Dabigatran

Products

Dabigatran is commercially available in capsule form (Pradaxa). It has been approved in many countries since 2012. It was first approved in 2008.

Structure and properties

Dabigatran (C25H25N7O3, Mr = 471.5 g/mol) is present in drugs as mesilate and in the form of the prodrug dabigatran etexilate, which is metabolized in the organism by esterases to dabigatran. The reaction is independent of CYP450. Dabigatran etexilate is a yellow-white to yellow powder that is soluble in water at 1.8 mg/ml and has a non-peptidic structure.

Effects

Dabigatran (ATC B01AE07) has antithrombotic and antiplatelet properties. It is a potent, competitive, reversible, and direct thrombin inhibitor. Thrombin is a serine protease that catalyzes the conversion of fibrinogen to fibrin and plays a central role in blood clotting. Dabigatran is being considered as a possible successor to phenprocoumon or warfarin. Unlike the vitamin K antagonists, it has linear, predictable pharmacokinetics and does not require monitoring. Phenprocoumon has a delayed onset of action, narrow therapeutic range, is prone to interactions, and requires close monitoring.

Indications

Dosage

According to the SmPC. Dabigatran is usually taken in the morning and evening, independently of meals. It has a half-life of 11-14 hours.

Contraindications

  • Hypersensitivity
  • Severe renal insufficiency
  • Combination with P-gp inhibitors such as quinidine, dronedarone, ritonavir, tipranavir, nelfinavir, saquinavir, ciclosporin, and tacrolimus.
  • Systemic treatment with ketoconazole or itraconazole.
  • Bleeding
  • Patients with hemorrhagic diathesis or with hemostasis impaired spontaneously or by medication.
  • Organ lesions with risk of clinically relevant bleeding including hemorrhagic cerebrovascular insult in the past 6 months
  • Impaired liver function or liver disease that is expected to impact survival
  • Artificial heart valve replacement

For complete precautions, see the drug label.

Interactions

  • Agents with an effect on blood clotting.
  • Ticagrelor
  • Amiodarone
  • Verapamil

Dabigatran does not interact with CYP450 but is a substrate of the efflux transporter P-glycoprotein. P-gp inhibitors may increase plasma concentrations of dabigatran and are therefore contraindicated in some cases. Conversely, P-gp inducers may decrease plasma concentrations and attenuate the effects of dabigatran. When combined with pantoprazole, a reduction in AUC has been observed because the PPI lowers gastric pH.

Adverse effects

The most common potential adverse effects include bleeding in various organs, for example, gastrointestinal bleeding and nosebleeds, and indigestion. Overdose increases the risk of bleeding. The antibody fragment idarucizumab is available as an antidote to bleeding.