Categorisation of AEDs
In order to answer this question and to provide guidance and information to healthcare professionals and patients, the CHM has assessed the characteristics of each AED and defined clear categories according to potential risk.
Category 1 - High risk - phenytoin, carbamazepine, phenobarbital, primidone
For these drugs doctors are advised to ensure that their patient is maintained on a specific manufacturer's product
Category 2 - Medium risk - valproate, lamotrigine, perampanel, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate
For these drugs the need for continued supply of a particular manufacturer's product should be based on clinical judgement and consultation with the patient taking into account factors such as seizure frequency and treatment history
Category 3 - Low risk - levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin
For these drugs it is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific concerns such as patient anxiety, risk of confusion or dosing errors
In order to categorise AEDs in this way the CHM looked at product information for the brand leader products, information from standard texts and articles discussing therapeutic range and physicochemical characteristics of each drug.
The key properties of a drug that may indicate a risk of a formulation difference affecting bioavailability are the solubility of the drug and its permeability across cell membranes. These two characteristics form the basis of a Biopharmaceutical Classification System (BCS) used by the pharmaceutical industry. The CHM used this system to inform their decisions on where to place AEDs.
This system categorises drugs as follows:
- Class 1 - high solubility/high permeability - lowest risk of absorption variability.
- Class 2 - low solubility/high permeability.
- Class 3 - high solubility/low permeability.
- Class 4 - low solubility/low permeability - highest risk of absorption variability.
Class 1 drugs, with a low risk of absorption variability and hence a low risk of formulation sensitivity, have been automatically placed into category 3 unless they also have a narrow therapeutic range.
By default drugs were placed into category 2 unless the information available identified specific issues (category 1) or the risk of clinically significant differences between formulations was very low (category 3).
In addition to these physicochemical properties, the interaction profile of AEDs has influenced the category into which a drug was placed. All the category 1 drugs induce enzyme systems, including cytochrome P450 (CYP), and hence will reduce plasma concentrations of drugs metabolised by those enzymes. Whilst the newer AEDs are less likely to induce enzymes they are metabolised by CYP and so may be affected by concomitant administration of a category 1 drug.