dabigatran (Rx)

>10%

Dyspepsia and gastritis (35%; compared with warfarin [24%])

Any bleed (16.6%; compared with warfarin [18.4%])

1-10%

Major bleed (3.3%; compared with warfarin [3.6%])

Life-threatening bleed (1.5%; compared with warfarin [1.9%])

<1%

Intracranial hemorrhage (0.3%; compared with warfarin [0.8%])

Hypersensitivity, including urticaria, rash, pruritus (<0.1%)

Postmarketing Reports

Angioedema

Esophageal ulcers

Thrombocytopenia

Contraindications

Severe renal impairment (CrCl <15 mL/min) or hemodialysis

Hypersensitivity

Active pathologic bleeding

Impairment of hemostasis

Mechanical prosthetic heart valves

• Significantly more thromboembolic events (eg, valve thrombosis, stroke, TIAs, MI) observed with dabigatran than with warfarin
• Excessive major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) observed with dabigatran, compared with warfarin
• These bleeding and thromboembolic events, seen in the RE-ALIGN study (Am Heart J, June 2012), were observed in patients who were started on dabigatran postoperatively within 3 days after mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than 3 months prior to enrollment in the study; this clinical trial was terminated early because of these events

Cautions

Increased bleeding risk during labor and delivery

If possible, discontinue 1-2 days (CrCl ≥50 mL/min) or 3-5 days (CrCl <50 mL/min) before invasive or surgical procedure to decrease bleeding risk

Discontinuing anticoagulants for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke; minimize lapses in therapy

Ecarin clotting time (ECT) is a more accurate marker than aPPT, PT, or TT; aPPT gives an approximation of dabigatran’s anticoagulant activity if the ECT test is unavailable

Increased risk for stroke if temporarily discontinued

Additive risk of bleeding when coadministered with antiplatelet agents, warfarin, heparin, fibrinolytic therapy, and long-term NSAIDs or aspirin; however, coadministration with clopidogrel has not resulted in further prolongation of capillary bleeding times compared with clopidogrel monotherapy

Not recommended in patients with prosthetic heart valves; safety and efficacy not established

Renal impairment (CrCl 15-30 mL/min): Anticoagulant activity and half-life are increased in patients with renal impairment

Congenital or acquired coagulation disorders

Ulcerative GI disease and other gastritislike symptoms

Recent hemorrhage

Recent brain, spinal, or ophthalmic surgery

Use in patients undergoing neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis (see Black Box Warnings)

Coadministration with P-gp inducers and inhibitors

• P-gp inducers (eg, rifampin) reduce exposure to dabigatran and should generally be avoided
• P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran
• Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone
• DVT/PE treatment, renal impairment, and P-gp inhibitors: Avoid coadministration if CrCl <50 mL/min

• AF treatment, renal impairment, and P-gp inhibitors

  • CrCl 30-50 mL/min and P-gp inhibitors dronedarone or ketoconazole: Consider reducing the dose (see Dosage Modifications)
  • CrCl 30-50 mL/min: Use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment, however, these results should not be extrapolated to other P-gp inhibitors
  • CrCl <30 mL/min: Avoid coadministration with all P-gp inhibitors

Reversing anticoagulant effect

• Idarucizumab is commercially available for reversal of the anticoagulant effect of dabigatran in surgery/urgent procedures, or life-threatening or uncontrolled bleeding
• Can be dialyzed (protein binding is low, with the removal of about 60% of drug over 2-3 hr); however, the amount of data supporting this approach is limited
• Activated prothrombin complex concentrates, recombinant factor VIIa, or concentrates of coagulation factors II, IX, or X may be considered, but their use has not been evaluated in clinical trials
• Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran
• Consider administration of platelet concentrates in cases in which thrombocytopenia is present or long-acting antiplatelet drugs have been used

Pregnancy

Limited available data on use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes; there are risks to mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in mother and fetus associated with use of anticoagulants

Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions; published data describe that women with previous history of venous thrombosis are at high risk for recurrence during pregnancy

Use of anticoagulants, may increase risk of bleeding in fetus and neonate; monitor neonates for bleeding

Labor or delivery

• All patients receiving anticoagulants, including pregnant women, are at risk for bleeding; use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas; consider discontinuation or use of shorter acting anticoagulant as delivery approaches

Lactation

There are no data on presence of dabigatran in human milk, effects on breastfed child, or on milk production; drug and/or its metabolites were present in rat milk; breastfeeding is not recommended during therapy

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Prevents thrombus development through direct, competitive inhibition of thrombin (thrombin enables fibrinogen conversion to fibrin during the coagulation cascade)

Inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation

Absorption

Bioavailability: 3-7%

Peak plasma time: 1 hr

Distribution

Protein bound: 35%

Vd: 50-70 L

Metabolism

Prodrug dabigatran etexilate is converted to dabigatran

Dabigatran etexilate is a substrate of the efflux transporter P-gp

Not a substrate, inhibitor, or inducer of CYP450 enzymes

Elimination

Half-life

• Normal renal function: 12-17 hr
• Mild to moderate renal impairment: 14-17 hr
• Severe renal impairment: 28 hr

Excretion

• Urine (80%)

Instructions

Swallow capsule whole (do not chew, crush, or break)

If dose is missed, take as soon as possible on same day; skip missed dose if it cannot be taken at least 6 hours before the next scheduled dose; do not double dose to make up for a missed dose

Store in original container; once bottle is opened, capsules are stable for only 4 months