Skip to Content

Imipenem, Cilastatin, and Relebactam

Class: Carbapenems
Chemical Name: (5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Molecular Formula: C12H17N3O4SC16H25N2NAO5SC12H20N4O6S
CAS Number: 103730-39-8
Brands: Recarbrio

Medically reviewed by Drugs.com. Last updated on Jan 13, 2020.

Introduction

Imipenem, cilastatin sodium, and relebactam is a carbapenem β-lactam antibiotic.

Uses for Imipenem, Cilastatin, and Relebactam

Imipenem, cilastatin sodium, and relebactam has the following uses:

Imipenem, cilastatin sodium, and relebactam is a fixed combination of imipenem (a penem antibacterial), cilastatin (a renal dehydropeptidase inhibitor), and relebactam (a β-lactamase inhibitor) indicated for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, and complicated intra-abdominal infections (cIAI) caused by susceptible gram-negative bacteria in patients 18 years of age and older who have limited or no alternative treatment options.1

Approval of these indications is based on limited clinical safety and efficacy data for imipenem, cilastatin sodium, and relebactam.1

To reduce the development of drug-resistant bacteria and maintain the effectiveness of imipenem, cilastatin sodium, and relebactam and other antibacterials, the fixed combination should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.1

Imipenem, Cilastatin, and Relebactam Dosage and Administration

General

Imipenem, cilastatin sodium, and relebactam is available in the following dosage form(s) and strength(s):

Single-dose vials of 1.25 g for injection for constitution containing imipenem 500 mg (anhydrate equivalent), cilastatin 500 mg (free acid equivalent), and relebactam 250 mg (anhydrate equivalent).1

See the manufacturer's labeling for instructions for constituting supplied dry powder and subsequent required dilution.1

See the manufacturer's labeling for drug incompatibilities.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • Dosage of imipenem, cilastatin sodium, and relebactam is expressed as the total (sum) of the dosage of each of the 3 components. This dosage convention should be considered when prescribing, preparing, and dispensing the drug.1

  • Patients 18 years of age and older with creatinine clearance (Clcr) 90 mL/min or greater: Administer 1.25 g (imipenem 500 mg, cilastatin 500 mg, relebactam 250 mg) by intravenous (IV) infusion over 30 minutes every 6 hours.1

  • Patients 18 years of age and older with renal impairment: Dosage adjustments required (see Table).1 Those with Clcr less than 15 mL/min should not receive the drug unless hemodialysis is instituted.1

Clcr calculated using the Cockroft-Gault formula.

Estimated Clcr (mL/min)

Recommended Dose of Imipenem, Cilastatin Sodium, and Relebactam (mg) Administered by IV Infusion over 30 Minutes every 6 Hours

60 to 89

1 g (imipenem 400 mg, cilastatin 400 mg, and relebactam 200 mg)

30 to 59

0.75 g (imipenem 300 mg, cilastatin 300 mg, and relebactam 150 mg)

15 to 29

0.5 g (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg)

End-stage Renal Disease on Hemodialysis

0.5 g (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg)

Cautions for Imipenem, Cilastatin, and Relebactam

Contraindications

Imipenem, cilastatin sodium, and relebactam is contraindicated in patients with a history of known severe hypersensitivity to any component of the fixed combination.1

Warnings/Precautions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. Before initiating therapy with imipenem, cilastatin sodium, and relebactam, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactams, and other allergens.1

If a hypersensitivity reaction to imipenem, cilastatin sodium, and relebactam occurs, discontinue the drug immediately.1

Seizures and Other CNS Adverse Reactions

CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with the fixed combination of imipenem and cilastatin sodium (imipenem/cilastatin), a component of imipenem, cilastatin sodium, and relebactam, especially when recommended dosages of imipenem were exceeded. These have been reported most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function.1

Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions, including seizures, occur patients should undergo a neurological evaluation to determine whether imipenem, cilastatin sodium, and relebactam should be discontinued.1

Increased Seizure Potential Due to Interaction with Valproic Acid

Concomitant use of imipenem, cilastatin sodium, and relebactam with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Avoid concomitant use of imipenem, cilastatin sodium, and relebactam with valproic acid or divalproex sodium; consider alternative antibacterials other than carbapenems in patients whose seizures are well controlled on valproic acid or divalproex sodium.1

C. difficile-associated Diarrhea

C. difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including imipenem. cilastatin sodium, and relebactam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.1

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.1

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.1

Development of Drug-resistant Bacteria

Prescribing imipenem, cilastatin sodium, and relebactam in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.1

Specific Populations

Pregnancy

Risk Summary: Embryonic loss was observed in monkeys treated with imipenem/cilastatin and fetal abnormalities were observed in relebactam-treated mice; therefore, advise pregnant women of the potential risks to pregnancy and the fetus. There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with imipenem, cilastatin sodium, or relebactam or the fixed combination of imipenem, cilastatin sodium, and relebactam in pregnant women.1

Developmental toxicity studies with imipenem and cilastatin (alone or in combination) administered parenterally during organogenesis to mice, rats, rabbits, and monkeys at doses 1 to 5 times the maximum recommended human dose (MRHD of imipenem 500 mg/cilastatin 500 mg every 6 hours for total daily doses of imipenem 2 g/cilastatin 2 g) based on body surface area comparison, showed no drug-induced fetal malformations. Embryofetal development studies with imipenem/cilastatin administered to cynomolgus monkeys at doses similar to the MRHD (based on body surface area comparison) showed an increase in embryonic loss. In an embryofetal study, administration of relebactam to pregnant mice during the period of organogenesis was associated with a non-dose responsive increase in the litter incidence of cleft palate at a plasma relebactam exposure approximately equal to the human exposure at the MRHD (250 mg every 6 hours for a daily dose of 1 g) and an increased percent litter incidence of total skeletal malformations at a plasma exposure approximately 6 times the human exposure at the MRHD. Reproductive studies with relebactam administered parenterally to pregnant rats and rabbits during the period of organogenesis at plasma exposures up to 7 and 24 times, respectively, the plasma exposure in humans at the MRHD showed no adverse effects on pregnancy or embryofetal development. Relebactam administered to rats during gestation through lactation was not associated with fetal toxicity, developmental delays, or impaired reproduction in first-generation offspring at plasma exposures equivalent to 8 times the human exposure at the MRHD.1

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects is 2–4% and miscarriage is 15–20% of clinically recognized pregnancies within the U.S. general population.1

Animal Data for Imipenem and Cilastatin: Reproductive toxicity studies with imipenem and cilastatin (alone or in combination) administered parenterally to mice, rats, and rabbits showed no evidence of effects on embryofetal (mice, rats, and rabbits) or pre/postnatal (rats) development. In embryofetal development studies, imipenem was administered intravenously to rats (gestation days [GD] 7 to 17) and rabbits (GD 6 to 18) at doses up to 900 and 60 mg/kg/day, respectively, approximately 4 and 0.6 times the MRHD (based on body surface area comparison). Cilastatin was administered subcutaneously to rats (GD 6 to 17) and intravenously to rabbits (GD 6 to 18) at doses up to 1000 and 300 mg/kg/day, respectively, approximately 5 and 3 times the MRHD (based on body surface area comparison). Imipenem/cilastatin was administered intravenously to mice at doses up to 320 mg/kg/day (GD 6 to 15), which is approximately equivalent to the MRHD based on body surface area comparison, and to rats at intravenous doses up to 80 mg/kg/day and a subcutaneous dose of 320 mg/kg/day (GD 6 to 17). In a separate pre/postnatal development study, rats were administered subcutaneous imipenem/cilastatin at doses up to 320 mg/kg/day (GD 15 to day 21 postpartum). The subcutaneous dose of 320 mg/kg/day in rats is approximately double the MRHD based on body surface area comparison.1

Imipenem/cilastatin administered intravenously to pregnant cynomolgus monkeys during organogenesis (GD 21 to 50) at 100 mg/kg/day, a dose approximately equivalent to the MRHD (based on body surface area comparison), at an infusion rate mimicking human clinical use was not associated with fetal malformations, but there was an increase in embryonic loss relative to controls. Imipenem/cilastatin administered to pregnant cynomolgus monkeys during organogenesis at 40 mg/kg/day by bolus intravenous injection caused significant maternal toxicity, including death and embryofetal loss.1

Animal Data for Relebactam: In an embryofetal development study in pregnant mice, relebactam administered subcutaneously in doses of 80, 200, and 450 mg/kg/day during the period of organogenesis (GD 6 to 17) was not associated with maternal toxicity at doses up to 450 mg/kg/day. However, although individual skeletal malformations appeared only as single occurrences in the high dose group, the percent litter incidence of total skeletal malformations (skull and vertebral) was increased in the high-dose group (21% litter incidence) compared to the concurrent control value (5.3% litter incidence). The plasma relebactam exposure for the high dose associated with increased skeletal malformations was approximately 6 times greater than the human plasma exposure at the MRHD based on AUC comparison. Also, mice receiving the lowest administered dose of relebactam, 80 mg/kg/day, exhibited a higher percent litter incidence (15% litter incidence) of cleft palate (a rare malformation in mice) compared to the concurrent control value (0% litter incidence) and historical control values (up to 11% litter incidence). This finding did not increase in a dose-dependent manner with percent litter incidences of 0% and 5.3% in the mid- and high-dose groups respectively. The plasma AUC exposure for the low dose of relebactam associated with increased cleft palate was approximately equivalent to the human plasma AUC at the MRHD. In embryofetal development studies in rats and rabbits, intravenous relebactam was administered to rats in doses of 50, 150, and 450 mg/kg/day and to rabbits in doses of 35, 275, and 450 mg/kg/day. In these studies, relebactam administered during the period of organogenesis to pregnant rats (GD 6 to 20) and rabbits (GD 7 to 20) was not associated with maternal or embryofetal toxicity at doses up to 450 mg/kg/day corresponding to plasma AUC exposures of approximately 7 and 24 times, respectively, the human plasma AUC at the MRHD.1

In a pre/postnatal development study, relebactam administered intravenously in doses of 65, 200, and 450 mg/kg/day to rats from GD 6 to lactation day (LD) 20 produced no maternal toxicity and did not impair the physical and behavioral development or reproduction in first-generation offspring at doses up to 450 mg/kg/day corresponding to a plasma AUC exposure of approximately 8 times the plasma AUC exposure in humans at the MRHD.1

Studies in pregnant rats and rabbits showed that relebactam is transferred to the fetus through the placenta, with fetal plasma concentrations up to 5–6% of maternal concentrations observed on GD 20.1

Lactation

Risk Summary: There are insufficient data on the presence of imipenem/cilastatin and relebactam in human milk, and no data on the effects on the breast-fed child or the effects on milk production. Relebactam is present in the milk of lactating rats.1

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for imipenem, cilastatin sodium, and relebactam and any potential adverse effects on the breast-fed child from imipenem, cilastatin sodium, and relebactam or from the underlying maternal condition.1

Data: Relebactam administered intravenously to lactating rats at a dose of 450 mg/kg/day (GD 6 to LD 14) was excreted into the milk in concentrations approximately 5% that of maternal plasma concentrations.1

Pediatric Use

The safety and efficacy of imipenem, cilastatin sodium, and relebactam in patients younger than 18 years of age have not been established.1

Geriatric Use

Of the 216 patients treated with imipenem/cilastatin plus relebactam 250 mg in Trials 1 and 2, 67 (31%) were 65 years of age or older, including 25 (11.6%) patients 75 years of age and older.1

Imipenem, cilastatin sodium, and relebactam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function.1

Renal Impairment

Reduce imipenem, cilastatin sodium, and relebactam dosage in patients with a Clcr less than 90 mL/min.1

Common Adverse Effects

The most frequently reported adverse reactions occurring in greater than or equal to 2% of patients treated with imipenem/cilastatin plus relebactam 250 mg were diarrhea, nausea, headache, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, phlebitis/infusion site reactions, pyrexia, and hypertension.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Ganciclovir: Avoid concomitant use.1

  • Valproic acid or divalproex sodium: Avoid concomitant use.1

Actions and Spectrum

Mechanism of Action

Imipenem, cilastatin sodium, and relebactam is an antibacterial.1

Imipenem is a penem antibacterial, cilastatin sodium is a renal dehydropeptidase inhibitor, and relebactam is a β-lactamase inhibitor. Cilastatin limits the renal metabolism of imipenem and does not have antibacterial activity. The bactericidal activity of imipenem results from binding to penicillin-binding proteins (PBPs) 2 and 1B in Enterobacteriaceae and Pseudomonas aeruginosa and the subsequent inhibition of PBPs. Inhibition of PBPs leads to the disruption of bacterial cell wall synthesis. Imipenem is stable in the presence of some β-lactamases. Relebactam protects imipenem from degradation by certain serine β-lactamases, such as sulhydryl variable (SHV), temoneira (TEM), cefotaximase-Munich (CTX-M), Enterobacter cloacae P99 (P99), Pseudomonas-derived cephalosporinase (PDC), and Klebsiella-pneumoniae carbapenemase (KPC). Relebactam has no intrinsic antibacterial activity.1

Relebactam restored activity of imipenem/cilastatin in animal models of infection (e.g., mouse disseminated infection, mouse thigh infection, and mouse pulmonary infection) caused by imipenem-nonsusceptible KPC-producing Enterobacteriaceae and imipenem-nonsusceptible Ps. aeruginosa (imipenem-nonsusceptible due to production of chromosomal PDC and loss of outer membrane porin [OprD]).1

Spectrum

Imipenem, cilastatin sodium, and relebactam has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections:

Complicated Urinary Tract Infections (cUTI) – Aerobic Gram-negative Bacteria: Klebsiella aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa.1

Complicated Intra-abdominal Infections (cIAI) – Aerobic Gram-negative Bacteria: Citrobacter freundii, Klebsiella aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa.1

Complicated Intra-abdominal Infections (cIAI) – Anaerobic Gram-negative Bacteria: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium nucleatum, Parabacteroides distasonis.1

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for imipenem, cilastatin sodium, and relebactam against isolates of similar genus or organism group. However, the efficacy of imipenem, cilastatin sodium, and relebactam in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials:

Aerobic Gram-positive Bacteria: Enterococcus faecalis, methicillin-susceptible Staphylococcus aureus, Streptococcus anginosus, Streptococcus constellatus.1

Aerobic Gram-negative Bacteria: Citrobacter koseri, Enterobacter asburiae.1

Anaerobic Gram-positive Bacteria: Eggerthella lenta, Parvimonas micra, Peptoniphilus harei, Peptostreptococcus anaerobius.1

Anaerobic Gram-negative Bacteria: Fusobacterium necrophorum, Fusobacterium varium, Parabacteroides goldsteinii, Parabacteroides merdae, Prevotella bivia, Veillonella parvula.1

In vitro studies have demonstrated no antagonism between imipenem/relebactam and amikacin, azithromycin, aztreonam, colistin, gentamicin, levofloxacin, linezolid, tigecycline, tobramycin, or vancomycin.1

Resistance

Clinical isolates may produce multiple β-lactamases, express varying levels of β-lactamases, have amino acid sequence variations, or have other resistance mechanisms that have not yet been identified. Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.1

Mechanisms of β-lactam resistance in gram-negative organisms include the production of β-lactamases, up-regulation of efflux pumps, and loss of outer membrane porins. Imipenem/relebactam retains activity in the presence of the tested efflux pumps. Imipenem/relebactam has shown activity against some isolates of Ps. aeruginosa and Enterobacteriaceae that produce relebactam-susceptible β-lactamases concomitant with loss of entry porins. Imipenem/relebactam is not active against most isolates containing metallo-β-lactamases (MBLs), some oxacillinases with carbapenemase activity, as well as certain alleles of GES.1

Imipenem/relebactam demonstrated in vitro activity against some Enterobacteriaceae isolates genotypically characterized for some β-lactamases and extended-spectrum β-lactamases (ESBLs) of the following groups: KPC, TEM, SHV, CTX-M, CMY, DHA, and ACT/MIR. Many of the Enterobacteriaceae isolates that were not susceptible to imipenem/relebactam were genotypically characterized and the genes encoding MBLs or certain oxacillinases were present.1

Imipenem/relebactam demonstrated in vitro activity against genotypically characterized Ps. aeruginosa isolates containing certain known resistance factors, including some chromosomal PDC alleles with ESBLs and those with loss of outer membrane porin that co-expressed up-regulated efflux pumps (MexAB, MexCD, MexJK, and MexXY). Genotypically characterized Ps. aeruginosa isolates that were not susceptible to imipenem/relebactam encoded some MBL, KPC, PER, GES, VEB, and PDC alleles.1

Methicillin-resistant staphylococci should be considered resistant to imipenem. Imipenem is inactive in vitro against Enterococcus faecium, Stenotrophomonas maltophilia, and some isolates of Burkholderia cepacia.1

No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to carbapenems (including imipenem) and to cephalosporins may be susceptible to imipenem, cilastatin sodium, and relebactam.1

Advice to Patients

Serious Allergic Reactions

Advise patients, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur that require immediate treatment. Ask them about any previous hypersensitivity reactions to imipenem, cilastatin sodium, and relebactam, carbapenems, penicillins, cephalosporins, other β-lactams, or other allergens.1

Seizures and Central Nervous System Reactions

Counsel patients, their families, or caregivers to inform a healthcare provider if they have central nervous system disorders, such as stroke or history of seizures. Seizures have been reported during treatment with imipenem, especially when recommended dosages were exceeded, and with closely related antibacterial drugs.1

Drug Interaction with Valproic Acid

Counsel patients, their families, or caregivers to inform a healthcare provider if they are taking valproic acid or divalproex sodium. If treatment with imipenem, cilastatin sodium, and relebactam is necessary, supplemental anticonvulsant medication to prevent and/or treat seizures may be needed.1

Potentially Serious Diarrhea

Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including imipenem, cilastatin sodium, and relebactam and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection that may require treatment. If severe watery or bloody diarrhea develops, tell the patient to contact his or her healthcare provider.1

Antibacterial Resistance

Patients should be counseled that antibacterial drugs, including imipenem, cilastatin sodium, and relebactam, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When imipenem, cilastatin sodium, and relebactam is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by imipenem, cilastatin sodium, and relebactam or other antibacterial drugs in the future.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Imipenem, Cilastatin Sodium, and Relebactam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Powder, for Solution

1.25 g (500 mg of imipenem anhydrous, 500 mg of cilastatin, and 250 mg of relebactam anhydrous)

Recarbrio

Merck Sharp & Dohme Corp.

AHFS Drug Information. © Copyright 2021, Selected Revisions January 13, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Merck Sharp & Dohme Corp. RECARBRIO (imipenem anhydrous, cilastatin, and relebactam anhydrous) INTRAVENOUS prescribing information. 2019 Jul. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=be32f468-738b-40df-a425-591e12f65159