Dabigatran (Pradaxa)

Dosing

The presence of chronic kidney disease is an independent risk factor for increased bleeding events, including hemorrhagic stroke. Please carefully consider the risks and benefits of any oral anticoagulant prior to initiating therapy.

CrCl	FDA Recommended Dose  Treatment of DVT/PE	FDA Recommended Dose Stroke Prevention in AF	UW Medicine Restrictions	AUC	Cmax	T 1/2
> 80 ml/min	150mg BID after 5-10 days of parenteral anticoagulant therapy	150 mg BID	UWMedicine: RESTRICTED IF CrCl < 50 ml/min	–	–	14 hrs
50 – 80 ml/min				1.5 x increase	1.1 x increase	17 hrs
30 – 50 ml/min				3.2 x increase	1.7 x increase	19 hrs
<  30 ml/min	Not recommended	CrCl 15-30 ml/min: 75mg BID (Based on computer modeling; not studied in patients)	Consider alternative therapy RESTRICTED	6.3 x increase	2.1 x increase	28 hrs
		CrCl < 15 ml/min: not recommended	Consider alternative therapy RESTRICTED
Hemodialysis	Not recommended	Not recommended	Consider alternative therapy RESTRICTED			34 hrs (~65% removed by HD)

Stangier J, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49(4):259-268.

 

Indications

An oral direct thrombin inhibitor approved for :

1. Stroke prevention in atrial fibrillation (150 mg twice daily)
2. Treatment of DVT/PE in patients who have been treated with a parenteral anticoagulant for 5-10 days (150 mg twice daily)
3. Long-term prevention of recurrent DVT/PE in patients who have been previously treated for DVT/PE (150 mg twice daily)
4. Prevention of DVT/PE following hip replacement (110 mg after surgery and hemostasis, then 220 mg daily)

 

Administration

• Do not break, chew or crush capsules
• Keep capsules in original container – do not store or place them in other containers
• After opening the original container, capsules expire in 120 days

 

Drug Interactions

Pharmacodynamic Interactions

The concurrent use of dabigatran with other anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatory agents is expected to increase the risk of bleeding in comparison to use of dabigatran alone.

Pharmacokinetic Interactions

The absorption of the pro-drug dabigatran etexilate is mediated by P-glycoprotein (P-gp). P-gp inhibitors can increase the absorption of dabigatran etexilate, ultimately increasing both AUC and Cmax of dabigatran, the active drug. Conversely, P-gp inducers can reduce the absorption of dabigatran etexilate, ultimately decreasing AUC and Cmax of dabigatran, the active drug.

Based on the observation that in the RE-LY trial, patients with moderate renal impairment exhibited a 2.3-fold increase in dabigatran compared to patients with normal renal function, the FDA has stated that “any interaction that will result in an increase in the exposure to dabigatran greater than 2.5-fold (or greater than 150%) will require a dose/regimen adjustment”. However, it is possible that changes in exposure that are lower than this threshold may cause clinically significant changes. Therefore, caution is advised with the concurrent use of dabigatran and all P-gp inhibitors and inducers.

Based on observations with verapamil it is possible that administration of dabigatran etexilate two hours prior to any P-gp inhibitor may reduce or eliminate the impact of the interaction, but there is insufficient evidence at this time to make this conclusion definitively.  Using this strategy with P-gp inducers is not likely to minimize the impact of drug interactions.

Drug Class	Examples (based on human in vivo data1)	Known or Probable Effect	US PI Recommendation	Suggested Management Guidelines2
P-gp Inhibitors	alfentanil, amiodarone**, atorvastatin, azithromycin, carvedilol, clarithromycin**, cobicistat, conivaptan, cyclosporine, diltiazem, dronedarone**, duloxetine, erythromycin, fenofibrate, grapefruit juice, indinavir, itraconazole, ivacaftor*, ketoconazole**, lapatinib, ledipasvir, lomitapide, lovastatin, mefloquine, nelfinavir, nicardipine, nifedipine*, ponatinib posaconazole, propafenone, quinidine**, ranolazine*, ritonivir, saquinavir, simvastatin, sunitinib, tacrolimus, tamoxifen, telaprevir, telithromycin, ticagrelor**, tolvaptan*, verapamil** *Weak P-gp inhibitor **Cited as example in US PI, with pharmacokinetic data cited	Variable increase in dabigatran concentrations	AF: Consider dose reduction to 75mg twice daily if administered with dronedarone or ketoconazole in pts with CrCl 30-50 ml/min. AF: Avoid use with any P-gp inhibitor in patients with severe renal impairment (CrCl < 30 ml/min) VTE: Avoid use with any P-gp inhibitor in pts with CrCl < 50ml/min	AVOID USE with cyclosporine, dronedarone, itraconazole, ketoconazole, or tacrolimus AVOID USE with any P-gp inhibitor in patients with moderate to severe renal impairment (CrCl < 50 ml/min) or in any patient aged > 75 years. When concomitant use of a P-gp inhibitor cannot be avoided, administer dabigatran at least 2 hours before P-gp inhibitor
P-gp inducers	carbamazepine, dexamethasone, fosphenytoin, phenytoin, rifampin*, St. John’s wort, tipranavir *Cited as example in US PI, with pharmacokinetic data cited	Significant reduction in dabigatran concentration Effect may persist for several weeks following discontinuation of inducers of P-pg.	AVOID USE	AVOID USE
Antacids	H2 antagonists, proton pump inhibitors	Modest reduction in dabigatran concentration	None	When practical, administer dabigatran at least 2 hours before antacids

(1)  based on human in vivo data, in Cytochrome P450 Enzymes and Transporters Table, from Hansten PD and Horn JR.  The Top 100 Drug Interactions: A Guide to Patient Management, 2014 ed, H&H Publications, Freeland WA 2014.

(2) based on probable effects on daibgatran, taking into consideratoin known characteristics of the precipitant drug according to human in vivo data

 

Conversion to/from Dabigatran

Conversion	UW Medicine Recommendation
From warfarin to dabigatran	Stop warfarin and start dabigatran when INR < lower limit of therapeutic range
From dabigatran to warfarin (NOTE: Dabigatran is not intended to be used as a short term “bridge” to warfarin. These recommendations refer to transitioning patients who are taking dabigatran on a long term basis and are switching to warfarin instead)	CrCl > 50 mL/min: start warfarin and stop dabigatran 3 days later CrCl 31-50 mL/min: start warfarin and stop dabigatran 2 days later CrCl 15-30 mL/min: start warfarin and stop dabigatran 1 day later (dabigatran may alter INR results; therefore, using INR to guide when to stop dabigatran is not reliable)
From LMWH/ fondaparinux to dabigatran	Stop parenteral anticoagulant and administer dabigatran 0-2 hours before next parenteral dose would have been given
From IV heparin to dabigatran	Administer first dose of dabigatran at time of discontinuation of IV heparin infusion
From dabigatran to parenteral anticoagulant	CrCl > 30 mL/min: Start parenteral anticoagulant 12 hours after the last dose of dabigatran CrCl < 30 mL/min: Start parenteral anticoagulant 24 hours after the last dose of dabigatran
From dabigatran to apixaban, edoxaban or rivaroxaban	Stop dabigatran and begin the other agent at the time that the next dose of dabigatran would have been given

Peri-Procedural Management of Dabigatran

CrCl	T1/2	Time of last dose of dabigatran before procedure (peri-procedural bridging is generally not required)
		Standard risk of bleeding	High risk of bleeding (Major surgery, spinal puncture or placement of spinal/epidural catheter, and other situations in which complete hemostasis may be required)
> 80 ml/min	14 hrs	At least 24 hrs	At least 48 hrs
50 – 79 ml/min	17 hrs	At least 36 hrs	At least 72 hrs
30-49 ml/min	19 hrs	At least 48 hrs	At least 96 hrs
15-29 ml/min	28 hrs	At least 72 hrs	At least 120 hrs
< 15 ml/min	34 hrs	Consider measuring drug activity with the dabigatran assay to determine absence of drug effect

 

Reversal and Management of Bleeding

 

 

Management Plan

Therapeutic Monitoring

Dabigatran is not intended to be monitored using routine coagulation testing.  In certain clinical situations in which the presence or absence of anticoagulant effect induced by dabigatran needs to be measured, the UW Medicine Dabigatran Assay can be used.

Learn more about Dabigatran Assay (DABIGL)

 

Relevant Clinical Trials

Stroke Prevention in Atrial Fibrillation

• Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12)1139-1151. (RE-LY)

Treatment of DVT/PE

• Schulman S, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361(24):2342-2352. (RE-COVER)

Extended Treatment of DVT/PE0

• Schulman S, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368(8):709-718. (RE-MEDY, RE-SONATE)

Hip Replacement

• Eriksson BI, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370(9591):949-956. (RE-NOVATE)
• Eriksson BI, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105(4):721-729. (RE-NOVATE II)