Dabigatran Etexilate

Dosage Forms

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

Capsule, Oral:

Pradaxa: 75 mg

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

Pradaxa: 110 mg, 150 mg [contains fd&c blue #2 (indigotine)]

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

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid; initially slow postoperatively

Distribution

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

Protein Binding

35%

Use in Specific Populations

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 (PE) in patients who have been treated with a parenteral anticoagulant for 5 to 10 days; to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

Nonvalvular atrial fibrillation: Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Venous thromboembolism prophylaxis in total hip arthroplasty: Prophylaxis of DVT and PE in patients who have undergone total hip arthroplasty.

Use: Off Label

Venous thromboembolism prophylaxis in total knee arthroplastybyes

Data from a randomized, double-blind, non-inferiority trial in patients undergoing total knee arthroplasty (TKA) supports the use of dabigatran for postoperative thromboprophylaxis Eriksson 2007. Additional trials may be necessary to further define the role of dabigatran in this setting.

Based on the 2012 American College of Chest Physicians Evidence-Based Clinical Practice guidelines for antithrombotic therapy and prevention of thrombosis, dabigatran is effective and recommended for the prevention of deep vein thrombosis or pulmonary embolism in patients undergoing TKA.

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 strong P-glycoprotein inhibitors (eg, oral ketoconazole); concomitant use with other anticoagulants including unfractionated heparin (except when used to maintain central venous or arterial catheter patency or during catheter ablation for atrial fibrillation), 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

Dosage and Administration

Dosing: Adult

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Oral: 150 mg twice daily. Note: Patients who are particularly concerned about the risk of bleeding or those assessed to be at increased risk of bleeding, may be considered candidates for an alternative lower dose regimen of 110 mg twice daily (off-label dose) (Eikelboom 2013; Manning 2018; Mannucci 2013).

Post-percutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation (off label): Oral: 110 mg or 150 mg twice daily; administer with an appropriate antithrombotic regimen including clopidogrel (preferred P2Y12 inhibitor in this situation) with or without aspirin, depending on the risks for thrombosis and bleeding; dabigatran dose depends on patient specific thrombotic and bleeding risk factors (ACC/AHA [January 2014, January 2019]); Cannon 2017; Sarafoff 2018).

Venous thromboembolism:

Deep vein thrombosis and/or pulmonary embolism (treatment): Note: Dabigatran has not been studied in patients with active cancer; another anticoagulant is likely more appropriate (ASCO [Key 2019]; Kearon 2016).

After at least 5 days of initial therapy with a parenteral anticoagulant, transition to dabigatran in hemodynamically stable patients:

Oral: 150 mg twice daily.

Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and is dependent on many factors, such as presence of provoking events, patient risk factors for recurrence and bleeding, and individual preferences.

Provoked venous thromboembolism: 3 months (provided provoking risk factor is no longer present) (Kearon 2016).

Unprovoked pulmonary embolism or deep vein thrombosis (proximal or isolated distal): ≥3 months depending on risk of venous thromboembolism (VTE) recurrence and bleeding (Baglin 2012; Kearon 2012; Kearon 2016).

Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.

Venous thromboembolism prophylaxis in total hip arthroplasty or total knee arthroplasty (alternative to low molecular weight heparin): Oral:

Total hip arthroplasty: Initial: Oral: 110 mg given 1 to 4 hours after completion of surgery and establishment of hemostasis or when dabigatran is not initiated on day of surgery, give an initial dose of 220 mg after hemostasis has been achieved; then continue maintenance dose of 220 mg once daily for a minimum of 10 to 14 days. Optimal duration of prophylaxis is unknown but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days; some experts suggest a duration in the higher end of range (30 days) for ttotal hip arthroplasty (Eikelboom 2001; Falck-Ytter 2012; Pai 2018).

Total knee arthroplasty (off-label use): Initial: Oral: 110 mg given 1 to 4 hours after completion of surgery and establishment of hemostasis or when dabigatran is not initiated on day of surgery, give an initial dose of 220 mg after hemostasis has been achieved; then continue maintenance dose of 220 mg once daily (Eriksson 2007a) for a minimum of 10 to 14 days; may be extended up to 35 days. Optimal duration of prophylaxis is unknown. Some experts suggest a duration in the lower end of the range (10 to 14 days) for total knee arthroplasty (Eikelboom 2001; Falck-Ytter 2012; Pai 2018).

Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail:

Transitioning from another anticoagulant to dabigatran:

Transitioning from low molecular weight heparin or fondaparinux (therapeutic dose) to dabigatran:

General transition recommendation: Initiate dabigatran within 2 hours prior to the time of the next scheduled dose of the parenteral anticoagulant.

Venous thromboembolism initial treatment (alternate recommendation): For acute VTE, some experts start dabigatran within 6 to 12 hours after the last dose of a twice daily low molecular weight heparin regimen and within 12 to 24 hours after a once daily regimen (Hull 2018).

Transitioning from unfractionated heparin continuous infusion to dabigatran: Start dabigatran when unfractionated heparin is stopped (consult local protocol if aPTT is above or below the target range).

Transitioning from warfarin to dabigatran: Discontinue warfarin and initiate dabigatran when the INR is <2.

Transitioning from dabigatran to another anticoagulant:

Transitioning from dabigatran to low molecular weight heparin, fondaparinux, or unfractionated heparin continuous infusion: After the last dose of dabigatran, wait 12 hours (CrCl ≥30 mL/minute) or 24 hours (CrCl <30 mL/minute) before starting a parenteral anticoagulant.

Transitioning from dabigatran to warfarin: One option is to stop dabigatran, start warfarin the same day, and bridge with a parenteral anticoagulant until the desired INR is reached (Leung 2019). An alternative is to overlap the two agents. If this is done, the timing of warfarin initiation is based on CrCl as outlined below:

CrCl >50 mL/minute: Initiate warfarin 3 days before discontinuing dabigatran.

CrCl 30 to 50 mL/minute: Initiate warfarin 2 days before discontinuing dabigatran.

CrCl 15 to 30 mL/minute: Initiate warfarin 1 day before discontinuing dabigatran.

CrCl <15 mL/minute: Dabigatran should not be used.

Note: Dabigatran can elevate the INR, complicating interpretation if overlapped with warfarin. To minimize interference, check INR near the end of dabigatran dosing interval. Warfarin's effect on the INR will be better reflected only after dabigatran has been stopped for ≥2 days.

Transitioning between direct oral anticoagulants: Start the new direct oral anticoagulant (DOAC) when the next dose of the previous DOAC was scheduled to be given (Leung 2019).

Transitioning between anticoagulants in the perioperative setting: See 2017 AHA Scientific Statement, "Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting."

Dosing adjustment with concomitant medications:

Deep vein thrombosis and pulmonary embolism (treatment) or venous thromboembolism prophylaxis in total hip arthroplasty or total knee arthroplasty:

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

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

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

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

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

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

Dosing: Geriatric

Deep vein thrombosis and/or pulmonary embolism, nonvalvular atrial fibrillation (to prevent stroke and systemic embolism), venous thromboembolism prophylaxis: Oral: Numerous reports of excess anticoagulation, including fatalities, have been observed with use in older adults (ISMP [Smetzer 2012]; ISMP [Smetzer 2015]).

Patients >65 years: Refer to adult dosing. No dosage adjustment required unless renal impairment exists; however, risk of bleeding increases with age.

Patients ≥75 years: Use with extreme caution or consider other treatment options (see Warnings/Precautions) (Beers Criteria [AGS 2019]; ISMP [Smetzer 2012]; ISMP [Smetzer 2015]). No dosage adjustment provided in manufacturer’s labeling based on age alone (unless renal impairment coexists); however, risk of bleeding increases with age.

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

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

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

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

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

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

Cobicistat: May increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

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 renal function and indication for dabigatran. Refer to full monograph for details. 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

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

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

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Fluconazole: May enhance the anticoagulant effect of Dabigatran Etexilate. Monitor therapy

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. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Consider therapy modification

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

Ibrutinib: May enhance the anticoagulant effect of Dabigatran Etexilate. Ibrutinib may increase the serum concentration of Dabigatran Etexilate. Monitor therapy

Inotersen: May enhance the anticoagulant effect of Anticoagulants. 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 renal function and indication for dabigatran. Refer to full monograph for details. Consider therapy modification

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

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

Lovastatin: May enhance the anticoagulant effect of Dabigatran Etexilate. Monitor therapy

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

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination

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

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (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

Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. 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 whenever possible. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Exceptions: Dronedarone; Ketoconazole (Systemic); Ritonavir. Monitor therapy

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

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

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

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

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

Simvastatin: May enhance the anticoagulant effect of Dabigatran Etexilate. Monitor therapy

Sodium Zirconium Cyclosilicate: May decrease the serum concentration of Dabigatran Etexilate. Management: Separate the administration of sodium zirconium cyclosilicate and dabigatran by at least 2 hours. Consider therapy modification

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

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

Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Monitor therapy

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: Carefully consider the anticipated risks and benefits of this combination. Increase monitoring for evidence of bleeding if these agents are combined and consider avoiding the use of this combination in the presence of reduced renal function. Consider therapy modification

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

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

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

Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

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%, postmarketing, and/or case reports: Allergic edema, anaphylactic shock, anaphylaxis, angioedema, 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)

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: The most common complication is bleeding, including severe and potentially 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). Discontinue in patients with active pathological bleeding. Important: Idarucizumab is commercially available and is the most effective agent 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. Depending on the bleeding severity, activated oral charcoal should be considered if ingestion occurred within 1 to 2 hours of presentation. The following alternative options may also be considered depending on specific clinical scenario: 4-factor unactivated prothrombin concentrate (PCC) (eg, Kcentra) or 4-factor activated prothrombin complex concentrate (aPCC) (eg, FEIBA). Some studies and case reports have shown moderate success in correcting coagulation tests with some of these agents; however, correction of coagulation tests does not imply reversal of the anticoagulation effect of the medication (AHA/ASA [Hemphill 2015; EHRA [Heidbuchel 2015]; NCS/SCCM [Frontera 2016]). Platelet concentrates should be considered when thrombocytopenia is present or long-acting antiplatelet drugs have been used.
• Thromboembolic events: [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. In patients with non-valvular atrial fibrillation who had an acute ischemic stroke while receiving a direct oral anticoagulant (DOAC) (eg, dabigatran), guidelines generally support withholding oral anticoagulation until 1 to 2 weeks after the ischemic stroke (time frame may vary with shorter times for transient ischemic attack or small, non-disabling stroke and longer times for moderate to severe stroke) (AHA [Raval 2017]; AHA/ASA [Kernan 2014]; EHRA [Heidbuchel 2015]).

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Evaluate the risk versus benefit of possible decreased drug absorption against the consideration of alternative anticoagulants; efficacy may be decreased after gastric bypass or sleeve gastrectomy. Apixaban’s absorption appears to occur primarily in the small intestine. Peak apixaban concentrations and total AUC are reduced by 60% when released in the distal small intestine and further reduced to 90% and 84%, respectively, when released in the ascending colon (Frost 2013).

– Rivaroxaban: Peak concentrations and AUC were reduced by 56% and 29%, respectively, when released into the proximal small intestine and further reduced in the distal small intestine or colon (manufacturer labeling 2019). Patients with significantly altered GI tracts are represented by small series and case reports (Hakeam 2017). The available data are conflicting for absorption alterations, derived from small populations, and underrepresent individual direct oral anticoagulants and surgeries (Kroll 2017; Kroll 2018; Lee 2013; Rottenstreich 2018).

• 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).
• 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. May consider dose reduction in patients with nonvalvular AF and moderate to severe chronic kidney disease (CKD; CrCl 15 to 30 mL/minute); dabigatran is not recommended for patients with AF and end-stage CKD or on hemodialysis (AHA/ACC/HRS [January 2014]). Dabigatran is considered contraindicated in patients with severe renal impairment (CrCl ≤30 mL/minute) (ACCP [Guyatt 2012]). 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; use is contraindicated in patients with mechanical prosthetic heart valves. In addition to several case reports, one clinical trial reported significantly more thromboembolic events and an excess of major bleeding in patients with mechanical prosthetic heart valves receiving dabigatran compared to those receiving adjusted-dose warfarin (Chu 2012; Price 2012; Stewart 2012). Avoid use of DOACs in patients with moderate to severe mitral stenosis (AHA/ACC/HRS [January 2019]). However, a DOAC may be used in patients with AF and native aortic valve disease, tricuspid valve disease, or mitral regurgitation when anticoagulation is required (AHA/ACC/HRS [January 2014, 2019]; AHA/ACC [Nishimura 2017]).

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 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 (Kalabalik 2015).

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.

Monitoring Parameters

CBC, aPTT, PT, serum creatinine, and liver function tests prior to initiation, when clinically indicated, and at least annually (AHA/ACC/HRS [January 2014, 2019]; Leung 2019); signs of bleeding.

Routine coagulation testing is not required or necessary for direct oral anticoagulants (DOACs). There are currently no FDA-approved assays or calibration reagents available.

In clinical situations when assessment of the anticoagulant effect is useful (eg, acute care, periprocedural settings, absorption), evaluating a recent creatinine clearance and time since the last dose was ingested is usually sufficient for guiding clinical decisions. The following coagulation testing may also be helpful in quantitative assessments to exclude clinically relevant dabigatran levels: Dilute thrombin time, ecarin clotting time, or ecarin chromogenic assays (ACC [Tomaselli 2017]; AHA [Raval 2017]; Leung 2019).

If a sensitive reagent is used, normal partial thromboplastin time usually excludes clinically relevant serum concentrations although a therapeutic range has not been established for quantification. Thrombin time is highly sensitive and a normal value excludes clinically relevant levels (ACC [Tomaselli 2017]; AHA [Raval 2017]).

Pregnancy

Pregnancy Considerations

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). Use of direct acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth (Cohen 2016).

Information related to the use of dabigatran etexilate in pregnancy is limited (Beyer-Westendorf 2016; Lameijer 2018). Data are insufficient to evaluate the safety of direct acting oral anticoagulants during pregnancy (Guyatt 2012) and use in pregnant females is not recommended (Regitz-Zagrosek [ESC 2018]). Agents other than dabigatran etexilate are preferred for the treatment of AF or VTE in pregnant patients (Kearon 2016; Lip 2018; Regitz-Zagrosek [ESC 2018]). Patients should be switched to an alternative anticoagulant if pregnancy occurs during therapy. Fetal monitoring that includes evaluations for fetal bleeding and assessments for risk of preterm delivery are recommended if the direct acting oral anticoagulant is continued (Cohen 2016).

Until safety data are available, adequate contraception is recommended during therapy for females of childbearing potential. Females planning a pregnancy should be switched to alternative anticoagulants prior to conception (Cohen 2016).

Patient Education

What is this drug used for?

• It is used to thin the blood so that clots will not form.
• It is used to treat blood clots.

Frequently reported side effects of this drug

• Abdominal pain
• Nausea
• Heartburn

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bleeding like 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 severe or persistent bleeding.
• Severe dizziness
• Passing out
• A fall hitting the head
• Severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes
• Confusion
• Loss of strength and energy
• Severe headache
• Edema
• Severe abdominal pain
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.