Antiepileptic drugs are drugs that are primarily used to control epileptic seizures, although they are used for other conditions as well. This section of the website provides information about switching between manufacturers’ products of oral antiepileptic drugs, including switching between branded products and generic products, and between different generic products of a particular drug,

Background

When a generic medicine is shown to be bioequivalent (has the same effect on the body) to the original (‘reference’) product, as defined by the relevant regulations and guidelines, these products can be considered to be clinically equivalent.

However, concerns about switching between different manufacturers’ products of antiepileptic drugs (AEDs) have been raised by patients and prescribers. These include switching between branded original and generic products, and between different generic products of a particular drug.

Different AEDs vary considerably in their characteristics, which influence the risk of whether or not switching between different manufacturers’ products of a particular drug may cause adverse effects or loss of seizure control.

Following a review of the available evidence, the UK Commission on Human Medicines (CHM) considered the characteristics of AEDs and advised that they could be classified into three categories, based on therapeutic index (a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes or toxicity), solubility and absorption, to help prescribers and patients decide whether it is necessary to keep using a supply  of a specific manufacturer’s product.

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 concerns such as patient anxiety, and risk of confusion or dosing errors.

The final report from the CHM highlighting their recommendations is below:

Formulation switching of antiepileptic drugsPDF file (opens in new window) (135Kb)

Advice for healthcare professionals

If a patient should 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 (marketing authorisation holder’).

This advice relates only to AEDs used for the treatment of epilepsy and does not apply to the use of AED for indications such as mood stabilisation or neuropathic pain.

Letter to healthcare professionals from the Commission on Human MedicinesPDF file (opens in new window) (876Kb)

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.

Information for patients

Patients should take careful note of the name and manufacturer of their antiepileptic medicine and should check with their doctor or pharmacist if they are dispensed an unfamiliar medicine.

The MHRA has produced a patient information sheet which summarises the key messages for patients resulting from the updated advice on the use of AEDs and outlines what this new information means for them. This patient sheet can be found at the following below:

Patient information sheetPDF file (opens in new window) (363Kb)

National Institute for Health and Care Excellence (NICE) guidance on AEDs

The current NICE guideline on AEDs published in January 2012 contains the following statement with regard to the need for continuity of supply:

'Consistent supply to the child, young person or adult with epilepsy of a particular manufacturer's AED preparation is recommended, unless the prescriber, in consultation with the child, young person, adult and their family and/or carers as appropriate, considers that this is not a concern. Different preparations of some AEDs may vary in bioavailability or pharmacokinetic profiles and care needs to be taken to avoid reduced effect or excessive side effects. Consult the summary of product characteristics (SPC) and 'British national formulary' (BNF; available at http://bnf.org) on the bioavailability and pharmacokinetic profiles of individual AEDs, but note that these do not give information on comparing bioavailability of different generic preparations.'

The CHM advises that there is a need to maintain continuity of supply of a specific product in the case of certain AEDs, but not for all. In broad terms three categories of AEDs are identified in terms of potential concerns related to switching between different manufacturer’s products of a particular drug.

Following discussions with the MHRA, NICE will be updating its advice to healthcare professionals via the publishing of a Medicines Evidence Commentary in line with the MHRA Drug Safety Update and also including a cross reference to the CHM advice in their AED Guideline.

The BNF has also been contacted with regard to updating its information on AEDs.

Implications for marketing authorisation holders (MAHs)

The need to enable a consistent supply of a particular product from a specified marketing authorisation holder (MAH) while maintaining the access of generic products to the market will have a number of regulatory implications.

Trade associations, MAHs and parallel import licence (PLPI) holders have already been contacted in relation to the following actions and proposals:

  • Product names

Marketing authorisations for all AED products marketed under a generic name comprising only the INN should be updated so that the product name  in section 1 of the Summary of Product Characteristics (SmPC)  includes the name of the MAH (ie INN + MAH). The patient information leaflet (PIL) and labelling can remain unchanged, provided that the MAH name or logo is clearly displayed.

This requirement, while specifically requested to allow continuity of supply in line with the CHM advice for AEDs, is also in line with Article 11(1) of Directive 2001/83/EC as amended, with reference to the definition stated in Article 1(20). (external link)

  • Own label suppliers

The practice of using own label suppliers (OLS) causes a problem for the prescription and dispensing of a specific product, since the same OLS could be named on more than one generic MA for an AED. Because of this, the MHRA is requests that MAHs remove OLSs from the MA of AED products.

The MHRA would, however, welcome any proposals from MAHs wishing to continue using OLS livery that would present a practical and reliable resolution to this issue.

A separate letter is being sent to those MAHs which our records show hold authorisations naming an OLS. All MAHs are encouraged to contact the MHRA at an early stage where an OLS issue requires discussion.

  • Duplicate licences

There is a theoretical possibility that a MAH may hold multiple MA’s for the same product (‘duplicate licences’), which may have the same generic name. In these cases, it would be possible to vary any of the licences in the future so as to yield different products (but with the products still bearing the name ‘INN + MAH’).

As such, where a MAH holds more than one licence for a particular product, they should confirm the marketing status of these products (as per their obligation under Article 23a of the Directive). The products may then need to be named differently to allow them to be distinguished from each other.

  • Parallel import (PLPI) product names

The product name for a parallel imported AED product should be the name under which the UK cross-referred product is marketed. Alternatively, the name of the product in the source country can be used, providing this will not lead to any confusion or doubt over continuity of supply to the patient.

The MHRA will consider any proposals from importers wishing to use an alternative name that will not cause confusion and will ensure continuity of supply to the patient.

Approval of generic antiepileptic drugs

Normally, if a generic medicinal product is shown to be bioequivalent to the originator ‘reference’ product as defined by the relevant regulations and guidelines, the products can be considered to be clinically equivalent. This is the basis for approval of generic medicinal products.

The conventional bioequivalence criteria require the 90% confidence interval for the generic/reference product ratio for mean Area Under the plasma drug concentration-time Curve (AUC) and maximum plasma concentration (Cmax) to lie within the range 80 to 125%.

In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90 to 111%.

Where Cmax is of particular importance for safety, efficacy or drug level monitoring, the 90 to 111% acceptance interval should also be applied for this parameter.

It is not possible to define a set of criteria to categorise drugs as narrow therapeutic index drugs (NTIDs) and it must be decided case by case if an active substance is an NTID based on clinical considerations. Some but not all AEDs are considered to be NTIDs.

Concerns have been raised by some patients and prescribers that these bioequivalence criteria might not always be sufficient to ensure equivalent safety and efficacy when switching between different marketed antiepileptic products.


Page last modified: 25 November 2013