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Initial U.S. Approval: 2010
The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is -Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate.
Dabigatran etexilate mesylate is a yellow-white to yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol.
The 150 mg capsule for oral administration contains 172.95 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate, and the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. The capsule shell is composed of carrageenan, FD&C Blue No. 2 (150 mg only), FD&C Yellow No. 6, hypromellose, potassium chloride, titanium dioxide, and black edible ink. The 75 mg capsule contains 86.48 mg dabigatran etexilate mesylate, equivalent to 75 mg dabigatran etexilate, and is otherwise similar to the 150 mg capsule.
Mechanism of Action
Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties
INDICATIONS AND USAGE
PRADAXA is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation
Active pathological bleeding.
History of serious hypersensitivity reaction to PRADAXA.
WARNINGS AND PRECAUTIONS
Risk of bleeding: PRADAXA can cause serious and, sometimes, fatal bleeding. Promptly evaluate signs and symptoms of blood loss.
Temporary discontinuation: Avoid lapses in therapy to minimize risk of stroke.
P-gp inducers and inhibitors: Effects on dabigatran exposure
P-gp inducers rifampin: Avoid coadministration with PRADAXA.
P-gp inhibitors dronedarone and systemic ketoconazole in patients with moderate renal impairment (CrCl 30-50 mL/min): Consider reducing PRADAXA dose to 75 mg twice daily.
P-gp inhibitors in patients with severe renal impairment (CrCl <30 mL/min): PRADAXA use not recommended.
USE IN SPECIFIC POPULATIONS
Geriatric use: Risk of bleeding increases with age
Most common adverse reactions (>15%) are gastritis-like symptoms
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DOSAGE AND ADMINISTRATION
For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily, with or without food. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of PRADAXA is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.
In patients with moderate renal impairment (CrCl 30-50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce dabigatran exposure similar to that observed in severe renal impairment. Consider reducing the dose of PRADAXA to 75 mg twice daily.
Renal function should be assessed by calculating the CrCl prior to initiation of treatment with PRADAXA. While on treatment, renal function should be assessed in clinical situations which may be associated with a decline in renal function. In patients with CrCl <50 mL/min or >75 years of age, renal function should be assessed at least once a year.
Instruct patients to swallow the capsules whole. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure.
If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.
Converting from or to Warfarin
When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the international normalized ratio (INR) is below 2.0.
When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:
For CrCl 50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
For CrCl 30-50 mL/min, start warfarin 2 days before discontinuing PRADAXA.
For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA.
For CrCl <15 mL/min, no recommendations can be made.
Because PRADAXA can contribute to an elevated INR, the INR will better reflect warfarin’s effect after PRADAXA has been stopped for at least 2 days.
Converting from or to Parenteral Anticoagulants
For patients currently receiving a parenteral anticoagulant, start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin).
For patients currently taking PRADAXA, wait 12 hours (CrCl 30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant.
Surgery and Interventions
If possible, discontinue PRADAXA 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.
If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. Bleeding risk can be assessed by the ecarin clotting time (ECT). This test is a better marker of the anticoagulant activity of dabigatran than activated partial thromboplastin time (aPTT) or thrombin time (TT). If ECT is not available, the aPTT test provides an approximation of PRADAXA’s anticoagulant activity. INR tests are unreliable in patients on PRADAXA.
DOSAGE FORMS AND STRENGTHS
Capsules: 75 mg and 150 mg
HOW SUPPLIED/STORAGE AND HANDLING
PRADAXA 75 mg capsules have a cream-colored opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with "R75". The color of the imprinting is black. The capsules are supplied in the packages listed:
NDC 0597-0149-54 Unit of use bottle of 60 capsules
NDC 0597-0149-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)
PRADAXA 150 mg capsules have a light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with "R150". The color of the imprinting is black. The capsules are supplied in the packages listed:
NDC 0597-0135-54 Unit of use bottle of 60 capsules
NDC 0597-0135-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Once opened, the product must be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect from moisture.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Store in the original package to protect from moisture.
Keep out of the reach of children.
Package Insert data:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Revised: November 2011
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Copyright 2011 Boehringer Ingelheim Pharmaceuticals, Inc.
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