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Imipenem, cilastatin, and relebactam: Drug information

Imipenem, cilastatin, and relebactam: Drug information
(For additional information see "Imipenem, cilastatin, and relebactam: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Recarbrio
Pharmacologic Category
  • Antibiotic, Carbapenem;
  • Beta-Lactamase Inhibitor
Dosing: Adult

Dosage guidance:

Dosing: Doses are expressed as the combined amount of imipenem, cilastatin, and relebactam.

Clinical considerations: Not recommended for routine empiric use.

Intra-abdominal infection, complicated

Intra-abdominal infection, complicated:

Note: Reserve for patients with or at risk for extensively drug-resistant pathogens (nonsusceptible to ≥1 agent in all but 2 or fewer antimicrobial classes) (eg, carbapenem-resistant Enterobacterales) (Ref).

IV: 1.25 g every 6 hours. Total duration of therapy is 4 to 7 days following adequate source control (Ref); for infections managed without surgical or percutaneous intervention, a longer duration may be necessary (Ref).

Pneumonia, hospital-acquired or ventilator-associated

Pneumonia, hospital- acquired or ventilator-associated:

Note: Reserve for patients with or at risk for extensively drug-resistant pathogens (nonsusceptible to ≥1 agent in all but 2 or fewer antimicrobial classes) (eg, carbapenem-resistant Enterobacterales) (Ref).

IV: 1.25 g every 6 hours. Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days, but a longer course may be required for severe or complicated infection (Ref).

Urinary tract infection, complicated

Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms):

Note: Reserve for patients with or at risk for extensively drug-resistant pathogens (nonsusceptible to ≥1 agent in all but 2 or fewer antimicrobial classes) (eg, carbapenem-resistant Enterobacterales) (Ref).

IV: 1.25 g every 6 hours. Switch to an appropriate oral regimen once symptoms improve, if culture and susceptibility results allow. Total duration of therapy ranges from 5 to 14 days and depends on clinical response and the antimicrobial chosen to complete the regimen (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Estimation of renal function for the purpose of dosage adjustment should be done using the Cockcroft-Gault formula.

Altered kidney function:

IV:

CrCl ≥90 mL/minute: No dosage adjustment necessary (Ref).

CrCl 60 to 89 mL/minute: 1 g (imipenem 400 mg/cilastatin 400 mg/relebactam 200 mg) every 6 hours (Ref).

CrCl 30 to 59 mL/minute: 750 mg (imipenem 300 mg/cilastatin 300 mg/relebactam 150 mg) every 6 hours (Ref).

CrCl 15 to 29 mL/minute: 500 mg (imipenem 200 mg/cilastatin 200 mg/relebactam 100 mg) every 6 hours (Ref).

CrCl <15 mL/minute: The manufacturer’s labeling recommends against use in patients not receiving or scheduled to receive hemodialysis. In the absence of data, 500 mg (imipenem 200 mg/cilastatin 200 mg/relebactam 100 mg) every 12 hours may be considered (Ref).

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).

IV: No dosage adjustment necessary (Ref).

Hemodialysis, intermittent (thrice weekly): Dialyzable (imipenem [55%], cilastatin [63%], and relebactam [unknown]) (Ref).

IV: 500 mg (imipenem 200 mg/cilastatin 200 mg/relebactam 100 mg) every 6 hours (Ref).

Peritoneal dialysis:

IV: Not recommended in manufacturer’s labeling (has not been studied). In the absence of data, may consider 500 mg (imipenem 200 mg/cilastatin 200 mg/relebactam 100 mg) every 8 hours (Ref).

CRRT:

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.

Very limited information available; removal likely based on in vitro data and simulations of CRRT conditions with the 3-drug combination (Ref).

IV: 1.25 g (imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg) as a single dose, followed by 750 mg (imipenem 300 mg/cilastatin 300 mg/relebactam 150 mg) every 6 hours (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration):

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.

No information available; some removal likely based on drug characteristics (Ref).

IV: 1.25 g (imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg) as a single dose (Ref), followed by:

PIRRT days: 750 mg every 8 hours or 750 mg every 6 hours (Ref).

Non-PIRRT days: 500 mg every 8 hours (Ref).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, hepatic impairment is not likely to have any effect on exposure.

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Hematologic & oncologic: Anemia (11%)

Hepatic: Increased serum aspartate aminotransferase (12%)

1% to 10%:

Dermatologic: Skin rash (4%)

Endocrine & metabolic: Hypokalemia (8%), hyponatremia (6%)

Gastrointestinal: Constipation (4%), diarrhea (8%)

Hematologic & oncologic: Thrombocytopenia (<4%)

Hepatic: Increased serum alanine aminotransferase (10%)

Miscellaneous: Fever (4%)

Frequency not defined: Gastrointestinal: Clostridioides difficile associated diarrhea

Contraindications

Severe hypersensitivity (eg, anaphylaxis) to cilastatin, imipenem, relebactam, or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Carbapenems have been associated with CNS adverse effects, including confusional states and seizures (myoclonic); use caution with CNS disorders (eg, brain lesions, history of seizures) and adjust dose in renal impairment to avoid drug accumulation. Drug accumulation may increase seizure risk.

• Hypersensitivity reactions: Serious hypersensitivity/anaphylactic reactions, some fatal, have been reported with beta-lactams. Carefully inquire about previous hypersensitivity reactions to penicillins, carbapenems, cephalosporins, other beta-lactams, and other allergens. Discontinue treatment and institute supportive care if a hypersensitivity reaction occurs.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including Clostridioides difficile-associated diarrhea (CDAD); CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required. Increased seizure risk has been reported in patients with significant renal dysfunction. Do not use in patients with CrCl ≤15 mL/minute unless hemodialysis is instituted within 48 hours.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Recarbrio: Imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg (1 ea)

Generic Equivalent Available: US

No

Pricing: US

Solution (reconstituted) (Recarbrio Intravenous)

1.25 g (per each): $368.32

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

IV: Infuse over 30 minutes.

Use: Labeled Indications

Intra-abdominal infection, complicated: Treatment of complicated intra-abdominal infections in patients ≥18 years of age with limited or no alternative options caused by the following susceptible gram-negative microorganisms: Bacteroides cacace, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bifidobacterium stercoris, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis, and Pseudomonas aeruginosa.

Pneumonia, hospital acquired or ventilator associated: Treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) in patients ≥18 years of age caused by the following susceptible gram-negative microorganisms: Acinetobacter calcoaceticus-baumannii complex, E. cloacae, E. coli, Haemophilus influenzae, K. aerogenes, K. oxytoca, K. pneumoniae, P. aeruginosa, and Serratia marcescens.

Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms): Treatment of complicated urinary tract infections, including pyelonephritis, in patients ≥18 years of age with limited or no alternative options caused by the following susceptible gram-negative microorganisms: E. cloacae, E. coli, K. aerogenes, K. pneumoniae, and P. aeruginosa.

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination

CycloSPORINE (Systemic): Imipenem may enhance the neurotoxic effect of CycloSPORINE (Systemic). Risk C: Monitor therapy

Fecal Microbiota (Live) (Oral): May diminish the therapeutic effect of Antibiotics. Risk X: Avoid combination

Fecal Microbiota (Live) (Rectal): Antibiotics may diminish the therapeutic effect of Fecal Microbiota (Live) (Rectal). Risk X: Avoid combination

Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Imipenem. Specifically, the risk of seizures may be increased. Management: Avoid concomitant use of these agents unless the prospective benefits of therapy outweigh the risks. Risk D: Consider therapy modification

Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of Imipenem. Risk C: Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification

Valproate Products: Carbapenems may decrease the serum concentration of Valproate Products. Management: Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure medication. Risk D: Consider therapy modification

Pregnancy Considerations

Imipenem and cilastatin cross the placenta (Cho 1988; Heikkilä 1992). Information specific to relebactam has not been located.

Also refer to the imipenem/cilastatin monograph for additional information.

Breastfeeding Considerations

Imipenem is present in breast milk (Chung 2002; Ito 1988). Excretion of relebactam is not known.

Also refer to the imipenem/cilastatin monograph for additional information.

Monitoring Parameters

Periodic renal function tests; signs of hypersensitivity/anaphylaxis.

Mechanism of Action

Imipenem: Binds to PBP 2 and PBP 1B in Enterobacteriaceae and P. aeruginosa and subsequently inhibits penicillin-binding proteins, leading to the disruption of bacterial cell wall synthesis.

Cilastatin: Renal dehydropeptidase inhibitor that limits renal metabolism of imipenem.

Relebactam: Beta-lactamase inhibitor that protects imipenem from degradation by certain serine beta-lactamases (eg, Sulhydryl Variable, Temoneira, Cefotaximase-Munich, E. cloacae P99, Pseudomonas-derived cephalosporinase, and Klebsiella-pneumoniae carbapenemase).

Pharmacokinetics (Adult Data Unless Noted)

Distribution: Vdss: Imipenem: 24.3 L; cilastatin: 13.8 L; relebactam: 19 L.

Protein binding: Imipenem: ~20%; cilastatin: ~40%; relebactam: ~22%.

Metabolism: Imipenem is metabolized in the kidney by dehydropeptidase I; cilastatin prevents imipenem metabolism by this enzyme. Relebactam is minimally metabolized.

Half-life elimination: Imipenem: 1 hour; relebactam: 1.2 hours.

Excretion: Urine (as unchanged drug: imipenem: ~63%; cilastatin: ~77%; relebactam: >90%).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: AUC is increased in patients with CrCl 15 to 89 mL/minute (imipenem: 1.1 to 2.6-fold; cilastatin: 1.2 to 5.5-fold; relebactam: 1.2 to 4.7-fold).

Anti-infective considerations:

Parameters associated with efficacy:

Imipenem and cilastatin (in combination with relebactam):

Interrelationship between imipenem and cilastatin exposure, relebactam exposure, minimum inhibitory concentration (MIC), and efficacy is not fully elucidated; efficacy is time dependent (see Imipenem and Cilastatin monograph), but MIC changes with changing relebactam concentrations (MICdynamic). Maximal efficacy was achieved at fT > MICdynamic >40% to 50% (Bhagunde 2012; Wu 2018).

Relebactam (in combination with imipenem and cilastatin):

AUC, associated with free 24-hour AUC (fAUC24) of relebactam to imipenem and cilastatin-relebactam MIC ratio.

Gram negative organisms (including P. aeruginosa): Goal: 2.7 (bacteriostasis), 4.7 (1-log kill), 7.5 (2-log kill) (Bhagunde 2019a; Bhagunde 2019b; Mavridou 2015).

Postantibiotic effect: Imipenem and cilastatin: See Imipenem and Cilastatin monograph.

Parameters associated with toxicity: Imipenem and cilastatin: See Imipenem and Cilastatin monograph.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (CZ) Czech Republic: Recarbrio;
  • (DE) Germany: Recarbrio;
  • (FI) Finland: Recarbrio;
  • (FR) France: Recarbrio;
  • (GB) United Kingdom: Recarbrio;
  • (HU) Hungary: Recarbrio;
  • (IE) Ireland: Recarbrio;
  • (IT) Italy: Recarbrio;
  • (JP) Japan: Recarbrio;
  • (NL) Netherlands: Recarbrio;
  • (NO) Norway: Recarbrio;
  • (PL) Poland: Recarbrio;
  • (PR) Puerto Rico: Recarbrio;
  • (PT) Portugal: Recarbrio;
  • (QA) Qatar: Recarbrio;
  • (RO) Romania: Recarbrio;
  • (SE) Sweden: Recarbrio;
  • (SI) Slovenia: Recarbrio;
  • (SK) Slovakia: Recarbrio
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