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 Limited Unit 16, Trade City, Avro Way Brooklands Business Park Weybridge Surrey KT13 0YF United Kingdom Tel: +44 (0)1932 690325 Web: www.specialproducts.biz

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 0.035 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

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

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? 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 Clinical Study 1 (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

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

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 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)

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

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)

Making Buccal Midazolam More Effective

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%.

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

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

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 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.