Imipenem/cilastatin/relebactam

Name: Imipenem/cilastatin/relebactam

Dosing & Uses

Dosage Forms & Strengths

imipenem/cilastatin/relebactam

injection, powder for reconstitution

  • 500mg/500mg/250mg per vial (ie, 1.25g/vial)

Urinary Tract Infection

Indicated for treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, in individuals with limited or no other treatment options

1.25 g IV q6hr x 4-14 days

Intra-abdominal Infections

Indicated for treatment of complicated intra-abdominal infections (cIAIs) for individuals with limited or no other treatment options

1.25 g IV q6hr x 4-14 days

Dosage Modifications

Renal impairment

  • CrCl 60-89 mL/min: 1 g IV q6hr
  • CrCl 30-59 mL/min: 0.75 g IV q6hr
  • CrCl 15-29 mL/min: 0.5 g IV q6hr
  • CrCl
  • Peritoneal dialysis: Inadequate information to recommend usage
  • ESRD on hemodialysis
    • 0.5 g IV q6hr
    • Imipenem, cilastatin, and relebactam are cleared from the circulation during hemodialysis
    • For patients maintained on hemodialysis, administer after hemodialysis and at intervals timed from the end of that hemodialysis session

Hepatic impairment

  • Imipenem, cilastatin, and relebactam are primarily cleared renally; therefore, hepatic impairment is not likely to have any effect on systemic exposures

Dosing Considerations

Treatment duration depends on severity, infection location, and clinical response

Susceptible gram-negative microorganisms

  • cUTIs: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa
  • cIAIs: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, E cloacae, E coli, Fusobacterium nucleatum, K aerogenes, Klebsiella oxytoca, K pneumoniae, Parabacteroides distasonis, and P aeruginosa

Usage

  • To reduce the development of drug-resistant bacteria and maintain the effectiveness of antibacterial drugs, use only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria
  • When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy
  • In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy

Adverse Effects

1-10%

Diarrhea (6%)

Nausea (6%)

Headache (4%)

Vomiting (3%)

Increased ALT or AST (3%)

Phlebitis or infusion site reactions (2%)

Pyrexia (2%)

Hypertension (2%)

Anemia (1%)

Increased lipase (1%)

CNS adverse effects (1%)

Warnings

Contraindications

History of severe hypersensitivity to imipenem, cilastatin, or relebactam, or any other component

Cautions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions reported in patients receiving therapy with beta-lactams; carefully assess allergy history for previous hypersensitivity to carbapenems, penicillins, cephalosporins, other beta-lactams, and other allergens

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents; if CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C difficile may need to be discontinued

Prescribing antibiotics in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases risk of drug-resistant bacteria

CNS adverse effects

  • CNS adverse reactions (eg, seizures, confusional states, myoclonic activity) reported with imipenem/cilastatin, especially if imipenem exceeds recommended dosage
  • Most commonly reported in patients with CNS disorders (eg, brain lesions, seizures) and/or compromised renal function
  • Continue anticonvulsant therapy in patients with known seizure disorders
  • If CNS adverse reactions occur, patients should undergo a neurological evaluation to determine if drug should be discontinued

Drug interaction overview

  • Ganciclovir: Generalized seizures reported with coadministration of ganciclovir and imipenem/cilastatin
  • Increased seizure potential with valproic acid
    • Coadministration with valproic acid or divalproex sodium may increase risk of breakthrough seizures
    • Avoid concomitant use or consider alternative antibacterial drugs other than carbapenems
    • In vitro animal data suggest carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid

Pregnancy & Lactation

Pregnancy

Data are insufficient in pregnant women to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes

Animal studies

  • Administration during organogenesis to mice, rats, rabbits, and monkeys at doses 1-5 times the maximum recommended human dose ([MRHD] of imipenem 500 mg/cilastatin 500 mg q6hr for total daily doses of imipenem 2g/cilastatin 2g) based on BSA 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 BSA comparison) showed an increase in embryonic loss
  • In an embryofetal study, parental administration of relebactam to pregnant mice during the period of organogenesis was associated with a nondose-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 q6hr 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

Lactation

There are insufficient data on the presence of imipenem/cilastatin and relebactam in human milk, and no data on the effects on the breastfed child, or the effects on milk production

Relebactam is present in milk of lactating rats

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Administration

IV Compatibilities

0.9% NaCl

D5W

D5W/0.9% NaCl

D5W/0.45% NaCl

D5W/0.225% NaCl

IV Incompatibilities

Propofol in D5W or 0.9% NaCl

IV Preparation

Drug has low aqueous solubility; to ensure complete dissolution, it is important to adhere to the following instructions

IV preparation for normal renal function dose

  • Step 1
    • For diluents available in 100-mL prefilled infusion bags, proceed to step 2
    • For diluents not available in 100-mL prefilled infusion bags, aseptically withdraw 100 mL of the desired diluent and transfer it to an empty infusion bag, then proceed to step 2
  • Step 2
    • Withdraw 20 mL (as two 10-mL aliquots) of diluent from the appropriate infusion bag and constitute the vial with one 10-mL aliquot of the diluent
    • Reconstituted suspension is for IV infusion only after dilution in an appropriate infusion solution
  • Step 3
    • After reconstitution, shake vial well and transfer resulting suspension into the remaining 80 mL in the infusion bag
  • Step 4
    • Add the second 10 mL aliquot of infusion diluent to the vial and shake well to ensure complete transfer of vial contents; repeat transfer of the resulting suspension to the infusion solution before administering
    • Agitate the resulting mixture until clear

IV preparation for impaired renal function dose

  • After preparation as instructed above, remove from the 100-mL prepared bag the volume indicated below and discard
  • CrCl 60-89 mL/min (1-g dose): Discard 20 mL; resulting volume is 80 mL
  • CrCl 30-59 mL/min (0.75-g dose): Discard 40 mL; resulting volume is 60 mL
  • CrCl 15-29 or ESRD on hemodialysis (0.5-g dose): Discard 60 mL; resulting volume is 40 mL

IV Administration

Inspected visually for particulate matter and discoloration before administration; solution should appear colorless to yellow; discard if discoloration or visible particles observed

Infuse IV over 30 min

Storage

Unopened vials

  • Store at controlled room temperature of 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)
  • Keep vials in carton until use

Reconstituted vials

  • Controlled room temperature (20-25°C [68-77°F]): Stable up to 2 hr
  • Refrigeration (2-8°C [36-46°F]): Stable up to 24 hr
  • Do not freeze
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