenous infusions of relebactam (50 to 625 mg) co-administered with 500 mg imipenem/500 mg cilastatin every 6 hours up to 7 days in healthy adult males with normal renal function.

Drug metabolising enzymes

Studies evaluating the potential for imipenem or cilastatin to interact with CYP450 enzymes have not been conducted.

Relebactam at clinically relevant concentrations does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro in human liver microsomes. Relebactam showed no potential for in vitro induction of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes. Thus, relebactam is unlikely to cause clinical drug-drug interactions via CYP-mediated pathways.

Imipenem, cilastatin, and relebactam are all cleared primarily via renal excretion unchanged, with metabolism as a minor elimination route. Thus, Recarbrio is unlikely to be subject to drug-drug interactions when coadministered with CYP inhibitors or inducers.

Membrane transporters

Relebactam does not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: OATP1B1, OATP1B3, OAT1, OAT3, OCT2, P-gp, BCRP, MATE1, MATE2K, or BSEP.

Relebactam is actively secreted into the urine. It is not a substrate of OAT1, OCT2, P-gp, BCRP, MRP2, or MRP4 transporters, but is a substrate of OAT3, OAT4, MATE1 and MATE2K transporters. The active tubular secretion accounts for only approximately 30 % of the total clearance of relebactam, thus, the extent of drug-drug interaction due to inhibition of the tubular transporters is expected to be of minimal clinical significance, which was confirmed with a clinical drug-drug interaction study with probenecid and Recarbrio (see section 4.5).

Special populations

Renal impairment

In a clinical pharmacokinetic study and population pharmacokinetic analysis, clinically relevant differences in exposure (AUC) were observed for imipenem, cilastatin, and relebactam based on the extent of renal impairment.

In the clinical study, imipenem geometric mean AUCs were up to 1.4 – fold, 1.5 – fold, and 2.5 – fold higher in patients with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects with normal renal function. The respective cilastatin geometric mean AUCs were up to 1.6 – fold, 1.9 – fold, and 5.6 – fold higher. Relebactam geometric mean AUCs were up to 1.6 – fold, 2.2 – fold, and 4.9 – fold higher in patients with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects with normal renal function. In patients with End Stage Renal Disease (ESRD) on haemodialysis, imipenem, cilastatin, and relebactam are efficiently removed by haemodialysis.

To maintain systemic exposures similar to patients with normal renal function, dose adjustment is recommended for patients with renal impairment. ESRD patients on haemodialysis should receive Recarbrio after haemodialysis session (see section 4.2).

Hepatic impairment

Imipenem, cilastatin, and relebactam are primarily cleared renally; therefore, hepatic impairment is not likely to have any effect on Recarbrio exposures (see section 4.2).

Elderly/gender

In a geriatric/gender study and population pharmacokinetic analysis no clinically relevant differences in exposure (AUC) were observed for imipenem, cilastatin, and relebactam based on age or gender, apart from the effect of renal function (see section 4.2).

Race

Only a limited number of non-white patients were included in the clinical studies, but no major effect of race on imipenem, cilastatin, and relebactam pharmacokinetics is expected.

5.3 Preclinical safety data

Imipenem/cilastatin

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity studies.

Animal studies showed that the toxicity produced by imipenem, as a single entity, was limited to the kidney. Co-administration of cilastatin with imipenem in a 1:1 ratio prevented the nephrotoxic effects of imipenem in rabbits and monkeys. Available evidence suggests that cilastatin prevents the nephrotoxicity by preventing entry of imipenem into the tubular cells.

A teratology study in pregnant cynomolgus monkeys given imipenem/cilastatin sodium at doses of 40/40 mg/kg/day (bolus intravenous injection) resulted in maternal toxicity including emesis, inappetence, body weight loss, diarrhoea, abortion, and death in some cases. When doses of imipenem/cilastatin sodium (approximately 100/100 mg/kg/day or approximately 3 times the recommended daily human intravenous dose) were administered to pregnant cynomolgus monkeys at an intravenous infusion rate which mimics human clinical use, there was minimal maternal intolerance (occasional emesis), no maternal deaths, no evidence of teratogenicity, but an increase in embryonic loss relative to control groups (see section 4.6).

Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenem/cilas­tatin.

Relebactam

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproduction toxicity, or genotoxicity. Carcinogenicity studies have not been conducted with relebactam.

Relebactam administered intravenously to lactating rats at a dose of 450 mg/kg/day (GD 6 to LD 14), was excreted into the milk with concentration of approximately 5 % that of maternal plasma concentrations.

Animal studies show that relebactam given as a single entity caused renal tubular degeneration in monkeys at AUC exposure 7-fold the human AUC exposure at the maximum recommended human dose (MRHD). Renal tubular degeneration was shown to be reversible after dose discontinuation. There was no evidence of nephrotoxicity at AUC exposures less than or equal to 3-fold the human AUC exposure at the MRHD.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydrogen carbonate

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products

except those mentioned in section 6.6.

6.3 Shelf life

Dry powder

30 months.

After constitution and dilution

Diluted solutions should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous infusion should not exceed two hours.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Keep vials in the outer carton in order to protect from light.

For storage conditions after constitution and dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

20 mL glass vial, with 20 mm rubber stopper and aluminium crimp cap seal.

This medicinal product is supplied in packs of 25 vials.

6.6 Special precautions for disposal

Recarbrio is supplied as a dry powder in a single-dose vial that must be constituted and further diluted using aseptic technique prior to intravenous infusion as outlined below:

To prepare the infusion solution, contents of the vial must be transferred to 100 mL of an appropriate infusion solution (see sections 6.2 and 6.3): 9 mg/mL (0.9 %) sodium chloride. In exceptional circumstances where 9 mg/mL (0.9 %) sodium chloride cannot be used for clinical reasons 5 % glucose may be used instead.

Withdraw 20 mL (10 mL times 2) of diluent from the appropriate infusion bag and constitute the vial with 10 mL of the diluent. The constituted suspension must not be administered by direct intravenous infusion.

After constitution, shake vial well and transfer resulting suspension into the remaining 80 mL of the infusion bag.

Add the additional 10 mL of infusion diluent to the vial and shake well to ensure complete transfer of vial contents; repeat transfer of the resulting suspension to the infusion solution before administering. Agitate the resulting mixture until clear.

Constituted solutions of Recarbrio range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

For patients with renal insufficiency, a reduced dose of Recarbrio will be administered according to the patient’s CrCl, as determined from Table 7. Prepare 100 mL of infusion solution as directed above. Select the volume (mL) of the final infusion solution needed for the appropriate dose of Recarbrio as shown in Table 7.

Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if discoloration or visible particles are observed.

Table 7: Preparation of Recarbrio doses

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Compatible medicinal products

The physical compatibility of Recarbrio with selected injectable medicinal products was evaluated in two commonly available diluents at a Y-infusion site. Compatible medicinal products with the corresponding compatible diluent (i.e. 5 % Dextrose Injection or 0.9 % Sodium chloride Injection) are listed below. Recarbrio should not be co-administered through the same intravenous line (or cannula), with other medicinal products not listed below, as no compatibility data are available. Refer to the respective prescribing information of the co-administered medicinal product(s) to confirm compatibility of simultaneous co-administration. This medicinal product must not be mixed with other medicinal products except those mentioned below.

List of Compatible Injectable Medicinal Products for use with 5 % Dextrose or 0.9 % Sodium chloride Injection as Diluents

dexmedetomidine

dopamine

epinephrine

fentanyl

heparin

midazolam

norepinephrine

phenylephrine

Compatible intravenous bags and infusion set materials

Recarbrio is compatible with the following intravenous container bags and infusion set materials. Any intravenous bags or infusion set materials not listed below should not be used.

Intravenous Container Bag Materials

Polyvinyl chloride (PVC) and polyolefin (polypropylene and polyethylene)

Intravenous Infusion Set Materials (with tubing)

PVC + Di-(2-ethylhexyl)phtha­late (DEHP) and polyethylene (PE)-lined PVC

Incompatible medicinal products

Recarbrio for solution for infusion is physically incompatible with propofol in 5 % Dextrose (also named Glucose) or 0.9 % Sodium chloride.

Merck Sharp & Dohme (UK) Limited 120 Moorgate

London

EC2M 6UR

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 53095/0053

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021