Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom
Pharmacotherapeutic group: Antiepileptics
ATC Code: N03AB02
Phenytoin is effective in various animal models of generalised convulsive disorders and reasonably effective in models of partial seizures but relatively ineffective in models of myoclonic seizures.
It appears to stabilise rather than raise the seizure threshold and prevents spread of seizure activity rather than abolish the primary focus of seizure discharge.
The mechanism by which phenytoin exerts its anticonvulsant action has not been fully elucidated, however, possible contributory effects include:
After injection phenytoin is distributed into body fluids including the cerebrospinal fluid (CSF).
Its volume of distribution has been estimated to be between 0.52 and 1.19 litres/kg, and it is highly protein bound (usually 90% in adults).
In serum, phenytoin binds rapidly and reversibly to proteins. About 90% of phenytoin in plasma is bound to albumin. The plasma half-life of phenytoin in man averages 22 hours with a range of 7 to 42 hours.
Phenytoin is hydroxylated in the liver by an enzyme system which is saturable. Small incremental doses may produce very substantial increases in serum levels when these are in the upper range of therapeutic concentrations.
The parameters controlling elimination are also subject to wide interpatient variation. The serum level achieved by a given dose is therefore also subject to wide variation.
See section 4.4.
Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see section 4.2 Dosing in Special Populations – Elderly).
Phenytoin causes embryofetal death and growth retardation in rats, mice, and rabbits. Phenytoin is teratogenic in rats (craniofacial defects including cleft palate, cardiovascular malformations, neural and renal defects, and limb abnormalities), mice (cleft lip, cleft palate, neural and renal defects, limb abnormalities, and digital and ocular abnormalities) and rabbits (cleft palate, limb abnormalities, and digital and ocular abnormalities). The defects produced are similar to major malformations observed in humans and abnormalities described for fetal hydantoin syndrome. The teratogenic effects of phenytoin in animals occur at therapeutic exposures, and therefore a risk to the patients cannot be ruled out.
Two-year carcinogenicity studies in mice and rats showed an increased number of hepatocellular adenomas in mice, but not rats, at plasma concentrations relevant for humans. The clinical significance of these rodent tumours is unknown.
Genetic toxicity studies showed that phenytoin was not mutagenic in bacteria or in mammalian cells in vitro. It is clastogenic in vitro but not in vivo.
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