imipenem/cilastatin/relebactam (Rx)

Brand and Other Names:Recarbrio
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Dosing & Uses

AdultPediatricGeriatric

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 <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

  • 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

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Interactions

Interaction Checker

and imipenem/cilastatin/relebactam

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            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
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            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

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            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.

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            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
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            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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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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