Author: Rachael Hansford

Press release on behalf of Veriton Pharma Ltd
Published online: 2/10/17

Veriton Pharma Ltd is announced as the new company name for Special Products Ltd.

This name change has occurred both to incorporate the company’s past heritage with its future ambitions to make trusted medicines available for everyday living.

The Chief Commercial Officer commented:

With the launch of Epistatus^® 10mg in 1mL Oromucosal Solution Midazolam (as maleate), on the 8th of September 2017, and our extensive range of existing unlicensed medicines, we would like to assure our customers and partners that the excellent service and quality they have come to expect from us as a company will continue and all contacts at the company will remain the same.

With its legacy of technical expertise, which began in a world-renowned children’s hospital over 20 years ago, Veriton Pharma sources and supplies licensed medicines for CNS and over 75 high-quality, UK batch manufactured unlicensed medicines in the fields of epilepsy, neurology and rare paediatric conditions that licensed products cannot meet.

Headquartered in Weybridge, UK, Veriton Pharma, is a privately owned, speciality pharmaceutical company, which also has regional offices in the Middle East and Australia.

For further information about Veriton Pharma, visit www.veritonpharma.com

Epistatus Prescribing Information

EPISTATUS^® 10mg oromucosal solution midazolam (as maleate). Please consult Summary of Product Characteristics before prescribing.

Presentation & composition: oromucosal solution. Each 1mL of solution contains 10mg of midazolam (as maleate). Excipients with a known effect: ethanol 197mg/mL, liquid maltitol 675mg.

Indication: Treatment of prolonged, acute, convulsive seizures in children and adolescents aged 10 to less than 18 years. Epistatus must only be used by parents / caregivers where the patient has been diagnosed to have epilepsy.

Dosage:  For children and adolescents aged 10 to less than 18 years the standard dose is 10 mg (1.0 mL). Carers should only administer a single dose. If the seizure has not stopped within 10 minutes after administration, emergency medical assistance must be sought. Patients should be kept under supervision by a carer who remains with the patient. A second or repeat dose when seizures re-occur after an initial response should not be given without prior medical advice.

Administration: For oromucosal use only. Using the pre-filled oral syringe provided, administer, over a period of 2-3 seconds, approximately half of the prescribed dose to each buccal cavity. For detailed instructions please refer to the Summary of Product Characteristics.

Contra-indications: Hypersensitivity to midazolam, benzodiazepines or to any of the excipients. Myasthenia gravis; severe respiratory insufficiency; sleep apnoea syndrome; severe hepatic impairment.

Warnings & Precautions: Caution in patients with chronic respiratory insufficiency (may further depress respiration). For oromucosal use only. Take care to avoid the risk of choking. Midazolam should be used with caution in patients with chronic renal failure or impaired hepatic function (may accumulate); or cardiac function (may decrease clearance). Debilitated patients are more prone to the central nervous system (CNS) effects of benzodiazepines and, therefore, lower doses may be required. Midazolam should be avoided in patients with a medical history of alcohol or drug abuse. May cause anterograde amnesia. Contains maltitol and ethanol.

Interactions: Please consult the Summary of Product Characteristics for full details. Midazolam is metabolized by cytochrome P450 3A4 isozyme (CYP3A4). Inhibitors and inducers of CYP3A4 may increase and decrease the plasma concentration respectively. In the presence of CYP3A4 inhibition the duration of effect of a single dose of oromucosal midazolam may be prolonged; careful clinical monitoring is recommended. Midazolam may interact with other hepatically metabolized medicinal products. Co-administration with other sedative / hypnotic agents and CNS depressants, including alcohol, is likely to result in enhanced sedation and respiratory depression. Additional alcohol intake should be strongly avoided.

Pregnancy and lactation: Midazolam may be used during pregnancy if clearly necessary. The risk for new-born infants should be considered in the event of administration in the third trimester. Midazolam passes in low quantities into breast milk (0.6%); it may not be necessary to stop breast-feeding following a single dose.

Driving and machines: midazolam has a major influence on the ability to drive or use machines. The patient should be warned not to drive or use machines until fully recovered.

Side effects: Respiratory depression occurs at a rate of up to 5% although this is a known complication of convulsive seizures as well as being related to benzodiazepine use. Common: sedation, somnolence, depressed level of consciousness, respiratory depression, nausea & vomiting.  Uncommon: pruritus, rash, urticaria. Following injection, additional adverse reactions have very rarely been reported (including respiratory arrest and cardiac arrest); these may be of relevance to oromucosal administration.  Consult the Summary of Product Characteristics before prescribing.

Legal classification: POM

NHS Price: 10mg in 1mL prefilled syringe – £45.76

Marketing authorisation number: PL 16786/0003

Marketing authorisation holder: Veriton Pharma Limited, Unit 16, Trade City, Avro Way, Brooklands Business Park, Weybridge, Surrey, KT13 0YF, United Kingdom.

Date of last revision:  July 2017.

EDM/1036/2017

Date of preparation August 2017

Special Products Ltd has announced today, 8th September 2017, that Epistatus^® 10 mg Oromucosal Solution, Midazolam, is now available to prescribe. The NHS price for a single 10mg in 1mL prefilled syringe is £45.76.

Epistatus^® is licensed for use in the treatment of prolonged, acute convulsive seizures in children and adolescents aged 10 to less than 18 years, who have been diagnosed with epilepsy¹. Buccal midazolam is recommended by NICE² for the management of prolonged acute convulsive seizures, and is preferred by most patients and carers compared to the administration of rectal diazepam ^3,4.

Epistatus is presented “ready-to-use” in a novel, pre-filled, single-dose syringe, to provide carers with the confidence that they are administering the correct dose^1,5. The pre-filled syringe is contained within a specially-designed, secure and tamper-evident protective packaging.

The importance of having an alternate licensed preparation for use in the treatment of prolonged, acute convulsive seizures, especially in a different mode of delivery is an asset to both clinicians and patients.

Dr Rohit Shankar FRCPsych, Consultant in Adult Developmental Neuropsychiatry – CFT and Hon. Associate Clinical Professor – Exeter Medical School

In response to market research and insights, Special Products Ltd has invested heavily in the development of this new bespoke syringe, which is designed to allow simple administration of the dose into the buccal cavity⁵.

For further information on Epistatus 10 mg oromucosal midazolam pre-filled syringes, please visit http://www.epistatus.co.uk

References:

1. Epistatus 10mg oromucosal solution. Summary of Product Characteristics.
2. National Institute for Health and Care Excellence (2012). The epilepsies: the diagnosis and management of epilepsies in adults and children in primary care. NICE clinical guideline CG 137.
3. Nakken K and Lossius M. Buccal midazolam or rectal diazepam for treatment of residential adult patients with serial seizures or status epilepticus. Acta Neurol Scand: (2011); 124:99-103.
4. Ashrafi MR et al. Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children. European Journal of Paediatric Neurology (2010); doi10.1016/j.ejpn.2010.05.009.
5. Data on file – Excerpts from Epistatus Patent Application.

• CLARITY Extension data published in the MS Journal shows 75% of patients who received 2 annual short courses of Mavenclad (Cladribine Tablets) remained relapse free over 4 years
• The majority of patients who experienced Grade 3 lymphopenia in Years 1 and 2 recovered to Grade 0-1 by the end of the study

Merck announced on 5th September 2017 the publication of the results of the CLARITY Extension study in Multiple Sclerosis Journal. The trial, an extension of the Phase III CLARITY study, demonstrated that treatment of patients with relapsing remitting multiple sclerosis (MS) with MAVENCLAD^®(Cladribine Tablets) for two years, followed by two years of treatment with placebo, had clinical benefits similar to those seen with four years of treatment with MAVENCLAD^®, with a low risk of severe lymphopenia.

The CLARITY Extension study included 806 patients out of 1,184 patients who completed the CLARITY study. The CLARITY Extension study assessed several clinical efficacy endpoints including annualised relapse rate (ARR) and confirmed 3-month Expanded Disability Status Scale (EDSS) progression. The proportion of patients who remained relapse-free at the end of four years was similar to the patients who received Cladribine Tablets 3.5 mg/kg in CLARITY followed by placebo in CLARITY Extension (75.6%), and those who received Cladribine Tablets 3.5 mg/kg in both studies (81.2%). The proportion of patients who remained free of 3-month EDSS progression was also similar between the treatment groups (72.4% vs 77.4%).

Today’s publication further strengthens the evidence for the use of MAVENCLAD^® in MS, demonstrating significant, durable benefits in patients not receiving active treatment after the two short courses. The data from this publication and other recent articles suggest that MAVENCLAD^® selectively targets the adaptive immune system, particularly the B-cell compartment, and therefore allows the immune system to reconstitute while still preventing MS disease activity in the majority of treated patients.

Prof. Gavin Giovannoni
A lead investigator in the CLARITY studies &
Chair of Neurology, Barts and The London School of Medicine and Dentistry. 

The safety outcomes were comparable to those seen in CLARITY; adverse event rates were similar in patients who received Cladribine Tablets in CLARITY followed by placebo in CLARITY Extension, and those who received Cladribine Tablets in both studies. In CLARITY, patients with active relapsing-remitting multiple sclerosis were randomized to placebo or 1 of 2 cumulative doses of Cladribine Tablets (3.5 or 5.25 mg/kg body weight) for 2 years. In CLARITY Extension, patients were administered placebo or a cumulative dose of Cladribine Tablets 3.5 mg/kg body weight. In patients who received Cladribine Tablets 3.5 mg/kg in CLARITY and placebo in CLARITY Extension, the majority of those who experienced Grade >3 lymphopenia recovered to Grade 0-1 by the completion of CLARITY Extension. Most AEs were classified as mild or moderate.

In the patient group receiving placebo in CLARITY Extension following Cladribine Tablets 3.5 mg/kg in CLARITY, 3.1% of patients discontinued because of AEs. The most frequent AE in patients receiving Cladribine Tablets in the CLARITY Extension study was lymphopenia. The majority of lymphopenia events were classified as mild or moderate, and the majority of patients who experienced lymphopenia Grade ≥3 actually experienced Grade 3 only. In CLARITY Extension, herpes zoster infections were most frequent in patients receiving the highest cumulative dose of Cladribine Tablets (4.8%), however the incidence of herpes zoster in all other treatment groups was similar irrespective of cumulative dose (1.1-2.0%).

Today’s data add to the growing evidence for the use of MAVENCLAD^® in patients with relapsing MS. At Merck we are very excited about the difference MAVENCLAD^®could make in the lives of patients with this debilitating condition.

Luciano Rossetti
Head of Global R&D for the biopharma business of Merck.

In August, the European Commission (EC) granted Marketing Authorisation for MAVENCLAD^® for the treatment of adults with highly active relapsing MS* in the 28 countries of the European Union (EU) in addition to Norway, Liechtenstein and Iceland. Merck plans additional filings for regulatory approval in other countries, including the United States.

*Defined as: patients with 1 relapse during the previous year and ≥ 1 T1 Gd+ lesion or ≥ 9 T2 lesions while on therapy with other DMDs; OR patients with ≥ 2 or more relapses in the previous year, whether on DMD treatment or not.

CLARITY Extension Study Design

The CLARITY Extension study involved 806 patients out of 1,184 patients from the CLARITY study, allowing assessment of the effects of 2 years’ additional treatment with Cladribine Tablets beyond the 2-year CLARITY regimen. Patients who received Cladribine Tablets 3.5 mg/kg or 5.25 mg/kg in the CLARITY study were randomised to receive either Cladribine Tablets 3.5 mg/kg or placebo in CLARITY Extension, and patients who received placebo in the original CLARITY study received Cladribine Tablets 3.5 mg/kg in CLARITY Extension.

About MAVENCLAD^®

MAVENCLAD^® (cladribine tablets) is approved in the European Union for the treatment of highly active relapsing multiple sclerosis^[*] (RMS). MAVENCLAD^® is a short-course oral therapy that selectively and periodically targets lymphocytes thought to be integral to the pathological process of relapsing MS (RMS). MAVENCLAD^® is currently under clinical investigation and not yet approved for the treatment for any use in the United States or Canada. In August 2017, the European Commission (EC) granted marketing authorisation for MAVENCLAD^® for the treatment of relapsing forms of multiple sclerosis (RMS) in the 28 countries of the European Union (EU) in addition to Norway, Liechtenstein and Iceland.

The clinical development programme for MAVENCLAD^® includes:

• The CLARITY (Cladribine Tablets Treating MS Orally) study: a two-year Phase III placebo-controlled study designed to evaluate the efficacy and safety of MAVENCLAD^® as a monotherapy in patients with RRMS.
• The CLARITY extension study: a two-year Phase III placebo-controlled study following on from the CLARITY study, designed to evaluate the safety and efficacy of MAVENCLAD^® over an extended administration for four years.
• The ORACLE MS (Oral Cladribine in Early MS) study: a two-year Phase III placebo-controlled study designed to evaluate the efficacy and safety of MAVENCLAD^® as a monotherapy in patients at risk of developing MS (patients who have experienced a first clinical event suggestive of MS).
• The ONWARD (Oral Cladribine Added ON To Interferon beta-1a in Patients With Active Relapsing Disease) study: a Phase II placebo-controlled study designed primarily to evaluate the safety and tolerability of adding MAVENCLAD^® treatment to patients with relapsing forms of MS, who have experienced breakthrough disease while on established interferon-beta therapy.
• PREMIERE (Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Studies) study: interim long-term follow-up data from the prospective registry, PREMIERE, to evaluate the safety and efficacy of MAVENCLAD^®. This includes more than 10,000 patient years of data with over 2,700 patients included in the clinical trial program, and more than 10 years of observation in some patients.

EU Indication

MAVENCLAD^® (cladribine tablets) is indicated for the treatment of adult patients with highly active relapsing multiple sclerosis (RMS) as defined by clinical or imaging features.

Important EU Safety Information

Contraindications:

MAVENCLAD^® is contraindicated in patients with hypersensitivity to the active substance, human immunodeficiency virus (HIV), active chronic infection (tuberculosis or hepatitis), active malignancy, moderate to severe renal impairment (creatinine clearance <60 mL/min), and those who are pregnant and breast-feeding. MAVENCLAD^® is also contraindicated in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy.

Special warnings and precautions for use:

The most clinically relevant adverse reactions were lymphopenia and herpes zoster.

Haematological monitoring

Decreases in neutrophil count, red blood cell count, haematocrit, haemoglobin or platelet count compared to baseline values have been observed in clinical studies, although these parameters usually remain within normal limits.

Additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other substances that affect the haematological profile

Lymphocyte counts must be determined

• before initiating MAVENCLAD^® in year 1,
• before initiating MAVENCLAD^® in year 2,
• 2 and 6 months after start of treatment in each treatment year. If the lymphocyte count is below 500 cells/mm³, it should be actively monitored until values increase again.

Infections

Cladribine can reduce the body’s immune defence and may increase the likelihood of infections. HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of cladribine.

The incidence of herpes zoster was increased in patients on cladribine. If lymphocyte counts drop below 200 cells/mm³, anti-herpes prophylaxis according to local standard practice should be considered during the time of grade 4 lymphopenia. Interruption or delay of MAVENCLAD^® may be considered until proper resolution of the infection.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported for parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen.

In the clinical study data base of cladribine in MS (1,976 patients, 8,650 patient years) no case of PML has been reported. However, a baseline magnetic resonance imaging (MRI) should be performed before initiating MAVENCLAD^® (usually within 3 months).

Real-world data confirms clinical effectiveness of Zebinix^® (eslicarbazepine acetate) for the treatment of partial-onset epilepsy in adults

• Eslicarbazepine acetate data shows seizure freedom in 41.3% of patients at 12 months, and retention rates of 73.4%.¹
• Results from the Euro-Esli study presented 5th September 2017 at the 32^ndInternational Epilepsy Congress (IEC) in Barcelona, Spain.¹

Bial and Eisai have announced data confirming the effectiveness and tolerability of Zebinix^® (eslicarbazepine acetate) in routine clinical practice, thereby complementing evidence from clinical trials.[i] The Euro-Esli study is an exploratory pooled analysis of data from 14 European clinical practice studies, analysing data of 2,058 patients aged between 14-88 years old with partial-onset seizures (POS), with or without secondary generalisation.¹ Full results were presented at the IEC in Barcelona, Spain.¹

“It is most reassuring to see similar efficacy results with eslicarbazepine acetate in a routine clinical setting compared to that of clinical trials; we can be confident that this treatment is effective amongst the diversity of our ‘real’ epilepsy patients,” explains Dr Vicente Villanueva, Neurologist and Epileptologist, Hospital Universitario y Politécnico La Fe, Valencia, Spain. “Real-world studies like the Euro-Esli study are important because they provide significant insight into how a drug performs in a routine medical setting, allowing us to assess the drug, to ultimately improve patient outcomes.”

Epilepsy is one of the most common neurological conditions in the world, affecting approximately six million people in Europe.² An epileptic seizure is a clinical manifestation of the condition, thought to result from an abnormal discharge of a set of neurons in the brain.[ii] Seizures can vary in manifestation, from brief lapses of attention to severe and prolonged convulsions.[iii] Depending on the type, seizures may involve one part of the body or the whole body, and may affect consciousness.³ Seizures can also vary in frequency from less than one per year, to several per day.³ Epilepsy has many possible causes but often the cause is unknown.³

The Euro-Esli study (in over 2,000 patients with epilepsy) showed that at 3, 6 and 12 months, seizure freedom rates in patients aged 14-88 years treated with eslicarbazepine acetate were 30.6%, 38.3% and 41.3% respectively. Retention rates were 95.4%, 86.6% and 73.4% and responder rates were 60.9%, 70.5% and 75.6%, respectively.¹ There were significant reductions from baseline to final visit in monthly frequencies of total (mean reduction 44.1%), simple partial (78.8%), complex partial (53.1%) and secondarily generalised (80.0%) seizures (p<0.001 for all).¹ Adverse events were reported for 34.0% of patients and led to discontinuation of 13.6% of patients.¹ The most frequently reported adverse events were dizziness (6.7%), fatigue (5.4%) and somnolence (5.1%).¹

These results improve our knowledge and understanding around the use of eslicarbazepine acetate in routine clinical practice and strengthen Bial’s commitment to developing and delivering beneficial treatment options for people living with epilepsy António Portela, CEO of Bial

These data underscore our commitment to our anti-epileptic drug product portfolio. We will continue to invest both in clinical trials and the generation of real-world evidence to improve the lives of patients living with epilepsy
Neil West, Vice President EMEA, Global Neurology Business Unit at Eisai

Eslicarbazepine acetate is indicated as monotherapy in the treatment of POS, with or without secondary generalisation, in adults with newly diagnosed epilepsy; and as adjunctive therapy in adults, adolescents, and children aged above six years, with POS with or without secondary generalisation.[iv]

About the Euro-Esli study¹

The Euro-Esli study was a large, exploratory, pooled analysis of real-world data from 14 European clinical practice studies, including data from 2,058 patients (52.1% male; mean age 44 years; mean epilepsy duration 20.9 years). Retention and effectiveness were assessed after 3, 6 and 12 months of treatment with eslicarbazepine acetate. Effectiveness assessments comprised percentage reduction from baseline in monthly seizure frequency, responder rate (≥50% seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs).

REFERENCES

[i] Villanueva V, et al. (2017) A European audit of real-world use of eslicarbazepine acetate as a treatment for partial-onset seizures: the Euro-Esli study. International Epilepsy Congress (IEC) 2017; Barcelona, Spain, Poster p0918

[ii] World Health Organization. (2010) Epilepsy in The WHO European Region: Fostering Epilepsy Care in Europe. Cruquius, Paswerk Bedrijven. Available from: http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf [Accessed August 2017].

[iii] World Health Organization. (2017) Epilepsy Fact Sheet. Available from: http://www.who.int/mediacentre/factsheets/fs999/en/ [Accessed August 2017].

[iv] Eisai. (2017) Zebinix^® (eslicarbazepine acetate) Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000988/WC500047225.pdf  [Accessed August 2017].

[v] Hebeisen S, et al. (2015) Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: A comparison with carbamazepine, oxcarbazepine and lacosamide. Neuropharmacology. 89, 122-135

[vi] Elger C, et al. (2007) Eslicarbazepine acetate: A double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia. 48, 497-504.

[vii] Elger C, et al. (2009) Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial onset seizures: A randomised, double-blind, placebo-controlled, parallel-group phase III study.Epilepsia. 50, 454-63.

[viii] Ben-Menachem E, et al. (2010) Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Research. 89(2-3), 278-85.

[ix] Gil-Nagel A, et al. (2009) Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurologica Scandinavica. 120, 281-87.