EPISTATUS(Buccal Midazolam)

SPECIAL PRODUCTS LIMITED

Special Products Limited is UK pharmaceutical company with a focus on development and distribution of medicines to improve the therapy available to patients with rare disorders, particularly in medical specialities of neurology, paediatric and metabolic disorders

Our vision

Our vision is to improve therapy options for patients by developing and producing high-quality, stable formulations of existing compounds to treat

rare diseases in children and adults

A Global Business

Established in 1997

Suppling over 60 different products to more than 25 countries

Europe, Asia, Middle East, North America and the Pacific Area

Multi-million € Business

Contact Details

Head Office:

Special Products LimitedUnit 16, Trade City, Avro WayBrooklands Business ParkWeybridgeSurrey KT13 0YFUnited Kingdom

Tel: +44 (0)1932 690325Web: www.specialproducts.biz

MIDAZOLAM

In ItaliaIndicazioniSedazione in pre anestesia e anestesia

PosologiaIM: Adulti 0,07-0,10 mg /Kg; Bambini 0,15 – 0,20 mg /Kg. EV: Adulti 0.035 mg/Kg.Via rettale: 0,3-0,5 mg/Kg sconsigliata sotto i 6 mesi.

FormulazioniIpnovel (Roche) - OSP 1K fascia C Midazolam IBI - OSP 1K fascia H Hameln (Hospira) - OSP 1K fascia C 15 mg/3ml e 5mg/ml uso im e ev

Da Informatore farmaceutico 2010

DIAZEPAM per uso rettale

In ItaliaIndicazioniProfilassi intermittenti convulsioni febbrili

PosologiaUso rettale 0,5-1 mg /Kg, sotto i tre mesi solo in ospedale

FormulazioniMICROPAM (Actavis) - fascia C 10 mg e 5mg /2,5ml contenitori monodose

Da Informatore farmaceutico 2010 – Farma 7

Can Buccal Midazolam Replace Rectal Diazepam?

Primary performance criteria for a product to stop prolonged seizures

Stops seizures quickly (< 10 minutes)

Easy and quick to administer

Safe and reliable

Acceptable to patient and carer

Stops seizures recurring

Why Change from Rectal Diazepam?

1. Unreliable

Rectum can be congested with faeces

Absorption is blocked

Why Change from Rectal Diazepam?

2 Less acceptable to patient and carer

Embarrassing for patient

Carer could be accused of sexual assault

Why Change from Rectal Diazepam?

3 Patient is drowsy for <24 hours

(diazepam is very lipophyllic and is released slowly from the body fat)

Why use Midazolam?

Advantages: Fat soluble enough to cross the blood/brain barrier

Water soluble enough for some to remain in the serum and stop further seizures

Leaves body fat at a predictable rate

half life: 3 hours in adults

1.5 hours in young children

Patient is not drowsy for a long time

Why use the Buccal route?

Easy administration

Not embarrassing for patient

Safer for carer:

No accusations of sexual abuse

No need to lift patient from wheelchair

Can be administered when the teeth are closed

Can Buccal Midazolam Replace Rectal Diazepam?

Proofs of Concept

Clinical Study 1 (Scott, 1999 – The Lancet Vol. 353)

Buccal midazolam and rectal diazepam fortreatment of prolonged seizure in childhood and adolescence: a randomise trial

Study DesignBuccal midazolam administered 5 minutes after seizure starts

Clinical Study 1

Residential school with on-site medical facilities

(rapid treatment)42 young people (from 5 to19 years) with

severe epilepsyAdministered randomly:

10mg buccal midazolam

OR

10mg rectal diazepam

Results

40 episodes (14 patients) treated with buccal midazolam 75% of patients responded

mean: 6 minutes (4-10) 39 episodes (14 patients) treated with rectal

diazepam 59% of patients responded

mean: 8 minutes (4-12) Mean total seizure duration:

Midazolam 17 minutes (range: 12-20) Diazepam 15 minutes (range: 13-20)

Clinical Study 2 (McIntyre 2005 – The Lancet Vol. 366)

Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizure in children: a randomised controlled trial

Proof of Concept:Could midazolam become the preferred method of treatment for status epilepticus by ambulance paramedics?(treatment after a delay)

Study design

Multi-centre (4 UK paediatric hospitals) Emergency Room treatment Randomised (buccal midazolam or rectal

diazepam) Age range: 6 months -15 years 177 patients (219 episodes)

Study Design Dose: 0.3-0.5mg/kg

Age of patient Dose of Midazolam

6-12 months 2.5mg (0.25ml)1-4 years 5mg (0.5ml)5-9 years 7.5mg (0.75ml)10-18 years 10mg (1.0ml)

Maximum single dose:10mg

Study design

Primary outcome measure: Cessation of visible signs of seizure

activity within 10 minutes without:

1 respiratory depression requiring assisted

breathing

2 another seizure within 1 hour

Results

Buccal midazolam treatment:

109 episodes (92 patients)

Rectal diazepam treatment:

110 episodes (85 patients)

Results

Buccal Midazolam was more effective than rectal Diazepam p< 0,001

Results

No adverse events were reported during the study with buccal midazolam nor with rectal diazepam

Results

Therapeutic success was higher for those receiving buccal midazolam than for those receiving rectal diazepam for:- Cessation of seizure within 10 min- Respiratory depression- Another seizure within 1 h

Results

Median time for seizure to stop:

Buccal midazolam:

8 minutes (range 5-20)

Rectal diazepam:

15 minutes (range 5-31)

Results

Clinical trial 3(Ashrafi, 2010 – European Journal of Paediatric Neurology 1-5)

Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children

Study design

Two paediatric teaching hospitals Emergency Room treatment Randomised (buccal midazolam or rectal

diazepam) Median Age:

Midazolam: 24 months Diazepam: 48 months

49 patients in each group

Study Design Dose: 0.3-0.5mg/kg

Age of patient Dose of Diazepam or Midazolam

6-12 months 2.5mg (0.25ml)1-4 years 5mg (0.5ml)5-9 years 7.5mg (0.75ml)10-18 years 10mg (1.0ml)

Maximum single dose:10mg

Results

49 patients treated with buccal midazolam:

42 (88%) of patients responded within 4 minutes

49 (100%) of patients responded within 5 minutes

Results

49 patients treated with rectal

diazepam

24 (49%) of patients responded within 4 minutes

40 (82%) of patients responded within 5 minutes

49 (100%) of patients responded within 8

minutes

Results

The time for drug administration and drug effect was significantly less with buccal midazolam than with rectal diazepam.

P< 0,001

 BUCCAL MIDAZOLAM

 SUMMARY OF TRIAL DEMONSRATING THE

EFFICACY

Author SaltConcentration

Dose(midazolam

base)

Age Time to stop seizures(range)

Scott et al1

1999

Early

Administration

Hydrochloride

5mg in 1ml

10mg 5-22 years 75% in 10 minutesMedian 6 minutes

(IQR 4-10 minutes)

McIntyre et al2

2005

Emergency

Room

Hydrochloride

5mg in 1ml

2.5mg5.0mg7.5mg10mg

6-12 months1-4 years5-9 years10+ years

61% in 10 minutes(Median:8 minutes)(IQR 5-20 minutes)

Ashrafi et al3

2010

Emergency

Room

Maleate

10mg in 1ml

2.5mg5.0mg7.5mg10mg

6-12 months1-4 years5-9 years10+ years

88% in 4 minutes100% in 5 minutes

(Median: 4 minutes)

SUMMARY OF EFFICACY

Making Buccal Midazolam More

Effective

Formulating to:

1 Stop seizures quickly (<5 minutes)

1.1 Maximise the amount of Midazolam in the closed ring lipophyllic, absorbable form.

At pH3, Midazolam hydrochloride injection, has about 75% of the midazolam in the closed ring lipophyllic form which is absorbable.

In comparison, Midazolam maleate at pH5 has 98% in the lipophyllic form increasing the amount that can be absorbed quickly by 30%.

1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 60

10

20

30

40

50

60

70

80

90

100

Midazolam Open/Closed ring in Water at Various pH

%Closed Ring (Midazolam) %Open Ring

pH

%

pH 5.0

Formulating to:

1 Stop seizures quickly (<5 minutes)

1.1 Promote absorption

Optimise the solvent of the Midazolam free base in the closed ring lipophyllic, absorbable form.

Ethanol was selected since it:

Promotes absorption

Miscible with saliva

Use midazolam maleate which is soluble in ethanol

1 Stops seizures quickly (< 5 minutes)

1.2 Maximise the concentration for the Midazolam in Epistatus.

Midazolam hydrochloride injection contains only 5mg midazolam base in 1ml.

Doubling the concentration to 10mg in 1ml doubles the concentration gradient across the mucosal membrane and, theoretically, doubles the absorption rate

Formulating to:

Epistatus - current presentation (to be licensed)

Pack with 4x1ml doses midazolam at 10mg/ml for buccal administration

Adult dose: 10mg (1ml) Child dose: 0.3mg/kg body weight Pack contains 4x 1ml oral syringes with

0.05ml & 0.10ml graduations Many UK Hospital protocols and patient

plans available as a guide UK training material: administration guide

for patient & CD, Epistatus demo pack

Epistatus - current position

MHRA* license submission Q1-2011 (license end 2011(?) then MRP Europe)

UK & Ireland sales since 2001 No serious adverse reactions so far 500,000+ seizures treated 2010 in UK,

Ireland, Scandinavia, Greece, Turkey, Middle East, Australia

NICE approval 2004 in UK Pre-filled syringe UK launch 2010 in twin

packs with choice of 2.5/5.0/7.5/10.0 mg

(*Medicine and healthcare Regulatory Agency)

NICE

NICE

ITALIAN REGULATORY MATTERS

Buccal midazolam is not registered

neither for route of administration (buccal),

nor indication (emergency treatment of status

epilepticus as an alternative to administration of

rectal diazepam)

 

According with D.LVO 216 April 2006 Titolo II art. 5:

Art. 5.Casi di non applicazione del titolo III

1. Le disposizioni del titolo III non si applicano ai medicinali preparati industrialmente su richiesta, scritta e non sollecitata, del medico, a ciò ritenuto idoneo dalle

norme in vigore, il quale si impegna ad utilizzare i suddetti medicinali su un determinato paziente proprio o

della struttura in cui opera, sotto la sua diretta e personale responsabilità; a tale ipotesi si applicano, ai

fini della prescrizione, le disposizioni previste per le preparazioni magistrali dall'articolo 5 del decreto-legge 17 febbraio 1998, n. 23, convertito, con modificazioni,

dalla legge 8 aprile 1998, n. 94.