Effectiveness and Toxicity of Phenobarbital, Primidone, and Sodium Valproate in the Prevention of Febrile Convulsions, Controlled by Plasma Levels

Abstract

The effectiveness and toxicity of phenobarbital (PB), primidone (PRM), and sodium valproate (VPA), used exclusively in monotherapy, were compared in 95 children affected with febrile convulsions. Treatment was restricted to either complicated or simple febrile convulsions with risk factors. The effectiveness and toxicity of each drug were related to the daily dose and the steady-state plasma levels. PB (4.8 +/- 0.7 mg/kg/day) achieved plasma levels of 16.4 +/- 2.8 micrograms/ml and prevented febrile convulsions in 80% of the patients. Side effects were observed in 76.7% of the patients, a change in dose being required only in 13.3%. PRM (17.8 mg/kg/day) yielded PB plasma levels of 14.1 +/- 3.7 micrograms/ml and was effective in 88.2% of the patients. The incidence of side effects was 53%, but no change in treatment was required. VPA (35.2 +/- 5.9 mg/kg/day) achieved plasma levels of 57.2 +/- 15.3 micrograms/ml (measured before the first dose in the morning) and was effective in 91.7% of the patients. Side effects were detected in 45% (significantly lower than after PB, p less than 0.01), and required a change in treatment in 14.3%. No differences in doses and plasma levels were found between patients with or without recurrence of febrile convulsions and with or without side effects; an exception was the higher doses of VPA administered to patients who showed side effects. It is concluded that PRM and VPA were at least as effective and well tolerated as PB. Because the plasma levels of the three drugs were near the lower limit of the therapeutic range, it remains to be elucidated whether higher doses may increase the benefit without adding unacceptable toxicity.

Sodium valproate induced increased frequency of micturition and enuresis

“…[8] Other studies on use of Valproate in children. [79–12] have recoreded enuresis as side effect, the frequency being 1-7%. But surprisingly these studies are quite old and we could not find recent citations.…”

Febrile Seizures: Clinical Practice Guideline for the Long-term Management of the Child With Simple Febrile Seizures

“…As with phenobarbital, adverse effects include behavioral disturbances, irritability, and sleep disturbances. 18 …”

“…[13][14][15][16] Primidone Primidone, in doses of 15 to 20 mg/kg per day, has also been shown to reduce the recurrence rate of febrile seizures. 17,18 It is of interest that the derived phenobarbital level in a Minigawa and Miura study 17 was below therapeutic (16 g/mL) in 29 of the 32 children, suggesting that primidone itself may be active in preventing seizure recurrence. As with phenobarbital, adverse effects include behavioral disturbances, irritability, and sleep disturbances.…”

Authors' response

“…Examining the literature reveals that in a study summarising the results of 16 trials and 1140 patients treated with different doses of valproate, side effects were observed in 26% of the patients, but discontinuation of the therapy was required in only 2% 7. Furthermore, in 48 children dosed with 30 mg/kg/day or more of sodium valproate for 22 months, a change in therapy was required in 5 patients (average dose=∼47 mg/kg/day) and withdrawal was required in 2 patients (average dose=∼43 mg/kg/day) 8. Similarly, in a study that followed up 118 patients for an average period of 18 months on valproate monotherapy with a mean dosage of ∼19.4 mg/kg/day, only four patients (3.4%) elected to discontinue treatment 9.…”