CHM has identified phenytoin as the AED with the most potential for product variability. As such we will discuss its classification and the rationale for it. Phenytoin is a BCS class 4 drug which means it has low solubility and low permeability and makes it at high risk of variation in absorption. Phenytoin is incompletely absorbed from the small intestine following oral administration and its elimination is subject to considerable inter-patient variability. Any differences in product formulation, however minor, could theoretically have a major impact on bioavailability.

Coupled with this is the narrow therapeutic range of phenytoin - dose limiting side effects and toxicity can occur at therapeutic drug levels and dosages have to be adjusted slowly according to patient response. A small change in bioavailability could lead to toxicity or loss of seizure control. Phenytoin is also associated with significant drug-drug interactions, in particular with other AEDs including carbamazepine, valproate, lamotrigine and tiagabine.

There is another specific reason why phenytoin has been placed into category 1, namely the fact that phenytoin exists as free base and as the sodium salt. The BNF states that preparations containing phenytoin sodium are not bioequivalent to those containing phenytoin base (i.e. Epanutin® suspension and Epanutin Infatabs®). 100mg of phenytoin sodium is approximately equivalent to 92mg of phenytoin base and this difference in content will be clinically significant if switching between products. The BNF advises care when switching between formulations and that plasma-phenytoin concentrations should be monitored.

In light of the new CHM recommendations it is imperative that patients stabilised on a particular formulation of phenytoin are supplied with the same product at each dispensing. When this is not possible, due to a manufacturing issue or stock shortage, extreme care must be taken to choose a suitable alternative and to monitor plasma concentrations. Every effort should be made to obtain product from any possible source in an attempt to maintain continuity of supply. The prescriber must be informed of any potential supply issue as soon as it becomes apparent so that steps can be taken to minimise the risk of adverse events.