Primidone Sodium valproate

Drugs acting on GABA/glutamate - hypnotics/anxiolytics barbiturates, benzodiazepines, chlormethiazole, chloral derivatives, baclofen - anticonvulsants phenobarbitone, primidone, phe-nytoin, sodium, valproate, carbamazepine - alcohol, phencyclidine, ketamine... 

Antiepilepsy. General note of caution observe the infant for sedation and poor suckling. Primidone, ethosuximide and phenobarbital are present in milk in high amounts phenytoin and sodium valproate less so. 

Sodium valproate appears to be a nonspecific inhibitor and impairs the metabolism of phenytoin, phenobarbitone and primidone. 

Antiepilepsy drugs pass into breast milk (see p. 116), phenobarbital, primidone and ethosuximide in significant quantities, phenytoin and sodium valproate less so. There is a risk that the baby will become sedated or suckle poorly but, provided a watch is maintained for these effects, the balance of advantage favours breast feeding whilst taking antiepilepsy drugs. 

Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (enzyme induction) the effect of phenytoin is variable. Clonazepam and sodium valproate are safe. 

Treatments of first choice for cortical myoclonus are valproic acid (sodium valproate) and clonazepam. Primidone and phenobarbital may also be useful. Piracetam has advantages in these circumstances, as its addition to existing treatments is rarely accompanied by sedation. 

Minor to modest falls in serum ethosuximide levels may occur if carbamazepine, primidone or phenytoin are also given, whereas methylphenobarbital or sodium valproate may cause a rise in ethosuximide levels. The effect of all these changes on seizure control is uncertain. Lamotrigine appears not to affect ethosuximide levels. 

Piracetam does not appear to alter the levels of sodium valproate or primidone. No interaction has been found between piracetam and carbamazepine, clonazepam, phenobarbital, or phenytoin. 

The addition of piracetam (2 to 4 g three times daily, increased to a maximum of 18 to 24 g daily) did not affect plasma levels of sodium valproate or primidone in patients with myoclonus. The exact number of patients taking these drugs is unelear, sinee the report just states that 28 patients were taking clonazepam, sodium valproate, or primidone, alone or in combination. Another similar report, briefly noted the same finding. The manufacturer notes that, although based on a small number of patients, no interaction has been found between piracetam and clonazepam, carbamazepine, phenytoin, phenobarbital and sodium valproate. No special precautions appear to be required if piracetam is used with these antiepileptics. 

None of these interactions is extensively documented but all appear to be established and of clinical importance. Serum ciclosporin levels should be well monitored if carbamazepine, phenobarbital or phenytoin are added and the ciclosporin dosage increased appropriately. Primidone is metabolised to phenobarbital by the liver, and therefore would be expected to reduce ciclosporin levels. Information about oxcarbazepine is very limited but small reductions in its dose, together with an increase in ciclosporin dose, may be adequate to control any interaction. However, more study is required before oxcarbazepine can be recommended as a suitable alternative. The effects of the interaction may persist for a week or more after the anticonvulsant is withdrawn. Sodium valproate seems not to alter ciclosporin levels, but the case reports of nephritis and hepatotoxicity suggest some caution is warranted. 

Further evidences reveal that valproate sodium may also deerease binding to eertain serum proteins or bloek the hepatic metabolism of phenobarbital. Therefore, administration of the drug to patients in a steady state, while on phenobarbital eoneurrently (or primidone, which gets metabolized to phenobarbital) may enhance the plasma levels of phenobarbital from 35-200%, a quantum jump, thereby eausing an excessive somnolence. However, the present evidenee amply substantiates that this is caused exelusively by an immediate lowering in the prevailing rate of elimination of phenobarbital. 

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