Meropenem and Valproic Acid: Interaction Details

a) In a retrospective study of adult Chinese patients receiving both valproic acid and meropenem (n=50), plasma concentrations of valproic acid significantly decreased during concomitant administration with meropenem (24.6 +/- 4.3 mcg/mL compared with 88.8 +/- 13.6 mcg/mL prior to coadministration), but seizure frequency or duration did not differ. Seizure duration was shorter after coadministration was stopped compared with before coadministration. Valproic acid concentrations recovered from 24.6 to 39.8 mcg/mL within 14 days after stopping meropenem ⁷.

b) In a 10-year retrospective study, concomitant use of valproic acid and a carbapenem (imipenem/cilastatin n=46; meropenem n=68, or ertapenem n=48) resulted in a subtherapeutic valproic acid (VPA) serum level (50 mcg/mL) in 92% of patients. The VPA serum concentration significantly decreased by 69.1% with ertapenem and by 65.2% with meropenem, while a nonsignificant decrease of 11.9% occurred with imipenem/cilastatin. A decrease in VPA serum levels during concomitant therapy was associated with a significant increased risk of seizures (OR, 0.96 [95% CI, 0.95 to 0.98]) and a nonsignificant increase in status epilepticus (OR, 0.98 [95% CI, 0.96 to 1]) ⁶.

c) In a retrospective study of 36 patients, mean valproic acid plasma concentrations were reduced within 24 hours of meropenem coadministration and remained reduced for more than 14 days after discontinuation of meropenem, regardless of valproic acid dose. Various valproic acid dose forms were tested at dosages of less than 1000 mg/day (group 1), 1000 to less than 2000 mg/day (group 2), 2000 to less than 3000 mg/day (group 3), and 3000 mg/day or greater (group 4). Following meropenem administration, the mean valproic acid plasma concentration significantly decreased from 50.8 +/- 4.5 mcg/mL to 9.9 +/- 2.1 mcg/mL (p less than 0.001); a mean decrease of 82.1% +/- 2.7%. Valproic acid concentrations remained low (18.6 +/- 3.4 mcg/mL) for 7 days after meropenem discontinuation and then gradually increased to baseline levels (44.7 +/- 5.2 mcg/mL) after 8 to 14 days. The effect on valproic acid concentrations was similar in all dosage groups. In blood samples collected within 24 hours of meropenem administration, the mean valproic acid plasma concentration was 9.9 +/- 3.2 mcg/mL. There was no significant difference in the mean reduction of valproic acid levels with high-dose (83.4% +/- 3.8%) compared with low-dose (81% +/- 4.8%) meropenem. Concomitant use of meropenem with valproic acid is not recommended and an increase in valproic acid dose to 3000 mg or greater during meropenem therapy did not increase valproic acid concentration above 20 mcg/mL ³.

d) A retrospective study of 39 patients with concurrent treatment with valproic acid and meropenem demonstrated an average decrease of valproic acid levels of 66% within 24 hours. In patients receiving meropenem after the start of valproic acid, the mean plasma concentrations of valproic acid decreased from 64.3 mg/L to 22.5 mg/L. Therapeutic valproic acid plasma concentrations range from 50 to 100 mg/L. Patients receiving valproic acid after meropenem did not achieve therapeutic plasma levels of valproic acid, with mean levels of 11.8 mg/L. Despite additional loading doses and increased maintenance doses, only one patient achieved therapeutic plasma levels after the maintenance dose was increased to 12 grams daily. Due to adverse patient outcomes or incomplete data, 20 patients were evaluated for causality and clinical relevance of the interaction. The interaction was rated probable in 16 and possible in 4 of the 20 patients. Eleven of these patients experienced an increase in seizures, electroencephalogram changes, or both. Valproic acid concentrations achieved therapeutic range approximately 8 days after concurrent use of the two medications ceased, and seizure activity was controlled ⁸.

e) The coadministration of meropenem with valproic acid produced a pronounced decline in valproic acid plasma concentrations. In a case report, a 21-year-old woman was administered valproic acid 1920 mg as a continuous IV infusion over 24 hours in an attempt to control recurrent tonic-clonic seizures. A valproic acid serum concentration of 52.5 mcg/mL was attained on treatment day 6, with therapeutic serum concentrations maintained on days 8, 10, and 12. On day 13, the patient developed a fever for which IV meropenem 1 gram 3 times daily was started. Two days later, numerous myoclonic events were observed in the woman's arms and face; valproic acid serum concentration was measured at 42 mcg/mL. Valproic acid dose was increased to 2880 mg (continuous IV infusion over 24 hours), yet tonic-clonic seizures recurred on day 17 in conjunction with a further decline of valproic acid serum concentration to 7 mcg/mL. Valproic acid dose was increased the following day to 3600 mg; however, valproic acid serum concentrations did not exceed 10 mcg/mL. Intravenous cefTAZidime and ciprofloxacin were substituted for meropenem on day 19, after which serum concentration of valproic acid increased over the next several days, eventually attaining therapeutic levels, with cessation of seizure activity ⁹.

f) As described in a case series, serum concentration levels of VPA were substantially decreased by the concurrent administration of meropenem for the treatment of Acinetobacter infections. A 14-year-old boy with epilepsy had been treated for 2 years with VPA 50 mg/kg/day, prior to receiving meropenem and tobramycin for pneumonia. VPA serum concentrations subsequently declined to subtherapeutic levels (nadir of 15 mcg/mL) despite an increase in VPA dose to 200 mg/kg/day. On day 7 after completing meropenem therapy, valproic acid serum concentrations returned to therapeutic levels (114 mcg/mL). A 7-month-old girl with West syndrome, receiving anticonvulsant treatment with VPA 75 mg/kg/day. Baseline VPA plasma concentrations were within therapeutic range (69 to 90 mcg/mL) prior to receiving concomitant treatment with meropenem and vancomycin for nosocomial pneumonia. VPA was increased to 130 mg/kg/day, yet plasma VPA declined to as low as 18 mcg/mL. The patient continued to receive meropenem for 14 days, without seizure activity, and sustained an increase in plasma VPA concentrations to 81 mcg/mL on the third day after completing meropenem therapy. A 14-month-old girl, was receiving VPA 75 mg/kg/day for anticonvulsant control of West syndrome symptoms. Baseline VPA serum concentrations were 85 mcg/mL. The patient received meropenem therapy for a urinary tract infection; within 3 days of beginning meropenem therapy, VPA plasma concentrations decreased to a nadir of 10 mcg/mL, yet returned to within therapeutic range 3 days after completing the course of meropenem treatment ¹⁰.

g) In 2 patients, substantial reductions occurred in VPA plasma concentrations when meropenem was added to previously stable dose regimens of VPA. The first patient, a 65-year-old woman, received an infusion of VPA 1200 mg IV over 24 hours following shunt placement for management of a subdural hemorrhage. Therapeutic valproic acid concentration levels were maintained with a dose range of 1200 mg to 1600 mg daily. After approximately 23 days, meropenem 1 g IV 3 times daily was administered with amikacin to treat a Gram-negative bacillus infection. On the day following initiation of meropenem, the VPA serum concentration declined from approximately 55 mg/mL to 25 mg/L (per graphic analysis), despite supplementation of VPA dose. In the second case report, a 57-year-old woman was given a prophylactic infusion of valproic acid (dose unspecified) IV along with phenytoin 100 mg 3 times daily administered on postop days 9 to 15. Due to development of a lung infection with Klebsiella and Pseudomonas organisms, IV meropenem and amikacin were administered at an indeterminate point in time during the postoperative course, accompanied by an unspecified supplementation of VPA dose. Despite VPA dose augmentation, serum concentration of VPA declined from 44 mg/L to 5 mg/L within 24 hours of beginning meropenem. For this second patient, the plasma elimination half-life of VPA was found to have declined from an expected mean of 15 hours to only 4 hours ¹¹.