Marion General Hospital Formulary EvaluationMonograph

Generic Name (Trade Name): Dabigatran (Pradaxa)Manufacturer: Boehringer-Ingelheim Dosage Forms (NDC #): oral tabletAHFS Class: Anticoagulant Storage: 25°C, store in original package to protect from moisture, once opened use within 4 months.

Description and Pharmacology: Dabigatran is an anticoagulant that directly inhibits thrombin to prevent the formation of a clot.

Pharmacokinetics

See supplementary handout

FDA-Approved Indications1

Reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. (1.1) Treatment of DVT and PE Reduction in risk of recurrent DVT/PE following initial therapy

Clinical Trials

Title Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY)Objective Compare efficacy and safety of dabigatran with warfarin in patients with non-valvular

A.fib. Design Multi-center, multi-national randomized double blind study

18,113 patientsFollow up: 2 years

Methods Treatment arms: Dabigatran 110mg BID and 150mg BID vs. Warfarin dosed to target INR of 2-31°: Composite of stroke and systemic embolism1° safety outcome: major bleeding

Results Dabigatran 110mgBID vs. 150mg BID vs. warfarinRate of stroke or systemic embolism (annual event rate): 1.5%( p=0.34) vs. 1.1%(p<0.001) vs. 1.7%Major bleeding (annual event rate): 2.7%(p=0.003) vs. 3.1% (p=0.31)vs. 3.4%

Conclusions Both Dabigatran strengths showed reduce rate of stroke or systemic embolism when compared to warfarin. Dabigatran dosed 150mg BID was the only one to show statistical significance. Both doses of Dabigatran showed less intra-cerebral, lifethreatening and total bleeding compared to warfarin. Dabigatran showed no difference in major bleeding with 150mg strength but did with 110mg strength.

Comments

Title Treatment and Reduction in the Risk of Recurrence of DVT and PE (RE-COVER and RE-COVER II)

Objective Compare efficacy and safety of dabigatran vs. warfarin for the treatment of acute VTE with an added goal to confirm the results in RE-COVER 1 with results from RE-COVER II

Design Randomized, double blind phase III non-inferiority trial2539 patients: RE-COVER I2568 patients: RE-COVER II

Methods Treatment arms: Dabigatran 150mg BID after initial treatment with LMWH or UFH vs. warfarin dosed to a target INR of 2-3 after > 5 days of parenteral anticoagulationPrimary outcomes: VTE and VTE related deathSafety outcome: Major bleeding

Results Dabigatran vs. WarfarinRE-COVER I:

Symptomatic VTE and VTE related deaths: 30/1274 pts (2.4%) vs. 27/1265pts (1.9%) p<0.001

Major bleeding: 20/1274 pts (1.6%) vs. 24/1265 pts(1.9%) Major or clinically relevant non-major bleeding: 71pts (5.6%) vs. 111pts

(8.8%), p=0.002, Relative Risk Reduction: 37%RE-COVER II:

Recurrent VTE and VTE-related death: 30/1279 pts (2.3%) vs. 28/1289 pts (2.2%) HR: 1.08 p<0.001

Major bleeding 15pts (1.2%) vs. 22pts (1.7%) HR: 0.69 Rates of any bleeding: 200 events (15.6%) vs. 285 events (22.1%), Relative

Risk Reduction: 33%Conclusions Dabigatran demonstrated non-inferiority to warfarin in the patients with acute VTE in

the prevention of recurrent or fatal VTE. Dabigatran also demonstrated lower risk of bleeding.

Comments

Safety and Tolerability

Contraindications: Active pathological bleeding, hypersensitivity reaction to Dabigatran, mechanical prosthetic heart valve

Warnings and Precautions: Can cause serious and fatal bleeding Use in patients with bioprosthetic heart valves is not recommended

.

Adverse Drug Effects

See supplementary handout

Drug Interactions

P-gp inducers: Avoid co-administration P-gp inhibitors:

o Dronedarone or ketoconazole: reduce dose if CrCl 30-50mL/mino Verapamil, amiodarone,quinidine, clarithromycin, and ticagrelor: no dose adjustmento Patients with CrCl <30 mL/min: Not recommended

Medication Error Possibility

None identified

Dosing and Administration See supplementary handout.

References

1. Dabigatran [Package Insert]. Ridgefield: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.

2. RE-LY. Anticoagulation-trials website: http://www.anticoagulant-trials.eu/studies-a-z/detail/study/re-ly.html. March 2015. Accessed April 21, 2015.