Dabigatran changed the landscape and set a new standard for oral anticoagulation in 2010. It was the first oral alternative to warfarin and the inaugural member of the drug class Direct Acting Oral Anticoagulants (DOACs).
It is still the only oral anticoagulant in the subclass of Direct Thrombin Inhibitor. Let me walk you through everything you need to know to use dabigatran safely and effectively.
How Dabigatran Works
Dabigatran is absorbed as an inactive prodrug that is converted into active drug by hepatic enzymes (in the liver).
Dabigatran inhibits thrombin in the common pathway of the coagulation cascade.
Thrombin activates the conversion of fibrinogen to fibrin during the coagulation cascade. Fibrin is the structural protein that forms the mesh network of a clot. Therefore inhibiting thrombin will prevent the formation of fibrin and in turn, a stable clot.
When is Dabigatran Needed
Indications
- Atrial fibrillation
- Venous thromboembolism (treatment & prevention)
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How to Use Dabigatran
Dabigatran has unique storage requirements.
Dabigatran is available as capsules and oral pellets.
The approved indications and intended age groups are not the same for the different dosage forms.
The oral bioavailability of dabigatran increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule.
Therefore the capsules should not be broken, chewed, or opened before administration. The formulations are not interchangeable.
Dabigatran should be dispensed and stored in the manufacturer’s bottle and used within 4 months of being opened. Advise patients not to store this medication in their pill organizers. The drug is easily hydrolyzed by humidity which reduces it’s potency. The capsules are available is unit dose blister packs as well.
The Evidence for Dabigatran
Dabigatran was evaluated in the RE-LY trial compared with dose-adjusted warfarin. Efficacy was assessed by the rate of stroke and systemic embolism. Safety was assessed as the rate of major bleed.
Dabigatran showed superiority over warfarin for prevention of stroke and systemic embolism. There was a non-significant difference in major bleed at the higher dose (150mg BID) and a significantly lower risk of major bleed at the lower dose (110mg BID).
How to Dose Dabigatran
The standard dosing of dabigatran is 150mg BID. It requires renal dose adjustment, consideration of drug interactions and should be avoided in patients with significant renal impairment including dependence on hemodialysis.
Drug Interactions with Dabigatran
Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes.
Dabigatran is a substrate of the efflux transporter P-gp. Learn more about the clinical significance of this class of interactions in the Cytochrome and P Glycoprotein unit.
P-gp are efflux pumps, they will pump drugs out of cells.
Therefore, if the pump’s activity is induced, more drug will be pumped out resulting in the possibility of reduced clinical effect i.e. increased risk of thrombosis.
Avoid Combination: dabigatran + PGP Inducers
Clinically significant P-gp inducers: carbamazepine, fosphenytoin, green tea, lorlatinib, phenytoin, rifampin, St John’s Wort.
Theoretically, inhibition of P-gp efflux pumps would increase serum concentrations of dabigatran and therefore increase the risk of toxicity. However, what has been observed in a large retrospective cohort is that concurrent use of ketoconazole (a strong P-gp inhibitor) was not associated with a significant increase in risk for major bleeding.
Consider Therapy Modification/Monitor Therapy: dabigatran + P-gp Inhibitors
The recommendations for the use of dabigatran with P-gp inhibitors is indication and patient specific and should always be reviewed.
Clinically significant PGP inhibitors: ketoconazole, itraconazole, posaconazole, ritonavir, erythromycin, clarithromycin, grapefruit.
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