NICE Backs Pradaxa(R) (Dabigatran Etexilate) - The First Oral Anticoagulant In Over Fifty Years

Main Category: Blood / Hematology
Also Included In: Regulatory Affairs / Drug Approvals;  Cardiovascular / Cardiology
Article Date: 30 Jul 2008 - 4:00 PDT

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Boehringer Ingelheim welcomed the National Institute for Health and Clinical Excellence (NICE)'s Final Appraisal Determination (FAD) which gives a draft recommendation that Pradaxa® (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 or elective total knee replacement surgery.1 Pradaxa® is the first oral anticoagulant for preventing venous thromboembolism (VTE) to be licensed in the UK for more than 50 years.

With correct use of thromboprophylaxis including anticoagulation, VTE is preventable. However, with existing therapies, NICE has recently reported that approximately 30 per cent of surgical patients are affected by deep vein thrombosis2 and a House of Commons Health Committee report has highlighted that up to 32,000 patients die each year after developing blood clots in hospital - exceeding the combined total deaths from breast cancer, AIDS and road traffic accidents and more than 25 times the annual deaths from MRSA.3 During 2006/7, in the UK 131,378 patients underwent hip and knee replacement surgery.4 These procedures carry a high risk of VTE and therefore necessitate effective anticoagulation to protect patients from potentially fatal clots.5,6

Pradaxa® is an oral, once daily anticoagulant with no drug-food interactions and a low potential for interactions with drugs metabolised with cytochrome P450 enzymes.#7

The charity AntiCoagulation Europe (ACE), which works to prevent thrombosis and provide information for patients, welcomed NICE's draft decision. Executive Director, Eve Knight, said:

"A key reason patients at risk of blood clots after surgery do not receive adequate protection is that existing appropriate anticoagulants may be perceived to be associated with poor compliance, in particular injectable thromboprophylactics. An oral anticoagulant that does not require anticoagulation monitoring is a major advance and will enable patients to continue with important preventative therapy after surgery and hospital discharge for the full guideline-recommended duration, without the need for injections."

Following orthopaedic surgery, at least 40 per cent of patients in the UK do not receive an effective form of thromboprophylaxis contrary to guideline recommendations that this is necessary for a minimum duration of 10 days and up to 35 days (for hip and knee replacement).3,5 Despite this guidance and the availability of highly effective thromboprophylaxis options, clinical practice varies widely2 and thromboprophylaxis is often not maintained once patients leave hospital. This may be due in part to the complexities of dosing with currently available thromboprophylactic agents, which require administration - often by the patient - by injection.

Dr Sheuli Porkess, Head of Medical and Scientific Affairs at Boehringer Ingelheim, UK, commented:

"As a novel oral once daily anticoagulant, Pradaxa® has the potential to improve patient care post hip and knee replacement surgery. We are very pleased that this decision from NICE brings this a step closer - particularly so swiftly after European marketing authorisation in March 2008."

Pradaxa® is a novel direct thrombin inhibitor with a rapid onset and offset of action and a predictable anticoagulation effect.8,9 It prevents thrombus formation by specifically and selectively inhibiting thrombin, the final and essential enzyme in the coagulation cascade that enables conversion of fibrinogen into fibrin.10,11

Final NICE guidance for National Health Service clinical practice is expected to be issued shortly. Pradaxa® was approved for marketing in all EU member countries by the EMEA in March 200812 and has already received positive recommendations from local Health Technology bodies in Scotland (Scottish Medicines Consortium) and Denmark (IRF) in June 200813,14 and it has been available in Germany and the UK since April. Marketing approval has also been granted in Canada.15

# Drug interactions for Pradaxa®: 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)

The standard recommended dosage of Pradaxa® is a fixed oral dose of 220 mg given once daily.7 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.7 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.7

Boehringer Ingelheim continues to evaluate the efficacy and safety of Pradaxa® in a range of thromboembolic disease conditions through the extensive clinical trial programme, RE-VOLUTION™, which involves over 38,000 patients worldwide. Recent progress includes the announcement in January 2008 of the completion of enrolment of 18,113 patients in RE-LY™, the largest stroke prevention in atrial fibrillation outcomes trial to date.

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.

http://www.boehringer-ingelheim.com

References

1. http://www.nice.org.uk/guidance/index.jsp?action=download&o=41440

2. 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

3. 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 here.

4. National Joint Registry for London and Wales. 4th Annual Report. 2007. Available at http://www.njrcentre.org.uk

5. 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

6. Douketis J et al. The Perioperative Management of Antithrombotic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):299S-339S

7. Pradaxa, Summary of Product Characteristics, 2008

8. Stangier J et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64:292-303

9. Stangier J et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008;47:47-59

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

11. van Ryn J et al. Dabigatran inhibits both clot - bound and fluid phase thrombin in vitro: Effects compared to heparin and hirudin. Abstract Arteriosclerosis, Thrombosis and Vascular Biology (ATVB), Atlanta, GA, USA, May 2008

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

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

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

15. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/regist/reg_innov_dr-eng.php Last accessed 23 July 2008

Prescribing Information (UK)

PRADAXA®

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 >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 < 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 > 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 >12 hours). Patients < 50 kg or >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, < 2%. Common (≥ 1/100, <1/10): 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 £21.00 EU/1/08/442/001; 60 capsules £126.00 EU/1/08/442/003 110mg 10 capsules £21.00 EU/1/08/442/005; 60 capsules £126.00 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 March 2008.

Adverse events should be reported and information can be found at http://www.yellowcard.gov.uk .

Boehringer Ingelheim