No alternative

Epilepsy is different from other long-term conditions. The psychological and social consequences of seizures are substantial and can include loss of driving licence, employment and independence. There is no doubt that prescribing generic drugs reduces expenditure on medication and that these savings could allow spending on other aspects of epilepsy, however, prescribing generic anti-epileptic drugs (AEDs) may result in hidden costs such as extra clinic appointments, time to explain formulation changes, the cost of infrequent but serious adverse effects and medico-legal issues.

Changing AEDs may result in dizziness, sedation, nausea and fatigue, all of which impact on day to day living. The cost saving is not worth the potential harm caused.

The impact of epilepsy
Epilepsy is the UK's most common serious neurological condition affecting one in 131 people and touching the lives of many thousands more. Every year 30,000 people develop epilepsy and there are 1,000 epilepsy-related deaths annually. It is a very individual condition as there are more than 40 different seizure types. A diagnosis of epilepsy can have a devastating effect on the individual, their lifestyle and their family.

Around two thirds of patients will respond to AEDs, but the remaining third will continue to have seizures.  Non pharmacological options, such as surgery, are feasible in only a few selected cases and so AEDs are the mainstay of treatment. Of those taking AEDs, 80 per cent are best controlled with one AED and 10-15 per cent are best controlled with two or more AEDs.

The main goal is complete seizure freedom with no adverse side effects – a reduction of 50 per cent in seizures is really of little benefit. The treatment should be non obtrusive with no adverse interactions and a reduction in morbidity and mortality.

Treatment options
The annual cost of AEDs to the NHS is £165m, which equates to 0.94 per cent of the total drugs budget. AEDs were first introduced in the UK in 1912. It took 70 years for the first nine AEDs to be licensed, but just 18 years for the 10 most recent AEDs in the UK to gain their licences. AEDs tend to be low- to medium-cost drugs, but annually, there is a large volume of prescriptions. New drugs are more expensive than the older ones and so it is the widely prescribed new drugs in the UK that are now most susceptible to drug substitution.

The National Society for Epilepsy's (NSE) therapeutic drug monitoring unit in Buckinghamshire is the largest in the UK. It receives referrals from throughout the UK and Europe and its clinicians use highly developed interpretive skills to analyse the full range of AEDs licensed in this country.

The choice of AED is influenced by the type of seizure, the epilepsy syndrome, the individual circumstances of the patient, the side effects of the drug and personal preferences.

AEDs have a narrow therapeutic index. There is less than a two-fold difference between the minimum toxic concentration and the minimum effective concentration, particularly for carbamazapine, phenytoin and valproate. In some individuals there are even narrower differences between efficacy and toxicity.

Not all AEDs are the same. In the case of phenytoin there are very strong biological reasons for use of the same preparation. Slow release formulations, such as carbamazepine and valproate, should not be generically substituted. Lamotrigine is fully and quickly absorbed, so biological differences are less likely.

Bioequivalence does not equate to the therapeutic benefit. Switching from one generic to another may result, in the worst case scenario, in a 56 per cent change of available AED. Bioequivalence has only been tested in small numbers of healthy volunteers, but people with epilepsy may have concurrent illnesses and may be taking other drugs.

The above facts have been recognised by the 2004 NICE Guidelines, which state: "Changing the formulation or brand of AED is not recommended because different preparations may vary in bioavailability or have different pharmacokinetic profiles and, thus, increased potential for reduced effect or excessive side effects."

Generic formulations can fail to meet bioequivalence standards. There has been a series of reports of increased seizures associated with generic substitution, which other countries have recognised. In addition, switching can result in confusion and increase the potential for errors due to the medications existing in a wide range of different appearances and sizes.

Lessons learnt
Compulsory generic switching of AEDs was undertaken in Ontario, Canada. AEDs were prescribed only as generics. A resulting study aimed to quantify the switchback rates from generic to branded AEDs, in comparison to other long-term drugs and to document the potential adverse clinical consequences of generic switching. The study concluded that the switchback rate for AEDs was greater than for non AEDs – 21 per cent compared with 2.9 per cent. The Ontario data also suggested poor patient acceptance of switching AEDs to generic compounds and indicated increased clinical problems associated with the change to generics.

The American Academy of Neurology (AAN) has the following position statement on generic substitution: "AEDs differ from other classes of drugs making generic substitution problematic. With AEDs, small variations in concentrations between named brands and their generic equivalents can cause toxicity or trigger seizures. The AAN opposes legislation impeding physicians to determine which AED to prescribe. The AAN believes that formulary policies should recognise and support physician autonomy in prescribing, and patients in accessing, the full range of AEDS. The AAN opposes policies resulting in arbitrary switching among AEDs including generic substitution of AEDs at the point of sale, without consent of physician and patient. The AAN believes the use of AEDs in epilepsy should be distinguished from the use of AEDs in other disorders.

"Unlike other diseases, a single breakthrough seizure due to change in AED can have devastating consequences, including loss of driver's license, injury and even death."

Further, the pricing and availability of generic drugs is volatile. For some drugs there are only small numbers of licence holders and price competition may not arise. Manufacturers are not obliged to continue producing drugs with a low profit margin, which could lead to problems of continuity of supply.

Consistency of supply is always my key message to patients – never mind branded over generic or one version of a generic over another; stick to the exact formulation that is working for you.

NSE recently initiated a round table discussion between key players from the pharmaceutical industry as a whole to gauge views on the PPRS substitution proposal. There was a great understanding of the very special circumstances affecting epilepsy. The unanimous message from that meeting was clear, make anti-epileptic drugs completely exempt from the PPRS. NSE has submitted a report and recommendations to the Department of Health; a response to which is now awaited.

The Author
Professor John Duncan is medical director of the National Society for Epilepsy
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