Consistency of Supply

10 June 2005

It is the view of Epilepsy Action that for the epilepsy patient, consistency of supply is important. Epilepsy patients should receive the same version of anti-epileptic drug (AED) whenever they get a repeat prescription unless their clinician prescribes otherwise. It should be from the same manufacturer, and indeed from the same country of manufacture. This applies to ‘branded’ generics and the usual brand leaders alike.

About Epilepsy Action

Epilepsy Action is Europe’s largest member-led epilepsy organisation, providing information, advice and support. The vast majority of the members and service users either have epilepsy or are relatives or carers of people with epilepsy; over 550,000 individuals are helped directly every year.

Epilepsy Action’s Packaging Survey

Over the years, many people have contacted Epilepsy Action to report that, having been given a different version of their antiepileptic drug (AED), their health has been affected. Such reports used to be linked with switching to and from generic and branded versions, but more recently have also been associated with switching between parallel imported drugs. The practice of what has been termed ‘pick ‘n’ mix’ dispensing – dispensing a bundle of mixed versions of a drug – has also been identified as a problem.

To quantify the problem, a questionnaire was designed to ask members about their experiences with different versions of AEDs1. Terms such as ‘generic drug’ and ‘parallel imports’ were avoided so as not to cause confusion or tap into preconceived ideas. A total of 1851 individuals completed the questionnaire.

When they were asked whether in the past 12 months they had been given different versions of their medication, bundles of mixed versions, or medication in plain or unprinted packaging, 31 per cent, 24 per cent, and 34 per cent, respectively, of those who responded said that they had. Then, when asked whether being given a different version of their drug had had any impact on their epilepsy, two per cent felt their epilepsy had improved, 70 per cent had experienced no change, and 23 per cent said it was worse – which in epilepsy is taken to mean more frequent, more severe or breakthrough seizures, whilst five per cent did not know. Regarding side-effects, one per cent felt that these had improved, 67 per cent experienced no change, and 32 per cent said they had more or different side-effects.

Other issues have come to light as a result of this survey, including the fact that different drugs have different names in different countries which has caused anxiety and confusion for patients in receipt of parallel imports. For example, Tegretol Retard becomes Divitabs when purchased in France. Respondents also contacted us to say that bubble packs were often damaged and that mixed bundles often contained incorrect dosages.

Responses included: 'My daughter was given a foreign brand. Although the tablet looked the same she started having her complex partial seizures. She felt an aura coming on. Doctor now writes no parallel imports and she has no problems'.

'My daughter took the Spanish version for 3-4 months, during which time there was no change in her epilepsy, but she was slow and sluggish. I started to get her tablets from another chemist which dispensed the English version. She is much brighter and the tablets always come in the original box with a leaflet.'

The Impact of Seizures and Side-Effects

It is important to appreciate why an unnecessary increase in seizures, breakthrough seizures or worsening of side-effects is unacceptable to patients. A single seizure can have a major impact on an individual’s life. It means the automatic loss of a driving licence for a year, which can lead to loss of employment and can cause further problems if the individual is the family’s only driver or lives in a rural area.

Seizures obviously bring with them the risk of injury from jerking or falling. Some people experience a loss of confidence, particularly if the seizure takes place at work or in a public place. Ultimately, there is the risk of epilepsy-related death – about 1000 people die every year in the UK of epilepsy related causes. Research has shown that at least 400 of these deaths are potentially avoidable if the optimum treatment had been given2.

Side-effects from AEDs are a major issue for many people with epilepsy, and can affect employment, education, and social life. Some claim that they would rather have occasional seizures than live with daily side-effects, and the right balance between seizure control and side-effects can be difficult to achieve. Side-effects include cognitive impairment, weight gain or loss, loss of hair or growth of body hair, bone damage, psychiatric disorders, potentially life-threatening rashes, etc.

The Precautionary Principle

There is significant and compelling anecdotal evidence from clinicians and patients that indicates a number of people experience difficulties in the management of their condition when switching from branded to generic or between generic AEDs.

Epilepsy Action would welcome a rigorous research programme into epilepsy and AEDs to clarify why a consistent supply of medication for people with epilepsy is so important. Our position is that until strong evidence is available (in relation to any particular AED) that switching brands is shown not to be detrimental to people with epilepsy, then the precautionary principle should apply, i.e. avoiding switching formulation or brand of AED unless it can be shown that it is safe to switch.

We are aware that patients’ seizure control is influenced by many factors e.g. alcohol, lack of sleep, patterns of light etc. Our clinical advisors also note that stress can trigger seizures in some people with epilepsy. Such stress could occur when changes to the packaging and appearance of regular medication takes place and could therefore possibly cause lack of seizure control or breakthrough seizures. However, the trigger is not Epilepsy Action’s major concern, but the outcome which we believe should be avoided at all costs.

Are Generic Products Identical?

The statement that all versions of a generic drug are identical is often made. To most people, ‘identical’ means totally the same in every conceivable way. However, just as identical twins are rarely absolutely identical, in medication the word may mean ‘so similar that it makes little difference’. In the drug treatment of epilepsy, however, subtle differences can have profound effects3.

The active ingredients of different (generic) versions of a drug have to be the same – that is within an agreed percentage. However, tiny differences in the way in which those ingredients are handled can impact in the way in which they are absorbed by the body4. For example, even very small differences in particle size can affect the rate of absorption. Inactive ingredients, including binding materials and colourings, may also differ5.

It is known that some AEDs (especially older AEDs) have very narrow therapeutic ranges. Licensing authorities permit a +/- 20% difference in bioavailability between a generic and an original product6. While this is of little consequence for most products, it may have serious consequences in epilepsy. Small changes in bioavailability can result in poorer control of seizures, with serious implications for the quality of life for people with epilepsy7.

It is also our understanding that when doctors prescribing AEDs try to increase doses they often do it by small increments, as little as 10 per cent. This is because even such small dose increases can be expected to have a clinical impact. Given this, an unintentional dose change (by changing brand which might have a +/- 20 per cent active ingredient variation) could have an unintentional clinical impact.

The National Institute for Health and Clinical Excellence8 advises that:

'Changing the formulation or brand of any 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.'

Although both the NICE and SIGN9 clinical guidelines clearly recommend maintaining consistency of supply to individual patients, there is no mechanism for ensuring that these guidelines are incorporated into clinical practice.

We believe there is a collective responsibility between specialist, general practitioner, patient and pharmacist to ensure that consistency of supply is maintained. As patents expire on the newer AEDs, the default position will be to prescribe generically. Yet, the financial savings to be made from prescribing generically rather than by brand may not outweigh patient management costs e.g. the cost of extra A&E admissions and hospital stays.

Epilepsy Action’s position is that patients’ concerns should be taken seriously. It is the responsibility of everyone in the patient management pathway to be aware of the consistency of supply issue and to ensure that the best possible treatment is given to all patients with epilepsy.

The Current Situation - Lamictal

Epilepsy Action is currently raising awareness of the fact that on 29 May 2005 a major change in the treatment of an estimated 80,000 people with epilepsy took place. The anti-epileptic drug Lamictal (lamotrigine), manufactured by GlaxoSmithKline, came off patent and generic alternatives became available. The potential for some of the issues noted above to impact on this large group of patients has lead us to consult with our panel of clinical advisers and raise awareness of the issues with the following groups:

• People with epilepsy
• GPs
• Pharmacists
• Prescribing Advisers
• The Department of Health

Epilepsy Action notes that the Department of Health (DoH) has issued guidance in this area which states:

'The Medicines and Healthcare products Regulatory Agency (MHRA) is the responsible licensing authority. MHRA will ensure that bioequivalence is established between the brand Lamictal and potential generic alternatives. Some commentators have suggested that there should be no switching of products used in the treatment of epilepsy. But in this instance, there is no compelling evidence to suggest that switching from the originating brand to a generic alternative will have an adverse clinical outcome. However, it is open to prescribers to modify their usual generic prescribing if, in their clinical judgement, the circumstances of individual patients warrant such action.' 10

We are concerned that the statement does not offer balanced advice to prescribers that is based on the latest NICE guidance and fails to fully reflect the potential risks to people with epilepsy who are currently taking Lamictal. Whilst the DoH notes there is no evidence in this instance to suggest a switch will have an adverse effect- there is no evidence to suggest that it will not as Lamictal is only now coming off patent.

We are not aware of any firm evidence as to whether Lamictal and the impending generic versions of lamotrigine will vary in bioavailability or have different pharmacokinetic profiles. Equally we are not aware of any evidence that they will not.

Given the potential impact on an individual of breakthrough seizures in terms of driving, employment, general well-being, etc, or the impact on seizure control, it is our view that the precautionary principle should be followed in relation to switching brand when prescribing or dispensing lamotrigine.

Conclusion

Any recommendation on this area should focus on stabilisation of prescribing so that patients always receive the same drug, whether branded or not. Any change to a patient’s medication should be made after a considered and informed discussion between the patient and their clinician. We believe the potential impact of switching AED brand should be treated in the same way.

PDF version

1 Epilepsy Action: Anti-Epileptic Medication Packaging Survey. October 2003 back

2 Hanna NJ, Black M, Sander JWS, Smithson WH, Appleton R, Brown S, Fish DR (2002) The National Sentinel Clinical Audit of Epilepsy-Related Death: Epilepsy- death in the shadows. The Stationery Office back

3 Crawford P, Hall W, Chappell B et al (1996). ‘Generic Prescribing for Epilepsy. Is it Safe?’ Seizure; 5:1-5 back

4 Besag F M C. (2000) ‘Is Generic Prescribing Acceptable in Epilepsy?’ Drug Safety no.3, pp173-182 back

5 Richens A (1997). ‘Impact of Generic Substitution of Anticonvulsants on the Treatment of Epilepsy’. CNS Drugs; 8 (2): 124-133. Also: Guberman A and Corman C (2000). ‘Generic Substitution for Brand Name Antiepileptic Drugs: A Survey’. The Canadian Journal of Neurological Sciences; 27: 37-43. back

6 Richens, ‘Impact of Generic Substitution’. In the UK, the Medicines and Healthcare Products Regulatory Agency stipulates +/- 10% in the case of phenytoin. back

7 Crawford et al. ‘Generic Prescribing’. back

8 The epilepsies: diagnosis and management of the epilepsies in adults and children. National Institute for Clinical Excellence guideline (2004). back

9 ‘Formulations of AEDs are not interchangeable and generic substitution should not be employed’. Diagnosis and management of epilepsy in adults. Scottish Intercollegiate Guidelines Network (2003) 3.2 back

10 Treatment for epilepsy: generic lamotrigine,1 March 2005, DoH, gateway 4639 back