When a change isn’t as good as a holiday: AED brand substitution

The use of generic drugs in epilepsy is a highly controversial issue. While the FDA and TGA have stated that antiepileptic drugs (AEDs) of different brand names are bioequivalent, there is valid reason to believe the drugs are not therapeutically equivalent and therefore not interchangeable.1 Potential implications involved with switching between antiepileptic brands include direct costs such as doctor and pathology costs, as well as indirect costs such as breakthrough seizures leading to increased anxiety, seizures while driving resulting in road traffic accidents, toxicity, and absenteeism, to name a few.2 The benefit of generic medication is purely economic yet,3 ironically, the cost of switching to generic medication can potentially account for greatly increased medical and lifestyle expenses.4

The Australian, American, German, Scottish and French societies for epilepsy all share a common position on the issue, namely that generic substitution should be avoided once patients have their seizures under control. If switching between medications is required this must be on the advice and with the strict monitoring of the prescribing doctor.⁵

Epilepsy Australia continues to present its argument to the TGA and the Federal Government in order to remove AEDs from the brand substitution scheme.⁶ In February 2009, the National Prescribing Service issued a statement urging doctors and pharmacists to treat AEDs as critical dose medications.¹

Professor Roy Beran is Associate Professor of Neurology at the University of New South Wales and Professor of Neurology at Griffith University, and is a neurologist specialising in epilepsy treatment. He said, "If an epileptic patient is stable on a product, that is the product on which they should remain."

While there is a wealth of information regarding generic use in epilepsy,^1-9 substantial evidence is lacking. There has been no valid, controlled, prospective clinical trial to investigate the effects of switching antiepileptic medication. It is suggested that doctors, pharmacists and patients be provided with the facts, risks and recommendations for brand substitution until appropriate evidence is available.⁵

With up to 400,000 Australians suffering from epilepsy, antiepileptics are some of the most common neuropharmaceuticals prescribed. Nevertheless, their mechanism of action largely remains a mystery.

Epilepsy is a common neurological disorder affecting more than 400,000 Australians,⁶ and is estimated to affect 2% of the population worldwide.⁵ There is still much that is unknown about the mechanism of action of AEDs.⁷ What is known is that AEDs are a very unique and complicated strand of neuropharmaceuticals:

The minimum therapeutic serum concentration required differs less than two-fold from its minimum toxicity concentration;²
They are critical dose medicines. In some cases, patients will require a dose very close to the therapeutic limit of the AED;⁵
Certain AEDs have very unusual biopharmaceutical properties. Phenytoin saturates the cytochrome P450 isozyme responsible for its metabolism and, as a result, the changes in plasma concentrations are non-linear and unpredictable. This is especially evident in patients who have altered hepatic functioning, such as the elderly. These patient populations are not represented in bioequivalence testing.¹⁰
The relationship between some of the newer AED plasma concentrations and seizure control has not yet been clearly identified, making it difficult to extrapolate from bioequivalence tests.²

For these reasons, the substitution of generic AEDs is believed to put the patient at potential risk of exceeding the therapeutic limits, and either experiencing a greater range of side effects or losing control of their epilepsy.¹⁰ For critical dose and narrow therapeutic window medications such as AEDs, a 20–25% absorption, distribution, metabolisation or elimination difference between the generic and branded drug, although statistically bioequivalent, may be too wide a range to deem the drugs therapeutically equivalent.²

Professor Roy Beran said, "I do not believe the cost benefit ratio justifies the risk associated with changing a patient’s medication. For instance, lamotrigine has nine different generic compounds, all with lamotrigine as the active ingredient, but all may have slightly different bioavailabilities. Hence it is not just transferring from a brand to a generic but also substituting from a generic to a different generic, or a generic to a brand. Even amongst the generics, one is changing medication."

Their controversial history presents AEDs as high risk medication until further research is conducted.

In Australia during the 1960s, the excipients in the AED Dilantin (phenytoin) were altered slightly, though the active ingredient remained the same. Following this formulation change, there was an increase in phenytoin toxicity, found to be caused by an increased systemic absorption. The formulation has since been reverted to the original compounds. This original finding sparked the first concerns about AED formulation changes and the role of generics.^2,4

In 1988, the FDA investigated a number of seizure breakthroughs in patients who were receiving a generic form of carbamazepine. The drug has since been withdrawn from the market.2

There has been only one controlled, randomised, open-label, crossover study performed regarding epileptic generic substitution. The researchers compared Depakane (valproic acid) to a generic form of valproic acid. This study yielded no significant effects between the drugs in terms of seizures or blood levels.¹⁰

Unfortunately, the current evidence is contradictory and limited. Although there are numerous retrospective studies that statistically confirm the increased seizure and side effect profile of patients on generic medication, it is almost impossible to ascertain causality between these variables. The previous retrospective studies with surveys of patients’ and doctors’ opinions and reported problems are not adequate for establishing the risk of switching AEDs.⁸ Further research into the area is needed.^2,10

While the risk associated with AEDs is generally linked to the use of generics, the problems are likely to be involved with any switch between antiepileptics. One rule seems to be dominant in the literature: if a patient is seizure-free on any AED, there should be no reason for them to switch.

The bioavailability of the generic and branded forms of AEDs are deemed biologically equivalent by the regulatory bodies, so the question is why there are these negative effects with the generic drugs.¹⁰

It is the therapeutic properties of the drugs that seem to be causing the reported side effects.⁴ Contrary to general belief, the prescribing of generic AEDs does not appear to be the problem presented by the evidence, but switching between brands.¹⁰ Although the evidence for adverse effects with generic AEDs is not strong, the statistical significance that has been found in retrospective studies is a cause for concern.

The following are conservative and reasonable recommendations for prescribing in the area until further research is conducted:

For a newly diagnosed patient, prescribing a generic medication is a reasonable choice if the doctor and patient are comfortable with the decision.¹⁰
For patients who are currently either taking a generic or branded medication, if their epilepsy is not under control it is again reasonable to switch to a generic form.¹⁰
For patients who have had their epilepsy under control for some time, generic substitution is best avoided.¹⁰

The importance of educating patients in the medication they are taking should not be underestimated. In 1996, a retrospective study collected information on patient attitudes towards their medication. While 74% of patients in the study reported they pay very close attention to their medication and would notice and query if it was different from the usual prescription, 19% said they would notice but would never query the pharmacist or doctor about the change, and an alarming 6.5% do not pay close enough attention to the drugs to be able to notice if they were given something different.¹³ With approximately 26% of epilepsy patients admitting to not speaking up about, or not even noticing, changes in their medications, there is a great need for education of patients by doctors and pharmacists.¹¹

Prof Beran said, "The reason we prescribe any medication for any disease is to improve quality of life. If this goal is achieved there is no reason to change anything. If improved quality of life is not achieved then one must re-examine the treatment options, starting from the first principle: is the right type of antiepileptic medication to treat the specific type of epilepsy? Secondly, perhaps a larger dose is required. Once these variables have been examined, one can start thinking about converting to another medication."

When a patient is switching brands for whatever reason, the pharmacist plays a very important role in making sure the patient is clear about their expectations of the new drug and is informed about the possible risks and side effects.² The pharmacist should also educate the patient in the importance of strictly complying with the dosing schedule.^1,2

As indicated by the lack of substantial evidence, there is a lot about the therapeutic profiles of AEDs that is still unknown. Epilepsy foundations around the world are asking the same questions about the controversial subject:

What is the scope of the problem?³
What is the entire range of side effects and are there any adverse effects associated with switching between AEDs?³
Is there any way to pinpoint at risk individuals? Crawford et al (1996) found that 70% of patients who had changed medications reported no problems, so what is the difference between these people and those who experienced adverse effects?^3,11

Without further research and trials, it is simply impossible to determine the actual risk associated with generic AEDs or the switch from one form of drug to another. Until the unknown has been looked into further, it is best to err on the side of caution.¹⁰

If there is a valid reason for the patient to swap medications, they must do so with regular guidance, monitoring and oversight from the prescriber.⁶ Monitoring may require an initial and several follow-up blood tests to determine drug plasma concentrations and titrate the new drug dose accordingly.¹²

"I like to use blood levels to determine whether the plasma concentrations are within the therapeutic range. The problem with using efficacy alone is that you may be hitting toxic levels and therefore the patient may experience unnecessary side effects, which they do not always report," said Prof Beran.

When assessing a patient for a potential drug switch, account for the natural history of the patient’s underlying epilepsy. What reactions have they had to AEDs in the past, and what concurrent medication are they on?¹²

References

NPS Media Release: Critical dose medicines and brand substitution: issues with anti-epileptic drugs [online]. National Prescribing Service. 6 February 2009 [cited 7 April 2009]. Available from URL: http://www.nps.org.au/ news_and_media_home/ media_releases/ repository/ Critical_dose_medicines_and_brand_substitution
Krämer G, Biraben A, Carreno M, Guekht A, de Haan GJ, Jedrzejczak J, et al. Current approaches to the use of generic antiepileptic drugs. Epilepsy Behav. 2007; 11(1): 46-52.
An interview with Steven C. Schachter, M.D. [online]. Epilepsy Foundation. 2006 [cited 3 April 2009]. Available from URL: http://www.epilepsyfoundation.org/ generics/ schachterinterview.html
Vajda FJE. Generic substitution in epilepsy: A controversial issue. The Epilepsy Report [online]. Epilepsy Australia. October 2006 [cited 3 April 2009]. Available from URL: http://www.epilepsyaustralia.net/ Publications/ Archives/v ajda_generics.pdf
ESA Position Statement: Generic drug use in epilepsy [online]. Epilepsy Society of Australia. 3 October 2008 [cited 7 April 2009]. Available from URL: http://www.epilepsy-society.org.au/ pages/ generic_AEDs.php
Treatment for epilepsy: Generic medications and substitution [online]. Epilepsy Australia [cited 7 April 2009]. Available from URL: http://www.epilepsyaustralia.net/ Epilepsy_Information/ Treatment_options/ Treatment_options.aspx#Generic
Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology [5th edition]. London: Elsevier Science; 2003.
Anticonvulsants [online]. Australian Medicines Handbook. January 2007 [cited 9 September 2007]. Available from URL: http://www.amh.net.au
Drugs used in epilepsy [online]. Therapeutic Guidelines: Neurology. Version 2, 2003. [cited 9 September 2007]. Available from URL: http://www.tg.com.au.
Gidal BE, Tomson Y. Debate: Substitution of generic drugs in epilepsy: Is there cause for concern? Epilepsia. 2008; 49(Suppl 9): 56-62.
National Prescribing Service. Know the active ingredient [online]. 15 October 2008.[cited 3 April 2009]. Available from URL: http://www.chf.org.au/ Docs/ Downloads/ fac-know-the-active-ingredient.pdf
Probyn AJ. Some drugs are more similar than others: Pseudo-generics and commercial practice. Aus Health Rev. 2004; 28(2): 207-17.