Dabigatran Etexilate
FDA Drug Information • Also known as: Dabigatran, Dabigatran Etexilate, Pradaxa
- Brand Names
- Dabigatran, Dabigatran Etexilate, Pradaxa
- Route
- ORAL
- Dosage Form
- CAPSULE
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: (A) PREMATURE DISCONTINUATION OF DABIGATRAN ETEXILATE CAPSULES INCREASES THE RISK OF THROMBOTIC EVENTS, and (B) SPINAL/EPIDURAL HEMATOMA (A) PREMATURE DISCONTINUATION OF DABIGATRAN ETEXILATE CAPSULES INCREASES THE RISK OF THROMBOTIC EVENTS Premature discontinuation of any oral anticoagulant, including dabigatran etexilate capsule s, increases the risk of thrombotic events. If anticoagulation with dabigatran etexilate capsules are discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration ( 2.6, 2.7, 2.8 ) and Warnings and Precautions (5.1)] . (B) SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients treated with dabigatran etexilate capsule s who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
Description
11 DESCRIPTION The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is β-Alanine, N -[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1 H -benzimidazol-5-yl]carbonyl]- N -2-pyridinyl-ethyl ester, methanesulfonate. The molecular formula is C 34 H 41 N 7 O 5 ●CH 4 O 3 S and the molecular weight is 723.86 g/mol. The structural formula is: Dabigatran etexilate mesylate is a yellow to white 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, very slightly soluble in acetone, practically insoluble in ethyl acetate. Dabigatran etexilate capsules are supplied in 75 mg, 110 mg, and 150 mg strengths for oral administration. Each capsule contains dabigatran etexilate mesylate as the active ingredient: 172.97 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate, 126.86 mg dabigatran etexilate mesylate, which is equivalent to 110 mg dabigatran etexilate, or 86.49 mg dabigatran etexilate mesylate which is equivalent to 75 mg dabigatran etexilate. The capsule fill also contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, fumaric acid, magnesium stearate and mannitol. The capsule shell is composed of FD&C blue No.1, hypromellose, iron oxide red, iron oxide yellow, titanium dioxide and edible black ink which consists of non-volatile ingredients ammonium hydroxide, iron oxide black, potassium hydroxide, propylene glycol and shellac. dabigatran etexilate structure
What Is Dabigatran Etexilate Used For?
1 INDICATIONS AND USAGE Dabigatran etexilate capsules are direct thrombin inhibitor indicated: To reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation ( 1.1 ) For the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in adult patients who have been treated with a parenteral anticoagulant for 5 to 10 days ( 1.2 ) To reduce the risk of recurrence of DVT and PE in adult patients who have been previously treated ( 1.3 ) For the prophylaxis of DVT and PE in adult patients who have undergone hip replacement surgery ( 1.4 ) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients Dabigatran etexilate capsules are indicated to reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation. 1.2 Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Dabigatran etexilate capsules are indicated for the treatment of deep venous thrombosis and pulmonary embolism in adult patients who have been treated with a parenteral anticoagulant for 5 to 10 days. 1.3 Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Dabigatran etexilate capsules are indicated to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in adult patients who have been previously treated. 1.4 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery Dabigatran etexilate capsules are indicated for the prophylaxis of deep vein thrombosis and pulmonary embolism in adult patients who have undergone hip replacement surgery. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Non-valvular Atrial Fibrillation in Adult Patients: For patients with CrCl >30 mL/min: 150 mg orally, twice daily ( 2.2 ) For patients with CrCl 15 to 30 mL/min: 75 mg orally, twice daily ( 2.2 ) Treatment of DVT and PE in Adult Patients: For patients with CrCl >30 mL/min: 150 mg orally, twice daily after 5 to10 days of parenteral anticoagulation ( 2.2 ) Prophylaxis of DVT and PE Following Hip Replacement Surgery in Adult Patients: For patients with CrCl >30 mL/min: 110 mg orally first day, then 220 mg once daily ( 2.2 ) Dabigatran etexilate capsules are NOT substitutable on a milligram-to- milligram basis with other dabigatran etexilate dosage forms. Review recommendations for converting to or from other oral or parenteral anticoagulants ( 2.6 , 2.7 ) Temporarily discontinue dabigatran etexilate capsules before invasive or surgical procedures when possible, then restart promptly ( 2.8 ) 2.1 Important Dosage Information Dabigatran etexilate is available in different dosage forms and not all dosage forms are approved for the same indications and age groups. In addition, there are differences between the dosage forms with respect to dosing due to differences in bioavailability. Do not substitute different dosage forms on a milligram-to-milligram basis and do not combine more than one dosage form to achieve the total dose [see Clinical Pharmacology ( 12.3 )]. 2.2 Recommended Dabigatran Etexilate Capsules Dosage for Adults Indication Dosage Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF CrCl > 30 mL/min: 150 mg twice daily CrCl 15 to 30 mL/min: 75 mg twice daily CrCl < 15 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dosage to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole. CrCl < 30 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Treatment of DVT and PE Reduction in the Risk of Recurrence of DVT and PE CrCl > 30 mL/min: 150 mg twice daily 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 Prophylaxis of DVT and PE Following Hip Replacement Surgery CrCl > 30 mL/min: CrCl ≤ 30 mL/min or on dialysis: 110 mg for first day, then 220 mg once daily Dosing recommendations cannot be provided CrCl < 50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dosage of dabigatran etexilate capsules is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15 to 30 mL/min), the recommended dosage of dabigatran etexilate capsules is 75 mg twice daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. Dosing recommendations...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Increased Risk of Thrombotic Events after Premature Discontinuation [see Warnings and Precautions ( 5.1 )] Risk of Bleeding [see Warnings and Precautions ( 5.2 )] Spinal/Epidural Anesthesia or Puncture [see Warnings and Precautions ( 5.3 )] Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves [see Warnings and Precautions ( 5.4 )] Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome [see Warnings and Precautions (5.6)] The most serious adverse reactions reported with dabigatran etexilate capsules were related to bleeding [see Warnings and Precautions (5.2) ] . Most common adverse reactions (> 15%) are gastrointestinal adverse reactions and bleeding ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Trials Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation The RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study provided safety information on the use of two doses of dabigatran etexilate capsules and warfarin [see Clinical Studies (14.1) ] . The numbers of patients and their exposures are described in Table 2. Limited information is presented on the 110 mg dosing arm because this dose is not approved. Table 2 Summary of Treatment Exposure in RE-LY Dabigatran etexilate capsules 110 mg twice daily Dabigatran etexilate capsules 150 mg twice daily Warfarin Total number treated 5,983 6,059 5,998 Exposure > 12 months 4,936 4,939 5,193 > 24 months 2,387 2,405 2,470 Mean exposure (months) 20.5 20.3 21.3 Total patient-years 10,242 10,261 10,659 Drug Discontinuation in RE-LY The rates of adverse reactions leading to treatment discontinuation were 21% for dabigatran etexilate capsules 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of dabigatran etexilate capsules were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea). Bleeding [see Warnings and Precautions (5.2) ] Table 3 shows the number of adjudicated major bleeding events during the treatment period in the RE-LY study, with the bleeding rate per 100 subject-years (%). Major bleeding is defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells, bleeding at a critical site or with a fatal outcome. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. Table 3 Adjudicated Major Bleeding Events in Treated Patients a a Patients during treatment or within 2 days of stopping study treatment. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. b Annual event rate per 100 pt-years = 100 * number of subjects with event/subject-years. Subject-years is defined as cumulative number of days from first drug intake to event date, date of last drug intake + 2, death date (whatever occurred first) across all treated subjects divided by 365.25. In case of recurrent events of the same category, the first event was considered. c Defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site or with fatal outcome. d Intracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. e...
Drug Interactions
7 DRUG INTERACTIONS P-gp inducers: Avoid coadministration with dabigatran etexilate capsules (5.5) P-gp inhibitors in adult patients with CrCl 30 to 50 mL/min: Reduce dosage or avoid (7) P-gp inhibitors in adult patients with CrCl <30 mL/min: Not recommended (7) 7.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients The concomitant use of dabigatran etexilate capsules with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3) ] . P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3) ] . 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. In patients with moderate renal impairment (CrCl 30 to 50 mL/min), reduce the dosage of dabigatran etexilate capsules to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dosage adjustment of dabigatran etexilate capsules. These results should not be extrapolated to other P-gp inhibitors [see Warnings and Precautions (5.5) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . The concomitant use of dabigatran etexilate capsules and P-gp inhibitors in patients with severe renal impairment (CrCl 15 to 30 mL/min) should be avoided [see Warnings and Precautions (5.5) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . 7.2 Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Avoid use of dabigatran etexilate capsules and P-gp inhibitors in patients with CrCl < 50 mL/min [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )]. 7.3 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of dabigatran etexilate capsules and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.2 , 12.3 )]. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
Contraindications
4 CONTRAINDICATIONS Dabigatran etexilate capsules are contraindicated in patients with: Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] History of a serious hypersensitivity reaction to dabigatran, dabigatran etexilate, or to one of the excipients of the product (e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions (6.1) ] Mechanical prosthetic heart valve [see Warnings and Precautions (5.4) ] Active pathological bleeding (4) History of serious hypersensitivity reaction to dabigatran etexilate capsules (4) Mechanical prosthetic heart valve (4)
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary The limited available data on dabigatran etexilate capsules use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulants (see Clinical Considerations) . In pregnant rats treated from implantation until weaning, dabigatran increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition at an exposure 2.6 times the human exposure. At a similar exposure, dabigatran decreased the number of implantations when rats were treated prior to mating and up to implantation (gestation Day 6). Dabigatran administered to pregnant rats and rabbits during organogenesis up to exposures 8 and 13 times the human exposure, respectively, did not induce major malformations. However, the incidence of delayed or irregular ossification of fetal skull bones and vertebrae was increased in the rat (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 % to 4% and 15 % to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. Fetal/Neonatal adverse reaction Use of anticoagulants, including dabigatran etexilate capsules, may increase the risk of bleeding in the fetus and neonate....
Overdosage
10 OVERDOSAGE Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with dabigatran etexilate capsules, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available for adult patients. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ].
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Dabigatran etexilate capsules 75 mg have a hypromellose capsule shell with a buff opaque body, light blue opaque cap, imprinted "APO" on cap and "D75" on body in black ink. Filled with light yellow to yellow colored powder. The capsules are supplied in the packages listed: NDC 60505-4347-6 Bottle of 60 capsules with child-resistant cap NDC 60505-4347-2 Carton of 60 capsules (10 x 6 unit-dose blister cards) Dabigatran etexilate capsules 110 mg have a hypromellose capsule shell with a buff opaque body, light blue opaque cap, imprinted "APO" on cap and "D110" on body in black ink. Filled with light yellow to yellow colored powder. The capsules are supplied in the packages listed: NDC 60505-4349-6 Bottle of 60 capsules with child-resistant cap NDC 60505-4349-2 Carton of 60 capsules (10 x 6 unit-dose blister cards) Dabigatran etexilate capsules 150 mg have a hypromellose capsule shell with a buff opaque body, light blue opaque cap, imprinted "APO" on cap and "D150" on body in black ink. Filled with light yellow to yellow colored powder. The capsules are supplied in the packages listed: NDC 60505-4348-6 Bottle of 60 capsules with child-resistant cap NDC 60505-4348-2 Carton of 60 capsules (10 x 6 unit-dose blister cards) Bottles Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Once opened, the product must be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect from moisture. Blisters Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original package to protect from moisture.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.