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 in adult and paediatric patients from birth for:

* Treatment of hospital-acquired pneumonia (HAP), including ventilator associated pneumonia(VAP) (see sections 4.4 and 5.1).

* Treatment of bacteraemia that occurs in association with, or is suspected to be associated with

HAP or VAP.

* Treatment of infections due to aerobic Gram-negative organisms with limited treatment options(see sections 4.2, 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 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 adult patients with a creatinineclearance (CrCl) ≥ 90 mL/min and Table 2 shows the recommended intravenous dose forpaediatric patients (from birth to < 18 years of age) with normal renal function (seesections 4.4 and 5.1).

Table 1: Recommended doses for adult patients with a CrCl ≥ 90 mL/min*†

Dose of Recarbrio

Infusion time Duration of

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

Hospital-acquiredpneumonia, including Every500 mg/500 mg/250 mg 30 7 to 14 daysventilator associated 6 hourspneumonia†‡

Infections due to aerobic

Gram-negative Duration in

Everyorganisms in patients 500 mg/500 mg/250 mg 30 accordance with the6 hourswith limited treatment site of infection§options†

*As calculated using the Cockcroft-Gault formula.†For 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, therecommended dose may not be sufficient (see section 4.4).‡Includes bacteraemia, in association with, or suspected to be associated with, HAP or VAP.§e.g., for cIAI and cUTI the recommended treatment duration is 5 to 10 days; treatment may continue up to14 days.

Table 2: Recommended doses for paediatric patients with normal renal function*

Body Dose of Recarbrio Infusion time

Age Frequency

Weight (imipenem/cilastatin/relebactam) (minutes)≥ 30 kg < 18 years 500 mg/500 mg/250 mg Every 6 hours 30≥ 3 months37.5 mg/kg (imipenem 15 mg/kg, cilastatinto Every 6 hours 602 kg to 15 mg/kg and relebactam 7.5 mg/kg)< 18 years< 30 kg

Birth to 37.5 mg/kg (imipenem 15 mg/kg, cilastatin

Every 8 hours 60< 3 months 15 mg/kg and relebactam 7.5 mg/kg)

*As measured by estimated glomerular filtration rate (eGFR) calculated using the bedside Schwartz formula.

The recommended treatment duration for paediatric patients with HAP/VAP is the same as for adults.

For treatment of infections due to aerobic Gram-negative organisms in paediatric patients with limitedtreatment options, duration of treatment should be based on prescriber discretion. See section 5.1.

Adult patients who have a CrCl less than 90 mL/min require dose reduction ofimipenem/cilastatin/relebactam as indicated in Table 3. For patients with fluctuating renal function,

CrCl should be monitored.

Paediatric patients weighing at least 30 kg with eGFR less than 90 mL/min/1.73 m2 require a dosereduction of imipenem/cilastatin/relebactam as indicated in Table 3. Imipenem/cilastatin/relebactam isnot recommended in paediatric patients weighing less than 30 kg with renal impairment.

Table 3: Recommended intravenous doses for adult patients with a CrCl < 90 mL/min andpaediatric patients (weighing at least 30 kg) with an eGFR of < 90 mL/min/1.73 m2

Estimated renal function(CrCl [mL/min]* or Recommended dose of Recarbrio2 † (imipenem/cilastatin/relebactam) (mg)‡eGFR [mL/min/1.73 m ] )

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 for adult patients.†eGFR calculated using the bedside Schwartz formula for paediatric patients weighing ≥ 30 kg.‡Administer intravenously. See Tables 1 and 2 for infusion duration and dosing frequency.§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).

Adult patients with CrCl less than 15 mL/min and paediatric patients (weighing at least 30 kg) with aneGFR less than 15 mL/min/1.73 m2 should not receive imipenem/cilastatin/relebactam unlesshaemodialysis is instituted within 48 hours. There is inadequate information to recommend usage ofimipenem/cilastatin/relebactam for patients undergoing 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 weighing less than 30 kg withrenal impairment, children weighing less than 2 kg, or preterm infants (less than 37 weeks post-menstrual age) have not been established. No data are available.

For intravenous infusion.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

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 imipenem/cilastatin/relebactam, careful inquiry should bemade concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins,other beta-lactams, and other allergens.

If an allergic reaction to imipenem/cilastatin/relebactam occurs, treatment must be discontinuedimmediately. Serious anaphylactic reactions require immediate emergency treatment.

Hepatic function

Hepatic function should be closely monitored during treatment with imipenem/cilastatin/relebactamdue to the risk of hepatic toxicity (such as increase in transaminases, hepatic failure, and fulminanthepatitis) (see section 4.8).

Use in patients with liver disease: patients with pre-existing liver disorders should have liver functionmonitored during treatment with imipenem/cilastatin/relebactam. There is no dose adjustmentnecessary (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, especially when recommended doses of imipenem wereexceeded. These reactions have been reported most commonly in patients with CNS disorders (e.g.,brain lesions or history of seizures) and/or compromised renal function.

Special awareness should be made to neurological symptoms or convulsions in children with knownrisk factors for seizures, or on concomitant treatment with medicinal products lowering the seizuresthreshold.

Increased seizure potential due to interaction with valproic acid

The concomitant use of imipenem/cilastatin/relebactam and valproic acid/divalproex sodium is notrecommended. Antibacterials other than carbapenems should be considered to treat infections inpatients whose seizures are well-controlled on valproic acid or divalproex sodium. If administration ofthis medicine is necessary, supplemental anti-convulsant therapy should be considered (seesection 4.5).

Clostridioides difficile-Associated Diarrhoea (CDAD)

Clostridioides difficile-associated diarrhoea (CDAD) has been reported withimipenem/cilastatin/relebactam. 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 theadministration of imipenem/cilastatin/relebactam (see section 4.8). Careful medical history isnecessary since CDAD has been reported to occur over two months after the administration ofantibacterial agents.

If CDAD is suspected or confirmed, discontinuation of therapy with imipenem/cilastatin/relebactam,and the administration of specific treatment for C. difficile should be considered. Medicinal productsthat inhibit peristalsis should not be given.

Patients with CrCl ≥ 150 mL/min

Based on pharmacokinetic-pharmacodynamic analyses, the dose of imipenem/cilastatin/relebactamthat 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.

Dose adjustment is recommended in patients with renal impairment (see section 4.2). There isinadequate information to recommend usage of imipenem/cilastatin/relebactam for patientsundergoing peritoneal dialysis.

Limitations of the clinical data

Patients who were immunocompromised, including those with neutropenia, were excluded fromclinical studies.

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 imipenem/cilastatin/relebactam to treat patients with infections due to aerobic Gram-negative organisms who have limited treatment options is based on experience withimipenem/cilastatin, pharmacokinetic-pharmacodynamic analysis for imipenem/cilastatin/relebactam,and on limited data from a randomised clinical study in which 21 evaluable patients were treated withimipenem/cilastatin/relebactam and 10 evaluable patients were treated with colistin andimipenem/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 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 extended-spectrumbeta-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemase (KPC)) and Class C beta-lactamases including Pseudomonas-derived cephalosporinase (PDC). Relebactam does not inhibitclass D carbapenemases such as Oxacillinase-48 (OXA-48) or class B metallo-beta-lactamases such as

New Delhi metallo-beta-lactamase (NDM) and Verona integron-encoded metallo-beta-lactamase(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).

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. Ganciclovir should not be used concomitantly withimipenem/cilastatin/relebactam unless the potential benefits outweigh the risks.

Valproic acid

Case reports in the literature have shown that co-administration of carbapenems, includingimipenem/cilastatin, to patients receiving valproic acid or divalproex sodium results in a reduction invalproic acid concentrations. The valproic acid concentrations may drop below the therapeutic rangeas a result of this interaction, therefore increasing the risk of breakthrough seizures. Although themechanism of this interaction is unknown, data from in vitro and animal studies suggest thatcarbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back tovalproic acid, thus decreasing the serum concentrations of valproic acid. The concomitant use ofimipenem/cilastatin/relebactam 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 imipenem/cilastatin/relebactam is co-administered withthe prototypical OAT-inhibitor probenecid, indicating a lack of clinically meaningful OAT-mediateddrug-drug interactions. Concomitant administration of imipenem/cilastatin and probenecid increasedthe plasma level and half-life of cilastatin, though not to a clinically meaningful extent. Therefore, thismedicine may be 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, especially when recommended doses of imipenem were exceeded (seesection 4.4). Therefore, caution should be exercised when driving or using machines.

The most frequently occurring adverse reaction (≥ 2 %) in adult patients receiving imipenem/cilastatinplus relebactam in pooled Phase 2 studies of complicated intra-abdominal infections (cIAI) andcomplicated urinary tract infections (cUTI), including pyelonephritis (N = 431) was diarrhoea. Themost frequently occurring adverse reactions (≥ 2 %) in patients receiving Recarbrio in a Phase 3 studyof HAP or VAP (N = 266) were diarrhoea, alanine aminotransferase increased, and aspartateaminotransferase increased.

The following adverse reactions have been reported during Phase 2 (imipenem/cilastatin plusrelebactam including 431 patients) and Phase 3 (Recarbrio including 266 patients) clinical studies andwith imipenem/cilastatin in clinical studies or during post-marketing experience withimipenem/cilastatin (see Table 4).

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 4: Tabulated list of adverse reactions

System Organ

Common Uncommon Rare Very rare Unknown

Class

Pseudomembranous

Infections and colitis* Gastro-infestations enteritis*

Candidiasis*

Pancytopenia*

Neutropenia* Haemolytic

Blood and anaemia*lymphatic system Eosinophilia* Leukopenia* Agranulocytosis*disorders Bone marrow

Thrombocytopenia* depression*

Thrombocytosis*

Immune system Anaphylacticdisorders reactions*

System Organ

Common Uncommon Rare Very rare Unknown

Class

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*

System Organ

Common Uncommon Rare Very rare Unknown

Class

Polyarthralgia

Musculoskeletal *and connectivetissue disorders Thoracicspine pain*

Acute renal failure*

Oliguria/anuria*

Polyuria*

Renal and Elevations in serumurinary disorders creatinine*

Urine discolouration(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

The safety of imipenem/cilastatin/relebactam was evaluated in one phase 2/3 clinical study inpaediatric participants from birth to less than 18 years of age (see section 5.1). Eighty-five participantswere enrolled and treated in the imipenem/cilastatin/relebactam arm out of whom there were10 adolescents, 31 children aged 6 to less than 12 years, 21 from 2 years to less than 6 years, 15 from3 months to less than 2 years, and 8 from birth (full-term) to less than 3 months. Based on this data,adverse reactions were generally comparable to those observed in adults.

Reporting 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 overdose.

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

Recarbrio was evaluated in an open-label, randomised, active-controlled, phase 2/3 clinical study in115 paediatric participants from birth (full-term) to less than 18 years of age with HAP/VAP (n=6),cUTI (n=55) or cIAI (n=54), which included a total of 85 patients treated withimipenem/cilastatin/relebactam and 28 patients treated with active control. The minimum antibiotictreatment duration was 5 days for cIAI and cUTI or 7 days for HAP/VAP, up to a maximum of14 days. For participants with cUTI or cIAI in the imipenem/cilastatin/relebactam arm, a switch tooptional oral step-down therapy was allowed after receiving at least 3 days of intravenousimipenem/cilastatin/relebactam therapy. The primary objective was safety and tolerability, and allstatistical analyses were descriptive. Efficacy in the paediatric population is established on the basis ofachieving similar systemic exposures as in adults.

At the early follow-up visit (EFU), 7 to 14 days after the end of therapy, 70.6 % (60/85) of paediatricparticipants in the imipenem/cilastatin/relebactam arm achieved a favourable clinical response (cure orsustained cure), compared to 75 % (21/28) in the comparator arm (modified Intention-To-Treat (ITT)population). A favourable clinical response at the late follow-up visit (LFU), 7 to 14 days after the

EFU visit was achieved by 69.4 % (59/85) and 75.0 % (21/28) of participants, respectively.

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 5. 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 6 and 7,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 5: 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 ½ (hr)* 1.1 (±0.1) 1.0 (±0.1) 1.7 (±0.2)

*Arithmetic mean (standard deviation) reported for t ½

AUC 0 - 6 hr = area under the concentration time curve from 0 to 6 hours; C max = maximumconcentration; CL = plasma clearance; t ½= 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 mgcilastatin/250 mg relebactam) every 6 hours in cIAI or cUTI adult patients with CrCl 90 mL/minor greater

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 ½ (hr)* 1.0 (±0.5) 1.2 (±0.7)

*Arithmetic mean (standard deviation) reported for t ½

AUC 0 - 24 hr = area under the concentration time curve from 0 to 24 hours; C max = maximumconcentration; CL = plasma clearance; t ½ = elimination half-life

Table 7: 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 HAP or VAP adult patients with CrCl 90 mL/minor 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 1 150 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 in adults, imipenem geometric mean AUCs were up to 1.4 - fold, 1.5 - fold, and2.5 - fold higher in patients with mild, moderate, and severe renal impairment, respectively, comparedto healthy subjects with normal renal function. The respective cilastatin geometric mean AUCs wereup to 1.6 - fold, 1.9 - fold, and 5.6 - fold higher. Relebactam geometric mean AUCs were up to1.6 - fold, 2.2 - fold, and 4.9 - fold higher in patients with mild, moderate, and severe renalimpairment, respectively, compared to healthy subjects with normal renal function. In patients with

End Stage Renal Disease (ESRD) on haemodialysis, imipenem, cilastatin, and relebactam areefficiently removed by 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.

The steady-state pharmacokinetic parameters of imipenem and relebactam in paediatric patients (birthto less than 18 years of age) with HAP/VAP, cUTI or cIAI following the recommended paediatricdosing regimens are summarised in Table 8.

Population pharmacokinetic analyses and target attainment simulations in paediatric patients with

HAP/VAP, cUTI or cIAI demonstrated that the recommended paediatric dosing regimens for patientsfrom birth to less than 18 years with normal renal function resulted in generally similar systemicexposures to adults with normal renal function given 1.25 g of imipenem/cilastatin/relebactam. Theseanalyses, including the assumption of proportional effects of renal impairment in adults and paediatricpatients, also predict that the recommended dose adjustments for patients weighing at least 30 kg witheGFR less than 90 mL/min/1.73 m2 result in systemic exposures similar to that in adult patients (seesection 4.2).

Dose adjustments are recommended for paediatric patients from birth to less than 18 years of ageweighing at least 30 kg with eGFR less than 90 mL/min/1.73 m2 (see section 4.2). There is insufficientinformation to recommend a dose adjustment in paediatric patients weighing less than 30 kg with renalimpairment.

Table 8: Population pharmacokinetic model based geometric mean (% geometric co-efficient ofvariation) steady-state plasma pharmacokinetic parameters

Imipenem Relebactam

Body

Age CL

Weight AUC0-24hr Cmax t1/2 CL AUC0-24hr Cmax t1/2 (L/hr/(µM.hr) (µM) (hr) (L/hr/kg) (µM.hr) (µM) (hr)kg)<18 years 662 116 1.67 0.235 428 61.1 1.85 0.156≥30 kg(N=38) (38.8) (23.3) (26.6) (25.9) (45) (27.2) (26.3) (28.7)≥3 monthsand 715 104 1.37 0.28 474 57.2 1.57 0.182<30 kg<18 years (27.4) (15.1) (19.6) (24.2) (49.9) (23.2) (29.2) (32.8)(N=66)

Birth to749 111 1.55 0.201 545 59.9 2.09 0.119<30 kg <3 months(21.6) (13.2) (20.3) (20.1) (44.5) (21.6) (39.4) (35.3)(N=27)

AUC0 - 24hr=area under the concentration time curve from 0 to 24 hours; Cmax=maximum concentration;t1/2=elimination half-life; CL=body weight normalised plasma clearance

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.

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 reconstitution 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 reconstituted and furtherdiluted using aseptic technique prior to intravenous infusion as outlined below:

Adult patients

To prepare infusion solution, contents of the vial must be transferred to 100 mL of an appropriateinfusion solution (see sections 6.2 and 6.3): 9 mg/mL (0.9 %) sodium chloride. In exceptionalcircumstances where 9 mg/mL (0.9 %) sodium chloride cannot be used for clinical reasons 5 %glucose may be used instead. Please note that pre-filled infusion bags are overfilled and, to obtaina correct concentration, it is important to be assured that exactly 100 mL of the diluent is usedin this step when a part of the content of the infusion bag is administered (e.g., in the case ofpaediatric weight-based dosing).

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

* After reconstitution, 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.

Adult patients with renal impairment and paediatric patients weighing at least 30 kg with renalimpairment

A reduced dose of Recarbrio will be administered according to the patient’s CrCl or eGFR, asdetermined from Table 9.

* Prepare 100 mL of infusion solution as directed above for adult patients.

* Select the volume (mL) of the final infusion solution needed for the appropriate dose of

Recarbrio as shown in Table 9.

Paediatric patients weighing 2 kg to less than 30 kg with normal renal function

* Prepare 100 mL of infusion solution as directed above for adult patients.

* The volume of the final infusion solution (with a concentration of 12.5 mg/mL) to beadministered is calculated based on patient weight as follows:o Infusion volume (mL) = (Weight (kg) x 37.5 mg/kg)/12.5 mg/mLo Note: The entire volume in the infusion bag (100 mL) will not be required.

* Transfer the calculated infusion volume from the prepared 100 mL solution to an adequatelysized infusion bag or infusion syringe.

* The infusion volume will be administered over 60 minutes via infusion or infusion syringepump.

Table 9: Preparation of Recarbrio solution for intravenous infusion in adult and paediatricpatients (weighing at least 30 kg)

Volume (mL) of Volume (mL)

Estimated renal function Dose of Recarbrio solution to be of final(CrCl [mL/min]* or (imipenem/cilastatin/relebactam) removed and infusioneGFR [mL/min/1.73 m2]†) (mg) discarded from solution neededpreparation for dose

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

Less than 90 to400/400/200 20 80greater than or equal to 60

Less than 60 to300/300/150 40 60greater than or equal to 30

Less than 30 togreater than or equal to 15 200/200/100 60 40or ESRD on haemodialysis

*CrCl calculated using the Cockcroft-Gault formula for adult patients†eGFR calculated using the bedside Schwartz formula for paediatric patients weighing ≥ 30 kg

Reconstituted solutions of Recarbrio range from colourless to yellow. Variations of colour within thisrange do not affect the potency of the product. Parenteral medicinal products should be inspectedvisually for particulate matter and discolouration prior to administration, whenever solution andcontainer permit. Discard if discolouration or visible particles are observed.

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

Date of the latest renewal: 19 September 2024

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

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