Altered drug release from Orfiril^® long following ethanol consumption – extent and consequences

Orfiril^® long is a widely used antiepileptic drug preparation despite being characterized by features associated with susceptibility to ethanol induced changes to drug release. In vitro dissolution studies revealed that 30 % ethanol was required in order to cause dose dumping of valproic acid within two hours at pH 1. However, after exposure to only 5 % of ethanol for 45 minutes at pH 1, the subsequent release of sodium valproate increased by ~ 10 % for the first two hours in ethanol-free media of pH 6.8. The drug solubility increases with pH, likely to also increase the vulnerability to ethanol. This indicates that Orfiril^® long is affected by exposure to low concentrations of ethanol as well, only that this effect was exclusively displayed at an elevated pH value not part of the standard regulatory recommendations. Even so, simplified pharmacokinetic simulations revealed no risk of a lower therapeutic effect. Postponing the drug intake in case of moderate drinking, likely to increase the risk of omission altogether, is therefore not necessary. However, for slim patients with a small volume of distribution and low tolerability, a longer duration of mild side effects such as drowsiness and nausea might be experienced.