dabigatran (Pradaxa)

Dosing and uses of Pradaxa (dabigatran)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

capsule

• 75mg
• 150mg

 

Stroke Prophylaxis With Atrial Fibrillation

Prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation

CrCl >30 mL/min: 150 mg PO BId

CrCl 15-30 mL/min: 75 mg PO BId

CrCl <15 mL/min or dialysis: No data available; not recommended

Dosing modifications (atrial fibrillation)

• Renal impairment and coadministration with P-gp inhibitors
  • CrCl 30-50 mL/min and coadministration with dronedarone or ketoconazole: Consider reducing dose to 75 mg BID (dose adjustment is not necessary when coadministered with other P-gp inhibitors)
  • CrCl <30 mL/min with concomitant use of any P-gp inhibitor: Avoid coadministration

AHA/ACC/HRS guidelines for atrial fibrillation

• Class 1: For patients with AF or atrial flutter <48-hour duration and with high risk of stroke, IV heparin or 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-hr, 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 <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 nonvalvular 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 CKD or on hemodialysis because of the lack of evidence from clinical trials regarding the balance of risks and benefits
• Circulation March 28, 2014

 

DVT or 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 >30 mL/min: 150 mg PO BId

CrCl ≤30 mL/min or on dialysis: Dosage recommendations cannot be provided

CrCl <50 mL/min 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 >30 mL/min: 110 mg PO 1-4 hr after surgery and after hemostasis has been achieved on first day, then 220 mg taken qDay for 28-35 days

If dabigatran is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg qDay

CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided

CrCl <50 mL/min 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 <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 IV heparin

Converting from dabigatran to warfarin or parenteral anticoagulants

• CrCl 50 mL/min or greater: Start warfarin 3 days before discontinuing dabigatran
• CrCl 30-50 mL/min: Start warfarin 2 days before discontinuing dabigatran
• CrCl 15-30 mL/min: Start warfarin 1 day before discontinuing dabigatran
• CrCl <15 mL/min: No recommendations can be made
• Converting to parenteral anticoagulant: Wait 12 hours (≥CrCl 30 mL/min) or 24 hours (CrCl <30 mL/min) 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/min) or 3 to 5 days (CrCl <50 mL/min) 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 dosage forms and strengths

<18 years: Safety and efficacy not established

 

Geriatric dosage forms and strengths

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

 

Pradaxa (dabigatran) adverse (side) effects

>10%

Dyspepsia and gastritis (35%; compared with warfarin [24%])

Any bleed (16.6%; compared with warfarin [18.4%])

 

1-10%

Major bleed (3.3%; compared with warfarin [3.6%])

Life-threatening bleed (1.5%; compared with warfarin [1.9%])

 

<1%

Intracranial hemorrhage (0.3%; compared with warfarin [0.8%])

Hypersensitivity, including urticaria, rash, pruritus (<0.1%)

 

Postmarketing Reports

Angioedema

Esophageal ulcers

Thrombocytopenia

 

Warnings

Black box 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 (eg, 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

 

Contraindications

Severe renal impairment (CrCl <15 mL/min) or hemodialysis

Hypersensitivity

Active pathologic bleeding

Impairment of hemostasis

Mechanical prosthetic heart valves

• Significantly more thromboembolic events (eg, valve thrombosis, stroke, TIAs, 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

 

Cautions

Increased bleeding risk during labor and delivery

If possible, discontinue 1-2 days (CrCl ≥50 mL/min) or 3-5 days (CrCl <50 mL/min) 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 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/min): Anticoagulant activity and half-life are increased in patients with renal impairment

Congenital or acquired coagulation disorders

Ulcerative GI disease and other gastritislike 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 Black box warnings)

Coadministration with P-gp inducers and inhibitors

• P-gp inducers (eg, 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 <50 mL/min
• AF treatment, renal impairment, and P-gp inhibitors
  • CrCl 30-50 mL/min and P-gp inhibitors dronedarone or ketoconazole: Consider reducing the dose (see Dosage modifications)
  • CrCl 30-50 mL/min: 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 <30 mL/min: 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 hr); 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

Pregnancy category: C

Lactation: Excretion in milk unknown; use with caution

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Pradaxa (dabigatran)

Mechanism of action

Prevents thrombus development through direct, competitive inhibition of thrombin (thrombin enables fibrinogen conversion to fibrin during the coagulation cascade)

Inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation

 

Absorption

Bioavailability: 3-7%

Peak plasma time: 1 hr

 

Distribution

Protein bound: 35%

Vd: 50-70 L

 

Metabolism

Prodrug dabigatran etexilate is converted to dabigatran  

Dabigatran etexilate is a substrate of the efflux transporter P-gp

Not a substrate, inhibitor, or inducer of CYP450 enzymes

 

Elimination

Half-life

• Normal renal function: 12-17 hr
• Mild to moderate renal impairment: 14-17 hr
• Severe renal impairment: 28 hr

Excretion

• Urine (80%)

 

Administration

Instructions

Swallow capsule whole (do not chew, crush, or break)

If dose is missed, take as soon as possible on same day; skip missed dose if it cannot be taken at least 6 hours before the next scheduled dose; do not double dose to make up for a missed dose

Store in original container; once bottle is opened, capsules are stable for only 4 months