Valproate/valproic acid adverse effects

Pancreatitis is a rare adverse effect of valproate and can occur in isolation or in association with liver toxicity. In a review of the patients of 366 physicians, 23% of patients taking valproic acid had asymptomatic increases in serum amylase activity but there were only 39 cases of valproate-associated pancreatitis (107). Pancreatitis usually presented with epigastric pain, nausea, and vomiting, and was more common in patients aged under 20 years and with mental retardation. In most cases the pancreatitis started within the first 3 months of treatment, but in 18% the onset was after 2 years. 

Valproic acid is available as sodium, magnesium, and calcium salts, as the free acid, and as a coordination compound, valproate semisodium (divalproex sodium), which comprises the sodium salt of valproic acid and free valproic acid in a 1 1 molar ratio. AH share the same active principle (valproic acid) and have virtually identical tolerability, although the formulation influences the incidence of gastrointestinal adverse effects. Valpromide (rINN) is a prodrug of valproate, to which it is converted with a half-hfe of less than 1 hour. Valnoctamide (rINN) is an isomer of valpromide. 

In a retrospective survey, gastrointestinal adverse effects were less common in 150 patients taking valproate semisodium than in an equal number taking valproic acid (15 versus 29%), despite the fact that serum valproic acid concentrations were comparable in the two groups (73). Patients taking valproate semisodium were less likely to discontinue medication because of gastrointestinal adverse effects (4 versus 13%). The difference was ascribed to the enteric-coated formulation of valproate semisodium. 

The authors of the report advise caution if pivmecillinam is added to treatment with valproate. Although this appears to be the only report of an adverse effect due to the combined effects of pivmecillinam and valproate on carnitine levels, the manufacturers advise the avoidance of both pivampicillin or pivmecillinam with valproic acid or valproate or other medication liberating pivalic acid. " ... 

Other reports state that falls, no changes - " and even a slight rise in carbamazepine levels have been seen in some patients also taking sodium valproate or valproic acid. The serum levels of carbamazepine-10,11-epoxide are reported to be increased by about 50 to 100%. "" This active metabolite may cause the development of marked adverse effects such as blurred vision, dizziness, vomiting, tiredness and even nystagmus. " Acute psychosis, tentatively attributed to elevated epoxide levels, occurred in one patient when carbamazepine was added to sodium valproate treatment. ... 

However, a bipolar patient with multidrug addiction had a decrease in plasma valproic acid levels of more than 50% shortly after starting an antiretroviral regimen including efavirenz. Even though the valproate dose was increased to 4 g daily, it was found diffrcult to achieve a target plasma level of 50 mg/dL. About 3 months later, following a valproate dose reduction to 1.5 g daily due to adverse effects, his level was unaltered, at 52 mg/dL. ... 

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