Dabigatran (Pradaxa) inhibits free and fibrin-bound thrombin that is used as an anticoagulant to prevent and treat deep vein thrombosis and pulmonary embolism especially in patients undergoing knee and hip replacement surgery.

Dabigatran (Pradaxa) Uses:

• Deep venous thrombosis and pulmonary embolism treatment and prevention:

  • Dabigatran is used in the 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.
  •  It is used to significantly reduce the risk of recurrence of DVT and pulmonary embolism in patients who have been previously treated.

• Nonvalvular atrial fibrillation:

  • In patients with non-valvular atrial fibrillation, it is used to prevent stroke and systemic embolization.

• VTE prophylaxis in total hip arthroplasty:

  • It can also be used in the prophylaxis of DVT and PE in patients who have had total hip arthroplasty (THA).

• Off Label Use of Dabigatran in Adults:

  • It is used as an off-label drug for VTE prophylaxis in patients with total knee arthroplasty (TKA)

Dabigatran (Pradaxa) Dose in Adults

Dabigatran (Pradaxa) Dose in the treatment of Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):

• Orally it can be given as 150 mg twice a day.
• It is noteworthy that candidates can be considered for an alternative lower dose regimen of 110 mg twice a day for off-label use especially in those patients who are at increased risk of bleeding.

Dabigatran (Pradaxa) Dose in the treatment of Post-percutaneous coronary intervention with stent placement and nonvalvular AF (alternative regimen) (off-label):

It is also used as an alternative to triple antithrombotic therapy (ie, dual antiplatelet therapy plus an oral anticoagulant) when concerns for bleeding outweigh the thrombotic risk.

• If the risk of thrombosis is high and bleeding risk is acceptable then triple therapy may still be an option.
• Orally it can be given as 110 mg or 150 mg twice a day in combination with clopidogrel which is preferred over prasugrel or ticagrelor due to lower risk of bleeding.
• Patient-specific thrombotic and bleeding risk factors define the dose for dabigatran.
• The patient is transitioned to the recommended dabigatran dosing for nonvalvular AF after completion of this regimen.

Dabigatran (Pradaxa) Dose in the treatment of Venous thromboembolism (VTE):

• Deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (treatment):

In patients with malignancy, the use of dabigatran is not studied. Another anticoagulant like LMWH and edoxaban is likely to be more appropriate.

• • The patient is transitioned to oral dabigatran after 5 days the completion of parenteral anticoagulant in hemodynamically stable patients.
  • Dosage: It is given as 150 mg twice a day.

• Duration of therapeutic anticoagulation (first episode, general recommendations):

  • The optimal duration of therapy is dependent on many factors, such as the presence of provoking factors, patient risk factors for recurrence and bleeding, and individual preferences.
  • Provoked VTE:
    • 3 months provided that provoking risk factor is no longer present.
  • Unprovoked PE or DVT (proximal or isolated distal):
    • For more than 3 months depending on the risk of VTE recurrence and bleeding.
  • Note: All patients who are receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at frequent intervals.

Dabigatran (Pradaxa) Dose in the VTE prophylaxis in total hip or knee arthroplasty (alternative to LMWH): Oral:

• Total hip arthroplasty (THA):

  • Initially, it can be given as 110 mg given orally 1 to 4 hours after completion of surgery and establishment of hemostasis or when dabigatran is not initiated on the day of surgery then give an initial dose of 220 mg after hemostasis has been achieved.
  • Then continue the maintenance dose of 220 mg once daily for a minimum of 10 to 14 days.
  • The optimal duration of prophylaxis is unknown but it can be given for a minimum of 10 to 14 days or can be extended for up to 35 days.
  • For THA some clinicians suggest a duration in the higher end of range i.e for 30 days.

• Total knee arthroplasty (TKA) (off-label use) :

  • In TKA it is given as 110 mg orally 1 to 4 hours after completion of surgery and establishment of hemostasis.
  • If dabigatran is not initiated on the day of surgery then give an initial dose of 220 mg after hemostasis has been achieved and then continue a maintenance dose of 220 mg once a day for a minimum of 10 to 14 days; it can be extended up to a period of 1 month.
  • The recommendation regarding the duration of prophylaxis is not studied.
  • Some experts suggest a duration in the lower end of the range for 10 to 14 days in  TKA.

Transitioning between anticoagulants:

It should be noted that local guidelines should be followed regarding the transitioning of one anticoagulant to another one.

Transitioning from another anticoagulant to dabigatran:

• Transitioning from LMWH or fondaparinux (therapeutic dose) to dabigatran:

  • General transition recommends that dabigatran should be initiated within 2 hours prior to the next scheduled dose of the parenteral anticoagulant.
  • VTE initial treatment (alternate recommendation):
    • For acute VTE, some experts start dabigatran within 6 to 12 hours after the last dose of a twice-daily LMWH regimen and within 12 to 24 hours after a once-daily regimen.

• Transitioning from unfractionated heparin (UFH) continuous infusion to dabigatran:

  • When UFH is stopped, dabigatran should be started. If aPTT is above or below the target range then local hospital guidelines should be consulted.

Transitioning from warfarin to dabigatran:

• When the INR is 2 or less, discontinue warfarin and initiate dabigatran.
• Some experts recommend transitioning to dabigatran when the INR is in therapeutic range and as close as possible to 2, particularly if the risk of bleeding may be increased.

Transitioning from dabigatran to another anticoagulant:

• Transitioning from dabigatran to LMWH, fondaparinux, or UFH continuous infusion:

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

• Transitioning from dabigatran to warfarin:

  • The 2 agents are overlapped.
  • Warfarin treatment initiation is adjusted based on CrCl:
  • CrCl >50 mL/minute:
    • 3 days before discontinuing dabigatran start warfarin.
  • CrCl 30 to 50 mL/minute:
    • 2 days before discontinuing dabigatran start warfarin.
  • CrCl 15 to 30 mL/minute:
    • warfarin should be started 24 hours before stopping dabigatran.
  • CrCl <15 mL/minute:
    • Dabigatran should not be used.

Note: Since dabigatran contributes to INR elevation, Only after dabigatran has been stopped for more than 2 days warfarin's effect on INR will be better reflected.

Dosing adjustment with concomitant medications:

• DVT and PE (treatment) or VTE prophylaxis in THA or TKA:

  • Avoid concomitant use with any P-glycoprotein inducer (eg, rifampin).
  • Avoid concomitant use with any P-glycoprotein inhibitor (eg, amiodarone, clarithromycin, dronedarone, ketoconazole [oral], quinidine, verapamil, and others) with CrCl <50 mL/minute.

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

  • Avoid concomitant use with any P-glycoprotein inducer (eg, rifampin).
  • Reduce dabigatran dose to 75mg twice a day if on Dronedarone or ketoconazole (oral) with CrCl 30 to 50 mL/minute.
  • Avoid concomitant use with any P-glycoprotein inhibitor (eg, amiodarone, clarithromycin, dronedarone, ketoconazole [oral], quinidine, verapamil, and others) with CrCl <30 mL/minute.

Use in Children:

Not indicated.

Dabigatran (Pradaxa) Category: C

• Ex-vivo human placenta dual fluid perfusion model revealed that dabigatran crossed at term. Dabigatran etexilate mesylate (prodrug) had limited placental transfer.
• Guyatt (2012). The data are not sufficient to assess the safety of direct-thrombin inhibitors in pregnancy. For the treatment of AF and VTE in pregnant patients, other agents are preferable.
• Monitor the neonate for bleeding if in-utero exposure is made

Dabigatran use during breastfeeding:

• It is unknown if dabigatran is secreted into breast milk.
• However, breastfeeding is not recommended by the literature.
• It is better to choose anticoagulants that have better data.

Dabigatran (Pradaxa) Dose in Liver disease:

Note: Clinical trials evaluating the safety and efficacy utilized the Cockcroft-Gault formula with the use of actual body weight.

• Manufacturer’s labeling: Adults:

  • DVT and pulmonary embolism (treatment and prevention):

    • CrCl >30 mL/minute:
      • Dose adjustment is not necessary unless the patient has a CrCl <50 mL/minute.
      • Patients receiving concomitant P-GP inhibitors should avoid co-administration.
    • CrCl ≤30 mL/minute:
      • The dose adjustment in this scenario has not yet been studied. Patients with CrCl ≤30 mL/minute were excluded from the respective clinical trials.
    • Hemodialysis:
      • Patients on Renal replacement therapy has not yet been studied for dose adjustments. Patients receiving hemodialysis were excluded from clinical trials (Schulman 2009; Schulman 2011; Schulman 2013).

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

    • CrCl >50 mL/minute:
      • No dosage adjustment is necessary.
      • Caution is advised 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, however, reduce the dose to 75mg twice a day, if the patient receiving concomitant dronedarone or oral ketoconazole.
      • 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 the patient is also of advanced age.
      • In patients with moderate-to-severe CKD, dose reduction can be considered although the safety and efficacy of this approach have not been established.
    • CrCl 15 to 30 mL/minute:
      • 75 mg twice a day unless the patient receiving a concomitant P-GP inhibitor, then avoid concurrent use.
    • Note: Patients with CrCl <30 mL/minute were excluded from the RE-LY trial. Safety and efficacy have not yet been established. Per the American College of Chest Physicians, dabigatran is contraindicated in patients with severe renal impairment (CrCl ≤30 mL/minute).
    • CrCl <15 mL/minute:
      • Per the American College of Chest Physicians, dabigatran is not recommended in patients with severe renal impairment (CrCl ≤30 mL/minute).
      • In addition, the AHA/ACC/HRS does not recommend dabigatran for patients with AF and end-stage CKD.
    • Hemodialysis:
      • There are no dosage adjustments provided in the literature because it has not yet been studied. The AHA/ACC/HRS  also does not recommend dabigatran for patients with AF on hemodialysis.
    • Note: Hemodialysis removes approximately 57% of the drug over 4 hours.

  • Post-operative thromboprophylaxis:

    • CrCl >30 mL/minute:
      • No dosage adjustment is indicated, however, avoid coadministration if the patient has a CrCl <50 mL/minute and is receiving concomitant P-gp inhibitors.
    • Note: In patients with moderate impairment (CrCl 30 to 50 mL/minute), the use of dabigatran is 150 mg once a day in Caucasian patients undergoing total hip or knee replacement achieved similar geometric mean steady-state trough concentrations to those seen in patients with mild impairment (CrCl 50 to <80 mL/minute) receiving 220 mg once daily.
    • CrCl ≤30 mL/minute:
      • There are no dosage adjustments provided in the literature and have not yet been studied.
      • Patients with CrCl <30 mL/minute were excluded from clinical trials.
    • Hemodialysis:
      • There are no dosage adjustments provided in the manufacturer’s labeling. The studies have shown limited data.

• Alternate recommendations:

  • Geriatric patients for ≥65 years:

    • CrCl <30 mL/minute:
      • Due to the lack of efficacy and safety evidence avoid use in older adults with CrCl <30 mL/minute.
      • Adjust dose in older adults with CrCl >30 mL/minute when given concurrently with interacting drugs.

Dose in Liver disease:

There are no dosage adjustments required as per the literature. Such pharmacodynamics were not studied.

Common Side Effects of Dabigatran (Pradaxa):

• Gastrointestinal:

  • Gastrointestinal symptoms

• Hematologic & oncologic:

  • Hemorrhage

Less Common Side Effects of Dabigatran (Pradaxa):

• Gastrointestinal:

  • Dyspepsia includes
    • Abdominal pain
    • Abdominal discomfort
    • Epigastric discomfort,
  • Gastrointestinal hemorrhage
  • Gastritis includes
    • Gastroesophageal reflux disease
    • Esophagitis
    • Erosive gastritis
    • Gastrointestinal hemorrhage
    • Hemorrhagic gastritis
    • Gastrointestinal ulcer

Contraindication to Dabigatran (Pradaxa):

• Severe hypersensitivity reactions such as anaphylaxis, anaphylactic shock due to dabigatran, or any other component of the formulation.
• Active pathological bleeding.
• Patients who have mechanical prosthetic heart valves

Canadian labeling: Additional contraindications not in US labeling

• Severe renal impairment (CrCl >30 mL/minute).
• Bleeding diathesis
• Patients with pharmacological or spontaneous hemostatic impairment, or patients with clinically significant active bleeding (including GI bleeding)
• Within the past 6 months, there have been bleeding events that could be considered clinically serious (eg, hemorhagic or cerebral infarction).
• Nursing women
• Concomitant therapy using strong P-glycoprotein Inhibitors (eg oral ketoconazole)
• Use with unfractionated Heparin in conjunction with anticoagulants (except when used to maintain central vein or arterial catheter patency, or catheter ablation for atrial fibrillation).
• Low molecular weight Heparins, Heparin derivatives (eg fondaparinux), Antithrombin Agents (eg bivalirudin) and Oral Anticoagulants (eg warfarins, Rivaroxabans, Apixabans) are not recommended during the transition of therapy from or towards dabigatran.

Warnings and precautions

• Bleeding

  • Bleeding is the most serious complication, and can lead to death.
  • Concomitant use with antiplatelet agents, heparin, renal impairment, elderly patients, especially those of low body weight, are all risk factors for bleeding.
  • Patients with active pathological bleeding should not be given dabigatran.
  • It is notable that Idarucizumab, which is commercially available, is the most efficient agent for dabigatran reversers.
  • Vitamin K and protamine do not affect the anticoagulant properties of dabigatran.
  • Dialyzable is Dabigatran. In 4 hours, approximately 57% of the drug is eliminated. This method does not have supporting data.
  • Activated charcoal can be used depending on the severity of the bleeding.
  • Depending on the clinical situation, there are also other options:
    • 4-factor unactivated prothrombin concentrate (PCC) (eg, Kcentra) OR
    • 4-factor activated prothrombin complex concentrate (aPCC) (eg, FEIBA).
  • Some cases and studies have demonstrated moderate success in correcting coagulation test results with certain agents. The correction of coagulation results does not mean that the anticoagulation effects of the medication will be reversed.
  • When platelet counts are low, or long-acting antiplatelet medications have been taken, you should consider platelet concentrates.

• Thromboembolic Events: [US Boxed Warning]

  • It is better to stop it earlier than is recommended.
  • Consider using another anticoagulant if dabigatran is needed to be withheld due to bleeding complications or the completion of treatment.
  • Guidelines recommend that patients with non-valvular arial fibrillation should not receive oral anticoagulation for at least 1 to 2 weeks following an acute ischemic attack.
  • It is possible for transient ischemic attacks or minor, non-disabling strokes to last shorter than others. For moderate-to-severe strokes, the timeframe may be longer.

• Hepatic impairment

  • Patients with moderate hepatic impairment (Child Puugh class B) showed high patient-patient variability. There was no consistent increase in either exposure or pharmacodynamics.
  • Patients with active liver disease were not eligible for the Randomized Evaluation of Long-term Anticoagulation Treatment (RE-LY).

• Renal impairment

  • It is important to evaluate renal function before and during treatment, especially if it is administered to patients with preexisting renal impairments or any other condition that could lead to a decline in renal function (eg hypovolemia, dehydration, concomitant medication with the potential to affect renal function).
  • The risk of bleeding may be increased by increasing the concentration of dabigatran in any degree or severity of renal impairment.
  • Serum concentrations may rise 3 times faster in moderate impairment than they would be for patients with normal renal function.
  • Nonvalvular AF patients are not eligible for US labeling. Dosing guidelines state that it is not possible to provide US labeling to patients with CrCl below 15 mL/minute.
  • The AHA/ACC/HRS suggests that patients with non-valvular AF or moderate-to-severe kidney disease (CKD) may be considered for dose reduction.
  • However, safety and efficacy have not been proven. Patients with AF, end-stage CKD, or on hemodialysis should not take Dabigatran.
  • According to guidelines from the American College of Chest Physicians, dabigatran should not be used in patients suffering from severe renal impairment (CrCl >=30 mL/minute).
  • If a patient develops acute kidney failure, withhold therapy.

• Heart disease of the valvular kind:

  • Patients with valvular disease or a bioprosthetic valve are not advised to use it. Limited data from studies are available. Patients with prosthetic hearts are not advised to use it.
  • In addition to several case reports, one clinical trial reported significantly more thromboembolic events like valve thrombosis, stroke, TIA, and MI and an excess of major bleeding, predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise, in patients with mechanical prosthetic heart valves receiving dabigatran compared to those receiving adjusted-dose warfarin.

Dabigatran: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC with differential.
• renal function tests.
• Prior to initiation and periodically as clinically indicated.
• For example in situations associated with a decline in renal function, and at least annually in all patients.

How to administer Dabigatran?

• Orally it can be administered 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 a 75% increase in absorption and potentially serious adverse reactions.

Mechanism of action of Dabigatran (Pradaxa):

• It is a prodrug that lacks anticoagulant activity and is converted in vivo into the active dabigatran.
• This specific, reversible, direct inhibitor of thrombin inhibits both fibrin-bound and free thrombin.
• By inhibiting thrombin-mediated effects (cleavage fibrinogen to fibrin monomers, activation factors V, VIII and XI), coagulation is prevented. It also inhibits platelet aggregation by inhibiting thrombin-induced platelet accumulation.

Absorption:

• Rapid; initially slow postoperatively

Protein binding:

• 35%

Metabolism:

• It metabolized in the liver.
• Dabigatran etexilate is rapidly and completely hydrolyzed to dabigatran (active form) by plasma and hepatic esterases.
• It undergoes hepatic glucuronidation to active acylglucuronide isomers which is similar in activity to the parent compound.
• It accounts for <10% of total dabigatran in plasma

Bioavailability:

• 3% to 7%

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.

Time to peak, plasma:

• Dabigatran: 1 hour.
• Its peak is delayed 2 hours by food (no effect on bioavailability)

Excretion:

• Urine (80%)

International Brand Names of Dabigatran:

• Pradaxa
• APO-Dabigatran
• Averodab
• Cogadexa
• Dabigat
• Dabiran
• Oxogartan

Dabigatran Brand Names in Pakistan:

No Brands Available in Pakistan.