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Viewpoint Indian Pediatrics 2002; 39:826-829 |
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Rationalization of an Antiepileptic Drug Formulation |
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We, in this article, seek to address a very basic issue: that is the common errors and miscalculations in the dosages of some of the routinely prescribed drugs and the inherent dangers involved. While such incidents are often underrated in their impact, we believe that our recent experience stands to highlight our claim and should serve as an ‘eye opener’. The drug in question in our case was phenytoin which is available in the market in two different strengths: Eptoin (each 5 mL containing 30 mg phenytoin) and Dilantin (each 5 mL containing 125 mg phenytoin). Past literature from the west stands testimony to the fact that errors have occurred earlier while prescribing the drug, but a cohesive approach on the part of the physician community and drug companies there seems to have prevented such avoidable and unfortunate incidents from recurring again(1-4). It is indeed thought provoking that a similar understanding is found lacking in our context. Table I- Common Market Preparations of Phenytoin
The story unfolds though: A three year old boy, weighing 11 kg, sustained a skull fracture after a fall from stairs followed by a seizure for which he was prescribed syrup Dilantin, 1 tsf tds (375 mg/day or 34 mg/kg/day) from a reputed government hospital. On the other hand, syrup Eptoin 1tsf tds, would have provided him the drug in therapeutic concentrations, albeit on the higher side of the recommended dosage. The exact duration for which the drug was prescribed could not be ascertained either from the medical records available or from the history given by the parents but the doctor had advised review after two weeks. After taking the drug for ten days, the child developed fever, a general-ized morbilliform erythematous rash pre-dominantly involving the trunk, recurrence of seizures, athetoid movements and altered sensorium, features which find mention in the literature under phenytoin toxicity(5-8). The child on admission in another hospital, where still the underlying cause went unrecognized, was administered a loading dose of intravenous phenytoin which failed to control his seizures. He was then brought to us in a state of altered sensorium with intermittent dystonic posturing. A clinical examination revealed hypertonia with hyperreflexia and upgoing plantars. A suggestive history, unremarkable C.S.F. findings (acellular with normal biochemistry) and other normal laboratory parameters, an elevated serum phenytoin level of 65.6 µg/mL (normal being 10-20 µg/mL), a good clinical response to the discontinuation of the drug confirmed our suspicions. The boy then recovered completely and was subsequently discharged. A follow up examination a week and also a month later revealed no evidence of any neurological sequelae. Table II-Common Combinations of Phenytoin and Phenobarbitone
Acute phenytoin toxicity in its part is known to manifest with such a diverse array of neurological signs and symptoms, so that a high index of clinical suspicion, coupled with a careful history of drug intake along with estimation of serum phenytoin levels are imperative to elucidate its spectrum. The most frequent neurological findings reported include nystagmus (95%), ataxia (88%), lethargy (22%) and seizures (19%). Less commonly movement disorders, ophthalmoplegia, opsoclonus, cerebellar atrophy, reversible focal neurological deficits present as complications of acute phenytoin intoxication from time to time(5). In adults the earliest sign of intoxication is nystagmus (level > 20µg/mL) followed by dysarthria and ataxia (level > 30µg/mL). If the level rises above 40 µg/mL somnolence may occur(7). Seizures have been reported at levels >30µg/mL(8). It is noteworthy in children that the usual toxic side effects such as nystagmus occur at high levels only, while ataxia may precede the former(7). Last but not the least, differences in plasma phenytoin levels produced by various phenytoin preparations for the same dosage prescribed are well known with a consistently greater bioavailability in the case of suspension than the capsules or tablets. This is explained on the basis of a smaller particle size of the free acid form found in the former compared with the sodium salt found in the latter(9). Again when tablets of phenytoin containing either phenytoin acid or phenytoin calcium are compared, the free acid formulations score over the salt preparations in terms of better bioavailability(10). In an another study in children, the blood level of phenytoin was found to be significantly higher when 100 mg capsules rather than 100 mg tablets were administered. When, on the other hand 30 mg capsules and tablets were compared, the situation was reversed(11). In a recent bioavailability study conducted in Thailand, three local brands of phenytoin sodium capsules were compared to Dilantin. It was found that the local brands were not bioequivalent with Dilantin(12). All such instances, therefore, merit an estimation of blood levels of phenytoin two to three weeks after any change in the form of medications(13). It is further noteworthy that the syrup or suspension preparations of various medications usually contain roughly half the dosage (per 5mL) of the pediatric tablet formulation of the same drug. Interestingly though, this axiom does not hold true for phenytoin: syp Dilantin (125 mg/5mL) containing 1.25 times the tablet strength (Eptoin tab - 100mg) and this has heightened the confusion. A list of the various market preparations of the drug is provided in Table I for comparison. In addition to the above mentioned preparation of the drug, some combinations of phenytoin and phenobarbitone are also available in the market which merit due consideration in the context of our discussion. Such combinations are considered irrational (Table II). We may be tempted to attribute such mistakes on the practicing physician’s lack of awareness, due weightage must be given to incidents where the chemists have wrongly substituted one brand for the other under the mistaken notion that both contain the drug in same concentrations(1). The onus of responsibility therefore lies on the doctor to ensure that his patient procures the right medication intended for him/her. It is hoped that a concerted approach involving the physicians and the drug manufacturers would result in the availability of such medications in uniform strengths and avert anymore future tragedies. Sheffali Gulati, C. S. Sriram, Veena Kalra, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110 029, India. E-mail: [email protected]
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