Epilepsy Ireland have been informed by the Health Products Regulatory Authority (HPRA) that the anti-epileptic drug, Levetiracetam 100mg/ml oral solution is now deemed an interchangeable medicine.
Medicines that are regarded as interchangeable are subject to generic substitution.
This means that pharmacists are obliged to dispense a version of the medication that is at or below a set ‘reference price’ even when the doctor has prescribed a specific brand that may be more expensive. For drugs that are not interchangeable, the pharmacist must dispense the brand specified on the prescription.
So, in this case, Keppra is the brand name and original version of the drug generically known as Levetiracetam. Following this decision, even if your prescription states “Keppra 100mg/ml Oral Solution”, you may be dispensed a generic version of the same drug.
Generic versions contain the same active substance, but it may have a different colour, flavour, shape or non-active substances. There may also be small differences in the concentration of the active substance.
Generic substitution helps to limit the cost that the State pays for medications. For the vast majority of medications, substituting a branded drug for a generic version is regarded as being perfectly safe.
With regard to anti-epileptic drugs (AEDs), there are no particular concerns that generic versions are less effective as branded drugs in controlling seizures when prescribed from the beginning of treatment with that particular medication.
However, there have been concerns and debates for many years about the safety of switching patients from a branded version of an AED to a generic or from one generic version to another. For interchangeable drugs, switching may occur regularly in some cases, depending on which version is the cheapest at the time of dispensing.
When generic substitution was first introduced a decade ago, Epilepsy Ireland had sought that AEDs be exempt from interchangeability (you can read more on this by reading the associated article in the 'News' section of our website). While our calls were not reflected in the final legislation, we did receive assurances from the HPRA that AEDs would not be assessed for interchangeability.
We are concerned that a decade later, Levetiracetam has now become the third AED to be deemed interchangeable, following earlier decisions on Gabapentin (Neurontin) and Pregabalin (Lyrica). However, their use is more limited than Levetiracetam (Keppra).
The specific safety concerns around AEDs are because many of them have a "narrow therapeutic range". As most people with epilepsy will be only too aware, finding an effective dose can be difficult and time consuming. Once that is found, any variation in the manufacture and composition of a medicine introduces a new factor that may disturb the balance and result in an otherwise avoidable breakthrough seizure. Switching between different generic versions is particularly problematic in this regard. Two different generic versions could in theory, have bioequivalence values at the two extremes of the permitted 80%-125% bioequivalence range from the branded drug.
It is important to note that Levetiracetam is not a “narrow therapeutic range” drug. The UK medicines regulator (MHRA) categorises AEDs into 3 groups based on safety of switching and Levetiracetam is in Category 3, the safest category. You can read more on this categorisation by visiting the MHRA website.
Some research has been conducted around the generic substitution of Levetiracetam and results have varied. Some studies found no significant differences in seizure frequency after switching while other studies, as well as several case reports, have found increased seizures after switching. Details of some of these studies are highlighted in the further information section at the end of this article.
The prominent view of Irish neurologists is that the risk of switching between different versions of Levetiracetam is low, but that it is preferable for patients to remain on the same version consistently from month to month, especially when seizure-free.
At present, it is not clear to us what steps the HPRA and HSE have taken to be satisfied that this change will not affect patient safety. It is also unclear whether other versions of Levetiracetam apart from the 100mg/ml oral solution (or indeed other AEDs) will be deemed interchangeable in future. We are engaging with HPRA and HSE on these issues and will post any updates on our website and social media.
N.B: How to ensure your AEDs are not generically substituted
We know this development may be worrying to our members, service users and their families, especially when unexpectedly presented with a “new” medication by the pharmacist.
Crucially, there are steps you can take to ensure that you are given the same version of your medication each month. We advise that patients taking Keppra 100ml/mg oral solution follow the steps outlined below. We also encourage all people with epilepsy on any AED to discuss generic substitution with their clinicians and to follow these steps if you are concerned about the risks of switching:
- Ask your prescriber to use the BRAND name or a specific named generic version on your AED prescription rather than the generic name (i.e. write Keppra, not Levetiracetam).
- Ensure “DO NOT SUBSTITUTE” is written or printed on your prescription (for each AED).
- At your pharmacy, check your medications immediately to ensure that they are the same as the ones you received last month. If they are not, insist that they are changed back.
If these steps are followed, a pharmacist is not permitted to substitute your medication.
For more information on all the above generally, visit the 'Generic Substitution and Interchangeability' section of our website.
Further Information on published research on Levetiracetam switching
Studies where no significant changes were noted
- Trimboli et al. evaluated 125 patients with epilepsy who switched from branded to generic levetiracetam. After six months, seizure frequency and the occurrence of side effects were not significantly different from baseline. You can read this study in full by visiting the Online Wiley Library website.
- Fanella et al. assessed 36 patients with epilepsy who switched from branded to generic levetiracetam. No patients reported seizures or adverse events. The switchback rate (i.e. patients who returned from a generic version to Keppra) was low at 8%. You can read this study in full by visiting the MDPI website.
- Reimers et al. evaluated 16 patients who switched from branded to generic levetiracetam. None of the patients who were seizure-free before switching experienced seizures while they received generic levetiracetam. None of the patients switched back to branded levetiracetam. You can read this study in full by visiting the Seizure website.
- Olsson et al. assessed 16 patients with epilepsy who switched from branded to generic levetiracetam and found clinically relevant improvements among patients who switched to generic levetiracetam. You can read this study by visiting the Epilepsy & Behaviour website.
- Markoula et al. assessed 12 patients with epilepsy who switched from branded to generic levetiracetam. The average seizure number was similar between branded and generic versions and patients experienced similar adverse events with both versions. You can read this study by visiting the Seizure website.
Studies where changes in seizure frequency/ adverse events were noted
- Chaluvadi et al. assessed 245 patients with epilepsy who switched from branded to generic levetiracetam. The proportion of patients who experienced increased seizures was significantly greater with generic levetiracetam than with branded levetiracetam (19.6% vs. 1.6%). Overall, 42.9% of patients switched back to branded levetiracetam. You can read this study by visiting the Online Wiley Library website.
- Tharavichitkun et al. assessed 75 patients with epilepsy who switched from branded to generic levetiracetam. After 6 months, no significant difference was observed in the mean seizure frequency from baseline. However, in patients with controlled seizures before the change, the seizure frequency increased significantly. You can read this study by visiting the MDPI website.
- Lee et al. evaluated 148 patients with epilepsy who switched from branded to generic levetiracetam. After 6 months, 76.4% were seizure-free, 4.7% experienced an increase in seizure frequency, and 6.8% experienced a reduction in seizure frequency. You can read this study by visiting the Seizure website.
- Paolini et al evaluated 28 patients with epilepsy who experienced 36 adverse events after they switched from branded to generic levetiracetam. All symptoms returned to baseline after they switched back to branded levetiracetam except in 7 patients who remained on generic levetiracetam.
There are also several case reports of patients with epilepsy have been published where patients experienced increases in seizure activity after they switched from branded to generic levetiracetam. You can find two examples of these on the Sage Journals website and Springer Links website.