Though long reported by a minority of patients with epilepsy, differences in effectiveness between generic and branded anti-epileptic drugs (AEDs) have not been systematically investigated until recently.

Drugs for epilepsy are different from drugs for other conditions
Researchers at the Montreal Neurological Institute in Quebec, Canada, investigated whether this is a greater problem for patients taking drugs for epilepsy than patients being treated for other conditions. Looking at a database of medical insurance payment records for 1,452 patients between January 2002 and March 2006, they worked out the rates of re-prescription of branded drugs for patients previously switched to a generic. They called this process "switchback".

They compared switchback rates for three AEDs (lamotrigine/
Lamictal®, clobazam/Frisium® and sodium valproate/Depakene®) with drugs for other conditions, including high cholesterol levels (simvastatin/Zocor®) and depression (fluoxetine/Prozac®).

Switchback rates for Lamictal were 12.9%. Many patients also required a higher dose of the generic version. The switchback rates to Frisium® and Depakene® were about 20%. In contrast, the rate for Zocor was 1.5%, and that for Prozac was 2.9%. Dr Frederick Andermann, the principal investigator, said the results were very striking and called for more research into individual patients' reasons for switchback.

Awareness of the issue among doctors and patients
Dr Michael Berg of the University of Rochester School of Medicine in New York, USA, ran a national online survey of attitudes to generic substitution of AEDs, including 550 adult patients with epilepsy and 606 doctors treating epilepsy. A total of 65% of physicians reported they had treated a patient who had experienced a breakthrough seizure after having been switched from a branded to a generic medicine, and 34% of patients said they had noticed a worsening of seizure control after a switch of medication.

Despite 75% of doctors and 65% of patients saying they were concerned by the issue, the study author pointed out that the issue is under-represented in scientific literature.

What are generic pharmaceuticals?
New pharmaceutical compounds are patented by the company that develops them. This allows the company to have exclusive rights to sell that compound for a fixed period (up to 20 years in the UK) to recoup their original investment, in exchange for making the structure of the drug public. Once the patent expires, other companies have the right to make and sell the same pharmaceutical compound. These new brands are called generics.

Generic pharmaceuticals are often cheaper than the original version. They are subject to the same stringent manufacturing requirements, and are quality-controlled products that work. They contain exactly the same active drug molecule, though the other ingredients of the medicine, such as stabilisers, bulking agents, texturing agents, and flavourings, may differ. These can change the speed and degree to which the drug is metabolised by the body.

Generics are not "worse" than branded drugs, just slightly different. For most medicines, they're not different enough for patients to notice. For AEDs, however, it appears that this is not the case in a minority of patients. For most, whose epilepsy is easily controlled without side-effects, the small changes between different preparations do not make a difference.

False economy
In some countries, for example Denmark, the national health service requires patients to be given the cheapest version of the drug they have been prescribed. Some private health insurers in other countries also require this. In Britain, if the doctor does not prescribe by brand, a different generic medicine can be dispensed each time by the pharmacist. There is then no consistency of supply and the formulation could be changed with each prescription.

These rules are there to save money, in itself a legitimate aim. However, in epilepsy the consequences of losing seizure control are much greater than the costs of a branded drug.

Breakthrough seizures can have a huge impact on the life of a person who was previously seizure free. Losing a driving licence often affects the person's ability to work, which in turn affects their whole family. The psychological impact of all of this is huge. Renewed seizures also mean additional visits to doctors and increased use of health services. It's estimated that managing uncontrolled seizures is five times more expensive than managing controlled seizures.

Since epilepsy is a long-term condition, it's likely that most patients will be switched between different versions of the same drug at some point. This is a significant number of people. However it's worth remembering not everybody with epilepsy will be sensitive to the differences between formulations: most people won't notice any difference.

It's not clear why AEDs are more affected by this issue than drugs for other conditions. The fact that patients vary hugely in their response to AEDs may have something to do with it. The difference between a dose of an AED high enough to be effective and one that's too high and causes side effects is also not large. It doesn't take much to tip the scales. This is not the case with drugs for other conditions.

Both studies reported above were presented at the 60th Annual Meeting of the American Epilepsy Society.

Read more here and see a video lecture with slides here (both links require a free login)