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Dabigatran Etexilate

Pronunciation

Pronunciation

(da BIG a tran ett EX ill ate)

Index Terms

  • Dabigatran Etexilate Mesylate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Pradaxa: 75 mg [contains fd&c yellow #6 (sunset yellow)]

Pradaxa: 110 mg [contains fd&c blue #2 (indigotine)]

Pradaxa: 150 mg [contains fd&c blue #2 (indigotine), fd&c yellow #6 (sunset yellow)]

Brand Names: U.S.

  • Pradaxa

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Direct Thrombin Inhibitor
  • Direct Oral Anticoagulant (DOAC)

Pharmacology

Prodrug lacking anticoagulant activity that is converted in vivo to the active dabigatran, a specific, reversible, direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin. Inhibits coagulation by preventing thrombin-mediated effects, including cleavage of fibrinogen to fibrin monomers, activation of factors V, VIII, XI, and XIII, and inhibition of thrombin-induced platelet aggregation.

Absorption

Rapid; initially slow postoperatively

Distribution

Vd: 50-70 L

Metabolism

Hepatic; dabigatran etexilate is rapidly and completely hydrolyzed to dabigatran (active form) by plasma and hepatic esterases; dabigatran undergoes hepatic glucuronidation to active acylglucuronide isomers (similar activity to parent compound; accounts for <10% of total dabigatran in plasma)

Excretion

Urine (80%)

Time to Peak

Plasma: Dabigatran: 1 hour; delayed 2 hours by food (no effect on bioavailability)

Half-Life Elimination

12-17 hours; Elderly: 14-17 hours; Mild-to-moderate renal impairment: 15-18 hours; Severe renal impairment: 28 hours (Stangier 2010)

Protein Binding

35%

Special Populations: Renal Function Impairment

Exposure to dabigatran increases with the severity of renal impairment. AUC increases 1.5, 3.2, and 6.3 times in patients with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 30 to 50 mL/minute), and severe (CrCl 15 to 30 mL/minute) renal impairment, respectively.

Use: Labeled Indications

Deep venous thrombosis and pulmonary embolism treatment and prevention: Treatment of deep venous thrombosis (DVT) and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days; to reduce the risk of recurrence of DVT and pulmonary embolism in patients who have been previously treated.

Nonvalvular atrial fibrillation (to reduce the risk of stroke and systemic embolism): Reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF)

Note: The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines for the management of AF recommend oral anticoagulation for patients with nonvalvular AF or atrial flutter with prior stroke, TIA, or a CHA2DS2-VASc score ≥2. As an alternative to warfarin, dabigatran may also be used for 3 weeks prior and 4 weeks after cardioversion in patients with AF or atrial flutter of ≥48 hours duration or when the duration is unknown (January 2014).

Postoperative thromboprophylaxis:

US labeling: Prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism in patients who have undergone hip replacement surgery.

Canadian labeling: Postoperative thromboprophylaxis in patients who have undergone total hip or knee replacement procedures

Contraindications

Serious hypersensitivity (eg, anaphylaxis or anaphylactic shock) to dabigatran or any component of the formulation; active pathological bleeding; patients with mechanical prosthetic heart valve(s)

Canadian labeling: Additional contraindications (not in US labeling): Severe renal impairment (CrCl <30 mL/minute); bleeding diathesis, patients with spontaneous or pharmacological hemostatic impairment or clinically significant active bleeding (including GI bleeding); lesions at risk of clinically significant bleeding (eg, hemorrhagic or ischemic cerebral infarction) within previous 6 months; nursing women; concomitant therapy with oral ketoconazole; concomitant use with other anticoagulants including unfractionated heparin (except when used to maintain central venous or arterial catheter patency), low molecular weight heparins, heparin derivatives (eg, fondaparinux), antithrombin agents (eg, bivalirudin), and oral anticoagulants (eg, warfarin, rivaroxaban, apixaban) except during transitioning of therapy from or to dabigatran

Dosing: Adult

DVT and pulmonary embolism (treatment and prevention): Oral:

US labeling: 150 mg twice daily (after 5 to 10 days of parenteral anticoagulation)

Canadian labeling: 150 mg twice daily (after 5 to 10 days of parenteral anticoagulation); dose reduction to 110 mg twice daily is recommended in patients at increased risk of bleeding, including patients ≥75 years with ≥1 risk factor for bleeding

Nonvalvular atrial fibrillation (to reduce the risk of stroke and systemic embolism): Oral:

US labeling: 150 mg twice daily.

Canadian labeling: 150 mg twice daily; dose reduction to 110 mg twice daily is recommended in patients at increased risk of bleeding, including patients ≥75 years with ≥1 risk factor for bleeding; however, efficacy in stroke prevention may be lessened with this dose.

Postoperative thromboprophylaxis: Oral:

US labeling:

Hip replacement: Initial: 110 mg given 1 to 4 hours after completion of surgery and establishment of hemostasis; if not initiated on the day of surgery, initiate therapy with 220 mg once daily after hemostasis has been achieved; maintenance: 220 mg once daily (total duration of therapy: 28 to 35 days; ACCP recommendation [Guyatt 2012]: Minimum of 10 to 14 days; extended duration of up to 35 days suggested)

Canadian labeling:

Knee replacement: Initial: 110 mg given 1 to 4 hours after completion of surgery and establishment of hemostasis OR 220 mg as 1 dose in postoperative patients in whom therapy is not initiated on day of surgery regardless of reason; maintenance: 220 mg once daily (total duration of therapy: 10 days; ACCP recommendation [Guyatt 2012]: Minimum of 10 to 14 days; extended duration of up to 35 days suggested)

Hip replacement: Initial: 110 mg given 1 to 4 hours after completion of surgery and establishment of hemostasis OR 220 mg as 1 dose in postoperative patients in whom therapy is not initiated on day of surgery regardless of reason; maintenance: 220 mg once daily (total duration of therapy: 28 to 35 days; ACCP recommendation [Guyatt 2012]: Minimum of 10 to 14 days; extended duration of up to 35 days suggested)

Conversion:

Conversion from a parenteral anticoagulant: Initiate dabigatran ≤2 hours prior to the time of the next scheduled dose of the parenteral anticoagulant (eg, enoxaparin) or at the time of discontinuation for a continuously administered parenteral drug (eg, IV heparin); discontinue parenteral anticoagulant at the time of dabigatran initiation.

Conversion to a parenteral anticoagulant:

US labeling: Wait 12 hours (CrCl ≥30 mL/minute) or 24 hours (CrCl <30 mL/minute) after the last dose of dabigatran before initiating a parenteral anticoagulant.

Canadian labeling: Wait 12 hours (DVT and pulmonary embolism treatment/prevention, nonvalvular atrial fibrillation) or 24 hours (postoperative thromboprophylaxis) after the last dose of dabigatran before initiating a parenteral anticoagulant.

Conversion from warfarin: Discontinue warfarin and initiate dabigatran when INR <2.0

Conversion to warfarin: Since dabigatran contributes to INR elevation, warfarin’s effect on the INR will be better reflected only after dabigatran has been stopped for ≥2 days. Start time must be adjusted based on CrCl:

CrCl >50 mL/minute: Initiate warfarin 3 days before discontinuation of dabigatran

CrCl 30 to 50 mL/minute: Initiate warfarin 2 days before discontinuation of dabigatran

CrCl 15 to 30 mL/minute: Initiate warfarin 1 day before discontinuation of dabigatran (dabigatran use is contraindicated in Canadian labeling when CrCl <30 mL/minute).

CrCl <15 mL/minute: There are no recommendations provided in the US manufacturer’s labeling.

Dosing adjustment with concomitant medications:

US labeling:

DVT and pulmonary embolism (treatment and prevention):

Any P-glycoprotein inducer (eg, rifampin): Avoid concurrent use.

Any P-glycoprotein inhibitor (eg, amiodarone, clarithromycin, dronedarone, quinidine, verapamil, and others) with CrCl <50 mL/minute: Avoid concurrent use.

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):

Dronedarone or ketoconazole (oral) with CrCl 30 to 50 mL/minute: Reduce dabigatran dose to 75 mg twice daily.

Any P-glycoprotein inducer (eg, rifampin): Avoid concurrent use.

Any P-glycoprotein inhibitor (eg, amiodarone, clarithromycin, dronedarone, quinidine, verapamil, and others) with CrCl <30 mL/minute: Avoid concurrent use.

Postoperative thromboprophylaxis (hip replacement):

Any P-glycoprotein inducer (eg, rifampin): Avoid concurrent use.

Any P-glycoprotein inhibitor (eg, amiodarone, clarithromycin, dronedarone, quinidine, verapamil, and others) with CrCl <50 mL/minute: Avoid concurrent use.

Canadian labeling: Note: Regardless of indication, avoid simultaneous initiation of verapamil and dabigatran; administer dabigatran at least 2 hours prior to verapamil.

Postoperative thromboprophylaxis: Strong P-gp inhibitors (eg, amiodarone, quinidine, verapamil): Use caution and consider reducing dabigatran to 150 mg once daily. In patients with CrCl 30 to 50 mL/minute and receiving verapamil, consider dabigatran dose reduction to 75 mg once daily. Avoid initiation of verapamil in postoperative patients who are already receiving dabigatran. Use with the strong P-gp inhibitor ketoconazole (oral) is contraindicated.

Dosing: Geriatric

US labeling:

DVT and pulmonary embolism/Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism)/postoperative thromboprophylaxis: Oral:

Patients >65 years: Refer to adult dosing. No dosage adjustment required unless renal impairment exists; however, risk of bleeding increases with age. Numerous reports of excess anticoagulation, including fatalities, have been observed with use in older adults (ISMP [Smetzer 2012]; ISMP [Smetzer 2015]).

Patients ≥75 years: Use with extreme caution or consider other treatment options (see Warnings/Precautions). No dosage adjustment provided in manufacturer’s labeling based on age alone (unless renal impairment coexists); however, risk of bleeding increases with age. Numerous reports of excess anticoagulation, including fatalities, have been observed with use in older adults (ISMP [Smetzer 2012]; ISMP [Smetzer 2015]).

Canadian labeling:

DVT and pulmonary embolism/Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Oral:

Patients <80 years: 150 mg twice daily; Note: The manufacturer labeling recommends that a dose reduction to 110 mg twice daily in patients >75 years with at least one other risk factor for bleeding (eg, moderate renal impairment [CrCl 30 to 50 mL/minute], concomitant treatment with strong P-gp inhibitors, or previous GI bleed); however, efficacy in stroke prevention may be lessened with this dose reduction.

Patients ≥80 years: 110 mg twice daily

Postoperative thromboprophylaxis: Oral: Patients >75 years: Use with caution; consider a dose of 150 mg once daily

Dosing: Renal Impairment

Note: Clinical trial evaluating safety and efficacy utilized the Cockcroft-Gault formula with the use of actual body weight (data on file; Boehringer Ingelheim Pharmaceuticals Inc 2012).

Manufacturer’s labeling: Adults:

DVT and pulmonary embolism (treatment and prevention):

US labeling:

CrCl >30 mL/minute: No dosage adjustment necessary unless patient has a CrCl <50 mL/minute and is receiving concomitant P-gp inhibitors, then avoid coadministration.

CrCl ≤30 mL/minute: There are no dosage recommendations provided in the manufacturer’s labeling (has not been studied). Patients with CrCl <30 mL/minute (Schulman 2009; Schulman 2011) or CrCl ≤30 mL/minute (Schulman 2013) were excluded from the respective clinical trials.

Hemodialysis: There are no dosage recommendations provided in the manufacturer’s labeling (has not been studied). Patients receiving hemodialysis were excluded from clinical trials (Schulman 2009; Schulman 2011; Schulman 2013).

Canadian labeling:

CrCl >50 mL/minute: No dosage adjustment is necessary

CrCl 30 to 50 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); dose selection should be based on risk/benefit assessment.

CrCl <30 mL/minute: Use is contraindicated.

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):

US labeling:

CrCl >50 mL/minute: No dosage adjustment necessary. Use with caution in mild renal impairment (CrCl 50 to 80 mL/minute) due to risk for increased dabigatran exposure (area under the curve may be increased 1.5 times higher than normal).

CrCl 30 to 50 mL/minute: No dosage adjustment necessary unless patient receiving concomitant dronedarone or oral ketoconazole, then reduce dabigatran to 75 mg twice daily. Use with caution in moderate renal impairment due to risk for increased dabigatran exposure (area under the curve may be increased 3 times higher than normal), particularly if patient is also of advanced age. In patients with moderate-to-severe chronic kidney disease, dose reduction may be considered although safety and efficacy of this approach has not been established (AHA/ACC/HRS [January 2014]).

CrCl 15 to 30 mL/minute: 75 mg twice daily unless patient receiving concomitant P-gp inhibitor, then avoid concurrent use. Note: Patients with CrCl <30 mL/minute were excluded from the RE-LY trial (Connolly 2009). Dose based on pharmacokinetic data; safety and efficacy has not been established. Per the American College of Chest Physicians, dabigatran is considered contraindicated in patients with severe renal impairment (CrCl ≤30 mL/minute) (Guyatt 2012).

CrCl <15 mL/minute: There are no dosage recommendations provided in the manufacturer's labeling (has not been studied). Per the American College of Chest Physicians, dabigatran is considered contraindicated in patients with severe renal impairment (CrCl ≤30 mL/minute) (Guyatt 2012). In addition, the AHA/ACC/HRS does not recommend dabigatran for patients with AF and end-stage chronic kidney disease (January 2014).

Hemodialysis: There are no dosage recommendations provided in the manufacturer’s labeling (has not been studied). The AHA/ACC/HRS does not recommend dabigatran for patients with AF on hemodialysis (January 2014). Note: Hemodialysis removes ~57% over 4 hours

Canadian labeling:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 50 mL/minute: No dosage adjustment is generally necessary; use with caution in moderate renal impairment due to risk for increased dabigatran exposure (area under the curve may be increased 3 times higher than normal), particularly if patient is also of advanced age. In patients with moderate to severe chronic kidney disease, dose reduction may be considered although safety and efficacy of this approach has not been established (AHA/ACC/HRS [January 2014]).

CrCl <30 mL/minute: Use is contraindicated.

Postoperative thromboprophylaxis:

US labeling:

CrCl >30 mL/minute: No dosage adjustment necessary unless patient has a CrCl <50 mL/minute and is receiving concomitant P-gp inhibitors, then avoid coadministration.

CrCl ≤30 mL/minute: There are no dosage recommendations provided in the manufacturer’s labeling (has not been studied). Patients with CrCl <30 mL/minute (Eriksson 2007; Eriksson 2011) were excluded from the respective clinical trials.

Hemodialysis: There are no dosage recommendations provided in the manufacturer’s labeling (has not been studied).

Canadian labeling:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 50 mL/minute: Initial: 75 mg given 1 to 4 hours after completion of surgery and establishment of hemostasis; Maintenance: 150 mg once daily unless patient receiving concomitant verapamil, then consider reducing dabigatran to 75 mg once daily.

CrCl <30 mL/minute: Use is contraindicated.

Alternate recommendations: Geriatric patients ≥65 years: CrCl <30 mL/minute: Avoid use due to increased risk of bleeding (Beers Criteria [AGS 2015]).

Dosing: Hepatic Impairment

US labeling: There are no dosage adjustments provided in manufacturer’s labeling; consistent changes in exposure or pharmacodynamics were not observed in a study of patients with moderate impairment.

Canadian labeling: There are no dosage adjustments provided in manufacturer’s labeling; no change in exposure was seen in a study of patients with moderate impairment (Child-Pugh class B). Use is not recommended in patients with severe impairment (Child-Pugh class C), acute liver disease, or with increased liver enzymes ≥2 times ULN.

Dosing: Obesity

The International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of dabigatran (and other direct oral anticoagulants) in patients with a BMI >40 kg/m2 or weight >120 kg due to the lack of clinical data in this population. If used in a patient with a BMI >40 kg/m2 or weight >120 kg, ISTH suggests measuring peak and trough levels using ecarin clotting time or dilute thrombin time with appropriate calibration or mass spectrometry. If drug level is below the expected range, ISTH suggests changing to a vitamin K antagonist rather than adjusting the dose of dabigatran (ISTH [Martin 2016]).

Administration

Oral: Administer with a full glass of water without regard to meals; however, if dyspepsia occurs, consider administration with meals. Do not break, chew, or open capsules, as this will lead to 75% increase in absorption and potentially serious adverse reactions.

Storage

Blister: Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Dispense and store in original package to protect from moisture.

Bottle: Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Dispense and store in original manufacturer’s bottle to protect from moisture; discard 4 months after opening original container.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Amiodarone: May increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by U.S. vs. Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Antacids: May decrease the serum concentration of Dabigatran Etexilate. Management: Dabigatran etexilate Canadian product labeling recommends avoiding concomitant use with antacids for 24 hours after surgery. In other situations, administer dabigatran etexilate 2 hours prior to antacids. Monitor clinical response to dabigatran therapy. Consider therapy modification

Anticoagulants: Dabigatran Etexilate may enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Exceptions: Acenocoumarol; Warfarin. Avoid combination

Antiplatelet Agents (P2Y12 Inhibitors): May enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Antiplatelet Agents (P2Y12 Inhibitors) may increase the serum concentration of Dabigatran Etexilate. Specifically, clopidogrel may increase dabigatran serum concentrations. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Aspirin: May enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling states that low dose aspirin could be considered, but the use of antiplatelets are not recommended for stroke prevention in patients with atrial fibrillation. Consider therapy modification

AtorvaSTATin: May decrease the serum concentration of Dabigatran Etexilate. Monitor therapy

Clarithromycin: May increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by U.S. vs. Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Dronedarone: May increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by U.S. vs. Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by U.S. vs. Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

NSAID (Nonselective): May enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with p-glycoprotein inducers when possible. Closely monitor for decreased levels/effects of dabigatran if concomitantly administering p-glycoprotein inducers, particularly strong inducers. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Proton Pump Inhibitors: May decrease serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

QuiNIDine: May increase the serum concentration of Dabigatran Etexilate. Management: Consider giving dabigatran 2 hrs before oral quinidine; other dose reductions may be needed. Specific recommendations vary by U.S. vs Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sulfinpyrazone: May enhance the anticoagulant effect of Dabigatran Etexilate. Avoid combination

Thrombolytic Agents: May enhance the anticoagulant effect of Dabigatran Etexilate. Management: Carefully monitor for bleeding. Dabigatran Canadian labeling recommends avoiding use with thrombolytic agents. Consider avoiding alteplase treatment of acute ischemic stroke in patients receiving dabigatran (see full drug monograph for details). Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Ticagrelor: May enhance the anticoagulant effect of Dabigatran Etexilate. Ticagrelor may increase the serum concentration of Dabigatran Etexilate. Management: Monitor closely for signs and symptoms of bleeding if dabigatran is used in combination with ticagrelor. Canadian product labeling recommends avoiding the concomitant use of these agents while US labeling makes no such recommendation. Consider therapy modification

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Verapamil: May increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Consider giving dabigatran 2 hrs before oral verapamil; other dose reductions may be needed. Specific recommendations vary by US vs Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Adverse Reactions

>10%:

Gastrointestinal: Gastrointestinal symptoms (eg, dyspepsia, gastritis-like symptoms; 25% to 40%; dose dependent)

Hematologic & oncologic: Hemorrhage (11% to 19%; major hemorrhage: ≤3%; hemorrhage [life-threatening]: 2%)

1% to 10%:

Gastrointestinal: Dyspepsia (8%; includes abdominal pain, abdominal discomfort, epigastric discomfort), gastrointestinal hemorrhage (≤6%; major: ≤2%), gastritis (3%; includes gastroesophageal reflux disease, esophagitis, erosive gastritis, gastrointestinal hemorrhage, hemorrhagic gastritis, gastrointestinal ulcer)

<1% (Limited to important or life-threatening): Allergic edema, anaphylactic shock, anaphylaxis, catheter site hemorrhage, cerebrovascular accident (in patients with prosthetic heart valve), decreased hematocrit, epidural hematoma (with spinal puncture or spinal/epidural anesthesia), esophageal ulcer, genitourinary tract hemorrhage, hemarthrosis, hypersensitivity reaction, intracranial hemorrhage (includes hemorrhagic stroke, subarachnoid bleeding, subdural hematoma), muscle hemorrhage, myocardial infarction, pericardial effusion (severe hemorrhagic; occurred postoperatively in patients with prosthetic heart valve; required intervention for hemodynamic compromise), retroperitoneal hemorrhage, spinal hematoma (with spinal puncture or spinal/epidural anesthesia), thrombocytopenia, thromboembolism (in patients with prosthetic heart valve), transient ischemic attacks (in patients with prosthetic heart valve)

ALERT: U.S. Boxed Warning

Thrombotic events:

Premature discontinuation of dabigatran increases the risk of thrombotic events. If anticoagulation with dabigatran is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

Spinal/Epidural hematoma:

Epidural or spinal hematomas may occur in patients treated with dabigatran who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery; optimal timing between the administration of dabigatran and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: The most common complication is bleeding, sometimes fatal bleeding. Risk factors for bleeding include concurrent use of drugs that increase the risk of bleeding (eg, antiplatelet agents, heparin), renal impairment, and elderly patients (especially if low body weight). Monitor for signs and symptoms of bleeding; discontinue in patients with active pathological bleeding. Important: Idarucizumab is commercially available for dabigatran reversal; protamine and vitamin K do not reverse or impact anticoagulant effects of dabigatran. Dabigatran is dialyzable (~57% removed over 4 hours); however, supporting data are limited for utilizing this method. The use of a PCC (Cofact, not available in the US) has been shown to be ineffective for dabigatran reversal (Eerenberg 2011); however, the manufacturer does suggest that PCC or recombinant factor VIIa may be considered, although their use has not been evaluated in clinical trials. Platelet concentrates should be considered when thrombocytopenia is present or long-acting antiplatelet drugs have been used. FEIBA NF was reported to have been effective in rapidly reversing the anticoagulant effects of dabigatran in one case study (Dager 2013).

Disease-related concerns:

• Hepatic impairment: Use in patients with moderate hepatic impairment (Child-Pugh class B) demonstrated large inter-subject variability; however, no consistent change in exposure or pharmacodynamics was seen. Patients with active liver disease were excluded from the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial (Connolly 2009). The Canadian labeling recommends avoiding use in patients with severe impairment (Child-Pugh class C), acute liver disease, or with increased liver enzymes ≥2 times ULN.

• Renal impairment: Evaluate renal function prior to and during therapy, particularly if used in patients with any degree of preexisting renal impairment or in any condition that may result in a decline in renal function (eg, hypovolemia, dehydration, concomitant use of medications with a potential to affect renal function); dabigatran concentrations may increase in any degree of renal impairment and increase the risk of bleeding. In moderate impairment, serum concentrations may increase 3 times higher than normal compared to concentrations in patients with normal renal function. However, in patients with nonvalvular AF, US labeling only requires dosage reduction in patients with severe renal impairment (CrCl 15 to 30 mL/minute) and dosing recommendations cannot be provided in patients with CrCl <15 mL/minute. According to the AHA/ACC/HRS, may consider dose reduction in patients with nonvalvular AF and moderate-to-severe chronic kidney disease (CKD), although safety and efficacy of this approach has not been established; dabigatran is not recommended for patients with AF and end-stage CKD or on hemodialysis (AHA/ACC/HRS [January 2014]). Per the American College of Chest Physicians, dabigatran is considered contraindicated in patients with severe renal impairment (CrCl ≤30 mL/minute) (Guyatt 2012). The Canadian labeling also contraindicates use in severe renal impairment (CrCl <30 mL/minute) and recommends indication-specific dose reductions in patients with moderate impairment (CrCl 30-50 mL/minute). Discontinue therapy in any patient who develops acute renal failure.

• Valvular heart disease: Use is not recommended in patients with valvular heart disease, including the presence of a bioprosthetic heart valve (has not been evaluated); use is contraindicated in patients with mechanical prosthetic heart valves. In addition to several case reports (Chu 2012; Price 2012; Stewart 2012), one clinical trial reported significantly more thromboembolic events (valve thrombosis, stroke, TIA, and MI) and an excess of major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) in patients with mechanical prosthetic heart valves receiving dabigatran compared to those receiving adjusted-dose warfarin.

Concurrent drug therapy issues:

• Antithrombotic agents: Due to an increased risk of bleeding, avoid use, if possible, with other direct thrombin inhibitors (eg, bivalirudin), unfractionated heparin or heparin derivatives, low molecular weight heparins (eg, enoxaparin), fondaparinux, thienopyridines (eg, clopidogrel), GPIIb/IIIa antagonists (eg, eptifibatide), aspirin, coumarin derivatives, sulfinpyrazone, and ticagrelor. NSAIDs should be used cautiously. Appropriate doses of unfractionated heparin may be used to maintain catheter patency.

• Drug/drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult Drug Interactions database for more detailed information.

Special populations:

• Elderly: Use with extreme caution or consider other treatment options. No dosage adjustment is recommended in the US manufacturer’s labeling based on age alone (unless renal impairment coexists); however, risk of bleeding increases with age. Numerous reports of excess anticoagulation, including fatalities, have been observed with use in older adults (ISMP [Smetzer 2012]; ISMP [Smetzer 2015]). In particular, an increased risk of GI bleeding has been observed in patients ≥75 years of age despite similar efficacy observed with dabigatran in the elderly as compared to warfarin-treated patients (Graham 2015; Sharma 2015). Dabigatran is associated with more than a 5-fold variation in plasma concentrations in patients receiving the same dose, indicating a wide therapeutic range. Significant factors affecting increased dabigatran plasma concentrations have been found to be increasing age, decreased CrCl, lower body weight and female gender. Renal function was the predominant patient characteristic determining plasma concentrations, with age as the most important covariate (Reilly 2014). Depending on individual patient characteristics, particularly advanced age and potential for renal impairment, consider other treatment options, particularly in the US where lack of other available dosing options exist (ie, 110 mg dose) (Kalbalik 2015). The Canadian labeling includes recommendations for dose reductions in elderly patients (refer to Dosing).

Other warnings/precautions:

• Spinal or epidural hematoma: [US Boxed Warning]: Spinal or epidural hematomas may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients who are anticoagulated; may result in long-term or permanent paralysis. The risk of spinal/epidural hematoma is increased with the use of indwelling epidural catheters, concomitant administration of other drugs that affect hemostasis (eg, NSAIDS, platelet inhibitors, other anticoagulants), in patients with a history of traumatic or repeated epidural or spinal punctures, or a history of spinal deformity or spinal surgery. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the optimal timing between the administration of dabigatran and neuraxial procedures is not known. Monitor frequently for signs and symptoms of neurologic impairment (eg, midline back pain, numbness/weakness of legs, bowel/bladder dysfunction); prompt diagnosis and treatment are necessary. In patients who are anticoagulated or pharmacologic thromboprophylaxis is anticipated, assess risks versus benefits prior to neuraxial interventions. Also see ‘Invasive or surgical procedures’.

• Invasive or surgical procedures: If possible, discontinue dabigatran 1-2 days (CrCl ≥50 mL/minute) or 3-5 days (CrCl <50 mL/minute) before invasive or surgical procedures due to the increased risk of bleeding; consider longer times for patients undergoing major surgery, spinal puncture, or insertion of a spinal or epidural catheter or port. If surgery cannot be delayed, the risk of bleeding is elevated; weigh risk of bleeding with urgency of procedure. Bleeding risk can be assessed by the ecarin clotting time (ECT) if available; if ECT is not available, use of aPTT may provide an approximation of dabigatran’s anticoagulant activity. Use a specific reversal agent (eg, idarucizumab) in case of emergency surgery or urgent procedures when reversal of anticoagulant effect of dabigatran is needed. Following peri-spinal procedures, the Canadian labeling recommends initiating therapy after hemostasis is obtained and no sooner than 2 hours following puncture or catheter removal; use is not recommended in patients undergoing anesthesia with post-operative indwelling epidural catheters.

• Discontinuation of therapy: [US Boxed Warning]: Upon premature discontinuation, the risk of thrombotic events is increased. If dabigatran must be discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider the use of another anticoagulant during the time of interruption.

Monitoring Parameters

Routine monitoring of coagulation tests not required. However, the measurement of activated partial thromboplastin time (aPTT) (values >2.5 x control may indicate overanticoagulation), ecarin clotting test (ECT) if available, or thrombin time (TT; most sensitive) may be useful to determine presence of dabigatran and level of coagulopathy; CBC with differential; renal function prior to initiation and periodically as clinically indicated (ie, situations associated with a decline in renal function) and according to the AHA/ACC/HRS, at least annually in all patients (January 2014)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. An ex vivo human placenta dual perfusion model illustrated that dabigatran crossed the placenta at term; dabigatran etexilate mesylate (prodrug) had limited placental transfer (Bapat 2014). Data are insufficient to evaluate the safety of direct thrombin inhibitors during pregnancy; use of oral agents during pregnancy should be avoided (Guyatt 2012). Consider the risks of bleeding and stroke if used during pregnancy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, nausea, heartburn. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that you cannot stop), severe dizziness, syncope, a fall hitting the head, signs of stroke (strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision), illogical thinking, loss of strength or energy, severe headache, edema, or severe adominal pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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