Ertapenem (ertapenem sodium)

Dosage of ertapenem sodium is expressed in terms of ertapenem.

Ertapenem sodium is administered by IV infusion or by IM injection. The manufacturer states that the drug may be administered once daily by IV infusion for up to 14 days or by IM injection for up to 7 days.

Store lyophilized powder vials at <=25degreesC.

Ertapenem does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro and does not inhibit the P-glycoprotein transport system or act as a substrate for P-glycoprotein-mediated transport.

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)

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)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Ertapenem/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.(1)

CLINICAL EFFECTS: Concurrent use of ertapenem may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Monitor tacrolimus levels in patients receiving concurrent ertapenem. The dosage of tacrolimus may need to be adjusted if ertapenem is initiated or discontinued.(1) When concurrent therapy of ertapenem and tacrolimus is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: A retrospective review of 13 renal transplant patients found that the addition of ertapenem to tacrolimus therapy decreased the mean dose of tacrolimus required to achieve desired therapeutic concentrations by 46%. Decreased tacrolimus requirements were noted 2 days after initiation of ertapenem. There was no change in serum creatinine during ertapenem therapy, indicating that a change in renal function was not responsible for the elevated tacrolimus levels.(1)

*Known hypersensitivity to ertapenem, other carbapenems, or any ingredient in the formulation.

*History of anaphylactic reaction to beta-lactams.

*IM injections are prepared using lidocaine hydrochloride and are contraindicated in patients with known hypersensitivity to local anesthetics of the amide type.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Clostridioides difficile infection
• Severe renal impairment

• Cerebral lesions
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Seizure disorder

Adverse effects occurring in >=5% of adult patients receiving ertapenem sodium, including those who were switched to an oral antimicrobial, include diarrhea, nausea, headache, and infused vein complication.

Adverse effects reported in pediatric patients were similar to those in adults.

More Frequent

• Injection site sequelae

Less Frequent

• Abnormal hepatic function tests
• Atelectasis
• Neutropenic disorder
• Tachycardia
• Thrombophlebitis

Rare or Very Rare

• Acute generalized exanthematous pustulosis
• Altered consciousness
• Anaphylaxis
• Biliary calculus
• Bradycardia
• Cardiac arrhythmia
• Clostridioides difficile infection
• DRESS syndrome
• Encephalopathy
• Eosinophilia
• Gastrointestinal hemorrhage
• Hallucinations
• Heart failure
• Hypersensitivity angiitis
• Hypothermia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Myoclonus
• Pancreatitis
• Pleural effusions
• Seizure disorder
• Severe dyspnea
• Stevens-johnson syndrome
• Toxic epidermal necrolysis
• Urinary retention
• Wheezing

More Frequent

• Diarrhea
• Headache disorder
• Nausea

Less Frequent

• Acute abdominal pain
• Altered mental status
• Candidiasis
• Chest pain
• Constipation
• Cough
• Dizziness
• Dyspepsia
• Dyspnea
• Edema
• Erythema
• Fatigue
• Fever
• Gastroesophageal reflux disease
• General weakness
• Hypertension
• Hypotension
• Insomnia
• Pharyngitis
• Pruritus of skin
• Skin inflammation
• Skin rash
• Symptoms of anxiety
• Thrombocytosis
• Vaginitis
• Vomiting

Rare or Very Rare

• Abdominal distension
• Anorexia
• Arthralgia
• Ataxia
• Chills
• Dehydration
• Dental discoloration
• Drowsy
• Dysgeusia
• Dyskinesia
• Flank pain
• Flushing
• Gait abnormality
• Gout
• Hematoma
• Hiccups
• Hypoesthesia
• Induration of skin
• Leg pain
• Malaise
• Muscle weakness
• Nervousness
• Otitis externa
• Pain
• Rhinitis
• Rhinorrhea
• Syncope
• Tremor
• Weight loss

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Safety and efficacy of ertapenem for labeled indications have been established in pediatric patients >=3 months to 17 years of age based on evidence from adequate and well-controlled clinical trials in adults, pharmacokinetic data in pediatric patients, and additional data from pediatric studies in patients >=3 months to 17 years of age.

The manufacturer states that safety and efficacy have not been established in infants <3 months of age.

Ertapenem is not recommended for the treatment of meningitis in pediatric patients due to insufficient cerebrospinal fluid (CSF) penetration.

Data on ertapenem use during pregnancy are insufficient to establish a drug-associated risk of birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, systemic exposure to ertapenem up to 1.2 times the human exposure at the maximum recommended human dose (MRHD) in rats and up to 3 times the MRHD in mice during the period of organogenesis did not result in developmental malformations. At systemic exposures of ertapenem 1.2 times the MRHD in pregnant rats during the period of organogenesis through lactation, there was no evidence of fetal toxicity, developmental delays, or impaired reproduction in offspring.

Ertapenem is distributed into breast milk. The effects on the breast-fed child or on milk production are not known. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed child from ertapenem or from the underlying maternal condition.

Following the last 1 g dose of IV therapy for pelvic infections (3-10 days of therapy), the ertapenem concentration in breast milk within 24 hours of the last dose ranged from <0.13 (lower limit of quantitation) to 38 mcg/mL in 5 women. By the fifth day after discontinuation of therapy, levels of ertapenem were undetectable in the breast milk of 4 women, and below the lower limit of quantitation (<0.13 mcg/mL) in 1 woman.

Because geriatric patients are more likely to have reduced renal function compared to younger adults, caution should be undertaken during dosage selection. Monitoring of renal function may be useful in geriatric patients receiving ertapenem.

No substantial differences in safety and efficacy relative to younger adults. Total and unbound area under the curve (AUC) concentrations of ertapenem are increased 37% and 67%, respectively, in geriatric patients compared with younger adults.