Can valproic acid cause hyponatremia?/nThe question concerns a two-year-old child treated with valp

Fråga: Can valproic acid cause hyponatremia? The question concerns a two-year-old child treated with valproic acid (Ergenyl 60 mg/ml) 8 ml daily, who was hospitalized due to hyponatremia.

Sammanfattning: A few adult, mostly elderly, patients with hyponatremia due to SIADH (syndrome of inappropriate secretion of antidiuretic hormone) have been described in connection to valproic acid therapy. After discontinuation of valproic acid, the patients have improved.

Svar: In the SPC for Ergenyl, it is mentioned that cases of hyponatremia have been reported (1). For the other two labels approved in Sweden, Absenor and Orfiril, hyponatremia or SIADH is not mentioned in the SPC (2,3).

A literature search revealed a few reports of hyponatremia in connection to valproic acid therapy. In all published cases, the hyponatremia was caused by SIADH (syndrome of inappropriate secretion of antidiuretic hormone) (4,5,6,7,8).

The first case concerns a 50-year-old man treated with valproic acid (2000 mg/day) for more than 20 years (4). He had no complaints, but laboratory values showed hyponatremia with a sodium level of 128 mmol/L (reference value 137-145 mmol/L) and a low plasma osmolality. SIADH was diagnosed, and valproic acid was suspected after other causes had been excluded. Repeated water loading test performed at different dosages of valproic acid (2000 mg, 1500 mg and 1000 mg) confirmed that the ability to excrete water was reduced in a dose dependent manner. The patient was thereafter treated with a lower dose (1500 mg/day) and was instructed to restrict fluid intake (4).

In another case a 62-year-old man treated with valproic acid (600 mg/day) for six years developed SIADH with hyponatremia (sodium 117-120 mmol/L), elevation of ADH (antidiuretic hormone), decreased plasma osmolality, disorientation and seizures. Valproic acid was suspected, and after correcting the electrolyte imbalance valproic acid was changed to zonisamide. Eighteen months later he had no clinical signs or symptoms of SIADH (5).

A recently published case report describes a 22-year-old man treated with valproic acid (1000 mg/day) for nine months, who was admitted due to abdominal pain, vomiting and nausea. Laboratory findings included hyponatremia (sodium 118 mmol/L) and low serum osmolality, and SIADH was diagnosed. Valproic acid therapy was discontinued and his electrolyte balance was corrected. The symptoms resolved immediately, and valproic acid was substituted for levetiracetam with a normal follow-up six weeks later (6).

In one case an 82-year-old man developed SIADH with a sodium level of 128 mmol/L. Eight days after discontinuation of valproic acid his sodium level had increased (142 mmol/L). Administration of valproic acid was restarted and he developed SIADH with hyponatremia (128 mmol/L) again, which improved after discontinuation of valproic acid (7).

In the Swedish adverse drug reactions register, there are three reports of hyponatremia in connection to valproic acid therapy (of a total of 319 reports). However, in one case co-administered carbamazepine was the main suspected drug (8).

SIADH is a known adverse effect of psychotropics (antidepressants, antipsychotic drugs), carbamazepine, cytotoxic drugs (cyclophosphamide, cisplatin, vinca alkaloids), chlorpropamide and clofibrate (9). The mechanism of valproic acid associated SIADH has not been established.

The cases of SIADH in connection to valproic acid therapy mentioned above are all well described, with dose dependency and resolving symptoms after discontinuation. However, since valproic acid is a relatively old drug with widespread use, and only few reports have been identified, this seems to be a very rare reaction.