Buccal midazolam: a new treatment for epileptic seizures

UCL research developed a new method of treating convulsive status epilepticus (a severe form of epileptic seizure). This has become the standard method of treatment, and is in widespread use around the world. Children can be treated more quickly in a community setting, reducing harm from delayed treatment.

Convulsive status epilepticus (CSE) is the name given to an epileptic seizure that does not stop by itself. It is the commonest neurological medical emergency in childhood and can cause significant illness or even death. For many years, the most commonly recommended treatment for this condition was a rectal preparation of diazepam - a method of administration that was difficult and unpleasant for many parents and carers, resulting in delayed or avoided treatment, with consequent higher risks to the patient.

Researchers at the UCL Institute of Child Health (ICH) investigated an alternative way of administering the same drug via the buccal cavity (the space between the gum and the cheek) as this would be a socially acceptable method which could be more easily administered by parents, carers and emergency medical technicians. Initial studies showed that when the drug was administered this way, it was easily absorbed and had a rapid effect on the brain.

Professor Scott's work on buccal midazolam has fundamentally changed practice in the management of status epilepticus. The research has led to the development of a new product that has not only proven to be an effective drug therapy for status epilepticus but also a more socially acceptable method of administration. - Young Epilepsy

The team then conducted a randomised controlled trial to directly compare the two treatments. This took place in a residential school attended by a number of students with severe epilepsy. Continuous seizures of more than five minutes' duration were randomly treated with buccal midazolam or rectal diazepam. The results showed that buccal midazolam was at least as effective as rectal diazepam, and was more socially acceptable. Subsequent trials in Europe and Africa confirmed these findings, and have even showed better results in certain circumstances, along with significantly quicker administration and greater acceptability. As a result of this work, buccal midazolam is now the drug of choice for the treatment of status epilepticus in the community. It was included in guidelines for the first time in 2005, when it was recommended as first-line therapy in the Advanced Paediatric Life Support. In the same year, the Scottish Intercollegiate Guidelines Network recommended the use of buccal midazolam, citing the study directly. In 2012, buccal midazolam was recommended in National Institute for Health and Clinical Excellence Clinical Guideline 137 on Epilepsy as first-line therapy for treating children, young people and adults with prolonged or repeated generalised, convulsive seizures in the community. The Scottish Medicines Consortium also approved buccal midazolam for use in Scotland in 2012 and estimated that for the approximately 1,000 patients who will receive it annually there would be a cost saving on the drugs budget of £100,000 per annum. In addition to the inclusion in National Guidelines, buccal midazolam is included in many local guidelines for treatment of status epilepticus in the UK and in other parts of the world.

Two pharmaceutical formulations of buccal midazolam are now available. The first, Epistatus (midazolam maleate), was developed by Professor Rod Scott and Professor Brian Neville (UCL ICH), and was brought to market under a commercial licence agreement between UCL Business and Special Products Ltd. It has been employed clinically for over 10 years, being manufactured under a 'specials' licence issued by the MHRA.

The second, Buccolam (midazolam hydrochloride), arose from work conducted at UCL School of Pharmacy which resulted in the foundation of Therakind Limited, a spin-out company designed to develop the product further. In 2010, a controlling interest in Therakind was sold to ViroPharma Inc. who applied to the European Medicines Agency for a centralised Paediatric Use Marketing Authorisation. This was granted in 2011, allowing distribution and access to Buccolam to the one million children and adolescents with epilepsy in Europe. Importantly, as Buccolam is a licensed product (unlike almost all other paediatric prescriptions), it is easier to obtain as a repeat prescription in the community rather than having to return to secondary or tertiary care - a significant advantage for patients and caregivers.

Professor Scott and colleagues have also worked with the charity Young Epilepsy to develop training programmes for professionals and schools on all aspects of epilepsy in children, including training packages for the administration of emergency medication.