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