Healthcare Industry News:  total knee 

Biopharmaceuticals Regulatory

 News Release - September 24, 2008

Nice Approves Pradaxa(R)*(Dabigatran Etexilate) - First New Oral Anticoagulant in the UK for Over 50 Years

LONDON, September 24 (HSMN NewsFeed) -- Clinicians and patient groups have welcomed today's announcement by the National Institute of Health and Clinical Excellence (NICE) recommending PradaxaŽ (dabigatran etexilate) as an option for the primary prevention of venous thrombembolic events in adults who have undergone elective total hip or total knee replacement surgery.(1) This positive NICE appraisal coincides with the recent publication of a government venous thromboembolism (VTE) risk assessment tool recommended for all patients admitted to hospital in England by the Department of Health.(2) Routine risk assessment is a fundamental step in ensuring patients at risk of developing VTE receive the appropriate therapy and management. VTE is a potentially fatal blood clotting disease which includes deep vein thrombosis (DVT) and pulmonary embolism (PE).

VTE is the most common cause of preventable hospital death in the UK.(3) Up to 32,000 patients die every year in the UK(4) after developing blood clots in hospital and a recent analysis by the All Party Parliamentary Thrombosis Group revealed that over 10,700 UK hospital patients may have died from blood clots in just seven months during 2007 as a result of clinical guidelines not being implemented.(3)

Until now, anticoagulant therapy to prevent blood clots after major orthopaedic surgery has generally required administration by injection. PradaxaŽ is the first new oral anticoagulant to be launched in the UK for over 50 years. It is a fixed dose, once daily capsule that may be taken with or without food.(5) NICE concluded that PradaxaŽ, as an oral therapy, without the need for monitoring, would reduce National Health Service (NHS) administration costs and may support adherence to treatment.(1)

The charity AntiCoagulation Europe welcomed NICE's recommendation. Chief Executive, Eve Knight, said:

"We are delighted with today's NICE announcement, and also very pleased that the long awaited Risk Assessment Tool has finally been published. It is appalling that patients are still developing and dying from VTE, which could be prevented by risk assessing every patient on admission to hospital and giving preventative treatment where needed. Pradaxa, a once daily oral therapy for use in post orthopaedic surgery, will enhance the treatment options available and enable clinicians and patients to make decisions on choice of treatment appropriate to their clinical needs."

Key facts

- NICE has recently reported that approximately 30 per cent of surgical patients are affected by DVT(6)

- During 2006/7, 131,378 patients underwent hip and knee replacement surgery in the UK(7)

- Total deaths (32,000) following development of blood clots in hospital, including those related to hip and knee replacement, exceed the combined total deaths from breast cancer, AIDS and road traffic accidents and equate to more than 25 times the annual deaths from MRSA(4)

- In contrast to the number of deaths, the NHS spends ten times as much on MRSA prevention as prevention of VTE from all causes(3)

- VTE is estimated to cost the NHS a total of GBP640 million every year to manage. 60 - 80 per cent of this could be saved through preventative measures(4)

- Although guidelines recommend preventative therapy for 10-35 days,(8) clinical practice varies widely and therapy is often not maintained following hospital discharge.(6)

VTE is known internationally as the 'silent killer' as often the first manifestation may be a potentially fatal PE.(3) This means risk assessment and prevention strategies are crucial. The new Department of Health risk tool aims to create a standardised national preventive strategy to make the goal of reducing death from VTE in all patients more attainable, potentially saving thousands of lives every year.

On confirmation of the NICE recommendation, Des Turner, Member of Parliament for Brighton Kemptown and Secretary of the All Party Parliamentary Thrombosis Group commented:

"Currently lives are being lost because of inadequate clot-prevention therapy. Research by the All Party Parliamentary Group on Thrombosis showed that over 10,700 UK hospital patients may have died from blood clots in just seven months during 2007 as a result of clinical guidelines not being implemented. NICE approval for Pradaxa will provide a real boost to patients undergoing hip and knee replacement surgery where potentially fatal clotting is a real risk. I will continue to campaign to ensure VTE is given the political and public prioritisation it deserves."

PradaxaŽ was approved by the EMEA for marketing in all EU member countries in March 2008 and since then swift progress has been made with positive recommendations from local Health Technology Assessment bodies in Scotland (Scottish Medicines Committee), Denmark (Danish Medicines Agency) and The Netherlands (The Health Care Insurance Board).(9-11) To date, PradaxaŽ has been launched in a total of eleven countries.

PradaxaŽ is one of a new class of drugs to tackle DVT and PE called direct thrombin inhibitors (DTI). DTIs directly block the enzyme thrombin which is central to the clotting process.(12)

Full details of the NICE guidance can be accessed via http://www.nice.org.uk

Notes to Editors

Wording of today's NICE announcement

Dabigatran etexilate, within its marketing authorisation, is recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or elective total knee replacement surgery.

The Committee acknowledged that oral administration of dabigatran etexilate, without the need for monitoring, would reduce administration costs and may support adherence to treatment. The Committee therefore concluded that dabigatran etexilate should be recommended as an option in the circumstances in which LMWH (or fondaparinux as an alternative) may be offered.

Standard Recommended Dosage of PradaxaŽ in VTE Prevention

The standard recommended dosage of PradaxaŽ in VTE prevention is a fixed oral dose of 220 mg given once daily.(5) A single capsule of 110 mg (half-dose) is administered orally between 1 and 4 hours following surgery, continuing with 2 capsules once daily thereafter for a total of 10 days in total knee replacement patients and 28-35 days in total hip replacement patients.(5) A second approved dosage of 150 mg taken as two capsules of 75 mg is recommended for specific patient populations, including patients over 75 years of age and those with moderate renal impairment.(5)

Further Indications Under Investigation

Boehringer Ingelheim continues to evaluate the efficacy and safety of PradaxaŽ within the global RE-VOLUTION(TM) clinical trial programme which involves over 38,000 patients. PradaxaŽ's efficacy and safety is being assessed for:

- Stroke prevention in atrial fibrillation (SPAF) in the RE-LY(TM) trial - the largest SPAF trial to date

- Enrollment of a total of 18,113 patients for the RE-LY(TM) trial was completed in December 2007

- Results are expected in 2009

- Treatment of acute VTE - results expected in 2009

- Secondary prevention of VTE

- Prevention of cardiac events in patients with acute coronary syndrome

About Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 135 affiliates in 47 countries and 39,800 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2007, Boehringer Ingelheim posted net sales of 10.9 billion euro while spending one fifth of net sales in its largest business segment Prescription Medicines on research and development.

For more information please visit http://www.boehringer-ingelheim.co.uk

References

(1) http://www.nice.org.uk/

(2) Hospital patients to be assessed for risk of blood clots. Publication of Risk Assessment, Department of Health (National), 19 September 2008. Available at http://www.dh.gov.uk/VTE

(3) Thrombosis: Awareness, Assessment, Management and Prevention. An Audit of Acute Hospital Trusts. November 2007. All Party Parliamentary Thrombosis Group. Available at: http://www.dvtreport.com

(4) The House of Commons Health Committee Report on the Prevention of Venous Thromboembolism in Hospitalised Patients - Second Report of Session 2004-05. The Stationery Office. February 2005. Available at http://www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/99/99.pdf

(5) Pradaxa, Summary of Product Characteristics, 2008

(6) Venous Thromboembolism: Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. April 2007. Commissioned by the National Institute for Health and Clinical Excellence. Available at http://www.nice.org.uk/nicemedia/pdf/VTEAppendices.pdf

(7) National Joint Registry for London and Wales. 4th Annual Report. 2007. Available at www.njrcentre.org.uk

(8) Geerts WH et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):381S-453S

(9) http://www.emea.europa.eu/humandocs/Humans/EPAR/pradaxa/pradaxa.htm Last accessed 23 July 2008

(10) http://www.scottishmedicines.org.uk/smc/6093.html Last accessed 23 July 2008

(11) http://www.medicinpriser.dk/Default.aspx?Navn=Pradaxa Last accessed 23 July 2008

(12) Di Nisio M et al. Direct thrombin inhibitors. N Eng J Med. 2005;353:1028-1040

Prescribing Information (UK)

PRADAXAŽ*

Capsules containing 75mg or 110mg dabigatran etexilate (as mesilate) Action: Direct thrombin inhibitor Indication: Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip or knee replacement surgery Dose and administration: Initial dose 110mg within 1-4 hours of completed surgery, then 220mg once daily. In moderate renal impairment (Cr Cl 30-50 ml/min) or patients greater than 75 years reduce dose: initial dose 75mg, then 150mg once daily. After knee replacement surgery continue treatment for a total of 10 days; after hip replacement surgery for 28-35 days. Delay initiation of treatment if haemostasis is not secured. If treatment is not started on the day of surgery initiate with 220 mg (or 150mg) once daily. Contra-indications: hypersensitivity to any component; severe renal impairment (CrCl less than 30 ml/min); clinically significant bleeding; organic lesion at risk of bleeding; impairment of haemostasis; hepatic impairment or liver disease expected to have any impact on survival; concomitant quinidine Warnings & precautions: Not recommended if liver enzymes are greater than 2 ULN; measure ALT in pre-operative evaluation. Close clinical surveillance (signs of bleeding or anaemia) is recommended throughout the treatment period, especially when haemorrhagic risk is increased: diseases associated with a risk of bleeding such as coagulation disorders, thrombocytopenia or functional platelet defects, active ulcerative GI disease, recent biopsy or major trauma, recent ICH or brain, spinal or ophthalmic surgery, bacterial endocarditis, concomitant NSAIDs (t1/2 greater than 12 hours). Patients less than 50 kg or greater than 110 kg; the elderly; patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events. If severe bleeding occurs, discontinue treatment and investigate the source of the bleeding. Avoid or use with caution agents which may increase the risk of haemorrhage. Not recommended in patients undergoing anaesthesia with postoperative indwelling epidural catheters; the first dose should be given a minimum of 2 hours after catheter removal; these patients require frequent observation for neurological signs and symptoms. Contains Sunset Yellow (E110) which may cause allergic reactions Interactions: anticoagulants and platelet aggregation agents; amiodarone (reduce Pradaxa dose to 150mg); caution with strong P-glycoprotein inhibitors (e.g. verapamil, clarithromycin) or inducers (e.g. rifampicin, St John's wort). Pregnancy and lactation: avoid pregnancy during treatment. Do not use in pregnancy unless clearly necessary. Discontinue breast-feeding during treatment Undesirable effects: Most common is bleeding (14%); major bleeds, including wound site bleeding, less than 2%. Common (greater than/equal to 1/100, less than1/10): anaemia; haematoma (including traumatic or postprocedural); wound, gastrointestinal, skin or post procedural haemorrhage; haematuria; decreased haemoglobin; wound secretion, postoperative or postprocedural anaemia, postprocedural discharge. See SPC for details of these and other undesirable effects. Pack sizes, NHS price and MA numbers: 75mg 10 capsules GBP21.00 EU/1/08/442/001; 60 capsules GBP126.00 EU/1/08/442/003 110mg 10 capsules GBP21.00 EU/1/08/442/005; 60 capsules GBP126.00 EU/1/08/442/007 Legal category POM Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Prepared in July 2008.

Adverse events should be reported. Reporting forms and information can be found at http://www.yellowcard.gov.uk . Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800-328-1627 (freephone).

Prepared from SPC1 for Pradaxa 75mg capsules and 110mg capsules, both dated March 2008. Updated with revised AE wording July 2008

* due to technological reason the black triangle cannot be displayed. However, as with all new medicines special reporting is required in relation to adverse events.

For further information, contact John Pugh at Boehringer Ingelheim on +44-(0)1344-746792.


Source: Boehringer Ingelheim

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