Dabigatran

Dabigatran is an anticoagulant that works by blocking the clotting protein thrombin. Dabigatran is used to prevent blood clots from forming because of a certain irregular heart rhythm (atrial fibrillation). Preventing these blood clots helps to reduce the risk of a stroke.

Dabigatran is available under the following different brand names: Pradaxa.

Dosage Forms and Strengths

Capsule

• 75 mg
• 100 mg

Dosage Considerations – Should be Given as Follows:

Stroke Prophylaxis With Atrial Fibrillation

• Prevention of stroke and systemic embolism associated with non-valvular atrial fibrillation
• CrCl greater than 30 mL/minute: 150 mg orally twice daily
• CrCl 15-30 mL/minute: 75 mg orally twice daily
• CrCl less than 15 mL/minute or dialysis: No data available; not recommended
• Dosing modifications (atrial fibrillation)
  • Renal impairment and coadministration with P-gp inhibitors
    • CrCl 30-50 mL/minute and coadministration with dronedarone or ketoconazole: Consider reducing dose to 75 mg twice daily (dose adjustment is not necessary when coadministered with other P-gp inhibitors)
    • CrCl less than 30 mL/minute with concomitant use of any P-gp inhibitor: Avoid coadministration

American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guidelines for atrial fibrillation:

• Class 1: For patients with atrial fibrillation (AF) or atrial flutter less than 48-hour duration and with high risk of stroke, intravenous (IV) heparin or low molecular weight heparin (LMWH), or administration of a factor Xa or direct thrombin inhibitor, is recommended as soon as possible before or immediately after cardioversion, followed by long-term anticoagulation therapy
• Class IIa: For patients with AF or atrial flutter of 48 hours or more, or when the duration of AF is unknown, anticoagulation with dabigatran, rivaroxaban, or apixaban is reasonable for at least 3 weeks prior to and 4 weeks after cardioversion
• Class IIb: For patients with AF or atrial flutter less than 48 hour duration who are at low thromboembolic risk, anticoagulation (IV heparin, LMWH, or a new oral anticoagulant) or no antithrombotic therapy may be considered for cardioversion, without the need for postcardioversion oral anticoagulation
• For patients with non-valvular AF unable to maintain a therapeutic INR level with warfarin, use of a direct thrombin or factor Xa inhibitor
• The direct thrombin inhibitor, dabigatran is not recommended in patients with AF and end-stage chronic kidney disease (CKD) or on hemodialysis because of the lack of evidence from clinical trials regarding the balance of risks and benefits
• Circulation March 28, 2014

Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Treatment

• Indicated for treatment of deep vein thrombosis (DVT) and pulmonary embolus (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days
• Also indicated to reduce the risk of recurrence of DVT and PE in patients who have been previously treated
• CrCl greater than 30 mL/minute: 150 mg orally twice daily
• CrCl up to 30 mL/minute or on dialysis: Dosage recommendations cannot be provided
• CrCl less than 50 mL/minute with concomitant use of P-gp inhibitors: Avoid coadministration

DVT or PE Prophylaxis

• Indicated for the prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) following hip replacement surgery
• CrCl greater than 30 mL/minute: 110 mg orally 1-4 hours after surgery and after hemostasis has been achieved on first day, then 220 mg taken once/day for 28-35 days
• If dabigatran is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once/day
• CrCl up to 30 mL/minute or on dialysis: Dosing recommendations cannot be provided
• CrCl less than 50 mL/minute with concomitant use of P-gp inhibitors: Avoid coadministration

Dosing Considerations

Converting to dabigatran from warfarin or parenteral anticoagulants

• Converting from warfarin: Discontinue warfarin and initiate dabigatran when INR less than 2.0
• Converting from parenteral anticoagulant: Give dabigatran 0-2 hours before time for next dose of the parenteral drug that was to have been administered or initiate at time of discontinuing continuous intravenous (IV) heparin

Converting from dabigatran to warfarin or parenteral anticoagulants

• CrCl 50 mL/minute or greater: Start warfarin 3 days before discontinuing dabigatran
• CrCl 30-50 mL/minute: Start warfarin 2 days before discontinuing dabigatran
• CrCl 15-30 mL/minute: Start warfarin 1 day before discontinuing dabigatran
• CrCl less than 15 mL/minute: No recommendations can be made
• Converting to parenteral anticoagulant: Wait 12 hours (CrCl 30 mL/minute or greater) or 24 hours (CrCl less than 30 mL/minute) after last dabigatran dose before initiating parenteral anticoagulant

Discontinuation for surgery and other interventions

• If possible, discontinue dabigatran 1 to 2 days (CrCl 50 mL/minute or greater) or 3 to 5 days (CrCl less than 50 mL/minute) before invasive or surgical procedures because of the increased risk of bleeding
• Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required
• Restart dabigatran promptly following surgery

Pediatric: Children under 18 years: Safety and efficacy not established

Geriatric: Increases risk of bleeding; bleeding can be significant and sometimes fatal; risk for bleeding or stroke increases with age over 75 years

Common side effects of dabigatran include:

• Indigestion
• Heatrtburn
• Abdominal/stomach pain or upset
• Diarrhea
• Bruising
• Minor bleeding (such as nosebleeds and bleeding from cuts)
• Major bleed
• Life-threatening bleed
• Intracranial hemorrhage
• Hypersensitivity, including hives, skin rash, itching

Serious side effects of dabigatran include:

• Severe heartburn
• Nausea
• Vomiting

Postmarketing side effects of dabigatran reported include:

• Skin swelling
• Esophageal ulcers
• Low blood platelets (thrombocytopenia)

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

• Severe interactions of dabigatran include:
  • defibrotide
  • mifepristone
  • prothrombin complex concentrate, human
• Dabigatran has serious interactions with at least 26 different drugs.
• Dabigatran has moderate interactions with at least 151 different drugs.
• Mild interactions of dabigatran include:
  • chlorella
  • mineral oil
  • verteporfin

This information does not contain all possible interactions or adverse effects. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns or for more information about this medicine.

Warnings

Premature discontinuation:

• Premature discontinuation of any oral anticoagulant, including dabigatran, increases the risk of thrombotic events
• If anticoagulation with dabigatran must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant

Spinal/epidural hematoma:

• Epidural or spinal hematomas may occur in patients who are receiving neuraxial anesthesia or undergoing spinal puncture
• These hematomas may result in long-term or permanent paralysis
• Monitor patients frequently for signs and symptoms of neurological impairment; if neurological compromise is noted, urgent treatment is necessary
• Consider the benefits and risks before neuraxial intervention in patients who are anticoagulated or to be anticoagulated

Factors that can increase the risk include:

• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], platelet inhibitors, other anticoagulants)
• History of traumatic or repeated epidural or spinal punctures
• History of spinal deformity or spinal surgery
• Optimal timing between the administration of dabigatran and neuraxial procedures is not known

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications

• Severe renal impairment (CrCl less than 15 mL/minute) or hemodialysis
• Hypersensitivity
• Active pathologic bleeding
• Impairment of hemostasis
• Mechanical prosthetic heart valves
  • Significantly more thromboembolic events (e.g., valve thrombosis, stroke, transient ischemic attacks [TIAs], heart attack [myocardial infarction, or MI]) observed with dabigatran than with warfarin
  • Excessive major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) observed with dabigatran, compared with warfarin
  • These bleeding and thromboembolic events, seen in the RE-ALIGN study (Am Heart J, June 2012), were observed in patients who were started on dabigatran postoperatively within 3 days after mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than 3 months prior to enrollment in the study; this clinical trial was terminated early because of these events

Effects of Drug Abuse

• No information available

Short-Term Effects

• See "What Are Side Effects Associated with Using Dabigatran?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Dabigatran?"

Cautions

• Increased bleeding risk during labor and delivery.
• If possible, discontinue 1-2 days (CrCl 50 mL/minute or greater) or 3-5 days (CrCl less than 50 mL/minute) before invasive or surgical procedure to decrease bleeding risk.
• Discontinuing anticoagulants for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke; minimize lapses in therapy.
• Ecarin clotting time (ECT) is a more accurate marker than aPPT, PT, or TT; aPPT gives an approximation of dabigatran's anticoagulant activity if the ECT test is unavailable.
• Increased risk for stroke if temporarily discontinued.
• Additive risk of bleeding when coadministered with antiplatelet agents, warfarin, heparin, fibrinolytic therapy, and long-term nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin; however, coadministration with clopidogrel has not resulted in further prolongation of capillary bleeding times compared with clopidogrel monotherapy.
• Not recommended in patients with prosthetic heart valves; safety and efficacy not established.
• Renal impairment (CrCl 15-30 mL/minute): Anticoagulant activity and half-life are increased in patients with renal impairment.
• Congenital or acquired coagulation disorders.
• Ulcerative gastrointestinal (GI) disease and other gastritis-like symptoms.
• Recent hemorrhage.
• Recent brain, spinal, or ophthalmic surgery.
• Use in patients undergoing neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis (see Warnings).
• Coadministration with P-gp inducers and inhibitors:
  • P-gp inducers (e.g., rifampin) reduce exposure to dabigatran and should generally be avoided
  • P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran
  • Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone
  • DVT/PE treatment, renal impairment, and P-gp inhibitors: Avoid coadministration if CrCl less than 50 mL/minute
  • AF treatment, renal impairment, and P-gp inhibitors
    • CrCl 30-50 mL/minute and P-gp inhibitors dronedarone or ketoconazole: Consider reducing the dose (see Dosage Modifications)
    • CrCl 30-50 mL/minute: Use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment, however, these results should not be extrapolated to other P-gp inhibitors
    • CrCl less than 30 mL/minute: Avoid coadministration with all P-gp inhibitors
• Reversing anticoagulant effect:
  • Idarucizumab is commercially available for reversal of the anticoagulant effect of dabigatran in surgery/urgent procedures, or life-threatening or uncontrolled bleeding
  • Can be dialyzed (protein binding is low, with the removal of about 60% of drug over 2-3 hours); however, the amount of data supporting this approach is limited
  • Activated prothrombin complex concentrates, recombinant factor VIIa, or concentrates of coagulation factors II, IX, or X may be considered, but their use has not been evaluated in clinical trials
  • Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran
  • Consider administration of platelet concentrates in cases in which thrombocytopenia is present or long-acting antiplatelet drugs have been used

Pregnancy and Lactation

• Use dabigatran with caution during pregnancy if benefits outweigh risks. Animal studies show risk and human studies are not available or neither animal nor human studies were done.
• Dabigatran excretion in milk is unknown. Use with caution if breastfeeding.