RECARBRIO 500mg / 500mg / 250mg powder infusion solution medication leaflet

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

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

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.

Powder for solution for infusion.

A white to light yellow powder.

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 limitedtreatment options (see sections 4.2, pct. 4.4, and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

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

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

Dose of Recarbrio

Infusion Duration of

Type of infection (imipenem/cilastatin/ Frequencyrelebactam) time treatment

Hospital-acquiredpneumonia, including Every500 mg/500 mg/250 mg 30 mins 7 to 14 daysventilator associated 6 hourspneumonia2,3

Infections due to aerobic Duration in

Gram-negative organisms in Every accordance with500 mg/500 mg/250 mg 30 minspatients with limited 6 hours the site oftreatment options2 infection41As calculated using the Cockcroft-Gault formula.2For HAP or VAP patients with CrCl ˃ 250 mL/min, and for patients with complicated intra-abdominalinfections (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 to14 days.

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 Recommended dosage of Recarbrio(mL/min)* (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) on200/200/100haemodialysis‡

*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 arecleared from the circulation during haemodialysis.

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

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

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

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

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

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.

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).

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patientsreceiving 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 multipleallergens. Before initiating therapy with Recarbrio, careful inquiry should be made concerningprevious hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams,and other allergens.

If an allergic reaction to Recarbrio occurs, treatment with Recarbrio must be discontinuedimmediately. Serious anaphylactic reactions require immediate emergency treatment.

Hepatic function

Hepatic function should be closely monitored during treatment with Recarbrio due to the risk ofhepatic toxicity (such as increase in transaminases, hepatic failure, and fulminant hepatitis) (seesection 4.8).

Use in patients with liver disease: patients with pre-existing liver disorders should have liver functionmonitored 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 reportedduring treatment with imipenem/cilastatin, components of Recarbrio, especially when recommendeddosages of imipenem were exceeded. These reactions have been reported most commonly in patientswith 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 whoseseizures are well-controlled on valproic acid or divalproex sodium. If administration of Recarbrio isnecessary, 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 mayrange in severity from mild diarrhoea to fatal colitis. CDAD must be considered in all patients whopresent with diarrhoea during or following the administration of Recarbrio (see section 4.8). Carefulmedical history is necessary since CDAD has been reported to occur over two months after theadministration of antibacterial agents.

If CDAD is suspected or confirmed, discontinuation of therapy with Recarbrio, and the administrationof specific treatment for C. difficile should be considered. Medicinal products that inhibit peristalsisshould not be given.

Patients with CrCl ≥ 150 mL/min

Based on pharmacokinetic-pharmacodynamic analyses, the dose of Recarbrio that is recommended forpatients 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 givento using alternative therapies for these patients.

Dose adjustment is recommended in patients with renal impairment (see section 4.2). There isinadequate 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 fromclinical 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 whohave limited treatment options is based on experience with imipenem/cilastatin, pharmacokinetic-pharmacodynamic analysis for imipenem/cilastatin/relebactam, and on limited data from a randomisedclinical study in which 21 evaluable patients were treated with Recarbrio and 10 evaluable patientswere treated with colistin and imipenem/cilastatin for infections caused by imipenem-non-susceptibleorganisms.

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 additionalantibacterial agents should be used when these pathogens are known or suspected to be contributing tothe 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 withimipenem/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 beconsidered when administering Recarbrio to patients who are on a controlled sodium diet.

Generalised seizures have been reported in patients who received ganciclovir concomitantly withimipenem/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, includingimipenem/cilastatin (components of Recarbrio), to patients receiving valproic acid or divalproexsodium results in a reduction in valproic acid concentrations. The valproic acid concentrations maydrop below the therapeutic range as a result of this interaction, therefore increasing the risk ofbreakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro andanimal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronidemetabolite (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 (seesection 4.4).

Oral anti-coagulants

Simultaneous administration of antibacterial agents with warfarin may augment its anticoagulanteffects. It is recommended that the INR should be monitored as appropriate during and shortly afterco-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 notincrease 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-druginteractions. Concomitant administration of imipenem/cilastatin and probenecid increased the plasmalevel and half-life of cilastatin, though not to a clinically meaningful extent. Therefore, Recarbrio maybe administered concomitantly with OAT inhibitors.

There are no adequate and well-controlled studies for the use of imipenem, cilastatin, or relebactam inpregnant women.

Animal studies with imipenem/cilastatin have shown reproductive toxicity in monkeys (seesection 5.3). The potential risk for humans is unknown. Animal studies with relebactam do notindicate 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 tothe 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 shownexcretion 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 todiscontinue breastfeeding or to discontinue Recarbrio therapy taking into account the benefit ofbreastfeeding for the child and the benefit of therapy for the woman.

There are no human data available regarding potential effects of imipenem/cilastatin or relebactamtreatment on male or female fertility. Animal studies do not indicate harmful effects ofimipenem/cilastatin or relebactam on fertility (see section 5.3).

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 withimipenem/cilastatin, components of Recarbrio, especially when recommended dosages of imipenemwere exceeded (see section 4.4). Therefore, caution should be exercised when driving or usingmachines.

The most frequently occurring adverse reaction (≥ 2 %) in patients receiving imipenem/cilastatin plusrelebactam in pooled Phase 2 trials of complicated intra-abdominal infections (cIAI) and complicatedurinary tract infections (cUTI), including pyelonephritis (N = 431) was diarrhoea. The most frequentlyoccurring 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 aminotransferaseincreased.

The following adverse reactions have been reported during Phase 2 (imipenem/cilastatin plusrelebactam including 431 patients) and Phase 3 (Recarbrio including 266 patients) clinical trials andwith imipenem/cilastatin in clinical studies or during post-marketing experience withimipenem/cilastatin (see Table 3).

Adverse reactions are classified according to MedDRA System Organ Class and frequency. Frequencycategories 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

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 Anaphylacticdisorders reactions*

Seizures*

Hallucinations* Encephalopathy*

Aggravation

Confusional states* Paraesthesia* of myasthenia Agitation*

Nervous systemgravis*disorders

Myoclonic activity* Focal tremor* Dyskinesia*

Headache*

Dizziness* Taste perversion*

Somnolence*

Vertigo*

Ear and labyrinth

Hearing loss*disorders

Tinnitus*

Cyanosis*

Cardiac disorders Tachycardia*

Palpitations*

Vascular

Thrombophlebitis* Hypotension* Flushing*disorders

Dyspnoea*

Respiratory,

Hyper-thoracic andventilation*mediastinaldisorders

Pharyngealpain*

Haemorrhagiccolitis*

Abdominalpain*

Diarrhoea†*

Heartburn*

Gastrointestinal † Staining of teeth

Nausea *disorders and/or tongue* Glossitis*

Vomiting†*

Tonguepapillahypertrophy*

Increasedsalivation*

Alanineaminotransferaseincreased†* Hepatic failure*

Hepatobiliary Fulminant

Jaundice*disorders hepatitis*

Aspartate Hepatitis*aminotransferaseincreased†*

Toxic epidermalnecrolysis*

Angioedema*

Hyperhidrosis

Skin and Urticaria* Stevens-Johnson *

Rash (e.g.,subcutaneous syndrome*exanthematous)*tissue disorders Pruritus* Skin texture

Erythema changes*multiforme*

Exfoliativedermatitis*

Polyarthralgia

Musculoskeletal *and connectivetissue disorders Thoracicspine pain*

Acute renal failure*

Oliguria/anuria*

Polyuria*

Renal and Elevations in serumurinary disorders creatinine*

Urine discoloration(harmless andshould not beconfused withhaematuria)*

Reproductive

Pruritussystem andvulvae*breast disorders

Fever* Chest

Generaldiscomfort*disorders and

Local pain andadministrationinduration at the Asthenia/site conditionsinjection site* weakness*

Coombs test positive*

Prolongedprothrombin time*

Blood

Increases in serum Decreased lactate

Investigations alkaline haemoglobin* dehydrogenaphosphatase* se

Increases in serum increased*bilirubin*

Elevations in bloodurea nitrogen*

*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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of overdose, discontinue Recarbrio, treat based on symptoms, and institute generalsupportive treatment. Imipenem, cilastatin, and relebactam can be removed by haemodialysis. Noclinical information is available on the use of haemodialysis to treat overdosage.

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

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 beta-lactamases, includingclass 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) orclass D carbapenemases. Relebactam has no antibacterial activity.

Mechanisms of resistance in Gram-negative bacteria that are known to affect imipenem/relebactaminclude 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 conferresistance to imipenem/relebactam in P. aeruginosa. The expression of efflux pumps in P. aeruginosadoes not affect activity of either imipenem or relebactam. Mechanisms of bacterial resistance thatcould decrease the antibacterial activity of imipenem/relebactam in Enterobacterales include porinmutations 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, orvancomycin.

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) forimipenem-relebactam and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx.

Time that unbound plasma concentrations of imipenem exceed the imipenem/relebactam minimuminhibitory concentration (% fT > MIC) has been shown to best correlate with efficacy. The ratio of the24 - hour unbound plasma relebactam AUC to imipenem/relebactam MIC (fAUC/MIC) has beendetermined 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 indicationthat were susceptible to imipenem and relebactam in vitro:

Hospital-acquired pneumonia, including ventilator-associated pneumonia

Gram-negative micro-organisms

* Escherichia coli

* Haemophilus influenzae

* Klebsiella pneumoniae

* Pseudomonas aeruginosa

* Serratia marcescens

In vitro studies suggest that the following pathogens would be susceptible to imipenem and relebactamin 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

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-negativebacterial infections (see section 4.2 for information on paediatric use).

General introduction

The steady-state pharmacokinetic parameters of imipenem, cilastatin, and relebactam in healthy adultswith normal renal function (CrCl 90 mL/min or greater), after multiple 30-minute intravenousinfusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam administered every 6 hours aresummarised in Table 4. The steady-state pharmacokinetic parameters of imipenem and relebactam inpatients 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 mgcilastatin + 250 mg relebactam administered every 6 hours are summarised in Tables 5 and 6,respectively. Pharmacokinetic parameters were similar for single- and multiple-dose administrationdue to minimal accumulation.

The C max and AUC of imipenem, cilastatin, and relebactam increase in proportion to dose. Theelimination half-lives (t ½) of imipenem, cilastatin, and relebactam are independent of dose.

Table 4: Steady-state geometric mean (% geometric co-efficient of variation) plasmapharmacokinetic parameters of imipenem, cilastatin, and relebactam after multiple intravenous30-minute infusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam every 6 hours inhealthy adults

Imipenem (n=6) Cilastatin (n=6) Relebactam (n=6)

AUC 0 - 6 hr (μM-hr) 138.0 (17.8) 98.0 (17.0) 81.6 (17.8)

C max (μM) 106.0 (26.8) 96.4 (21.8) 48.3 (24.9)

CL (L/hr) 12.0 (17.8) 14.2 (17.0) 8.8 (17.8)t 1/2 (hr)* 1.1 (±0.1) 1.0 (±0.1) 1.7 (±0.2)

*Arithmetic mean (standard deviation) reported for t 1/2

AUC 0 - 6 hr = area under the concentration time curve from 0 to 6 hours; C max = maximumconcentration; CL = plasma clearance; t 1/2= elimination half-life

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

Imipenem Relebactam

AUC 0 - 24 hr (µM-hr) 500.0 (56.3) 390.5 (44.5)

C max (µM) 88.9 (62.1) 58.5 (44.9)

CL (L/hr) 13.4 (56.3) 7.4 (44.5)t 1/2 (hr)* 1.0 (±0.5) 1.2 (±0.7)

*Arithmetic mean (standard deviation) reported for t 1/2

AUC 0 - 24 hr = area under the concentration time curve from 0 to 24 hours; C max = maximumconcentration; CL = plasma clearance; t 1/2 = elimination half-life

Table 6: Population pharmacokinetic model based steady-state geometric mean (% geometricco-efficient of variation) plasma pharmacokinetic parameters of imipenem and relebactam aftermultiple 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

Imipenem Relebactam

AUC0 - 24hr (µM-hr) 812.2 (59.4) 655.2 (47.9)

Cmax (µM) 159.1 (62.3) 87.6 (43.8)

CL (L/hr) 8.2 (59.4) 4.4 (47.9)

AUC0 - 24hr=area under the concentration time curve from 0 to 24 hours; Cmax=maximumconcentration; CL=plasma clearance

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 isindependent of concentration.

The steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and19.0 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-unboundplasma exposure ratio was 55 % and 54 % for imipenem and relebactam, respectively.

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

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

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

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

Following multiple-dose administration of 500 mg imipenem, 500 mg cilastatin, and 250 mgrelebactam to healthy male subjects, approximately 63 % of the administered imipenem dose, and77 % of the administered cilastatin dose are recovered as unchanged parent in the urine. The renalexcretion 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. Themean 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 clearanceof relebactam is greater than the glomerular filtration rate, suggesting that in addition to glomerularfiltration, active tubular secretion is involved in the renal elimination, accounting for ~ 30 % of thetotal clearance.

The pharmacokinetics of relebactam are linear across the 25 mg to 1150 mg dose range studied for asingle intravenous administration, and 50 mg to 625 mg dose range studied for multiple intravenousadministration every 6 hours up to 7 days. Minimal accumulation of imipenem, cilastatin orrelebactam was observed following multiple 30-minute intravenous infusions of relebactam (50 to625 mg) co-administered with 500 mg imipenem/500 mg cilastatin every 6 hours up to 7 days inhealthy adult males with normal renal function.

Drug metabolizing enzymes

Studies evaluating the potential for imipenem or cilastatin to interact with CYP450 enzymes have notbeen conducted.

Relebactam at clinically relevant concentrations does not inhibit CYP1A2, CYP2B6, CYP2C8,

CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro in human liver microsomes. Relebactam showedno 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, withmetabolism as a minor elimination route. Thus, Recarbrio is unlikely to be subject to drug-druginteractions when co-administered with CYP inhibitors or inducers.

Membrane transporters

Relebactam does not inhibit the following hepatic and renal transporters in vitro at clinically relevantconcentrations: 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 ofrelebactam, thus, the extent of drug-drug interaction due to inhibition of the tubular transporters isexpected to be of minimal clinical significance, which was confirmed with a clinical drug-druginteraction study with probenecid and Recarbrio (see section 4.5).

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

In the clinical study, imipenem geometric mean AUCs were up to 1.4 - fold, 1.5 - fold, and 2.5 - foldhigher in patients with mild, moderate, and severe renal impairment, respectively, compared to healthysubjects with normal renal function. The respective cilastatin geometric mean AUCs were up to1.6 - 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 removedby haemodialysis.

To maintain systemic exposures similar to patients with normal renal function, dose adjustment isrecommended for patients with renal impairment. ESRD patients on haemodialysis should receive

Recarbrio after haemodialysis session (see section 4.2).

Imipenem, cilastatin, and relebactam are primarily cleared renally; therefore, hepatic impairment is notlikely 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 differencesin 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).

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

Imipenem/cilastatin

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

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

A teratology study in pregnant cynomolgus monkeys given imipenem/cilastatin sodium at doses of40/40 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 ofimipenem/cilastatin sodium (approximately 100/100 mg/kg/day or approximately 3 times therecommended daily human intravenous dose) were administered to pregnant cynomolgus monkeys atan 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 embryonicloss relative to control groups (see section 4.6).

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

Relebactam

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, reproduction toxicity, or genotoxicity. Carcinogenicity studieshave 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 plasmaconcentrations.

Animal studies show that relebactam given as a single entity caused renal tubular degeneration inmonkeys at AUC exposure 7-fold the human AUC exposure at the maximum recommended humandose (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.

Sodium hydrogen carbonate

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Dry powder30 months.

After constitution and dilution

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

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.

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

This medicinal product is supplied in packs of 25 vials.

Recarbrio is supplied as a dry powder in a single-dose vial that must be constituted and further dilutedusing 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 anappropriate infusion solution (see sections 6.2 and 6.3): 9 mg/mL (0.9 %) sodium chloride. Inexceptional circumstances where 9 mg/mL (0.9 %) sodium chloride cannot be used for clinicalreasons 5 % glucose may be used instead.

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

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

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

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

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

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

Table 7: Preparation of Recarbrio doses

Volume (mL) of Solution Volume (mL) of

Creatinine Dosage of Recarbrioto be Removed and Final Infusion

Clearance (imipenem/cilastatin/relebactam) Discarded from Solution Needed for(mL/min) (mg)

Preparation Dosage

Greater than500/500/250 N/A 100or equal to 90

Less than 90to greater than 400/400/200 20 80or equal to 60

Less than 60to greater than 300/300/150 40 60or equal to 30

Less than 30to greater thanor equal to 15 200/200/100 60 40or ESRD onhaemodialysis

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

Compatible medicinal products

The physical compatibility of Recarbrio with selected injectable medicinal products was evaluated intwo commonly available diluents at a Y-infusion site. Compatible medicinal products with thecorresponding compatible diluent (i.e., 5 % Dextrose Injection or 0.9 % Sodium chloride Injection) arelisted 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 therespective prescribing information of the co-administered medicinal product(s) to confirmcompatibility of simultaneous co-administration. This medicinal product must not be mixed with othermedicinal 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. Anyintravenous 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 (alsonamed Glucose) or 0.9 % Sodium chloride.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/19/1420/001

Date of first authorisation: 13 February 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.