Recarbrio (imipenem/cilastatin sodium/relebactam)

No dosing information is available for this tab.

The fixed combination of imipenem, cilastatin, and relebactam (imipenem/cilastatin/relebactam) is administered by IV infusion over 30 minutes. The drug is available as a powder for injection that must be reconstituted and diluted prior to administration.

Store vials of imipenem/cilastatin/relebactam in the original carton at 20-25degreesC (excursions permitted between 15-30degreesC).

After reconstitution with an appropriate diluent and further dilution in an infusion bag, imipenem/cilastatin/relebactam can be stored at room temperature (up to 30degreesC) for up to 2 hours, or under refrigeration at 2-8degreesC for up to 24 hours. The solution should not be frozen.

No dosing information is available for this tab.

Relebactam does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, or induce 1A2, 2B6, or 3A4.

Relebactam does not inhibit organic anion transporting polypeptide (OATP) 1B1, OAT1B3, OAT1, OAT3, OCT2, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug and toxin extrusion (MATE) 1, MATE2K, or BSEP.

Relebactam is not a substrate of OAT1, OCT2, P-gp, BCRP, MRP2, or MRP4 transporters, but is a substrate of OAT3, OAT4, MATE1, and MATE2K.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Carbapenem Antibiotics/Valproic Acid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Carbapenems may inhibit the absorption of valproic acid from the gastrointestinal tract.(1-3) Meropenem may accelerate the renal excretion of valproate.(4) Carbapenems may increase valproic acid intake by erythrocytes.(5,6) Carbapenems may inhibit the metabolite of valproic acid, valproic acid-glucuronide, from being converted back into the active parent form.(7-9)

CLINICAL EFFECTS: Concurrent use of carbapenems and valproic acid without supplemental antiepileptic therapy is not recommended because it results in rapid, significant reductions in serum levels of valproic acid to non-therapeutic levels which may result in seizures. Dose escalation of valproic acid formulations does not counteract the decrease in serum levels and patients will require additional antiepileptic therapy. The effects may persist for several days beyond discontinuation of the carbapenem.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of carbapenem antibiotics in patients maintained on valproic acid when possible. If concurrent therapy is warranted, patients will require the addition of a supplemental anti-epileptic agent until valproic acid levels return to therapeutic range.

DISCUSSION: In a retrospective review of an 18 month period, charts of 39 patients who received concurrent therapy with valproate and meropenem were examined. A pharmacokinetic interaction was observed in all 39 patients, with an average decrease in valproate levels of 66%. The decrease occurred within 24 hours of the initiation of concurrent therapy. Electroclinical deterioration was seen in 55% of patients.(10) A prospective study evaluated ICU patients given levetiracetam or valproic acid to control seizures. Twenty-four of the 35 patients required meropenem. Each patient that was on valproic acid had valproic acid levels decrease following the addition of meropenum. (13) In a study in 23 healthy male subjects, concurrent doripenem (500 mg every 8 hours) decreased the maximum concentration, (Cmax) area-under-curve (AUC), and minimum concentration (Cmin) of valproic acid by 44.5%, 63% and 77.7%, respectively.(14) There are several case reports of decreased valproic acid levels following the addition of meropenem to therapy.(4,11,12,15-21) Some patients experienced increased seizures.(4 ,11,15,16,20) In some cases, decreased levels persisted despite increased doses of valproic acid.(11,12,15,17,18,21) Others required additional anti-seizure medications during concurrent therapy.(16) Decreased valproic acid levels have also been reported during concurrent ertapenem.(22-25) Seizures were reported in two patients.(22,25) In one patient, valproic acid levels returned to therapeutic levels within three days of discontinuation of ertapenem, despite no change in valproic acid dose.(25) Decreased valproic acid levels have also been reported during concurrent imipenem.(26) A retrospective study evaluated 52 patients given valproic acid and a carbapenem over a five year period. Patients received either ertapenem, imipenem/cilastatin, or meropenem (9, 17, and 26 patients, respectively). The average serum valproic acid concentration before and after carbapenem use was 58.6 +/- 19.2 and 23.7 +/- 16.3 mg/dL, respectively, which represented a decrease of 60% +/- 23% (p<0.001). Valproic acid concentrations were reduced with both intravenous and oral formulations of valproic acid (52% +/- 16% and 61% +/-24%, respectively). Valproic acid serum concentrations were subtherapeutic (<50 mg/L) in 90% of patients during carbapenem concurrent use. Use during ertapenem, imipenem/cilastatin, and meropenem decreased valproic acid concentrations by 72% +/- 17%, 42% +/- 22%, and 67% +/- 19%, respectively.(28) A retrospective study in 54 patients treated with valproic acid for at least three months for seizure control were evaluated for changes in valproic acid with concurrent carbapenem therapy. The mean change in valproic acid levels was 80%, 68%, and 51% in the meropenem, ertapenem, and imipenem group, respectively. During concurrent therapy, 48.1% of patients experienced aggravation of seizures and 25.9% died. Valproic acid levels of those experiencing aggravation of seizures were 17.7 +/- 9.9 mcg/mL versus 17.9 +/- 12.6 mcg/mL in those without aggravation (p=0.944).(29) A retrospective study in 381 neurosurgery inpatients evaluated valproic acid levels with concurrent meropenem therapy. Patients were grouped based on valproic acid dose of 1.2 g/day or 1.6 g/day with and without meropenem. In both 1.2 g/day and 1.6 g/day valproic acid groups, valproic acid levels were decreased after initiation of meropenem (67.3 +/- 4.6 mcg/mL v. 15.3 +/- 1.9 mcg/mL; 78.2% decrease, p<0.001 for 1.2 g/day valproic acid; 67.6 +/- 1.2 mcg/mL v. 18.1 +/- 2.6 mcg/mL; 72.5% decrease, p<0.001 for 1.6 g/day valproic acid. Valproic acid concentrations recovered to levels comparable to valproic acid alone more than seven days after meropenem discontinuation.(30)

Imipenem-Cilastatin/Ganciclovir,Valganciclovir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve additive or synergistic effects on the seizure threshold.

CLINICAL EFFECTS: Concurrent use of imipenem-cilastatin with ganciclovir may result in generalized seizures.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of imipenem-cilastatin states that imipenem-cilastatin and ganciclovir should not be coadministered unless the potential benefits outweigh the risks of seizures.(1)

DISCUSSION: Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin.(1)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

There are no moderate interactions for this drug.

*History of known severe hypersensitivity to any component in the formulation.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 2 (mild) GFR 60-89 ml/min
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Clostridioides difficile infection
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Lower seizure threshold
• Seizure disorder

There are no moderate contraindications for this drug.

HABP/VABP patients: The most frequent adverse reactions reported in >=5% of patients in clinical trials include increases in ALT/AST, anemia, diarrhea, hypokalemia, and hyponatremia.

cUTI and cIAI patients: The most frequent adverse reactions reported in >=2% of patients in clinical trials include diarrhea, nausea, headache, vomiting, ALT/AST increases, phlebitis/infusion site reactions, pyrexia, and hypertension.

More Frequent

• Abnormal hepatic function tests
• Hypertension
• Increased alanine transaminase
• Increased aspartate transaminase
• Thrombophlebitis

Less Frequent

• Anemia
• Hypokalemia
• Hyponatremia

Rare or Very Rare

• Acute hepatic failure
• Agranulocytosis
• Anaphylaxis
• Clostridioides difficile infection
• Hemolytic anemia
• Hypersensitivity drug reaction
• Jaundice
• Seizure disorder
• Skin rash
• Tremor

More Frequent

• Diarrhea
• Fever
• Headache disorder
• Nausea
• Vomiting

Less Frequent

• Elevated serum lipase

Rare or Very Rare

• Eosinophilia
• Injection site sequelae

No enhanced messaging available.

The safety and efficacy of imipenem, cilastatin, and relebactam in patients <18 years of age have not been established.

There is insufficient data on the use of imipenem/cilastatin/relebactam in pregnant women. In animal studies, embryonic loss and fetal abnormalities were reported with use.

There are insufficient data on the presence of imipenem/cilastatin/relebactam in human milk. The effects of the fixed-combination drug on breast-fed infants or on the production of milk are unknown. In animal studies, relebactam was present in milk.

Because of the greater frequency of reduced renal function in geriatric patients, care should be taken with dose selection. No dosage adjustment is necessary solely based on age.

No clinically significant differences have been observed in the pharmacokinetics of imipenem/cilastatin/relebactam in patients >=65 years of age. Because of the greater frequency of reduced renal function in geriatric patients, care should be taken with dose selection, and patients should be monitored closely for changes in renal function. No dosage adjustment is necessary solely based on age.