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Benefits of buccal midazolam in paediatric patients

PRACTICAL THERAPEUTICS
Ying Ying Xu, MPhil
Jenny KW Lam, PhD MRPharmS
Ian CK Wong, PhD FRPharmS
Department of Pharmacology and Pharmacy,
Li Ka Shing Faculty of Medicine,
University of Hong Kong,
Hong Kong SAR, China
Noha Iessa, MPharm (hons) PG Dip (Clinical Pharmacy)
Centre for Paediatric Pharmacy Research,
University College London School of
Pharmacy, London, UK
Email: wongick@hku.hk

Buccolam is the first and only licensed midazolam oromucosal solution in the EU presented in age-specific, single-use, prefilled oral syringes for the treatment of prolonged, acute, convulsive seizures in paediatric patients


Convulsive status epilepticus is the most common childhood neurological emergency in developed countries and it can lead to neurocognitive sequelae and death.(1,2) It is widely accepted that immediate diagnosis as well as rapid treatment of status epilepticus and prolonged seizures is crucial to prevent neurologic and systemic pathology. Although many pharmacological treatments are available for status epilepticus and prolonged seizures in hospital settings, there are very limited choices in community settings owing to the lack of intravenous access to patients. According to the National Institute for Health and Clinical Excellence (NICE) guideline on the epilepsies, issued in January 2012, buccal midazolam is recommended as first-line treatment in children with prolonged or repeated seizures in the community. Rectal diazepam can also be used if it is preferred, or if buccal midazolam is not available.(3) 

Midazolam
Midazolam is a short-acting drug that belongs to the benzodiazepine class. It acts by enhancing the activity of gamma-aminobutyric acid, which is one of the major inhibitory neurotransmitters in the brain, resulting in neural inhibition. The general properties of midazolam are similar to those of diazepam, except that it has a more potent amnestic action. Apart from status epilepticus, midazolam is also indicated for sedation with amnesia, sedation in intensive care and induction of anaesthesia. 

Midazolam is metabolised by CYP3A4 and undergoes extensive first-pass hepatic metabolism after oral dosing. 1-hydroxymidazolam is a primary metabolite that has weak pharmacological activities. Administration of midazolam by the buccal route can avoid first-pass metabolism and improve the bioavailability. Owing to its high lipophilicity at physiological pH, rapid absorption across the buccal membrane can be achieved. Following buccal administration, a rapid onset of action (<ten minutes) is observed and the maximum plasma concentration is reached within 30 minutes in children. 

Buccal route of administration
Buccal delivery is a type of oromucosal delivery (the other being sublingual delivery). The drug is absorbed via the buccal mucosa, which includes the lining of the cheeks, the gums, and the upper and lower lips. Instead of swallowing the medication directly, the buccal formulation, either a tablet or a solution, is designed to be dissolved and absorbed via the pouch of the cheek and gums/gingiva. The buccal route of administration offers advantages, such as rapid absorption and avoiding the first-pass effect. In addition, it is an easy and non-invasive means of administration, which is extremely important in serious diseases with sudden onset that require rapid treatment, such as seizures and heart attacks. 

An easy-to-use medication is always highly desirable for treating prolonged seizures in young patients in the community. Considering other routes of administration with fast absorption, such as the intravenous, intranasal and rectal routes, the onset of action of intravenous medicines is shorter but requires the assistance of well-trained healthcare professionals. Also, venous access could be difficult, especially in children. The intranasal route is relatively easy to use, but drug absorption is adversely affected in cases of nasal congestion or upper respiratory tract infections. The rectal route of administration is often a social embarrassment, particularly in public, and can be detrimental to the self-esteem of children and teenagers. In addition, rectal administration has the problem of potentially unpredictable absorption in the event of constipation or bowel movement disorders. By contrast, buccal administration is relatively simple with less limitations and more predictable absorption. It is a more acceptable choice of emergency administration for paediatric patients in the community. 

Buccal midazolam versus rectal diazepam
Choices of pharmacological treatments for status epilepticus and prolonged seizures in the community are limited. Before October 2011, rectal diazepam was the only licensed treatment for this condition in the EU, although the buccal midazolam (unlicensed use at that time) was considered to be more acceptable. To compare the efficacy of buccal midazolam and rectal diazepam for cessation of prolonged seizures, we pooled reported data from three independent randomised controlled trials (RCTs)(4–6) previously conducted in a total of 525 patients aged from three months to 19 years (no gender restrictions), with 628 seizure events.

The three RCTs (two of the three in the UK, and one in Uganda) were examined to fulfil the criteria for meta-analysis. Doses of midazolam and diazepam in all studies were the same in accordance to different age groups. The primary outcome was cessation of visible seizure activity within 10 minutes. The secondary outcomes were cessation of visible seizure activity within 10 minutes and no re-occurrence of seizures within one hour of drug administration. The meta-analysis indicated an overall relative risk (buccal midazolam/rectal diazepam) of 1.24 (95% CI 1.11–1.39, p=0.0002) in cessation of visible seizure activity within 10 minutes (Table 1), and a relative risk (buccal midazolam/rectal diazepam) of 1.42 (95% CI 1.22–1.66, p=0.00001) in cessation of visible seizure activity within 10 minutes without re-occurrence within one hour (Table 2).

It is clear that buccal midazolam is significantly more effective than rectal diazepam in terminating visible seizure activity within 10 minutes without recurrence within one hour of drug administration for the prolonged seizures in children. 

Other published reviews and non-randomised studies also reported buccal midazolam was either as effective or better than rectal diazepam.(7,8) A publicly available published report by the European Medicines Agency shows that the frequency and severity of adverse drug reactions reported for buccal midazolam were similar to that of the rectal diazepam comparative group.(9) The consequences were also very close for buccal midazolam and intravenous diazepam treatment. Regarding the unwanted side effects, buccal midazolam may cause respiratory depression, as is the case with other comparable medicines, but the number of reported adverse events, particularly with fatal outcomes and respiratory depression, are small and similar in numbers to rectal diazepam.(9,10) 

A previous survey has revealed that families prefer to use buccal midazolam to rectal diazepam. The most commonly stated reasons for this priority were: personal dignity; socially appropriateness; ease of administration in wheelchair users; and a quicker response than rectal diazepam.(11) For these reasons, buccal midazolam becomes the more favourable choice than rectal diazepam if they exert similar therapeutic potential.
After careful consideration of various factors including the safety and efficacy of buccal midazolam, the Committee for Medicinal Products for Human Use (CHMP) decided that the benefits of buccal midazolam overweighed its risks and granted a marketing authorisation valid throughout the EU in September 2011. Buccolam® (midazolam hydrochloride) has become an authorised treatment for prolonged acute convulsive seizures for paediatric use. Together with rectal diazepam, it is currently recommended by the NICE guideline as the first-line treatment.(9)

Administration of Buccolam®
Buccolam® is an oromucosal (buccal) solution of midazolam hydrochloride. It is the first and only licensed oromucosal midazolam product in the EU for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from three months to <18 years). It is also the first paediatric medicine to be granted a licence under the new EU 'paediatric-use marketing authorisation' (PUMA). 

Buccolam® is prepared as single-use, prefilled, oral syringes. There are four different preparations of Buccolam® designed for different doses and age groups of children: 

  • Yellow label: 2.5mg in 0.5ml, three months to <one year 


  • Blue label: 5mg in 1ml, one to <five years 


  • Purple label: 7.5mg in 1.5ml, five to <ten years 


  • Orange label: 10mg in 2ml, ten to <18 years.

For infants between zero and three months of age, Buccolam® is not recommended unless a hospital monitoring environment is at hand, because the safety and efficacy data has not been established for this group. 

To administer Buccolam®, a needle should not be attached to the syringe and it must not be injected. The full amount of solution should be inserted slowly into the space between the gum and the cheek. If a large volume is to be administered, approximately one half of the dose should be given slowly into one side of the mouth and the second half should be given slowly into the opposite side. Laryngo-tracheal insertion should be avoided to prevent accidental aspiration of the solution. Only one dose should be administered by the carers. If the seizure has not stopped within 10 minutes of administration, emergency medical assistance must be sought immediately. 

Adverse effects and contraindications
Adverse effects reported with Buccolam® are similar to those reported with other benzodiazepines. The most common side effects of Buccolam® are sedation, sleepiness, depressed levels of consciousness, respiratory depression and nausea and vomiting.(10)  Buccolam® should be used with caution in patients with chronic respiratory insufficiency because midazolam can further depress respiration and make breathing difficulties worse. Lower doses may be required for debilitated patients because the benzodiazepines tend to have an enhanced effect on the central nervous system (CNS).

The contraindications of Buccolam® include severe hepatic impairment, sleep apnoea syndrome, severe respiratory insufficiency, myasthenia gravis and allergies to midazolam. Grapefruit juice and alcohol will enhance the sedative effects of Buccolam®. Buccolam® overdose usually does not present as a life-threatening incident unless it occurs in those patients with pre-existing breathing difficulties or cardiac insufficiency, or when combined with other CNS depressants (including alcohol). Flumazenil, a benzodiazepine antagonist, may be used as an antidote to Buccolam® overdose.(10) 

Unlicensed buccal midazolam
Although various buccal midazolam preparations are available, Buccolam® is the only authorised formulation for prolonged acute convulsive seizures for paediatric use. Several factors should be considered when transferring patients from other buccal midazolam preparations to the authorised Buccolam®.

First, Buccolam® is the hydrochloride salt of midazolam, whereas other buccal midazolam preparations may use a different salt such as the maleate salt. Although there is some suggestion that the maleate salt may be better absorbed in the buccal cavity, there are adequate studies with midazolam hydrochloride to support the dosing schedule authorised for Buccolam®.(12) Second, Buccolam® (5mg/ml) is only half the strength of some other unlicensed preparations (10mg/ml) if administered at the same drug volume. The extra volume of Buccolam® may aid the absorption process because it is usually easier to achieve the buccal administration with a larger volume.(13) There are other factors that should be taken into account while considering different formulations of buccal midazolam. For example, Epistatus® is an unlicensed buccal midazolam formulation manufactured by Special Products Ltd, which contains midazolam 10mg in 1ml buccal liquid x 5ml.

Some changes had been made to this unlicensed product by extending its oral dosing pipettes from 1ml to 1.5ml for three batches since December 2011. The Medicines and Healthcare products Regulatory Agency (MHRA) issued a Class 4 Drug Alert of EL(12)A/08 (28 February 2012) and an additional alert of EL(12)A/10 (06 March 2012) to remind relevant clinics, general practitioners and community pharmacists of the potential risk of drug overdose in patients due to the unawareness of such modifications. After reviewing the risks, Special Products Ltd has decided to revert to the 1.0ml syringe. Another Drug Alert of EL(12)A/16 (24 April 2012) was therefore issued to notify this change. There will be no further supply of the 1.5ml syringe from April 2012. Unlike licensed products, special products can modify their presentations, formulations and production methods without prior assessment or approval from the regulatory authority; prescribing and administering unlicensed products instead of licensed products potentially increase the risk of medication errors as demonstrated by the MHRA’s warning. 

Conclusions
In prolonged seizures in children, Buccolam® is more effective than rectal diazepam in terminating seizures within ten minutes and preventing re-occurrence within one hour. Buccolam® also has a more convenient and acceptable route of administration for avoiding embarrassment. Patients in Europe should be informed the availability of Buccolam® so that they can make an informed choice to use rectal diazepam, unlicensed buccal midazolam or Buccolam® for the treatment of prolonged seizures in the community. 


Key points

  • Immediate diagnosis and rapid treatment of status epilepticus and prolonged seizures is crucial to prevent neurologic and systemic pathology.


  • Midazolam is a short-acting benzodiazepine which enhances the activity of gamma-aminobutyric acid, resulting in inhibition of epileptic activity.


  • Buccal midazolam is easy to be administered and is a more acceptable choice of emergency administration for paediatric patients in the community.


  • Buccal midazolam is more effective than rectal diazepam in terminating seizures within ten minutes and preventing re-occurrence within one hour.


  • Buccolam® (Buccal midazolam hydrochloride) is the first paediatric medicine to be granted a licence under the new EU 'paediatric-use marketing authorisation' for the treatment of prolonged seizures.



Declaration of interest
Professor Wong is the founder and a director of Therakind. Therakind is a spin-out company of the UCL School of Pharmacy, Great Ormond Street Hospital for Children NHS Trust and UCL Institute of Child Health, with funding from commercial and private investors. Therakind receives royalties from ViroPharma (the manufacturer of Buccolam®) for the development of Buccolam®. 

References


  1. Ackers R et al. Mortality rates and causes of death in children with epilepsy prescribed antiepileptic drugs: a retrospective cohort study using the UK General Practice Research Database. Drug Safety 2011;34(5):403–13.



  2. Chin RF et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:222–9.



  3. National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE clinical guideline 137;January 2012. http://guidance.nice.org.uk/CG137 (accessed 30 October 2012.



  4. Scott RC, Besag FM, Neville BG. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 1999;353:623–6.



  5. McIntyre J et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 2005;366:205–10.



  6. Mpimbaza A et al. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics 2008;121:e58–64.



  7. Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev 2008:CD001905.



  8. Sofou K et al. Management of prolonged seizures and status epilepticus in childhood: a systematic review. J Child Neurol 2009;24:918–26.



  9. European Medicines Agency. Buccolam. EPAR summary for the public. Last update September 2011. www.ema.europa.eu/Find medicine/Human medicines/European Public Assessment Reports (accessed 8 October 2012).



  10. Electronic Medicines Compendium (EMC). Summary of Product Characteristics (SPCs). Buccolam. Last update December 2011. http://www.medicines.org.uk/emc/ (accessed 30 October 2012).



  11. Wilson MT, Macleod S, O'Regan ME. Nasal/buccal midazolam use in the community. Arch Dis Child 2004;89:50–1.



  12. Medicines and Health products Regulatory Agency.Drug safety update. Buccal midazolam (Buccolam): new authorised medicine for paediatric use – care needed when transferring from unlicensed formulations October 2011;5(3):A2.



  13. Tomlin S. Medicines tailored for children – the introduction of buccal midazolam. Pharm J 2011;287:161.

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