The Department of Health has announced plans to make the generic substitution of medicines compulsory in UK pharmacies in 2010. This means that pharmacists will be obliged to dispense a generic version of a drug or treatment, regardless of whether or not the prescriber has specified the branded product. Only in cases where a "do not substitute" box has been ticked will the pharmacist be permitted to give the branded form.

This has caused a lot of concern for both patients and healthcare professionals, because of the disruption this could potentially bring to their treatment. There is a lot of speculation that the decrease in drug costs achieved by introducing generic substitution will be offset by an increase in healthcare requirements for people switching to a generic.

In the western world there are strict regulations surrounding generic medications. They must contain the same active ingredient as the respective branded version and be rigorously tested alongside it. However the rules only state that the absorption / concentration profiles of the generic must fit between an upper (X) / lower (Y) limit compared to the branded drug. This means that most patients who are switched to a generic will have a slightly higher / lower concentration of the active ingredient in their blood (known as the delivered dose) than before.

A company might manufacture a generic drug, and a specific dose of this drug might result in a delivered dose of X. However, an identical dose of the same type of generic, made by a different manufacturer, might give a delivered dose of Y. If switched to a generic, patients will have no control over its manufacturer, and so risk having different concentrations of drug in their blood with each prescription. Individual manufacturers may also vary a generic drug from batch to batch.

For many conditions, this variability in drug levels may not pose a problem; but for some people with epilepsy, even a small decrease in the delivered dose might result in breakthrough seizures and disastrous consequences, including head injury. In most cases, these will require medical attention. An increase in delivered dose could result in toxicity and a further need for hospital treatment.

In addition, breakthrough seizures could mean that people who are almost eligible to re-apply for a driving licence will have to wait until they have experienced another 12 month period seizure-free. This will potentially generate a lot of frustration.

These reasons have driven the Joint Epilepsy Council to petition the government for the exclusion of anti-epileptic drugs (AEDs) from their intended policy.

Just how real are these risks in epilepsy?

Earlier this year, a retrospective study by Dr Duh from the Analysis Group Inc., Boston, US, and colleagues compared the healthcare expenses of people prescribed the branded form of topiramate, with the expenses incurred when they took a generic version of the same drug. The team selected participants using the
Régie de l'Assurance-Maladie du Québec (Canada) database, and examined their medical pharmacy claims data between January 2006 and October 2007. They also analysed the effects of taking single versus multiple generics for topiramate.

The records of 948 people were observed, divided into distinct periods - 1) the branded period, in which only branded topiramate was prescribed, 2) the single generic period, in which one specific generic for topiramate was used and 3) the multiple generic period - in which there was use of more than one generic version of topiramate.

The results showed that the use of multiple generics for topiramate was associated with higher hospitalization rates, longer hospital stays and increased use of other prescription drugs, than the use of branded topiramate. All these factors lead to increased healthcare costs. These effects were less marked during the use of a single generic.

People who switched between different generics had almost a three times greater risk of head injury / fracture (most likely due to breakthrough seizures), than those in the 'branded period'. This helps to explain the higher hospitalization rates described above.

When the researchers analysed the cost implications of these results, they found that the total annual healthcare cost per patient was approximately $1,716 higher in the multiple-generic period than branded periods.

These results mirror the outcomes of a previous study, which demonstrated the effects of generic lamotrigine substitution. It also showed that the switch back rate from generic to branded drugs was a lot higher for AEDs than non-AEDs, which suggests a real difference in the efficacy of branded and generic drugs in the treatment of epilepsy.

However it should be noted that the study design is not unflawed, as there is a lot opportunity for bias. For example, patients were aware which type of drug they were taking (branded / generic) and this could have affected reporting of problems, especially in the latter case. In addition, the manufacturers of the branded form of topiramate, Topamax, were involved in the study, and they had a vested interest in it.

Despite this, the concerns of patients and physicians over generic drug use in epilepsy do appear to be justified. We hope that the Department of Health will be encouraged to exclude AEDs, and other drugs with narrow therapeutic margins, from compulsory generic substitution. We also hope that, where generic products are used, GPs and pharmacists will make every effort to ensure stability of supply for individual patients.

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