Imipenem + Cilastatin + Relebactam

Indications

Imipenem + Cilastatin + Relebactam is used for: Urinary Tract Infection, Intra-abdominal Infections

Adult Dose

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

Child Dose

<18 years: Safety and efficacy not established

Renal Dose

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 <15 mL/min and not on hemodialysis: Do not use unless hemodialysis is instituted within 48 hr 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

Administration

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

Contra Indications

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

Precautions

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

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

Interactions

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

Side Effects

Side effects of Imipenem + Cilastatin + Relebactam : 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%) <1% Increased blood creatinine

Mode of Action

Imipenem: Carbapenem; inhibits bacterial cell-wall synthesis by binding to penicillin-binding proteins resulting in bacterial cell lysis Cilastatin: Prevents renal metabolism of imipenem by competing with dehydropeptidase in the renal tubules Relebactam: Has no intrinsic antibacterial activity; protects imipenem from degradation by certain serine beta-lactamases such as sulfhydryl variable (SHV), temoneira (TEM), cefotaximase-Munich (CTX-M), E cloacae P99 (P99), Pseudomonas-derived ceph