Pradaxa

Pradaxa®(Dabigatran Etexilate)

Manufacturer: Boehringer Ingelheim Pharmaceuticals, Inc

FDA Approved Date: October 15, 2010

Pradaxa®/dabigatran etexilate

Date despre medicament• Farmacologia– Dabigatran exetilate este un pro-medicament,

care este convertit in vivo în dabigatran activ, un inhibitor reversibil, ce actioneaza direct asupra trombinei, care inhibă atât trombina liberă cit şi cea legată de fibrină.

– Inhibă coagularea, prin prevenirea efectelor mediate de trombina, inclusiv scindarea fibrinogenului în monomeri de fibrină,ce activeaza factorii V, VIII, XI şi XIII, şi inhibarea trombinei-indusa de agregarea plachetarahttp://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline. Accessed on 10/29/2010

http://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline


Aplicatiile clinice• Indicatii:–Prevenirea accidentului vascular cerebral

embolic şi sistemic la pacienţii cu fibrilaţie atrială nonvalvular

http://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline. Accessed on 10/29/2010



Aplicatii clinice

• Contraindicatii

– Hipersensibilitate severa(anafilaxie) la dabigatran sau la oricare dintre componentele sale

– Singerare patologica activa




Aplicatii clinice

• Precautii

– Pacienţii cu factori de risc pentru sângerare• Anticoagulante

– P-glycoprotein (p-gp) inductori / inhibitori

– Insuficienta hepatica• Folosirea la pacientii cu insuficienta hepatica moderata• Child-Pugh class B sau C• Transaminazele hepatice crescute> 2 ori




Clinical Application• Warnings and Precautions– Renal impairment• Use with caution in patients with severe renal impairment

(Clcr 15-30ml/min)

• Use in patients with Clcr < 15 ml/min is not recommended due to insufficient evidence to support use

Use of dabigatran is contraindicated in severe renal impairment (Clcr < 30ml/min) in Canada labeling




Drug Facts

Bereznicki et al New antithrombotics for atrial fibrillation. Cardiovascular Therapeutics 2010 (28) 278–286


Drug Facts

• Sarcina categoria : C

• Lactatie: Excretia in laptele matern nu se cunoaste


Drug Interactions

• Drug Interaction – P-glycoprotein inducer– Rifampin - AVOID combination with dabigatran

• Drug-Food interactions– Food has no affect on the bioavailability of

dabigatran but delays the time to peak concentrations by 2h


Reactii adverse

• Dispepsia(11.3) [5.8]• Oboseala(6.6) [6.2]• ameţeală(8.3) [9.4]• Dispnee(9.5) [9.7]• Edeme periferice (7.9) [7.8]• Diaree(6.5) [5.7]




Monitoring Parameters

• Activated Partial Thromboplastin Time (aPTT): values >2.5 time control may indicate overanticoagulation

• Ecarin Clotting Test (ECT) if available• Thrombin Time (TT)• CBC with differential • Bleeding


Prescriptie• Dozare– Oral: 150mg de 2 ori pe zi

– Insuficienta renala: • Clcr 15-30 mL/min : 75mg de 2 ori pe zi• Clcr <15 mL/min: nu sunt recomandari

– Insuficienta hepatica: nu necesita ajustare


Prescription Information

• Conversia pentru warfarin:-Se sisteaza administrarea de warfarin si se initiaza dabigatran cind INR < 2.0




Trial Information Dabigatran versus Warfarin in Patients with Atrial Fibrillation

• Objective– To compare the safety and efficacy of

dabigatran with warfarin for the prevention of stroke and systemic emboli

Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51


Trial Information• Study Design:

– Randomized Evaluation of Long Term anticoagulation Therapy (RE-LY)

– International, multicenter randomized phase III non-inferiority trial

– Blinded fashion: fixed doses of dabigatran 110mg and 150mg

– Unblinded fashion: adjusted dose warfarin

– 18,113 patients were enrolled in the study



Trial Information• Inclusion Criteria– Patients with atrial fibrillation documented on

electrocardiography at screening or within 6 months– Have at least one of the following characteristics:• Previous stroke or TIA• Left ventricular ejection fraction of < 40%• NYHA class II or higher heart failure symptoms

within 6 months before screening• Age ≥ 75 years• Or age 65-74years plus DM, HTN, or CAD



Trial Information• Exclusion criteria

– Presence of severe heart-valve disorder– Stroke within 14 days or severe stroke within 6

months before screening– Condition that increased the risk of hemorrhage– Clcr < 30 mL/min– Active liver disease– Pregnancy



Trial Information

• Intervention– Dabigatran was administered in a blinded

fashion , in capsules containing either 110mg or 150mg of the drug to be taken twice daily

– Warfarin was administered in an unblinded fashion in tablets of 1, 3 or 5 mg and was adjusted locally to INR of 2.0 to 3.0• INR was measured at least monthly

Treatment duration: 2 years



Trial Information• Primary outcome:– stroke or systemic embolism

• Primary safety outcome: – major hemorrhage

• Secondary outcomes: – stroke or systemic embolism and death

• Other outcomes: – MI, PE, TIA and hospitalization.



Trial Information• Results:– Stroke occurred in 182 patients receiving 110mg of

dabigatran (1.53% per year), 134 patients receiving 150mg of dabigatran (1.11% per year) and 199 patients receiving warfarin (1.69% per year).

– Both doses of dabigatran were non-inferior to warfarin (P<0.001)

– 150mg dose of dabigatran was superior to warfarin (P<0.001)

– Rates of hemorrhagic stroke were significantly lower in the group that received 150mg of dabigatran than warfarin group (P<0.001)



Trial Information• Results– The rate of myocardial infarction was higher with

both dabigatran groups than with warfarin group– Rate of major bleeding of life-threatening bleeding

were higher with warfarin than with either 110mg of dabigatran dose or 150mg dose of dabigatran.

– There was significantly higher rate of major gastrointestinal bleeding with dabigatran at the 150mg dose than with warfarin



Trial Information• Conclusion– In patient with atrial fibrillation, dabigatran given

at a dose of 110mg was associated with warfarin, as well as lower rates of major hemorrhage.

– Dabigatran administered at a dose of 150mg, as compared with warfarin , was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage



Trial Information• Strengths of the study

– Size of the population studied– Blinded comparison of dabigatran etexilate doses– Comprehensive strategies to minimize ascertainment and

reporting bias– Blinded adjudication of outcomes– Nearly complete (99.9%) follow-up ( only 20 patients were lost

to follow up)– Investigators were able to use low dose aspirin (<100mg/day)

and the warfarin arm contained both patients who had taken aspirin and those who had not

– The control of anticoagulation achieved in patients treated with warfarin (time in therapeutic range 64%) was comparable to other large trials of warfarin Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51


Trial Information• Weaknesses of the trial

– Selected group of patients, so the outcomes may not translate to everyone

– The rate of discontinuation is higher in dabigatran groups than in warfarin group


Should we use dabigatran based on this trial?

• This trial showed that dabigatran 110mg bid is as effective as warfarin and dabigatran 150mg bid is superior to warfarin for the prevention of stroke in patient with atrial fibrillation

• As an alternative anticoagulant, dabigatran has its limitations and safety concerns– An excess of dyspepsia– Gastrointestinal bleeding– Myocardial infarction– Potential for accumulation in the presence of renal

dysfunction Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51


• Dabigatran has the advantage of a wide therapeutic window , but drug compliance may still influence its safety and efficacy

• The need of twice daily dosing of dabigatran may increase a nonadherence to the treatment

• No specific antidote yet to reverse the antithrombotic activity of dabigatran

• Safety and efficacy in patients with renal and hepatic impairment

• Safety and efficacy in patients at high risk of bleedingTerry K W et al. Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data


• It is important to determine whether or not selective thrombin inhibitors contributes to myocardial infarction .

• Future studies are needed : RELY-ABLE study

Terry K W et al. Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data


Summary• Pradaxa®, dabigatran etexilate, is a direct thrombin

inhibitor that inhibits both free and fibrin-bound thrombin

• Dabigatran 150mg twice a day dosage showed superiority over warfarin in a- fib. RELY trial had shown dabigatran to be as effective as warfarin in the prevention of stroke

• Other indication : Postoperative thromboprophylaxis in patients who have undergone total hip or knee replacement procedures (Canadian labeling)


Summary• No dosage adjustment for hepatic impairment (US

labeling)

• Usual adult dosing is 150mg twice daily however, patients with CrCl (15ml/min<Clcr<30ml/min) need dose reduction to 75mg twice daily

• Dabigatran at a dose of 150mg twice daily was associated with risk of myocardial infarction in patient with a-fib

• Need for long term use study: RELY-ABLE trial

References

• Pradaxa package insert. http://www.pradaxa.com/ Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USA

• Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.

• Bereznicki et al New antithrombotics for atrial fibrillation. Cardiovascular Therapeutics 2010;28:278–86.

• Ma, T.K.W., et al., Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data,Pharmacology & Therapeutics 2010: 1-10

• http://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline. Accessed on 10/29/2010

• Blech S, Ebner T, Ludwig-Schwellinger E, et al, “The Metabolism and Disposition of The Oral Direct Thrombin Inhibitor, Dabigatran, in Humans,” Drug Metab Dispos, 2008;36:386-99.

http://www.pradaxa.com/


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