Dabigatran

A new oral direct thrombin inhibitor approved for stroke prevention in atrial fibrillation

Administration Considerations

Do not break, chew or crush capsules
Keep capsules in original container – do not store or place in other containers
After opening original container, capsules expire in 60 days

Effect of Renal Function on Dabigatran Pharmacokinetics

Clcr	Recommended Dose	AUC	Cmax	T 1/2
> 80 ml/min	150mg bid	-	-	13.8 hrs
50 – 80 ml/min		1.5 x increase	1.1 x increase	16.6 hrs
30 – 50 ml/min		3.2 x increase	1.7 x increase	18.7 hrs
< 30 ml/min	Clcr 15-30 ml/min: 75mg bid* * based on computer modeling; not studied in patients	6.3 x increase	2.1 x increase	27.5 hrs
< 30 ml/min	Clcr< 15 ml/min: Not recommended	6.3 x increase	2.1 x increase	27.5 hrs
10-20 ml/min on HD	Not recommended			34.1 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 Pharmacokinetics 2010; 49:259-68.

Suggestions for Conversion To/From Dabigatran

warfarin to dabigatran	stop warfarin and start dabigatran when INR < 2
dabigatran to warfarin	Clcr > 50 mL/min: start warfarin and stop dabigatran 3 days later Clcr 31-50 mL/min: start warfarin and stop dabigatran 2 days later Clcr 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)
LMWH/ fondaparinux to dabigatran	stop parenteral anticoagulant and administer dabigatran 0-2 hours before next parenteral dose would have been given
IV heparin to dabigatran	administer first dose of dabigatran at time of discontinuation of IV heparin infusion
dabigatran to parenteral anticoagulant	Clcr > 30 mL/min: Start parenteral anticoagulant 12 hours after the last dose of dabigatran Clcr < 30 mL/min: Start parenteral anticoagulant 24 hours after the last dose of dabigatran

Suggestions for Peri-Procedural Management of Dabigatran

Clcr	T ½	Time of last dose of dabigatran before procedure
		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	2-3 days
50 – 80 ml/min	17 hrs	At least 24 hrs	2-4 days
30-50 ml/min	19 hrs	At least 48 hrs	4 days
< 30 ml/min	~27 hrs (22-35)	2-5 days	> 5 days

Drug Interaction Potential

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

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 (see table below) it is possible that administration of dabigatran two hours prior to any P-gp inhibitor or inducer may reduce or eliminate the impact of the interaction, but there is insufficient evidence at this time to make this conclusion definitively.

Interacting Drug Class	Interacting Drug	Change in AUC	FDA Recommendation	Health Canada Recommendation	EMA Recommendation
Stomach Acid Suppressants	Antacids	35% decrease in first 24 hrs, then 11% decrease	Not mentioned	Give dabigatran 2 hours before antacid	Not mentioned
	H2 antagonists	unknown	Not mentioned	Not mentioned	No dose adjustment necessary
	Proton pump inhibitors	30% decrease (pantoprazole)	Not mentioned	No dose adjustment required	No dose adjustment necessary
P-glycoprotein Inducers	P-gp Inducers in General	(drug-specific)	Avoid	Use with caution	Avoid
	Carbamazepine	unknown	Not mentioned	Use with caution	Avoid
	Phenytoin	unknown	Not mentioned	Not mentioned	Avoid
	Rifampin	67% decrease	Avoid	Avoid	Avoid
	Ritonavir	unknown	Not mentioned	Not mentioned	Not recommended
	St John’s Wort	unknown	Not mentioned	Use with caution	Avoid
	Tenofovir	unknown	Not mentioned	Use with caution	Not mentioned
Other P-gp inducers	dexamethasone, doxorubicin, nefazodone, prazosin, tipranavir, trazodone, vinblastine
P-glycoprotein Inhibitors	P-gp Inhibitors in General	(drug-specific)	Avoid if Clcr<30 ml/min	Close clinical surveillance along with a sense of caution is required	Close clinical surveillance is required
	Amiodarone	58% increase (with 65% increase in renal clearance )	No dose adjustment required	No dosage adjustment recommended. Use with caution	No dose adjustment necessary
	Clarithromycin	15% increase	No dose adjustment required	No dose adjustment required	Monitor closely
	Cyclosporine	Unknown	Not mentioned	Not mentioned	Contraindicated
	Dronedarone	73-99% increase	If Clcr 30-50ml/min, consider dose reduction of 75mg bid	Not mentioned	Not recommended
	Itraconazole	Unknown	Not mentioned	Not mentioned	Contraindicated
	Ketoconazole (single dose)	138% increase	If Clcr 30-50ml/min, consider dose reduction of 75mg bid	Contraindicated	Contraindicated
	Ketoconazole (multiple dose)	153% increase	If Clcr 30-50ml/min, consider dose reduction of 75mg bid	Contraindicated	Contraindicated
	Posaconazole	unknown	Not mentioned	Not mentioned	Not recommended
	Quinidine	53% increase	No dose adjustment required	Give dabigatran 2 hrs before quinidine	No dose adjustment necessary
	Verapamil (single dose 1 hr before dabigatran)	143% increase	No dose adjustment required	Give dabigatran 2hrs before verapamil	Reduce dose to 110mg bid given at the same time as verapamil
	Verapamil (multiple dose 1 hr before dabigatran)	54% increase
	Verapamil IR (single dose concurrently with dabigatran)	108% increase
	Verapamil ER (single dose concurrently with dabigatran)	71% increase
	Verapamil IR (multiple dose 2 hrs after dabigatran)	No change
	Tacrolimus	unknown	Not mentioned	Not mentioned	Contraindicated
Other P-gp inhibitors	abiraterone, atorvastatin, carvedilol, conivaptan, crizotinib, darunavir, diltiazem, dipyridamole, erythromycin, fenofibrate, grapefruit juice, indinovir, lapatinib, lopinavir, mefloquine, mifepristone, nelfinavir, nicardipine, nifedipine, nilotinib, progesterone, propafenone, propranolol, quinine, ranolazine, reserpine, ritonavir, saquinavir, sunitinib, tamoxifen, telaprevir, testosterone, vandetanib, vemurafenib,

US prescribing information revised November 2011, available at:
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ba74e3cd-b06f-4145-b284-5fd6b84ff3c9

Health Canada Product Monograph revised June, 2011 available at:
http://webprod3.hc-sc.gc.ca/dpd-bdpp/info.do?lang=eng&code=84384

European Medicines Agency Summary updated August, 2011 available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000829/human_med_000981.jsp&mid=WC0b01ac058001d124

Therapeutic Monitoring

Dabigatran is not intended to be monitored using routine coagulation testing. Its fixed dosing is not intended to be adjusted on the basis of any coagulation laboratory parameter.

In certain clinical situations in which the presence of anticoagulant effect induced by dabigatran needs to be assessed, the UWMedicine Direct Thrombin Inhibitor Assay can be used.

These settings include:

to assess compliance
to evaluate possible underanticoagulation in treatment failures
to evaluate possible overanticoagulation in cases of hemorrhage
to assure appropriate dabigatran clearance prior to invasive procedures
to assure appropriate dabigatran clearance prior to thrombolytic therapy for acute ischemic stroke

Suggestions for Reversal and Management of Bleeding

There is NO REVERSAL AGENT OR ANTIDOTE for dabigatran. Very limited data, primarily non-human, are available to guide management of bleeding.

Mild Bleeding

delay next dose or discontinue therapy

Moderate to Severe Bleeding

symptomatic treatment
mechanical compression
surgical intervention
fluid replacement and hemodynamic support
blood product transfusion
oral charcoal (if dabigatran administered < 2 hrs prior)
hemodialysis (60% removal)

Life Threatening Bleeding

measures above
charcoal filtration
last resort: rVIIa or PCC (not anticipated to be effective)

van Ryn J, et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-27

Anticoagulation Services

Dabigatran

Relevant Clinical Trials

UW Medicine Dabigatran Clinical Screening Checklist

Medication Guide

Patient Education Documentation

Administration Considerations