Clozapine × Valproic acid

The clozapine SmPC describes the interaction as pharmacodynamic and does not name its mechanism. Clozapine itself lowers the seizure threshold, and the seizure risk rises with the dose (Clozaril label, FDA). It also causes neutropenia and myocarditis. With valproic acid added, the SmPCs report rare but serious seizures, including in people without epilepsy, and isolated cases of delirium. They also report a higher risk of clozapine-induced neutropenia and myocarditis (clozapine and valproate SmPCs). The drugs do not change each other's blood levels: a study in 11 patients with psychosis found no pharmacokinetic interaction (valproic acid label, FDA).

A seizure, including in a person without epilepsy, confusion and delirium (clozapine SmPC). Signs of neutropenia: fever, sore throat, mouth or throat ulcers, flu-like symptoms, any infection (clozapine SmPC). Signs of myocarditis, most often in the first two months of clozapine treatment: persistent resting tachycardia, palpitations, arrhythmia, chest pain, shortness of breath, rapid breathing, unexplained fatigue, flu-like symptoms (clozapine SmPC).

The SmPCs do not forbid the combination: valproate is given with clozapine under close monitoring of both treatments (clozapine and valproate SmPCs). On clozapine the absolute neutrophil count (ANC) is checked weekly for the first 18 weeks, then monthly to the end of the first year. Extra counts are taken after valproic acid is added, especially in the initial period (clozapine SmPC). With an ANC of 1000–1499/mm3 clozapine continues with counts twice a week until the count stabilises; below 1000/mm3 clozapine is stopped at once and never restarted (clozapine SmPC). With fever, sore throat or any infection the ANC is checked immediately (clozapine SmPC). Before valproate starts, a full blood count with platelets and coagulation tests is done (valproate SmPC). With persistent resting tachycardia, chest pain, shortness of breath or flu-like symptoms clozapine is stopped promptly and the patient is referred to a cardiologist. After myocarditis clozapine is not restarted (clozapine SmPC). After a seizure the clozapine dose is reduced and anticonvulsant treatment is started if needed (clozapine SmPC). The seizure risk rises with the dose, so clozapine is started low and increased slowly (Clozaril label, FDA). No dose adjustment for blood levels is needed, because no pharmacokinetic interaction was found (valproic acid label, FDA).