Meropenem-0.9% Nacl (meropenem in 0.9 % sodium chloride)

Meropenem is commercially available as the trihydrate; potency and dosage of the drug are expressed on the anhydrous basis.

Meropenem is administered by IV injection or IV infusion. Safety data supporting the administration of a 40 mg/kg (up to a maximum of 2 g) dose via IV injection are limited; administration by IV infusion is recommended for these higher doses.

Meropenem is available as a powder for injection in single-dose vials or with 0.9% sodium chloride in single-dose, dual-chamber containers. The dual-chamber containers should only be used in patients requiring an entire 500 mg or 1 gram dose of meropenem and not any fraction thereof.

Store vials of powder for injection at 20-25degreesC. Store unactivated dual-chamber units at 20-25degreesC (excursions permitted between 15-30degreesC); protect from freezing.

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)

Selected Carbapenem Antibiotics/Oat1 And Oat3 Inhibitors

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

MECHANISM OF ACTION: Inhibitors of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) may inhibit the renal excretion of doripenem(1), meropenem(2), and tebipenem(3) by competing with them for active tubular secretion.

CLINICAL EFFECTS: Concurrent use of OAT1 and OAT3 inhibitors may result in elevated levels of and toxicity from doripenem(1), meropenem(2) or tebipenem.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of doripenem states that concurrent use of OAT1 and OAT3 inhibitors is not recommended.(1) The US manufacturer of meropenem states that concurrent use of OAT1 and OAT3 inhibitors is not recommended.(2) The US manufacturer of tebipenem states concurrent use of tebipenem and OAT1 and OAT3 inhibitors is generally not recommended. If concurrent use with tebipenem is necessary, monitor more frequently for adverse reactions associated with tebipenem, such as diarrhea and headache.(3)

DISCUSSION: Probenecid has been shown to increase doripenem half-life (T1/2) and area-under-curve (AUC) by 53% and 75%, respectively.(1) In a study in six subjects, concurrent probenecid increased meropenem T1/2 by 33%.(4) Other studies have shown probenecid to increase the T1/2 of meropenem by 38% and the extent of meropenem systemic exposure by 58%.(2) In a study, coadministration of a single oral dose of 250 mg of tebipenem pivoxil with probenecid (OAT1 and OAT3 inhibitor) increased tebipenem maximum concentration (Cmax) by approximately 1.5-fold and plasma area-under-curve (AUC) by approximately 2.9-fold.(3) OAT1 inhibitors linked to this monograph include: cabotegravir and probenecid. OAT3 inhibitors linked to this monograph include: cabotegravir, leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(5)

There are no moderate interactions for this drug.

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

*History of anaphylactic reaction to beta-lactams.

There are no contraindication contraindications for this drug.

• 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)

• Cerebral lesions
• Lower seizure threshold
• Seizure disorder
• Thrombocytopenic disorder

Adverse effects reported in <=2% of patients receiving meropenem include headache, nausea, constipation, diarrhea, anemia, vomiting, and rash.

More Frequent

• Anemia

Less Frequent

• Apnea
• Injection site sequelae
• Shock

Rare or Very Rare

• Abnormal hepatic function tests
• Acute generalized exanthematous pustulosis
• Acute myocardial infarction
• Agranulocytosis
• Anaphylaxis
• Angioedema
• Asthma
• Bradycardia
• Cardiac arrest
• Clostridioides difficile infection
• DRESS syndrome
• Drug-induced hepatitis
• Epistaxis
• Erythema multiforme
• Gastrointestinal hemorrhage
• Heart failure
• Hemolytic anemia
• Hepatic failure
• Hyperbilirubinemia
• Hypertension
• Hypotension
• Hypoxia
• Ileus
• Increased alanine transaminase
• Increased aspartate transaminase
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Neutropenic disorder
• Nontraumatic hemoperitoneum
• Obstructive hyperbilirubinemia
• Pleural effusions
• Pulmonary edema
• Pulmonary thromboembolism
• Renal failure
• Rhabdomyolysis
• Seizure disorder
• Skin ulcer
• Stevens-johnson syndrome
• Syncope
• Tachycardia
• Thrombocytopenic disorder
• Thrombophlebitis
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Constipation
• Diarrhea
• Headache disorder
• Nausea
• Skin rash
• Vomiting

Less Frequent

• Glossitis
• Oral candidiasis
• Pruritus of skin

Rare or Very Rare

• Abdominal distension
• Acute abdominal pain
• Agitation
• Back pain
• Black tarry stools
• Candidiasis
• Chest pain
• Cough
• Delirium
• Dizziness
• Drowsy
• Dyspepsia
• Dyspnea
• Dysuria
• Fever
• Flatulence
• General weakness
• Hallucinations
• Hyperhidrosis
• Hypervolemia
• Insomnia
• Nervousness
• Pain
• Paresthesia
• Pelvic pain
• Peripheral edema
• Urinary incontinence

No enhanced messaging available.

Safety and efficacy of meropenem have been established in children >=3 months of age with complicated skin and skin structure infections and bacterial meningitis.

Safety and efficacy of meropenem have been established for the treatment of intra-abdominal infections in pediatric patients of all ages.

Data on meropenem use during pregnancy are insufficient to establish a drug-associated risk of birth defects or miscarriage.

Fetal toxicity and malformations were not reported in pregnant rats and monkeys when IV meropenem was administered during organogenesis at doses up to 2.4 and 2.3 times the maximum recommended human dose (MRHD) based on body-surface area (BSA), respectively. Additionally, no adverse effects were reported in rat offspring when meropenem was administered at doses 3.2 times the MRHD during late pregnancy and lactation.

Meropenem is excreted into breast milk; however, no information is available on the effects of meropenem on the breast-fed child or the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for the drug and the potential for any adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

Although the manufacturer makes no specific dosage recommendations in geriatric patients, these patients are more likely to have reduced renal function compared with younger adults; therefore, caution should be undertaken during dosage selection. Monitoring of renal function may be useful in geriatric patients receiving meropenem.

In clinical studies of meropenem, approximately 1100 patients (30%) were >=65 years of age and 400 patients (11%) were >=75 years of age. No substantial differences in safety and efficacy were identified relative to younger adults, but increased sensitivity cannot be ruled out.

A pharmacokinetic study in geriatric patients showed that the reduction in the plasma clearance of meropenem correlates with age-associated reductions in creatinine clearance.