Hydanphen is an antiepileptic drug. Each tablet contains 100 mg phenobarbital and 50 mg phenytoin.

Fråga: Hydanphen is an antiepileptic drug. Each tablet contains 100 mg phenobarbital and 50 mg phenytoin. It has been noted that patients receiving this medication (varying dosage) have subtherapeutic plasma concentrations of phenytoin. Why?

Sammanfattning: Since the two drugs have markedly different kinetics we do not recommend fixed drug combinations of this kind. A fixed drug combination of 100 mg phenobarbital and 50 mg of phenytoin is absolutely not recommended since the dosage of each drug has to be adjusted separately due to much different pharmacokinetics. Using the actual combination phenytoin will be underdosed if phenobarbitone is adequately dosed.

Svar: Phenobarbitone is a barbiturate acid derivative and has been used as an antiepileptic drug for many years (1). The drug is readily absorbed in the gastrointestinal tract. Elimination is by metabolic degradation (75 per cent) and by renal excretion (25 per cent). In patients with normal kidney function, half-life is approximately 4 days. Phenobarbitone is a classical inducer of drug metabolism (1). We generally recommend plasma/serum concentrations around 40-135 umol/L. Such concentrations are often achieved at dosages of 1-3 mg phenobarbitone per kg daily (2,3).

Phenytoin has been used as an anticonvulsant since 1938 (4). It is still considered to be a drug of first choice in most forms of epilepsy. Although phenytoin is a commonly used drug, it is often difficult to adjust its dosage to attain therapeutic drug concentrations due to the non-linear nature of phenytoin elimination. Phenytoin is mainly eliminated through para-hydroxylation by a cytochrome P-450-enzyme. This elimination is capacity limited already within the therapeutic drug concentration (5). This means that small changes in dosage might give rise to disproportionately large changes in plasma concentration. In addition, certain individuals seem to have a hereditary insufficient capacity to para-hydroxylate phenytoin (6).

The bioavailability of phenytoin can vary markedly between different oral preparations. Due to the dose dependent elimination, the half-life varies from about 15 hours at therapeutic concentrations to several days at very high plasma concentrations (7).

At therapeutic plasma concentrations, 90 per cent of phenytoin is bound to plasma proteins. The degree of binding varies in several diseases. The well established relationship between plasma concentrations and effect in monotherapy, the marked interindividual variations in the dose-concentration relationship and the capacity limited kinetics of phenytoin necessitate therapeutic drug monitoring. We usually recommend drug levels around 40-80 umol/L in adults and 40-100 umol/L in children. Such plasma concentrations were achieved at phenytoin dosages varying between 200 and 550 mg (sodium salt) daily (7).

The fixed combination drug Hydanphen, containing 100 mg phenobarbitone and 50 mg phenytoin has been said to give subtherapeutic plasma concentrations of phenytoin. This is not unexpected since a dose of 200 or 300 mg of phenobarbitone will yield a phenytoin dose of only 100-150 mg which is insufficient.