This advice was updated in November 2017 following a review by the Commission on Human Medicines. Patient-related factors should be considered when deciding whether it is necessary to maintain continuity of supply for a specific product. See Drug Safety Update volume 11, issue 4; November 2017: 5.
Article date: November 2013
Bioequivalence and antiepileptic drugs
When a generic medicinal product is shown to be bioequivalent to the originator (reference) product, as defined by the relevant regulations and guidelines, it follows that the products can be considered to be clinically equivalent. However, concerns about switching between different manufacturers’ products of an oral antiepileptic drug (AED) have been raised by patients and prescribers. These include switching between branded originator and generic products, and between different generic products of a particular drug. The main reasons for these concerns are the narrow therapeutic index of some AEDs and the potentially serious consequences of therapeutic failure. Drug–drug interactions and the relatively low solubility or bioavailability (or both) of some AEDs are other important factors.
Potential risk from switching between different manufacturers’ products
The Commission on Human Medicines (CHM) reviewed spontaneous adverse reactions received by MHRA and publications that reported potential harm arising from switching of AEDs in patients previously stabilised on a branded product to a generic. Following this review, CHM concluded that reports of loss of seizure control and/or worsening of side effects around the time of switching between products could be explained as chance associations, but that a causal role of switching could not be ruled out in all cases.
New categorisation to help minimise risk
The CHM considered the characteristics of AEDs and advised that they could be classified into three categories based on therapeutic index, solubility, and absorption to help prescribers and patients decide whether it was necessary to maintain continuity of supply of a specific manufacturer’s product. These categories are listed below:
Category 1 – phenytoin, carbamazepine, phenobarbital, primidone
For these drugs, doctors are advised to ensure that their patient is maintained on a specific manufacturer’s product
Category 2 – valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate
For these drugs, the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with patient and/or carer, taking into account factors such as seizure frequency and treatment history
Category 3 - levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin
For these drugs, it is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
Advice for prescribers:
- Different AEDs vary considerably in their characteristics, which influences the risk of whether switching between different manufacturers’ products of a particular drug may cause adverse effects or loss of seizure control
- AEDs have been divided into three categories to help healthcare professionals decide whether it is necessary to maintain continuity of supply of a specific manufacturer’s product
- If it is felt desirable for a patient to be maintained on a specific manufacturer’s product, this should be prescribed either by specifying a brand name, or by using the generic drug name and name of the manufacturer (otherwise known as the Marketing Authorisation Holder)
- Please report on a Yellow Card any suspected adverse reactions to AEDs (www.mhra.gov.uk/yellowcard)
- This advice relates only to AED use for treatment of epilepsy; it does not apply to their use in other indications (eg, mood stabilisation, neuropathic pain)
Additional advice for pharmacists:
- Dispensing pharmacists should ensure the continuity of supply of a particular product when the prescription specifies it. If the prescribed product is unavailable, it may be necessary to dispense a product from a different manufacturer to maintain continuity of treatment of that AED. Such cases should be discussed and agreed with both the prescriber and patient (or carer)
- Usual dispensing practice can be followed when a specific product is not stated
MHRA website information on prescribing and dispensing of antiepileptic drugs
See also letter sent via the Central Alerting System, Nov 11, 2013
Article citation: Drug Safety Update date volume 7 issue 4, November 2013: A1.
Published 11 December 2014