Imipenem-Cilastatin Sodium (imipenem/cilastatin sodium)

Dosage of imipenem/cilastatin is usually expressed in terms of the imipenem content of the fixed combination; dosage of imipenem monohydrate is expressed in terms of anhydrous imipenem.

Imipenem/cilastatin is administered by IV infusion. The fixed-combination preparation is commercially available as a powder that must be reconstituted and further diluted prior to IV infusion.

Imipenem/cilastatin should not be admixed with other antibacterials.

There is no enhanced messaging for this drug.

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.

*Hypersensitivity to any ingredient 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.

The most common adverse effects reported in >=0.2% of adults include phlebitis, nausea, diarrhea, vomiting, rash, pain and erythema at the injection site, fever, hypotension, seizures, dizziness, pruritus, vein induration, urticaria, and somnolence.

The most common adverse effects reported in >1% of pediatric patients >=3 months of age include diarrhea, rash, phlebitis, gastroenteritis, vomiting, IV site irritation, and urine discoloration.

The most common adverse effects reported in >1% of neonates and infants <3 months of age include convulsions, diarrhea, oliguria/anuria, oral candidiasis, rash, and tachycardia.

More Frequent

• Thrombophlebitis

Rare or Very Rare

• Acute hepatic failure
• Acute renal failure
• Agranulocytosis
• Anaphylaxis
• Anemia
• Angioedema
• Bone marrow depression
• Clostridioides difficile infection
• Drug fever
• Dyskinesia
• Dyspnea
• Encephalopathy
• Erythema multiforme
• Hemolytic anemia
• Hemorrhagic colitis
• Hepatitis
• Hyperbilirubinemia
• Hypotension
• Increased alanine transaminase
• Increased aspartate transaminase
• Jaundice
• Leukopenia
• Myoclonus
• Neutropenic disorder
• Oliguria
• Pancytopenia
• Seizure disorder
• Skin rash
• Stevens-johnson syndrome
• Tachycardia
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Diarrhea
• Injection site erythema
• Injection site pain
• Nausea
• Pruritus of skin
• Vomiting

Rare or Very Rare

• Acute abdominal pain
• Acute cognitive impairment
• Agitation
• Arthralgia
• Candidiasis
• Dental discoloration
• Dizziness
• Drowsy
• Dysgeusia
• Eosinophilia
• Gastritis
• General weakness
• Glossitis
• Hallucinations
• Headache disorder
• Hearing loss
• Heartburn
• Hypertrophic thickening of tongue
• Injection site sequelae
• Palpitations
• Paresthesia
• Polyuria
• Proteinuria
• Sialorrhea
• Sore throat
• Tinnitus
• Tremor
• Urine discoloration
• Vertigo
• Vulvovaginitis

No enhanced messaging available.

Safety and efficacy of imipenem/cilastatin in pediatric patients is supported by evidence from adequate and well-controlled studies in adults and clinical studies in pediatric patients.

Adverse effects reported with the drug in neonates and children are similar to those reported in adults and include GI effects (e.g., diarrhea, vomiting, gastroenteritis), rash, urogenital effects (e.g., urine discoloration, oliguria, anuria), and reactions at the site of IV infusion (e.g., phlebitis, IV site irritation). Such adverse effects generally have been reported in 1-4% of pediatric patients receiving imipenem and cilastatin. However, seizures have been reported in neonates and children <=3 months of age receiving the drug. Therefore, because of the risk of seizures, the manufacturer recommends that IV imipenem/cilastatin should not be used in pediatric patients with CNS infections. The manufacturer also recommends that because there are insufficient data to date evaluating IV imipenem/cilastatin in pediatric patients with impaired renal function who weigh <30 kg, the drug should not be used in these patients.

Diluents containing benzyl alcohol should not be used to prepare imipenem/cilastatin for IV administration to neonates. Administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity has not been demonstrated in pediatric patients older than 3 months of age, although small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity.

Data available from small numbers of postmarketing cases of imipenem/cilastatin use during pregnancy are insufficient to identify any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Developmental toxicity studies in animals (mice, rats, rabbits, monkeys) using imipenem and cilastatin (alone or in combination) administered at doses 0.4-2.9 times the recommended human dose (based on body surface area) showed no evidence of drug-induced fetal malformations. Embryofetal development studies using imipenem and cilastatin in cynomolgus monkeys at doses similar to the recommended human dose (based on body surface area) showed an increase in embryonic loss.

Data are insufficient regarding the presence of imipenem and cilastatin in human milk, and data are not available on possible effects on the breast-fed child or effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for imipenem/cilastatin and any potential adverse effects on the breast-fed child from the drugs or from the underlying maternal condition.

The manufacturer states that age-based dosage adjustment of imipenem/cilastatin is not necessary. However, because geriatric patients are more likely to have decreased renal function, dosage should be selected with caution in these patients and monitoring of renal function may be useful. Dosage should be modified in response to the degree of renal impairment.

In clinical studies of imipenem/cilastatin involving approximately 2800 adults 18 years of age or older, approximately 800 were >=65 years of age and 300 were >=75 years of age. There were no apparent differences in safety or effectiveness between these individuals and younger adults and other clinical experience has not revealed evidence of differences in response between these age groups. However, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.

Imipenem is substantially excreted by the kidney, and the risk of severe adverse reactions may be increased in patients with impaired renal function. Limited data indicate that the mean serum half-life of imipenem in healthy geriatric adults 65-75 years of age (with renal function normal for their age) is similar to that expected in individuals with slight renal impairment. The manufacturer states that age-based dosage adjustment is not necessary. However, because geriatric patients are more likely to have decreased renal function, dosage should be selected with caution in these patients and monitoring of renal function may be useful. Dosage should be adjusted in geriatric patients with renal impairment.