Generic Name: Dabigatran Etexilate Mesylate
Class: Direct Thrombin Inhibitors
Chemical Name: N - [[2 - [[[4 - (Aminoiminomethyl)phenyl]amino]methyl] - 1 - methyl - 1H - benzimidazol - 5 - yl]carbonyl] - N - 2 - pyridinyl - β - alanine
Molecular Formula: C25H25N7O3C34H41N7O5C34H41N7O5•CH4O3S
CAS Number: 211914-51-1

Warning(s)

  • Risk of Thrombosis Following Premature Discontinuance of Anticoagulation
  • Premature discontinuance of any oral anticoagulant, including dabigatran, increases risk of thrombotic events.1

  • If discontinuance is required for reasons other than pathologic bleeding or completion of a course of therapy, consider coverage with an alternative anticoagulant.1 (See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Cautions.)

  • Spinal/Epidural Hematoma Risk
  • Risk of epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, in patients who are anticoagulated and also receiving neuraxial (spinal/epidural) anesthesia or spinal puncture.1

  • Risk increased by use of indwelling epidural catheters or by concomitant use of drugs affecting hemostasis (e.g., NSAIAs, platelet-aggregation inhibitors, other anticoagulants).1

  • Risk also increased by history of traumatic or repeated epidural or spinal puncture, spinal deformity, or spinal surgery.1

  • Monitor frequently for signs and symptoms of neurologic impairment and treat urgently if neurologic compromise noted.1

  • Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for anticoagulant therapy.1 (See Spinal/Epidural Hematoma under Cautions.)

Introduction

Anticoagulant; a synthetic reversible direct thrombin inhibitor.1 2 10 13

Uses for Pradaxa

Embolism Associated with Atrial Fibrillation

Reduction in risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 2 3 5 18 20 21 30 32

The American College of Chest Physicians (ACCP), ACC, AHA, and other experts recommend antithrombotic therapy in all patients with paroxysmal, persistent, or permanent atrial fibrillation, unless such therapy is contraindicated.19 20 21 39 988 989 990 999 1007

Choice of antithrombotic therapy is based on patient's level of risk for stroke.988 989 990 999 1007 In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients at moderate to high risk of stroke, while aspirin is recommended in low-risk patients and those with contraindications to oral anticoagulant therapy.988 989 990 999 1007 1017 Patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or recent exacerbation of CHF.990 999 1007 In addition, female sex is considered an important risk factor for stroke in patients with atrial fibrillation, particularly in patients ≥75 years of age.1017

Slideshow: HealthQuiz - Basics About Stroke Signs and Symptoms

Antithrombotic therapy in patients with atrial flutter generally managed in the same manner as in patients with atrial fibrillation.999 1007

ACCP and other experts suggest the use of dabigatran as an alternative to warfarin in selected patients with atrial fibrillation at increased risk of stroke (e.g., warfarin-naive patients, those with difficulty maintaining therapeutic INRs with warfarin, those taking multiple drugs that may interact with warfarin).18 19 20 30 35 39 41 69 70 71 1007 Warfarin may continue to be preferred in certain patients such as those with severe renal insufficiency or liver disease, a history of dyspepsia or GI ulcer, hemodynamically important valvular heart disease or a prosthetic heart valve, and in those already achieving excellent anticoagulation control with warfarin (e.g., INR in therapeutic range >70% of the time).18 20 39 69 70 71 73

Relative efficacy and safety of dabigatran and other newer oral anticoagulants (e.g., apixaban, rivaroxaban) remains to be fully elucidated.66 67 68 70 989

AHA and ASA state that apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in selected women with paroxysmal or permanent atrial fibrillation and certain risk factors who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (Clcr <15 mL/minute),1038 lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function).1017

When selecting an appropriate anticoagulant, consider individual patient's risks of stroke and bleeding; patient compliance, preference, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; availability of facilities to monitor INR; and degree of current INR control in patients already taking warfarin.8 18 19 21 22 68 69 70 71 72 988 989 999 1007

Do not use in patients with prosthetic mechanical heart valves; increased risk of serious thromboembolic and bleeding events observed in such patients receiving dabigatran compared with warfarin therapy.1 49 (See Patients with Prosthetic Heart Valves under Cautions.)

Efficacy and safety not evaluated in patients with other forms of valvular heart disease, including those with bioprosthetic heart valves; use not recommended in such patients.1 49

Treatment and Secondary Prevention of DVT and/or PE

Treatment and secondary prevention of acute DVT and/or PE following initial treatment with a parenteral anticoagulant for 5–10 days.1 74 75

Also used as extended therapy to reduce the risk of recurrent DVT and PE in patients treated previously for the acute thromboembolic event.1 74 75 76

Recommended by ACCP as an acceptable option for long-term anticoagulation in patients with proximal DVT and/or PE after initial treatment with a parenteral anticoagulant; however, pending additional data with dabigatran, ACCP suggests use of warfarin or LMWH over dabigatran in such patients.1005

Cardioversion of Atrial Fibrillation/Flutter

Has been used for prevention of stroke and systemic embolism in patients undergoing pharmacologic or electric cardioversion for atrial fibrillation/flutter.1007

Although warfarin is traditionally used, dabigatran is recommended by ACCP as an acceptable choice of anticoagulant for precardioversion anticoagulation in patients with atrial fibrillation lasting >48 hours or of unknown duration; prolonged precardioversion anticoagulation generally is not required in patients with atrial fibrillation of short duration (e.g., ≤48 hours).1007

Thromboprophylaxis in Major Orthopedic Surgery

Has been used for prevention of thromboembolism in patients undergoing major orthopedic surgery (total hip-replacement or total knee-replacement surgery).1003

ACCP considers dabigatran an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery; however, a low molecular weight heparin (LMWH) generally is preferred.1003 Dabigatran may be a reasonable choice when an LMWH is not available or cannot be used.1003

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance.1003

Cerebral Embolism

Has been used for secondary prevention of cardioembolic stroke in patients with TIAs or ischemic stroke and concurrent atrial fibrillation.1009 ACCP suggests use of dabigatran (150 mg twice daily) over warfarin in such patients.1009

Antiplatelet agents generally preferred over oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA.1009

Pradaxa Dosage and Administration

General

  • Routine laboratory coagulation monitoring not required.1 10 41 If necessary (e.g., in case of overdosage, emergency surgery), may use ecarin clotting time (ECT) or aPTT to assess anticoagulant effects of dabigatran; do not use INR.1 10 44 46 48

Administration

Oral Administration

Administer orally twice daily without regard to meals.1

Do not remove capsules from bottle or blister package until time of use.36 (See Stability.)

Swallow capsules whole with full glass of water; do not chew, break, or empty the contents of the capsule.1

Administer a missed dose as soon as it is remembered on same day; however, do not administer missed dose if it cannot be taken ≥6 hours before next scheduled dose.1

Dosage

Available as dabigatran etexilate mesylate; dosage expressed in terms of the prodrug, dabigatran etexilate.1

Adults

Embolism Associated with Atrial Fibrillation
Oral

Patients with Clcr >30 mL/minute: 150 mg twice daily.1

Treatment and Secondary Prevention of DVT/PE

Patients with Clcr >30 mL/minute: 150 mg twice daily.1

Determine optimum duration of anticoagulation based on individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors for thrombosis, presence of cancer, risk of bleeding).1005 In general, ACCP states that anticoagulant therapy should be continued beyond the acute treatment period for ≥3 months, and possibly longer in patients with a high risk of recurrence and low risk of bleeding.1005

Transferring from Warfarin

Discontinue warfarin and begin dabigatran when INR is <2.1

Transferring to Warfarin

Initiate warfarin before discontinuing dabigatran.1

For Clcr >50 mL/minute, begin warfarin 3 days before discontinuing dabigatran.1

For Clcr 31–50 mL/minute, begin warfarin 2 days before discontinuing dabigatran.1

For Clcr 15–30 mL/minute, begin warfarin 1 day before discontinuing dabigatran.1

For Clcr <15 mL/minute, recommendations not available.1

Dabigatran may affect INR; INR for monitoring warfarin is more reliable ≥2 days after dabigatran discontinuance.1

Transferring from Parenteral Anticoagulants

Initiate dabigatran within 2 hours prior to what would have been the time of the next scheduled intermittent parenteral anticoagulant dose.1

Initiate dabigatran at the time of discontinuance of the continuously administered parenteral anticoagulant.1

Transferring to Parenteral Anticoagulants

Initiate parenteral anticoagulants after discontinuing dabigatran.1

For Clcr ≥30 mL/minute, begin parenteral anticoagulant 12 hours after the last dose of dabigatran.1

For Clcr <30 mL/minute, begin parenteral anticoagulant 24 hours after the last dose of dabigatran.1

Managing Anticoagulation in Patients Requiring Invasive Procedures

When possible, withhold dabigatran prior to invasive or surgical procedures.1 (See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Cautions.) When surgery cannot be delayed, weigh increased risk of bleeding against urgency of intervention.1 Bleeding risk best assessed using ECT; aPTT may be used if ECT is unavailable.1

For Clcr ≥50 mL/minute, withhold dabigatran beginning 1–2 days prior to procedure.1

For Clcr <50 mL/minute, withhold dabigatran beginning 3–5 days prior to procedure.1

Consider withholding drug for longer periods in patients who may require complete hemostasis (e.g., prior to major surgery, spinal puncture, placement of spinal or epidural catheter or port).1

Prescribing Limits

Adults

Embolism Associated with Atrial Fibrillation
Oral

Maximum 150 mg twice daily.1

Special Populations

Renal Impairment

Embolism Associated with Atrial Fibrillation
Oral

In patients with Clcr 15–30 mL/minute, reduce dosage to 75 mg twice daily.1

In patients with Clcr <15 mL/minute or receiving hemodialysis, manufacturer states dosage recommendations not available.1

In patients with Clcr 30–50 mL/minute and receiving concomitant therapy with dronedarone or systemic ketoconazole, consider dosage reduction to 75 mg twice daily.1 Avoid such concomitant use in patients with severe renal impairment (Clcr 15–30 mL/minute).1 (See Drugs Affecting P-glycoprotein Transport under Interactions.)

Treatment and Secondary Prevention of DVT/PE
Oral

In patients with Clcr <30 mL/minute or receiving dialysis, manufacturer states dosage recommendations cannot be provided.1

Avoid concomitant use of P-glycoprotein inhibitors in patients with Clcr <50 mL/minute.1 (See Drugs Affecting P-glycoprotein Transport under Interactions.)

Hepatic Impairment

No specific dosage recommendations at this time.1

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Pradaxa

Contraindications

  • Active pathologic bleeding.1

  • History of serious hypersensitivity reaction to dabigatran (e.g., anaphylaxis, anaphylactic shock).1

  • Patients with mechanical prosthetic heart valves.1 49

Warnings/Precautions

Risk of Thrombosis Following Premature Discontinuance of Anticoagulation

Premature discontinuance of any oral anticoagulant, including dabigatran, increases risk of thrombotic events (e.g., stroke) in the absence of adequate alternative anticoagulation.1 (See Boxed Warning.) If discontinuance of dabigatran required for reasons other than pathologic bleeding or completion of a course of therapy, consider coverage with an alternative anticoagulant.1 (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.)

Spinal/Epidural Hematoma

Epidural or spinal hematoma reported with concurrent use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1 Such hematomas have resulted in neurologic injury, including long-term or permanent paralysis.1 (See Boxed Warning.)

To reduce risk of bleeding with concurrent use of dabigatran and neuraxial anesthesia or spinal puncture, carefully consider the pharmacokinetic profile of dabigatran in relation to timing of such procedures.1

Frequently monitor for signs and symptoms of neurologic impairment (e.g., midline back pain, numbness/tingling or weakness in lower limbs, bowel or bladder dysfunction).1 If spinal hematoma suspected, diagnose and treat immediately; consider spinal cord decompression.1

Bleeding

Dabigatran increases the risk of hemorrhage and may cause serious, sometimes fatal bleeding.1 In the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) study, life-threatening bleeding occurred at a rate of 1.5% per year with dabigatran etexilate 150 mg twice daily versus 1.8% per year with adjusted-dose (INR 2–3) warfarin.1

Risk factors for hemorrhage include concomitant use of other drugs that generally increase bleeding risk (e.g., antiplatelet agents, heparin, thrombolytic therapy, chronic use of NSAIAs) and renal impairment.1 Overdosage also may lead to hemorrhagic complications.1

Serious, sometimes fatal bleeding events reported during postmarketing experience.42 43 In a large observational study conducted by FDA, dabigatran therapy was associated with an increased risk of major GI bleeding, but a lower risk of intracranial hemorrhage, compared with warfarin.80 However, discrepant findings have been reported with regard to major GI bleeding in other studies; while this variability may be due to age differences in the patient populations studied, FDA is continuing to evaluate this disparity.80 At this time, FDA believes that the benefits of dabigatran continue to outweigh its risks when used appropriately.42 43 80 Carefully follow dosing recommendations, particularly in patients with renal impairment, to reduce risk of bleeding.1 42 43

Promptly evaluate manifestations of blood loss (e.g., decrease in hemoglobin/hematocrit, hypotension).1 Discontinue dabigatran in patients with active pathologic bleeding and institute appropriate therapy. 1

There is no specific reversal agent for dabigatran.1 10 68 If bleeding occurs, generally manage with supportive measures (e.g., drug discontinuance, maintenance of adequate diuresis, mechanical compression, surgical hemostasis, transfusion of blood products); may consider use of hemodialysis and procoagulant reversal agents if these measures fail.1 10

Dabigatran can be dialyzed; however, results will likely vary depending on individual patient-specific characteristics.1 10 46

Limited data suggest that procoagulant reversal agents such as anti-inhibitor coagulant complex (also known as activated prothrombin complex concentrate), factor VIIa (recombinant), or coagulation factor concentrates II, IX, or X may be considered for reversal of anticoagulation; however, efficacy not established in clinical studies.1 10 44 46 47 Protamine sulfate and vitamin K not expected to affect anticoagulant activity of dabigatran.1 10 Consider use of platelet concentrates in case of thrombocytopenia or if long-acting antiplatelet drugs have been used.1 Also may consider early (e.g., within 1–2 hours) use of activated charcoal in the event of an overdosage.10

Patients with Prosthetic Heart Valves

Contraindicated in patients with mechanical prosthetic heart valves.1 49 Findings from a randomized, controlled study (RE-ALIGN) indicate an increased risk of thromboembolic events (valve thrombosis, stroke, TIA, MI) and major bleeding (mainly postoperative pericardial effusions) with dabigatran compared with warfarin therapy in such patients.1 49 81

Promptly transition patients with a mechanical heart valve who are receiving dabigatran to another anticoagulant.49 (See Advice to Patients.) Patient should not discontinue dabigatran without guidance from a healthcare professional, as sudden discontinuance may increase risk of stroke and thromboembolism.1 49 (See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Cautions.)

Not evaluated in patients with other forms of valvular heart disease, including those with bioprosthetic heart valves; do not use in such patients.1 49

Drugs Affecting P-glycoprotein Transport

Inducers of P-glycoprotein transport (e.g., rifampin) reduce exposure to dabigatran; generally avoid concurrent use.1

Inhibitors of P-glycoprotein transport (e.g., dronedarone, systemic ketoconazole) may increase systemic exposure to dabigatran in patients with renal impairment; dosage reduction may be necessary.1 (See Renal Impairment under Dosage and Administration.) Avoid concomitant use of P-glycoprotein inhibitors in patients with severe renal impairment (Clcr 15–30 mL/minute) receiving dabigatran for stroke prophylaxis and in those with Clcr <50 mL/minute receiving dabigatran for treatment of venous thromboembolism.1 (See Drugs Affecting P-glycoprotein Transport under Interactions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactic reactions, anaphylactic shock, allergic edema, angioedema, urticaria, rash, and pruritus reported.1

Specific Populations

Pregnancy

Category C.1 ACCP recommends that dabigatran be avoided in pregnant women because of a lack of data and experience.1012

Safety and efficacy during labor and delivery not established; consider risks of bleeding and of stroke with dabigatran use in this setting.1

Lactation

Not known whether dabigatran is distributed into milk.1 Discontinue nursing or the drug.1 ACCP recommends the use of alternative anticoagulants during breastfeeding.1012

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

In a large clinical trial in patients with atrial fibrillation, 82% were ≥65 years of age, and 40% were ≥75 years of age.1 Risk of bleeding increases with age.1 28

Renal Impairment

Increased exposure and anticoagulant effects in patients with renal impairment.1 Assess renal function prior to initiation of therapy and periodically thereafter as clinically indicated.1 Dosage adjustments may be necessary depending on degree of renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Hemorrhage and gastritis-like symptoms (i.e., GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, GI ulcer).1 3

Interactions for Pradaxa

Does not inhibit or induce, and is not a substrate for, CYP isoenzymes.1 13

Substrate for the P-glycoprotein transport system.1 41

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely.1 2 6 13

Drugs Affecting P-glycoprotein Transport

P-glycoprotein inducers: Potential pharmacokinetic interaction (reduced dabigatran exposure); avoid concomitant use.1

P-glycoprotein inhibitors: Potential pharmacokinetic interaction (increased dabigatran exposure).1 Concomitant use of these drugs in patients with moderate renal impairment (Clcr 30–50 mL/minute) expected to further increase exposure.1 Dosage adjustments or avoidance of concomitant therapy may be required1 (see Specific Drugs under Interactions).

Drugs Affecting Hemostasis

Potentially increased risk of bleeding when used concomitantly with other agents that increase bleeding risk.1 Monitor for and promptly evaluate manifestations of bleeding (e.g., decrease in hemoglobin/hematocrit, hypotension).1 (See Bleeding under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Amiodarone

Increased dabigatran concentrations and AUC; increased renal clearance of dabigatran1

No meaningful alteration of amiodarone pharmacokinetics1

Dosage adjustment not necessary1

Patients with nonvalvular atrial fibrillation: Avoid concomitant use in patients with severe renal impairment (Clcr 15–30 mL/minute)1

Patients with venous thromboembolism: Avoid concomitant use in patients with Clcr <50 mL/minute1

Increased renal clearance of dabigatran may persist after amiodarone discontinuance due to long amiodarone half-life1

Anticoagulants, other

Increased risk of bleeding1

Monitor for bleeding manifestations1

Aspirin

Increased risk of bleeding1 6

Potential increased risk of bleeding with chronic NSAIA use1

Monitor for bleeding manifestations1

Large clinical trial in patients with atrial fibrillation demonstrated a 2-fold increase in major bleeding events/year with concomitant aspirin and dabigatran; similar to observed increased risk with concurrent aspirin and warfarin6

Atorvastatin

Pharmacokinetic interaction unlikely1 9

Clarithromycin

Pharmacokinetic interaction unlikely1

Dosage adjustments not necessary1

Patients with nonvalvular atrial fibrillation: Avoid concomitant use in patients with severe renal impairment (Clcr 15–30 mL/minute)1

Patients with venous thromboembolism: Avoid concomitant use in patients with Clcr<50 mL/minute1

Clopidogrel

Increased risk of bleeding1 6

Potentially increased dabigatran concentrations and AUC1

Monitor for bleeding manifestations1

Large clinical trial in patients with atrial fibrillation demonstrated a 2-fold increase in major bleeding events/year with concomitant clopidogrel and dabigatran; similar to observed increased risk with concurrent clopidogrel and warfarin6

Diclofenac

Pharmacokinetic interaction unlikely1

Potentially increased risk of bleeding with chronic NSAIA use1

Monitor for bleeding manifestations1

Digoxin

Pharmacokinetic interaction unlikely1

Dronedarone

Increased systemic exposure (70–140%) to dabigatran; lesser degree of increase (30–60%) when dronedarone administered 2 hours after dabigatran1

Patients with nonvalvular atrial fibrillation: Consider dosage reduction to 75 mg twice daily in patients with moderate renal impairment (Clcr 30–50 mL/minute); avoid concomitant use in patients with severe renal impairment (Clcr 15–30 mL/minute)1

Patients with venous thromboembolism: Avoid concomitant use in patients with Clcr <50 mL/minute1

Enoxaparin

Increased risk of bleeding1

No alteration in dabigatran systemic exposure or pharmacodynamic assessments (i.e., aPTT, ECT, thrombin time [TT]) when dabigatran started 24 hours after last dose of enoxaparin1

Monitor for bleeding manifestations1

Heparin

Increased risk of bleeding1

Monitor for bleeding manifestations1

Ketoconazole

Increased dabigatran concentrations and AUC1

Patients with nonvalvular atrial fibrillation: Consider dosage reduction to 75 mg twice daily in patients with moderate renal impairment (Clcr 30–50 mL/minute); avoid concomitant use in patients with severe renal impairment (Clcr 15–30 mL/minute)1

Patients with venous thromboembolism: Avoid concomitant use in patients with Clcr <50 mL/minute1

NSAIAs

Increased risk of bleeding with chronic NSAIA use1

Monitor for bleeding manifestations1

Pantoprazole

Decreased dabigatran concentrations and AUC1 6 34

Pharmacokinetics of pantoprazole not affected1 34

Interaction not considered clinically important1 6 7

Quinidine

Increased dabigatran concentrations and AUC1

Dosage adjustment not necessary1

Patients with nonvalvular atrial fibrillation: Avoid concomitant use in patients with severe renal impairment (Clcr 15–30 mL/minute)1

Patients with venous thromboembolism: Avoid concomitant use in patients with Clcr <50 mL/minute1

Ranitidine

Pharmacokinetic interaction unlikely1

Rifampin

Potentially decreased dabigatran concentrations and AUC1

Avoid concurrent use1

Thrombolytic agents

Increased risk of bleeding1

Monitor for bleeding manifestations1

Ticagrelor

Increased steady-state peak plasma concentration and AUC of dabigatran; magnitude of increase dependent on dose and timing of dabigatran administration1

Dosage adjustment not necessary1

Patients with nonvalvular atrial fibrillation: Avoid concomitant use in patients with severe renal impairment (Clcr 15–30 mL/minute)1

Patients with venous thromboembolism: Avoid concomitant use in patients with Clcr <50 mL/minute1

Verapamil

Potentially increased dabigatran concentrations and AUC1

Dosage adjustment not necessary1

Patients with nonvalvular atrial fibrillation: Avoid concomitant use in patients with severe renal impairment (Clcr 15–30 mL/minute)1

Patients with venous thromboembolism: Avoid concomitant use in patients with Clcr <50 mL/minute1

Interaction dependent on verapamil formulation and timing of administration; verapamil immediate release given 1 hour prior to dabigatran increased dabigatran AUC 2.4-fold, while verapamil given 2 hours after dabigatran had negligible effects1

Warfarin

Increased risk of bleeding1

INR for monitoring warfarin more accurate ≥2 days after discontinuing dabigatran1 (see Transferring to Warfarin and see Transferring from Warfarin, under Dosage and Administration)

Pradaxa Pharmacokinetics

Dabigatran etexilate is absorbed after oral administration of dabigatran etexilate mesylate and hydrolyzed to the active moiety, dabigatran, by esterases in plasma and the liver.1 13 7 Dabigatran undergoes conjugation to acyl glucuronides that have similar pharmacologic activity to dabigatran and account for approximately 20% of the total plasma dabigatran concentration.1 11 12 13 The pharmacokinetics of dabigatran are generally described in terms of total plasma dabigatran concentrations, which includes the major acyl glucuronide metabolites.1 11 Dabigatran exhibits linear, dose-dependent pharmacokinetics.1

Absorption

Bioavailability

Absolute bioavailability of dabigatran following oral administration of dabigatran etexilate approximately 3–7%.1

Steady-state expected within 3 days when given 3 times daily.12

Onset

Peak plasma concentration attained approximately 1–2 hours following oral administration.1 11 13 Maximal effects on coagulation assays expected within 2 hours of administration; such effects correlate with peak plasma concentrations.1 11 13

Duration

Effects on anticoagulation assays decline by approximately 50% at 12 hours after administration.11

Food

High-fat meal delays time to peak plasma concentration by 2 hours but does not affect bioavailability.1

Special Populations

When dabigatran was administered 1–3 hours after completing hip arthroplasty, time to peak plasma concentrations was delayed to 6 hours but returned to normal day after surgery.2 12 There was no effect on AUC.2 12

In patients with mild, moderate, or severe renal impairment, AUC estimated to be increased 1.5-, 3.2-, or 6.3-fold respectively; peak plasma concentrations increased 1.1-, 1.7-, or 2.1-fold, respectively.1 14

Distribution

Extent

Not known whether dabigatran distributes into milk.1

Plasma Protein Binding

Approximately 35%.1 13

Elimination

Metabolism

Dabigatran etexilate is a prodrug of dabigatran;2 rapidly absorbed following oral administration and hydrolyzed in the plasma to dabigatran, the active moiety.1 11

Elimination Route

Bioavailable dabigatran excreted principally (80%) in urine as unchanged drug.1 13 Approximately 86% of total dose is eliminated in the feces.1

Half-life

12–17 hours.1 11

Special Populations

In patients with mild, moderate, or severe renal impairment, plasma half-life averages 15, 18, or 28 hours, respectively.1

In patients with moderate hepatic impairment (Child-Pugh class B), large interpatient variability apparent, but no consistent change in exposure or pharmacodynamic response.1 15 41

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1 Store in original package (i.e., bottles or blister pack) to protect from moisture.1

Advise patients about special storage and handling requirements.36 Dispense only in original bottle with desiccant cap to minimize product breakdown from moisture.36 While manufacturer currently advises use of capsules in bottle within 30 days after first opening bottle,1 FDA states that data under review indicate potency is maintained for 60 days after first opening bottle.36 (See Advice to Patients.)

Once bottle is opened, manufacturer recommends that drug be used within 30 days.1 Keep bottle tightly closed.1

Keep out of reach of children.1

Actions

  • Selective, competitive, reversible direct thrombin inhibitor.2 12 Prevents thrombus formation by binding free and clot-bound thrombin, thereby inhibiting the conversion of fibrinogen to fibrin.1 2 12 Also inhibits thrombin-mediated platelet aggregation.1 2 12

  • Administered and absorbed as dabigatran etexilate mesylate, an inactive ester prodrug; hydrolyzed by esterases in plasma and liver to dabigatran, the principal active moiety.1 7 11 13 Dabigatran metabolized to several acyl glucuronides with similar activity as dabigatran.1 11

  • Prolongs TT and ECT linearly over the range of therapeutic plasma concentrations.1 10 11 Prolongs aPTT in a curvilinear manner.1 10 11 INR may be elevated, but is not a reliable assessment of dabigatran activity.1 10 11 ECT is the preferred method for measuring anticoagulant activity of dabigatran; median trough (12 hours post-dose) value of 63 seconds with dabigatran etexilate 150 mg twice daily.1 10 May also use aPTT qualitatively, with a ratio >1 indicating presence of drug in plasma; average peak or trough values of 2 or 1.5 times control, respectively, with dabigatran etexilate 150 mg twice daily.1 10 12 39

Advice to Patients

  • Risk of bleeding.1 Patients should seek emergency medical care if they experience manifestations of serious bleeding (e.g., unusual bruising, including bruises with unknown cause or that enlarge; pink or brown urine; red or black, tarry stool; coughing up blood; vomiting blood; vomitus with the appearance of coffee grounds).1

  • Patients should consult healthcare provider for other manifestations of bleeding (e.g., pain, swelling, or discomfort in a joint, headaches, dizziness, weakness, recurrent nose bleeds, unusual bleeding from the gums, prolonged bleeding from a cut, heavier than normal menstrual or vaginal bleeding).1

  • Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., back pain, tingling or numbness in lower limbs, muscle weakness, stool or urine incontinence), particularly if they are receiving concomitant NSAIAs, platelet-aggregation inhibitors, or other anticoagulants; importance of immediately contacting a clinician if any of these symptoms occur.1

  • Risk of adverse GI reactions.1 Patients should consult healthcare provider if they experience dyspepsia, burning, nausea, abdominal pain/discomfort, epigastric discomfort, or indigestion.1

  • Patients should inform healthcare provider that they are taking dabigatran before scheduling any invasive or dental procedure.1

  • Importance of informing healthcare provider if patient has had or plans to have a heart valve replacement.1

  • Importance of swallowing capsules whole with a full glass of water, without breaking, chewing, or otherwise emptying the contents of the capsule.1 Do not sprinkle contents of capsules on food or into a beverage.1

  • Importance of taking dabigatran exactly as prescribed.1 Do not stop taking dabigatran without discussing with prescriber.1

  • Instruct patients to take missed dose as soon as remembered but only if it can be taken at least 6 hours prior to next scheduled dose.1

  • Importance of informing patient of special storage and handling requirements for drug.1 36 Store only in original container, not in pill boxes or organizers.1 36 Protect from moisture.1 Remove only one capsule from container right before use, then close bottle tightly.1 36 When more than one bottle is dispensed, only open one bottle at a time.1 Do not open or puncture blister on blister package until time of use.36 Per manufacturer, use capsules within 4 months after the bottle is first opened.1 (See Stability.)

  • Importance of providing patient a copy of manufacturer’s patient information.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dabigatran Etexilate Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

75 mg (of dabigatran etexilate)

Pradaxa

Boehringer Ingelheim

150 mg (of dabigatran etexilate)

Pradaxa

Boehringer Ingelheim

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 12/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Pradaxa 150MG Capsules (BOEHRINGER INGELHEIM): 60/$245.99 or 180/$706.93

Pradaxa 75MG Capsules (BOEHRINGER INGELHEIM): 30/$123.99 or 90/$353.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 14, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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