Introduction

Antibacterial; fixed combination of imipenem (a carbapenem β-lactam antibiotic), cilastatin (a renal dehydropeptidase inhibitor that prevents renal metabolism of imipenem), and relebactam (a β-lactamase inhibitor).

Uses for Imipenem, Cilastatin Sodium, and Relebactam

Respiratory Tract Infections

Treatment of hospital-acquired bacterial or ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible gram-negative microorganisms in patients ≥18 years of age: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella aerogenes, K. oxytoca, K. pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.

The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines recommend coverage for S. aureus, P. aeruginosa, and other gram-negative bacilli in all empiric regimens for clinically suspected ventilator-associated pneumonia or hospital-associated pneumonia. When empiric coverage of methicillin-sensitive S. aureus is indicated, carbapenems, including imipenem and meropenem, are suggested treatment options.

Urinary Tract Infections

Used in patients ≥18 years of age who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible gram-negative microorganisms: E. cloacae, E. coli, K. aerogenes, K. pneumoniae, and P. aeruginosa.

In cases of severe cUTI that includes high fever, sepsis, vomiting, or anticipated antimicrobial resistance to oral regimens, a parenteral agent such as a combination β-lactam and β-lactamase inhibitor may be warranted.

Practice guidelines from IDSA and European Society for Microbiology and Infectious Diseases (ESCMID) state that patients with pyelonephritis requiring hospitalization should receive an IV antimicrobial such as a carbapenem, extended-spectrum penicillin with or without an aminoglycoside, a fluoroquinolone, or an aminoglycoside with or without ampicillin; selection of an appropriate treatment should be based on susceptibility and local resistance data. Recommended duration of therapy for treatment of pyelonephritis is 10–14 days.

Intra-abdominal Infections

Used in patients ≥18 years of age who have limited or no alternative treatment options for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible gram-negative microorganisms: Bacteroides caccae, B. fragilis, B. ovatus, B. stercoris, B. thetaiotaomicron, B. uniformis, B. vulgatus, Citrobacter freundii, E. cloacae, E. coli, Fusobacterium nucleatum, K. aerogenes, K. oxytoca, K. pneumoniae, Parabacteroides distasonis, and P. aeruginosa.

Current guidelines from the Surgical Infection Society (SIS) do not address use of imipenem/cilastatin/relebactam. However, use of imipenem/cilastatin is recommended for empiric coverage for intra-abdominal infection, generally in high-risk patients.

Imipenem, Cilastatin Sodium, and Relebactam Dosage and Administration

General

Pretreatment Screening

• Before initiating therapy, take a complete history of any hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactams, and other allergens.

Patient Monitoring

• Monitor creatinine clearance in patients with fluctuating renal function.

Other General Considerations

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

Administration

Administer by IV infusion over 30 minutes. Available as a powder for injection that must be reconstituted and diluted prior to administration.

IV Administration

Reconstitution and Dilution

Reconstitute and further dilute commercially available powder for injection with a compatible diluent (0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose injection and 0.9% sodium chloride injection, 5% dextrose injection and 0.45% sodium chloride injection, or 5% dextrose injection and 0.225% sodium chloride injection).

Imipenem/cilastatin/relebactam has low aqueous solubility. To ensure complete dissolution of powder, adhere to the following instructions:

Step 1: For diluents in 100 mL prefilled infusion bags, proceed to step 2. For diluents not available in a prefilled infusion bag, aseptically withdraw 100 mL of an appropriate diluent and transfer to an evacuated infusion bag, then proceed to step 2.

Step 2: Withdraw 20 mL of diluent from the bag (as two 10-mL aliquots) and reconstitute the vial with one 10-mL aliquot of diluent.

Step 3: After addition of the first aliquot of diluent, shake the vial well, and transfer the contents into the remaining 80 mL of the infusion bag.

Step 4: Add the second 10-mL aliquot of infusion diluent to the vial and shake well to ensure complete dissolution of vial contents. Repeat transfer of the contents of the vial to the infusion bag. Agitate the final mixture in the infusion bag until the solution is clear.

Follow the above reconstitution and dilution instructions for all patients, regardless of renal function. The volume of the prepared solution to be administered is determined based on renal function. For patients with renal impairment, prepare a reduced dose of imipenem/cilastatin/relebactam (1 g, 0.75 g, or 0.5 g) by preparing a 100-mL solution containing 1.25 g (as described in the steps above), and then withdraw and discard the excess according to Table 1.

Rate of Administration

Administer each dose by IV infusion over 30 minutes.

Dosage

Adults

HABP/VABP, cIAI, cUTI

IV

Dosage of imipenem, cilastatin, 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.

Duration of therapy should be guided by severity and location of infection, as well as clinical response. The recommended duration of treatment is 4 to 14 days.

Dosage of imipenem/cilastatin/relebactam is based on imipenem susceptibility of the suspected or confirmed causative organism(s) and the patient’s renal function.

For treatment of infections proven or suspected to be caused by susceptible gram-negative bacteria in adults with Cl_cr ≥90 mL/minute, recommended dosage is 1.25 g (imipenem 500 mg, cilastatin 500 mg, relebactam 250 mg) by IV infusion every 6 hours. Reduced dosage is recommended in patients with Cl_cr <90 mL/minute. (See Renal Impairment under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

Dosage adjustments required in patients with renal impairment (see Table 2). In patients with end-stage renal disease receiving hemodialysis, administration should be timed to follow hemodialysis.

Cl_cr calculated using the Cockcroft-Gault formula

Geriatric Patients

Select dosage with caution and monitor patients closely for changes in renal function. No dosage adjustment is necessary solely based on age.

Contraindications

• History of known severe hypersensitivity to any component in the formulation.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity (anaphylactic) reactions, both serious and fatal, reported in patients receiving β-lactam therapy. Before starting treatment with imipenem/cilastatin/relebactam, any previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactams or other allergens must be investigated.

If a hypersensitivity reaction occurs, discontinue the drug immediately.

Seizures and Other CNS Adverse Reactions

Seizure, myoclonic activity, and states of confusion reported with imipenem and cilastatin, a component of imipenem/cilastatin/relebactam, particularly when recommended doses were exceeded. Mostly occurred in patients with a history of seizure disorder or brain lesions, and/or decreased renal function.

Continue patients with known seizure disorders on their anticonvulsant medication(s) when starting treatment with imipenem/cilastatin/relebactam. If any adverse CNS reaction occurs, including seizure, complete a neurologic evaluation to determine if the fixed-combination drug should be discontinued.

Increased Seizure Potential Due to Interaction with Valproic Acid

Concomitant use of valproic acid and carbapenems (e.g., imipenem and cilastatin) can increase the risk of breakthrough seizures. Avoid concomitant use of imipenem/cilastatin/relebactam in patients on valproic acid or divalproex sodium; consider an alternative antibiotic class other than carbapenems in patients whose seizures are well controlled on valproic acid or divalproex sodium.

Clostridioides difficile-associated Diarrhea

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly Clostridium difficile).

C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives and may range in severity from mild diarrhea to fatal colitis.

Consider CDAD in all patients who present with diarrhea following antibacterial use; obtain careful medical history since CDAD may occur as late as ≥2 months after antibiotic administration.

If CDAD is suspected, discontinue antimicrobial therapy not directed against C. difficile. Institute appropriate medical and pharmacologic management of C. difficile, as well as surgical evaluation as clinically indicated.

Development of Drug-resistant Bacteria

If there is a low likelihood of bacterial infection, use of imipenem/cilastatin/relebactam for treatment or prophylaxis is unlikely to provide benefit and can increase the risk of developing drug-resistant bacteria. Identify alternative antimicrobials for use if low likelihood of bacterial infection.

Specific Populations

Pregnancy

No adequate data in pregnant women. Has resulted in embryonic loss and fetal abnormalities in animal studies.

Lactation

Not known whether distributed into human milk; in animal studies, relebactam was present in milk. Potential effects on nursing infants or on milk production not known.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No clinically significant differences in pharmacokinetics in patients ≥65 years of age.

Renal Impairment

Reduce dosage in patients with a Cl_cr<90 mL/minute.

Common Adverse Effects

HABP/VABP patients (≥5%): increases in ALT/AST, anemia, diarrhea, hypokalemia, hyponatremia.

cUTI and cIAI patients (≥2%): diarrhea, nausea, headache, vomiting, ALT/AST increases, phlebitis/infusion site reactions, pyrexia, hypertension.

General

Pretreatment Screening

• Before initiating therapy, take a complete history of any hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactams, and other allergens.

Patient Monitoring

• Monitor creatinine clearance in patients with fluctuating renal function.

Other General Considerations

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

Administration

Administer by IV infusion over 30 minutes. Available as a powder for injection that must be reconstituted and diluted prior to administration.

IV Administration

Reconstitution and Dilution

Reconstitute and further dilute commercially available powder for injection with a compatible diluent (0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose injection and 0.9% sodium chloride injection, 5% dextrose injection and 0.45% sodium chloride injection, or 5% dextrose injection and 0.225% sodium chloride injection).

Imipenem/cilastatin/relebactam has low aqueous solubility. To ensure complete dissolution of powder, adhere to the following instructions:

Step 1: For diluents in 100 mL prefilled infusion bags, proceed to step 2. For diluents not available in a prefilled infusion bag, aseptically withdraw 100 mL of an appropriate diluent and transfer to an evacuated infusion bag, then proceed to step 2.

Step 2: Withdraw 20 mL of diluent from the bag (as two 10-mL aliquots) and reconstitute the vial with one 10-mL aliquot of diluent.

Step 3: After addition of the first aliquot of diluent, shake the vial well, and transfer the contents into the remaining 80 mL of the infusion bag.

Step 4: Add the second 10-mL aliquot of infusion diluent to the vial and shake well to ensure complete dissolution of vial contents. Repeat transfer of the contents of the vial to the infusion bag. Agitate the final mixture in the infusion bag until the solution is clear.

Follow the above reconstitution and dilution instructions for all patients, regardless of renal function. The volume of the prepared solution to be administered is determined based on renal function. For patients with renal impairment, prepare a reduced dose of imipenem/cilastatin/relebactam (1 g, 0.75 g, or 0.5 g) by preparing a 100-mL solution containing 1.25 g (as described in the steps above), and then withdraw and discard the excess according to Table 1.

Rate of Administration

Administer each dose by IV infusion over 30 minutes.

Dosage

Adults

HABP/VABP, cIAI, cUTI

IV

Dosage of imipenem, cilastatin, 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.

Duration of therapy should be guided by severity and location of infection, as well as clinical response. The recommended duration of treatment is 4 to 14 days.

Dosage of imipenem/cilastatin/relebactam is based on imipenem susceptibility of the suspected or confirmed causative organism(s) and the patient’s renal function.

For treatment of infections proven or suspected to be caused by susceptible gram-negative bacteria in adults with Cl_cr ≥90 mL/minute, recommended dosage is 1.25 g (imipenem 500 mg, cilastatin 500 mg, relebactam 250 mg) by IV infusion every 6 hours. Reduced dosage is recommended in patients with Cl_cr <90 mL/minute. (See Renal Impairment under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

Dosage adjustments required in patients with renal impairment (see Table 2). In patients with end-stage renal disease receiving hemodialysis, administration should be timed to follow hemodialysis.

Cl_cr calculated using the Cockcroft-Gault formula

Geriatric Patients

Select dosage with caution and monitor patients closely for changes in renal function. No dosage adjustment is necessary solely based on age.

Relebactam does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, or induce 1A2, 2B6, or 3A4.

Relebactam does not inhibit organic anion transporting polypeptide (OATP) 1B1, OAT1B3, OAT1, OAT3, OCT2, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug and toxin extrusion (MATE) 1, MATE2K, or BSEP.

Relebactam is not a substrate of OAT1, OCT2, P-gp, BCRP, MRP2, or MRP4 transporters, but is a substrate of OAT3, OAT4, MATE1, and MATE2K.

Specific Drugs