Adding valproic acid to carbamazepine.
- Carbamazepine is principally metabolized by CYP3A4, and is a potent inducer of CYP1A2, CYP2C9, CYP3A4 and UDP-glucuronosyltransferases.
- Valproic acid is principally metabolized by CYP2C9, CYP2C19, CYP2A6 and UDP-glucuronosyltransferases. Valproic acid is an inhibitor of the enzymes CYP2C9, epoxide-hydroxylase and UDP-glucuronosyltransferases.
- A synergistic effect is suggested.
Start valproic acid
- Define carbamazepine serum concentration (+ epoxide) before starting valproate. Check carbamazepine serum concentration (+ epoxide) again after 2 weeks and adapt dose if necessary. 
- Valproate can inhibit carbamazepine metabolic pathways, resulting in raised carbamazepine-epoxide concentrations.  Valproate can also displace protein-bound carbamazepine and therefore increase the levels of free carbamazepine. This may result in neurotoxicity even when valproate levels are low.
- Carbamazepine induces metabolism of both itself and valproate via Cytochrome P450 3A3/4 system, which may decrease the serum concentrations of both drugs and increase the risk of relapse.
- WHO Collaborating Centre for Drug Statistics Methodology ATC=N03AF01
- Farmacotherapeutisch Kompas; Toxicologie (dutch)
Farmacotherapeutisch Kompas - carbamazepine (dutch)
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KNMP; Informatorium Medicamentorum 2015; Monografie "carbamazepine" (Dutch)
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- Freeman et al. Mood stabilizer Combinations: A Review of Safety and Efficacy. Am J Psychiatry 1998;155:12-21
- Schalekamp T. et al, Interacties met Psychofarmaca, Stichting Health Base, Houten, 2002.
- Bernus et al. The mechanism of the carbamazepine-valproate interaction in humans. Br J Clin Pharmacol 1997;44:21
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