re: buccal midazolam...page 4 of 5 buccolam ® 10mg in 2ml (1mg midazolam base in 0.2ml)...

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Head of Medicines Management

Head Office, 99 Waverley Road

St Albans, Hertfordshire

AL3 5TL

4 May 2012

To All Health Care Professionals

HPFT/HCC Learning Disabilities Services in Hertfordshire

Dear Colleagues

Re: BUCCAL MIDAZOLAM

You will be aware that there have been recent alerts about the availability of different

buccal midazolam products which may have caused some confusion. These products

are available in different strengths and this could pose a risk to service users if you are

unaware of this. It is important where possible to continue using the same brand

to avoid switching the brand of product.

Service users accessing HPFT services are prescribed the buccal midazolam product

Epistatus which is available either in a bottle or in syringes. These should always be

prescribed by brand name. Epistatus is not licensed in adults or in children but has

been used as a “special” for several years in learning disability services across the UK

and in HPFT. All the training and shared care arrangements within learning disability

services relate to the Epistatus brand. There has been added confusion recently with

several MHRA alerts about certain batches and volumes of Epistatus being changed

(see links below to MHRA).

A new buccal midazolam product called Buccolam ® has been launched and is

licensed by the MHRA for children but not for adults. This product is available in a

different strength of midazolam per ml to Epistatus. Buccolam brand has sometimes

been prescribed by GPs and this may cause confusion to users and carers.

Clearly there is a desire to use this product within paediatrics as it is licensed by the

MHRA for children.

Because of this confusion and several incidents where the two products have been

interchanged and transferred without informing the users and carers a group of

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healthcare professionals from several organisations in Hertfordshire met to agree the

best course of action. The background and the current recommendation are outlined.

Background

An MHRA Drug Safety Update issued in October 2011 introduced the new licensed

buccal midazolam (Buccolam) and provided a warning about the care that is needed

when transferring from unlicensed formulations e.g Epistatus. http://www.mhra.gov.uk/home/groups/dsu/documents/publication/con131944.pdf

Since then there have been three further MHRA Drug Alerts about modifications

which have been made to the unlicensed Epistatus product in terms of the luer tip, the

markings on the plunger and the positioning of the plunger stop; together causing a

potential for overdose if not recognised.

http://www.mhra.gov.uk/Publications/Safetywarnings/DrugAlerts/CON143794



Following the MHRA alerts some guidance was issued from the National Patient

Safety Agency

http://www.nrls.npsa.nhs.uk/resources/type/signals/?entryid45=132975

NICE Clinical Guideline – Epilepsy CG137

Prolonged or repeated seizures and convulsive status epilepticus

http://guidance.nice.org.uk/CG137/NICEGuidance/pdf/English

• Only prescribe buccal midazolam or rectal diazepam for use in the community for

children, young people and adults who have had a previous episode of prolonged

or serial convulsive seizures. [new 2012]

• Administer buccal midazolam as first-line treatment in children, young people and

adults with prolonged or repeated seizures in the community. Administer rectal

diazepam if preferred or if buccal midazolam is not available. If intravenous

access is already established and resuscitation facilities are available, administer

intravenous lorazepam. [new 2012]

Buccal Midazolam Products available:

Epistatus 10mg in 1ml (1mg midazolam base in 0.1ml)

Presentations - there are two presentations:

1. A multi-dose pack of Epistatus is supplied as 5ml of liquid in a 30ml amber

bottle. The bottle is over-sized to enable the care person to grip it securely while

removing the child resistant closure. A 1ml overage is supplied to ensure that

4x1ml doses can be removed quickly and completely. Each 0.1ml of buccal

midazolam liquid contains 1mg of midazolam base.

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The pack contains a carton with instructions for use on the side panel, an

information leaflet, an amber glass bottle with tamper evident child resistant

closure and 4x 1ml purple oral dosing applicators calibrated with 0.1ml markings.

2. Pre-filled syringes (PFS packs)

Each pack contains 2 x 1ml purple oral dosing applicators. Each oral dosing

applicator is prefilled with one of the following doses – 2.5mg, 5mg, 7.5mg,

10mg. There are two oral dose applicaors in each child resistant pack.

Storage: 15 -250C

Shelf life: 2 years multi-dose pack. 1 year pre-filled syringes.

• Epistatus is an unlicensed special which has been used for several years in both

paediatrics and in adults for service users with Learning Disabilities

• Each service user in learning disability services has an individual management

plan with training provided to the staff and carers from specialist services.

• The MHRA has received a submission for licensing for adult and paediatric use

from Special Products Ltd.

• The midazolam salt in Epistatus is midazolam maleate. However, the clinical trial

papers relate to the hydrochloride salt on the basis of buccal administration of

midazolam hydrochloride injection. Information from Special Products Limited is

that they are hopeful about obtaining a licence for adults and children but they do

not have a date. The MHRA has asked them for evidence based on the midazolam

maleate product.

• It is very important to prescribe as brand Epistatus pre-filled syringe or bottle to

ensure continuity of the same strength.

Epistatus

Pack Size

Midazolam maleate (Epistatus)

10mg in 1ml *

5ml

Midazolam maleate

2.5mg in 0.25ml

2 syringes

Midazolam maleate

5mg in 0.5ml

2 syringes

Midazolam maleate

7.5mg in 0.75ml

2 syringes

Midazolam maleate

10mg in 1 ml

2 syringes

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Buccolam ® 10mg in 2ml (1mg midazolam base in 0.2ml)

Presentations

Pre-filled syringes containing 2.5mg, 5mg, 7.5mg and 10 mg midazolam

Licensed Dose and administration

Age range Dose Label colour

3 to 6 months in a hospital

setting (monitoring and

resuscitation available)

2.5mg in 0.5ml yellow

>6 months to <1year 2.5mg in 0.5ml Yellow

1 year to <5 years 5mg in 1ml Blue

5 years to <10 years 7.5mg in 1.5ml Purple

10 years to <18 years 10mg in 2ml Orange

• Buccolam is licensed in Paediatrics. No adult licence has been applied for.

• Volume administered would be larger than Epistatus as the strength of the solution

is half that of Epistatus

Comparative Cost

Buccal Midazolam Products Drug Tariff (March 12)

Per dose

Buccolam 10mg/2ml PFS (4) £91.50 £22.80

Buccolam 7.5mg/1.5ml PFS (4) £89.00 £22.30

Buccolam 5mg/1ml PFS (4) £85.50 £21.38

Buccolam 2.5mg/0.5ml PFS (4) £82.00 £20.50

Epistatus 10mg/ml (5ml) £90.68 £22.67

Factors to consider

• Errors have occurred in Hertfordshire with substitutions made by GPs and

Community Pharmacists between Epistatus and Buccolam (and other brands)

without professionals and carers being made aware of the difference in strength.

There are other specials supplied across Hertfordshire which may add to the

confusion ( Epi-Calm, UL Medicines, Suptamid)

• MHRA recommend that if a branded product is available, then this should be used

rather than an unlicensed product even if it is used for an “off-label” indication;

unless there is a good clinical reason for prescribing the unlicensed product.

Note: Buccolam is only licensed for Paediatrics.

Buccolam is not licensed for adults. Most service users in Learning Disability

services are adults. Epistatus is unlicensed for both.

• The Buccolam dose is twice the volume per mg dose to be placed in the mouth.

Concern was raised about aspiration or this larger volume being spat out or

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swallowed (where it would be ineffective). The manufacturers clearly state that

half the dose should be placed in one side of the mouth and half in the other.

• HPFT/HCC Learning Disability teams have been advising use of Epistatus for

several years and has developed shared care protocols and training (for bottles) for

healthcare professionals and carers. This affects a large number of service users

with learning disabilities and a switch to a different product would have

significant resource implications and a sudden switch would be unsafe in the short

term.

• Tertiary Referral Centres and surrounding organisations are in the process of

making a decision e.g. East Anglia Epilepsy Network, Great Ormond Street

In many cases switching to the licensed product Buccolam with others remaining

with Epistatus. Different products will cause confusion across organisations so it

is important to be aware of the different products.

• Buccolam Information leaflets for carers and product packaging states very boldly

that the use is only up to 18 years. Carers will be very concerned about the

suitability for adults with learning isability. The product packaging for Epistatus

is directed at all ages.

• HPFT/HCC clinicians and service users are familiar with the product.

Recommendation:

HPFT has recommended that we continue to prescribe the Epistatus by brand name

either in a bottle or in a syringe. The decision will be reviewed in 6 months time.

Buccolam is being prescribed by paediatricians in acute trusts and Hertfordshire

Community Trust and also by some tertiary referral hospitals. Therefore it is

important that we remain alert to the possibility that brands may be inadvertently

exchanged.

Reason for recommendation despite the MHRA guidance to use a licensed

product when available:

It was considered that the packaging and information leaflets for Buccolam will cause

concern for our users and carers as it emphasises that this is only licensed for children.

Training and individual care packages for Epistatus are in place for a large number of

service users in Learning Disability Services in HPFT. Systems are well established

for training and carer information.

Dr Kamalika Mukherji, Consultant Psychiatrist, Learning Disability Services HPFT

Alan Lim, Specialist Epilepsy Nurse, Learning Disability Services HPFT

Janet Howell, Head of Medicines Management HPFT May 2012

re: buccal midazolam...page 4 of 5 buccolam ® 10mg in 2ml (1mg midazolam base in 0.2ml)...

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