1. EPISTATUS (Buccal Midazolam)

2. 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

3. 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

4. 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

5. Contact Details Head Office: Special Products Limited
Unit 16, Trade City, Avro Way
Brooklands Business Park
Weybridge
Surrey
KT13 0YF
United Kingdom
Tel: +44 (0)
Web:

6. In Italia Posologia MIDAZOLAM Indicazioni Formulazioni
Sedazione in pre anestesia e anestesia
Posologia
IM: Adulti 0,07-0,10 mg /Kg; Bambini 0,15 – 0,20 mg /Kg. EV: Adulti mg/Kg.
Via rettale: 0,3-0,5 mg/Kg sconsigliata sotto i 6 mesi.
Formulazioni
Ipnovel (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

7. DIAZEPAM per uso rettale
In Italia
Indicazioni
Profilassi intermittenti convulsioni febbrili
Posologia
Uso rettale 0,5-1 mg /Kg, sotto i tre mesi solo in ospedale
Formulazioni
MICROPAM (Actavis) - fascia C
10 mg e 5mg /2,5ml contenitori monodose
Da Informatore farmaceutico 2010 – Farma 7

8. Can Buccal Midazolam Replace Rectal Diazepam?

9. 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

10. Why Change from Rectal Diazepam?
Unreliable
Rectum can be congested with faeces
Absorption is blocked

11. Why Change from Rectal Diazepam?
2 Less acceptable to patient and carer
Embarrassing for patient
Carer could be accused of sexual assault

12. Why Change from Rectal Diazepam?
3 Patient is drowsy for <24 hours
(diazepam is very lipophyllic and is released slowly from the body fat)

13. 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

14. 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

15. Can Buccal Midazolam Replace Rectal Diazepam? Proofs of Concept

16. Clinical Study 1 (Scott, 1999 – The Lancet Vol
Clinical Study (Scott, 1999 – The Lancet Vol. 353) Buccal midazolam and rectal diazepam for treatment of prolonged seizure in childhood and adolescence: a randomise trial Study Design
Buccal midazolam administered 5 minutes after
seizure starts

17. Clinical Study 1 Residential school with on-site medical facilities
(rapid treatment)
42 young people (from 5 to19 years) with severe epilepsy
Administered randomly:
10mg buccal midazolam OR
10mg rectal diazepam

18. 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)

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

20. 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)

21. 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

22. 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

23. Results
Buccal midazolam treatment: 109 episodes (92 patients) Rectal diazepam treatment: 110 episodes (85 patients)

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

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

26. 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

27. Results Median time for seizure to stop: Buccal midazolam:
8 minutes (range 5-20)
Rectal diazepam:
15 minutes (range 5-31)

28. Results

29. 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

30. Study design Two paediatric teaching hospitals
Emergency Room treatment
Randomised (buccal midazolam or rectal diazepam)
Median Age:
Midazolam: 24 months
Diazepam: months
49 patients in each group

31. 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

32. Results 49 patients treated with buccal midazolam:
42 (88%) of patients responded within 4 minutes
49 (100%) of patients responded within 5 minutes

33. 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

34. Results
The time for drug administration and drug effect was significantly less with buccal midazolam than with rectal diazepam.
P< 0,001

35. BUCCAL MIDAZOLAM SUMMARY OF TRIAL DEMONSRATING THE EFFICACY

36. 1999 Early Administration 2005 Emergency Room 2010 SUMMARY OF EFFICACY
Author
Salt
Concentration
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 minutes
Median 6 minutes
(IQR 4-10
minutes)
McIntyre et al2
2005
Emergency
Room
2.5mg
5.0mg
7.5mg
6-12 months
1-4 years
5-9 years
10+ years
61% in 10 minutes
(Median:8 minutes)
(IQR 5-20 minutes)
Ashrafi et al3
2010
Maleate
10mg in 1ml
88% in 4 minutes
100% in 5 minutes
(Median: 4 minutes)

37. Making Buccal Midazolam More Effective

38. Formulating to: 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%.

40. Formulating to: 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

41. Formulating to: 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

42. 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

43. Epistatus - current position
MHRA* license submission Q (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)

44. NICE

45. NICE

46. 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)

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