Dosing & Uses
Dosage Forms & Strengths
imipenem/cilastatin/relebactam
injection, powder for reconstitution
- 500mg/500mg/250mg per vial (ie, 1.25g/vial)
Bacterial Pneumonia
Indicated for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)
1.25 g IV q6hr x 4-14 days
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 <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
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
- HABP/VABP: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens
- 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
<18 years: Safety and efficacy not established
Substantially excreted by the kidney and risk of adverse reactions may be greater in patients with impaired renal function
Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection; consider monitoring renal function
No dosage adjustment is required based on age; dosage adjustment is based on renal function
See Adult Dosing
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (8)
- BCG intravesical live
imipenem/cilastatin/relebactam decreases effects of BCG intravesical live by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Intravesical BCG prescribing information states that antimicrobial therapy for other infections may interfere with the effectiveness of BCG intravesical. Antibiotics with activity against mycobacteria are of the greatest concern; however, avoiding all antimicrobial therapy during treatment is currently recommended.
- cholera vaccine
imipenem/cilastatin/relebactam decreases effects of cholera vaccine by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Avoid coadministration of cholera vaccine with systemic antibiotics since these agents may be active against the vaccine strain. Do not administer cholera vaccine to patients who have received oral or parenteral antibiotics within 14 days prior to vaccination.
- divalproex sodium
imipenem/cilastatin/relebactam will decrease the level or effect of divalproex sodium by unknown mechanism. Avoid or Use Alternate Drug. Data from in vitro and animal studies suggest carbapenems may inhibit hydrolysis of the valproic acid glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid/divalproex sodium.
- ganciclovir
ganciclovir, imipenem/cilastatin/relebactam. unknown mechanism. Avoid or Use Alternate Drug. Coadministration may increase risk of seizures. Avoid unless potential benefit outweighs the risk.
- microbiota oral
imipenem/cilastatin/relebactam decreases effects of microbiota oral by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Microbiota oral contains bacterial spores. Antibacterial agents may decrease efficacy if coadministered. Complete antibiotic regimens 2-4 days before initiating microbiota oral. .
- probenecid
probenecid increases levels of imipenem/cilastatin/relebactam by decreasing renal clearance. Avoid or Use Alternate Drug. Coadministration increases the plasma level and half-life of imipenem.
- valacyclovir
valacyclovir, imipenem/cilastatin/relebactam. unknown mechanism. Avoid or Use Alternate Drug. Coadministration may increase risk of seizures. Avoid unless potential benefit outweighs the risk.
- valproic acid
imipenem/cilastatin/relebactam will decrease the level or effect of valproic acid by unknown mechanism. Avoid or Use Alternate Drug. Data from in vitro and animal studies suggest carbapenems may inhibit hydrolysis of the valproic acid glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid/divalproex sodium.
Monitor Closely (5)
- BCG vaccine live
imipenem/cilastatin/relebactam decreases effects of BCG vaccine live by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. BCG vaccine prescribing information states that antimicrobial or immunosuppressive agents may interfere with the development of the immune response and should be used only under medical supervision.
- cyclosporine
cyclosporine, imipenem/cilastatin/relebactam. Other (see comment). Use Caution/Monitor. Comment: Cyclosporine may increase the neurotoxic effects of imipenem. Cases reports describe imipenem increasing or decreasing cyclosporine serum concentration levels.
- sodium picosulfate
imipenem/cilastatin/relebactam decreases effects of sodium picosulfate by altering metabolism. Use Caution/Monitor. Coadministration with antibiotics decreases efficacy by altering colonic bacterial flora needed to convert sodium picosulfate to active drug.
- sodium picosulfate/magnesium oxide/anhydrous citric acid
imipenem/cilastatin/relebactam decreases effects of sodium picosulfate/magnesium oxide/anhydrous citric acid by altering metabolism. Use Caution/Monitor. Coadministration with antibiotics decreases efficacy by altering colonic bacterial flora needed to convert sodium picosulfate to active drug.
- typhoid vaccine live
imipenem/cilastatin/relebactam decreases effects of typhoid vaccine live by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Postpone administering vaccine until at least 3 days after completing antibiotic regimen.
Minor (0)
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%)
<1%
Increased blood creatinine
Postmarketing Reports
Imipenem/cilastatin
- Blood and lymphatic system disorders: Agranulocytosis, increased eosinophils, hemolytic anemia
- Nervous system disorders: Seizure
- Hepatobiliary disorders: Hepatic failure, jaundice
- Skin and subcutaneous tissue disorders: Rash
- Laboratory investigations: Blood lactate dehydrogenase increased, positive Coombs test, eosinophil count increased
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.Pharmacology
Mechanism 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 cephalosporinase (PDC), and K pneumoniae carbapenemase (KPC)
Absorption
Peak plasma concentration
- Imipenem: 104.3 microM
- Relebactam: 64 microM
AUC
- Imipenem: 573.9 microM·hr
- Relebactam: 427.3 microM·hr
Distribution
Protein bound
- Imipenem: 20%
- Cilastatin: 40%
- Relebactam: 22%
Vd
- Imipenem: 24.3 L
- Cilastatin: 13.8 L
- Relebactam: 19 L
Metabolism
Imipenem/cilastatin: When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase, resulting in low imipenem urine levels; cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism so that when imipenem and cilastatin are given concomitantly, adequate concentrations of imipenem are achieved in the urine to enable antibacterial activity
Relebactam: Minimally metabolized; unchanged relebactam was the only drug-related component detected in human plasma
Elimination
Half-life
- Imipenem: 1 hr
- Relebactam: 1.2 hr
Plasma clearance
- Imipenem: 15.3 L/hr
- Relebactam: 8 L/hr
Urinary excretion
- Imipenem, cilastatin, and relebactam are mainly excreted by the kidneys
-
Imipenem/cilastatin
- Imipenem: 63% unchanged
- Cilastatin: 77% unchanged
- Renal excretion of imipenem and cilastatin involves both glomerular filtration and active tubular secretion
-
Relebactam
- >90% unchanged
- Unbound renal clearance of relebactam is greater than the glomerular filtration rate, suggesting that in addition to glomerular filtration, active tubular secretion is involved in the renal elimination, accounting for ~30% of the total clearance
Administration
IV Compatibilities
0.9% NaCl
D5W
D5W/0.9% NaCl
D5W/0.45% NaCl
D5W/0.225% NaCl
Compatible injectable drugs with D5W or 0.9% NaCl as diluents
- Dexmedetomidine
- Dopamine
- Epinephrine
- Fentanyl
- Heparin
- Midazolam
- Norepinephrine
- Phenylephrine
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
Images
Formulary
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