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dabigatran

dabigatran

introduction

  • Dabigatran is a potent, competitive and reversible direct thrombin inhibitor and is thus used as an oral anticoagulant for prevention of deep venous thrombosis (DVT) and new studies seem to show that it is more effective, and safer than warfarin for preventing stroke in patients with atrial fibrillation
  • Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits free thrombin, fibrin bound thrombin and thrombin induced platelet aggregation.
  • There is a clear correlation between plasma dabigatran concentration and degree of anticoagulant effect. However, this can only be measured by a combination of activated partial thromboplastin time (aPTT), prothrombin time (PT, expressed as international normalised ratio (INR)), thromboplastin time and Ecarin clotting time tests, no single one of which provides a complete assessment of the anticoagulant effect of dabigatran.
  • At recommended prophylactic doses of dabigatran etexilate, dabigatran may prolong the aPTT and the INR but these tests are relatively insensitive to the activity of dabigatran and are unsuitable alone as measures of anticoagulant activity.
  • However, in patients who are bleeding, aPTT tests may help determine an excess of anticoagulant activity.
  • Dabigatran concentration exceeding 450 to 500 nanogram/mL would result in an aPTT of greater than 2.5 times control. An aPTT greater than 2.5 times control is suggestive of excess anticoagulation.
  • no need to adjust adult dose for body weight.

pharmacokinetics

  • After oral administration, dabigatran etexilate (Pradaxa) is rapidly and completely converted to dabigatran, which is the active form in plasma.
  • The absolute bioavailability of dabigatran following oral administration of the pro-drug, dabigatran etexilate is approximately 6.5%.
  • Peak plasma concentrations are reached at six hours following administration, or at seven to nine hours if given 1-4 hours following surgery.
  • The volume of distribution of dabigatran = 60-70 L for an adult.
  • after oral dose, Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides.
  • after iv dose, Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 mL/minute corresponding to the glomerular filtration rate.
  • half-life is approx. doubled in patients with severe renal impairment (ClCr 10 to 30 mL/minute).

contra-indications

  • Known hypersensitivity to dabigatran.
  • severe renal impairment (ClCr < 30 mL/minute).
  • bleeding diathesis
  • Organ lesions at risk of clinically significant bleeding, including haemorrhagic stroke within the last six months.
  • indwelling spinal or epidural catheter and during the first two hours after removal
  • Hepatic impairment or liver disease expected to have any impact on survival
  • Concomitant treatment with strong P-glycoprotein inhibitors, e.g. quinidine
  • Initiation with oral verapamil (Isoptin) during dabigatran etexilate therapy is contraindicated. The interaction occurs with the prodrug, dabigatran etexilate and therefore, is limited to the duration of dabigatran etexilate treatment.
  • mechanical prosthetic heart valve - Phase II RE-ALIGN™ study showed an increased incidence of thromboembolic and bleeding events in this specific patient population treated with dabigatran compared to warfarin

precautions

  • Haemorrhagic risk
  • Concomitant use with moderate P-glycoprotein inhibitors which may thus increase bleeding risk, such as amiodarone, clarithromycin, cyclosporin, itraconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, tacrolimus and verapamil.
  • Spinal anaesthesia/ epidural anaesthesia/ lumbar puncture - risk of formation of spinal or epidural haematomas which may result in long-term or permanent paralysis.
  • Hip fracture surgery - insufficient data for its use in preventing DVT for hip surgery.
  • Impaired renal function
    • Dose reduction to 150 mg daily is recommended for patients with moderate renal impairment (ClCr 30 to 50 mL/minute).
    • Patients who develop acute renal failure should discontinue dabigatran etexilate.
  • Impaired hepatic function.
    • inadequate data on safety
  • the elderly - In general, patients should be treated with the standard dose of dabigatran etexilate 220 mg daily but watch closely and adjust dosage if renal function deteriorates or they are on a moderate P-glycoprotein inhibitor.
  • pregnancy (Cat C)
  • lactation - although only minimal amounts reached breast milk in rats
  • children < 18 yrs age as inadequate data.

adverse reactions

  • bleeding
    • appears to be comparable to enoxaparin in prevention of DVT post-op knee surgery.
    • can be urgently and completely reversed by iv idarucizumab (Praxbind)
    • dabigatran can be dialysed although no clinical experience of this.

drug interactions

  • anticoagulants and platelet aggregation agents
    • switching to a parenteral anticoagulant:
      • Wait 24 hours after the last dose before switching from dabigatran to a parenteral anticoagulant.
    • switching from a parenteral anticoagulant:
      • it is not recommended to start the administration of dabigatran before the next scheduled dose of the parenteral anticoagulant would have been due.
      • for patients switching from warfarin to dabigatran, give the first dose of dabigatran after the INR has fallen to less than 2.0. In practice, this usually means withholding one or two doses of warfarin.
      • for patients receiving parenteral subcutaneous anticoagulation, give the first dose of dabigatran just before the next scheduled injection of parenteral anticoagulation.
      • for patients receiving intravenous heparin, give the first dose of dabigatran about 2 hours after discontinuing intravenous heparin
  • non-steroidal anti-inflammatory drugs (NSAIDs) - although no effect on drug concentrations, the risk of bleeding from NSAID-induced peptic ulcer is higher.
  • P-glycoprotein inhibitors - see above under C/I and precautions.

dosage for adults

Prevention of venous thromboembolic event following major orthopaedic surgery of the lower limb (eg. TKR)

  • Treatment of dabigatran etexilate should be initiated orally within one to four hours of completed surgery with a single capsule (110 mg) and continuing with 2 capsules once daily thereafter for the required duration.
    • 220 mg once daily taken as 2 capsules of 110 mg.
    • if moderate renal impairment, use 150 mg once daily, taken as 2 capsules of 75 mg.
  • duration of Rx:
    • knee replacement surgery = 10 days
    • hip replacement surgery = 28-35 days

presentation

  • capsules - 75 mg (size 2, marked R75 on body), 110 mg (size 1, marked R110 on body): 10's, 60's (blister pack).
dabigatran.txt · Last modified: 2017/03/28 15:43 (external edit)