Medac launches first UK licenced injectable methotrexate therapy in Rheumatoid Arthritis

New UK licence for RA therapy provides:

• clearer labelling
• convenient storage (room temperature, 24 months shelf life)
• assurance of standard dosage
• ease of handling
• ease of use by patient
• potential for greater adoption in primary care
• improved compliance with first line RA treatment to prevent need for expensive biologicals
• potential for improved efficacy of combination therapy with biologicals

[London, 21 August 2006] Medac GmbH, the German oncology and autoimmune specialist, today announced the launch of Metoject®, the UK's first licensed injectable methotrexate (MTX), specifically designed for use in rheumatoid arthritis (RA) therapy. Metoject® is a weekly injectable MTX product that has already received marketing approval in Germany, Spain, and Sweden. It has so far been used in the treatment of over 20,000 RA patients across Europe.

MTX use as an unlicenced generic parenteral product has been limited to date for several reasons including: dose information is often incomplete without explicit details on injection volume and concentration; dose formulations are not standardised amongst suppliers; dangers associated with spillage; need for refrigeration (and therefore exposure to children in the home setting); possible mis-selection of dose from drop down menus in computerised GP and pharmacy systems. Many of these problems are also associated with oral formulations, but could be removed altogether with the introduction of a licenced standardised parenteral product.

The new Metoject® syringe is presented in its own sealed blister, which is then packaged in a separate box. Patient and dose details are clearly labelled on both the blister and the outside packaging (including differently coloured labels for different dose amounts). This aims to prevent confusion in managed care facilities and other settings where multiple RA patients may be present. Importantly, Metoject® syringes may be stored at room-temperature for up to two years, enabling the syringes to be kept without refrigeration and in areas out of reach from children. This contrasts currently available parenteral MTX formulations, which have a limited shelf life (typically up to 84 days), may require refrigeration to prevent bacterial contamination, and come in only simple plastic bags that afford minimal protection.

The barrel of the new product also incorporates a pair of large 'wings', enabling users with limited dexterity to more easily manipulate the device and self-administer their treatments. Patient feedback includes the fact that the Metoject® syringe system is more comfortable to use than existing products.

Pharmacological treatment of RA includes disease modifying anti-rheumatic drugs (DMARDs), biological agents such as anti-TNFa therapies, NSAIDs, analgesics and steroids. Of these, DMARDs, and methotrexate (MTX) in particular, are commonly accepted as forming the core of RA treatment programmes with concomitant use of analgesics or anti-inflammatories to control pain.
Guidelines from the National Institute for Clinical Excellence (NICE) and the British Society for Rheumatology (BSR), recommend biological therapies should only be considered after patients have not adequately responded to at least two disease-modifying anti-rheumatic drugs – of which one should be methotrexate.1,2

Currently, oral formulations are the most commonly prescribed form of MTX, possessing the obvious advantages for patients of being easy to self-administer and store at home. In most cases, parenteral prescriptions are reserved for those who are intolerant of oral methotrexate, despite folate supplementation, and others who demonstrate insufficient clinical response.

This has been supported in published literature and is suspected to be due to the impaired gastrointestinal absorption of oral MTX at higher doses.3,4  If such patients do not have access to parenteral MTX, a premature switch to biologic therapies may be necessary with significant cost implications.

An additional important aspect of methotrexate treatment is the pivotal role it plays in combination therapy.  Of the three licensed biologics presently available (infliximab, adalimumab, and etanercept), each has demonstrated improved efficacy and/or reduced side effects when administered with MTX.5

Existing parenteral formulations of MTX are unlicensed and produced only by specials manufacturers. This has hindered the acceptance of parenteral MTX within the GP community, leaving secondary care centres as the only option for many patients in need of repeat parenteral MTX prescriptions.

With the launch of Metoject® it is expected that there will be a gradual shift towards a shared care arrangement between primary and secondary centres. It is hoped that the development  of local care pathways will now incorporate the use of parenteral MTX in RA across home, primary and secondary care settings.

ENDS

Press enquiries: Paul Jarman, Ozone, 020 7861 3966 / pjarman@ozonecomms.co.uk

Note to editors:
RA affects more than half a million patients in the UK alone and is one of the most debilitating and unpredictable inflammatory conditions known. Although there is no cure for RA, treatment with disease modifying anti-rheumatic drugs (DMARDs) is commonly accepted as an effective approach for limiting the severity of disease and controlling symptoms; the gold standard DMARD is methotrexate (MTX). For some patients, however, oral MTX formulations can cause various gastrointestinal side effects, including nausea and vomiting. Recent evidence has also raised the concern that the absorption of oral MTX may become impaired or variable at higher doses leading to a decline in efficacy.6,7

Issues relating to generic (unlicenced) MTX
Current parenteral MTX administration and delivery practices vary across the UK. In some regions, for example, shared care protocols are established to enable patients to self-inject at home. In others, parenteral MTX is almost never used due to the difficulty secondary care providers encounter when prescribing the drug for an unlicensed indication or resistance to setting up a service relating to a low dose cytotoxic therapy. Geographical variations also occur in the dispensing practices of MTX, being provided by secondary care providers in some areas and via homecare companies in others, leading to significant differences in patient support. Similar discrepancies arise in patient training, monitoring, and waste collection practices, all of which introduce complications in the practical use of generic parenteral MTX formulations.

It is in the oncology setting in which MTX is administered in doses several orders of magnitude greater than in RA treatments, that the side-effect profile of the drug becomes pronounced. This has contributed to the reluctance of some hospital pharmacists and governance teams towards the use of parenteral MTX in RA, thereby hampering its implementation in the community.

Metoject® is also the only parenteral MTX product to have been evaluated in a large randomised trial, the results of which were reviewed at the risk assessment meeting.8 In this double-blind, double-dummy study, 384 MTX naïve patients were assigned treatment with 15 mg of MTX, delivered either by subcutaneous (s.c.) injection or via oral tablets. The patients were then evaluated according to criteria set by the American College of Rheumatology (ACR), examining joint mobility, pain, radiographic changes, and other relevant parameters. After 24 weeks, 78% of the s.c. administration group exhibited ACR response of 20 or more (indicating a 20% improvement in clinical symptoms) and 34% achieved remission of symptoms. This compares favourably to the oral administration group in which 67% of patients achieved an ACR score of 20 more and only 24% achieved remission.

 

References
1. National Institute of Clinical Excellence (2002) Patient information: guidance on the use of etanercept and Infliximab for the treatment of rheumatoid arthritis. London: NHS, NICE

2. Ledingham j and Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). British Society for Rheumatology Standards, Guidelines and Audit Working Group. Rheumatology 2005 44(2):157-163

3. Osman A and Mulherin D. Correspondence: Is parenteral methotrexate worth trying? Ann Rheum Dis 2001;60:432

4. Hamilton RA, Kremer JM. Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis. Br J Rheumatol 1997;36:86–90.

5. Klareskog L et al. The TEMPO study. The trial of Etanercept and Methotrexate with radiographic patient outcomes. Therapeutic effect of the combination of Etanercept and Methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double blind randomised controlled trial. Lancet 2004; 363: 675-81

6. Burbage G, Gupta R, Lim K. Intramuscular methotrexate in inflammatory rheumatic disease. Ann Rheum Dis 2001;60:1156

7. Bingham SJ et al. Parenteral methotrexate should be given before biological therapy. Rheumatology 2003; 42: 1009-10

8. Braun J et al. The Clinical Efficacy and Safety of Subcutaneous (s.c.) versus Oral Application of Methotrexate (MTX) in Patients with Active Rheumatoid Arthritis (RA) – Results of Randomized, Controlled Double-Blind, Multi-Centre Study. Poster presented at the American College of Rheumatology Annual Scientific Meeting in Germany, 2005. Full study in press.

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