These highlights do not include all the information needed to use DABIGATRAN ETEXILATE CAPSULES safely and effectively. See full prescribing information for DABIGATRAN ETEXILATE CAPSULES.
DABIGATRAN ETEXILATE capsules, for oral use
Initial U.S. Approval: 2010
Dabigatran etexilate capsules are a 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 5-10 days (1.2)
•To reduce the risk of recurrence of DVT and PE in adult patients who have been previously treated (1.3)
•Non-valvular Atrial Fibrillation in Adult Patients:
oFor patients with CrCl >30 mL/min: 150 mg orally, twice daily (2.2)
oFor patients with CrCl 15 to 30 mL/min: 75 mg orally, twice daily (2.2)
•Treatment of DVT and PE in Adult Patients:
oFor patients with CrCl > 30 mL/min: 150 mg orally, twice daily after 5-10 days of parenteral anticoagulation(2.2)
•Reduction in the Risk of Recurrence of DVT and PE in Adult Patients:
oFor patients with CrCl > 30 mL/min: 150 mg orally, twice daily after previous treatment (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)
Capsules: 75 mg, and 150 mg (3)
•Active pathological bleeding (4)
•History of serious hypersensitivity reaction to dabigatran(4)
•Mechanical prosthetic heart valve (4)
•Bleeding: Dabigatran can cause serious and fatal bleeding (5.2)
•Bioprosthetic heart valves: Dabigatranuse not recommended (5.4)
•Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatranuse not recommended (5.6)
Most common adverse reactions (>15%) are gastrointestinal adverse reactions and bleeding (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
•P-gp inducers: Avoid coadministration with dabigatran(5.5)
•P-gp inhibitors in adult patients with CrCl 30 to 50 mL/min: Reduce dose or avoid (7)
•P-gp inhibitors in adultpatients with CrCl <30 mL/min: Not recommended (7)
- Lactation: Breastfeeding not recommended (8.2)
- Geriatric Use: Risk of bleeding increases with age (8.5)
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.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 5/2024
1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients
1.2 Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
1.3 Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
2.1 Important Dosage Information
2.2 Recommended Dabigatran etexilate Capsules Dosage for Adults
2.4 Dosage Adjustments
2.5 Administration
2.6 Converting from or to Warfarin
2.7 Converting from or to Parenteral Anticoagulants
2.8 Discontinuation for Surgery and Other Interventions
5.1 Increased Risk of Thrombotic Events after Premature Discontinuation
5.2 Risk of Bleeding
5.3 Spinal/Epidural Anesthesia or Puncture
5.4Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
5.5 Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure
5.6Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome
6.1Clinical Trials Experience
6.2 Postmarketing Experience
7.1Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients
7.2Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmaco*kinetics
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14.1Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients
14.2Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
- *
- Sections or subsections omitted from the full prescribing information are not listed.
(A)PREMATURE DISCONTINUATION OF DABIGATRAN INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including dabigatran, increases the risk of thrombotic events. If anticoagulation with dabigatranis 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 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:
•use of indwelling epidural catheters
•concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
•a history of traumatic or repeated epidural or spinal punctures
•a history of spinal deformity or spinal surgery
•optimal timing between the administration of dabigatran and neuraxial procedures is not known [see Warnings and Precautions (5.3)].
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)].
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated [see Warnings and Precautions (5.3)].
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 5-10 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.
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.
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 co-administration | |
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 co-administration |
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 are 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 are 75 mg twice daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Dosing recommendations for patients with a CrCl < 15 mL/min or on dialysis cannot be provided.
Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
For patients with CrCl > 30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤ 30 mL/min or on dialysis cannot be provided [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
For patients with CrCl >30 mL/min, the recommended dose of dabigatran etexilate capsules are 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with aCrCl ≤30 mL/min or on dialysis cannot be provided [see Use in Specific Populations (8.6) and Clinical Pharmacology (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.
2.4 Dosage Adjustments
Adult patients with renal impairment
Assess renal function prior to initiation of treatment with dabigatran etexilate capsules. Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly. Discontinue dabigatran etexilate capsules in patients who develop acute renal failure while on dabigatran etexilate capsules and consider alternative anticoagulant therapy.
Generally, in adult patients the extent of anticoagulation does not need to be assessed. When necessary, use aPTT or ECT, and not INR, to assess for anticoagulant activity in adult patients on dabigatran etexilate capsules [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation
In patients with moderate renal impairment (CrCl 30 to 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. Reduce the dosage of dabigatran etexilate capsules to 75 mg twice daily [see Warnings and Precautions (5.5), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
Dosing recommendations for patients with CrCl ≤ 30 mL/min cannot be provided. Avoid use of concomitant P-gp inhibitors in patients with CrCl < 50 mL/min [see Warnings and Precautions (5.5), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Pediatric patients with renal impairment
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.
2.5 Administration
Dabigatran etexilate capsules should be swallowed whole. Dabigatran etexilate capsules should be taken with a full glass of water. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure [see Clinical Pharmacology (12.3)].
If a dose of dabigatran etexilate capsule 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 dabigatran etexilate capsules should not be doubled to make up for a missed dose.
Consider administration with food if gastrointestinal distress occurs with dabigatran etexilate capsules.
2.6 Converting from or to Warfarin
When converting patients from warfarin therapy to dabigatran etexilate capsules, discontinue warfarin and start dabigatran etexilate capsules when the INR is below 2.0.
When converting from dabigatran etexilate capsules to warfarin, adjust the starting time of warfarinas follows:
Adults
• For CrCl ≥ 50 mL/min, start warfarin 3 days before discontinuing dabigatran etexilate capsules.
• For CrCl 30 to 50 mL/min, start warfarin 2 days before discontinuing dabigatran etexilate capsules.
• For CrCl 15 to 30 mL/min, start warfarin 1 day before discontinuing dabigatran etexilate capsules.
• For CrCl < 15 mL/min, no recommendations can be made.
Because dabigatran etexilate capsules can increase INR, the INR will better reflect warfarin’s effect only after dabigatran etexilate capsules has been stopped for at least 2 days [see Clinical Pharmacology (12.2)].
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.
2.7 Converting from or to Parenteral Anticoagulants
For adult patients currently receiving a parenteral anticoagulant, start dabigatran etexilate capsules 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 adult patients currently taking dabigatran etexilate capsules, wait 12 hours (CrCl ≥ 30 mL/min) or 24 hours (CrCl < 30 mL/min) after the last dose of dabigatran etexilate capsules before initiating treatment with a parenteral anticoagulant [see Clinical Pharmacology (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.
2.8 Discontinuation for Surgery and Other Interventions
If possible, discontinue dabigatran etexilate capsules in adults 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
If surgery cannot be delayed, there is an increased risk of bleeding[see Warnings and Precautions (5.2)].This risk of bleeding should be weighed against the urgency of intervention[see Warnings and Precautions (5.1, 5.3)].Use a specific reversal agent (idarucizumab) in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is neededin adults. Efficacy and safety of idarucizumab have not been established in pediatric patients[see Warnings and Precautions (5.2)].Refer to the idarucizumab prescribing information for additional information. Restart dabigatran etexilate capsules as soon as medically appropriate.
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.
150 mg capsules with a white to light yellow colored blend compressing granular powder, pellets in size “0” capsule having white opaque cap imprinted “MD” and white opaque body imprinted with “150” with black ink.
75 mg capsules with a white to light yellow colored blend compressing granular powder, pellets in size “2” capsule having white opaque cap imprinted “MD” and white opaque body imprinted with “75” with black ink.
Dabigatranis 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)]
5.1 Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including dabigatran , in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If dabigatran etexilate capsulesis discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart dabigatranetexilate capsulesas soon as medically appropriate [see Dosage and Administration (2.6, 2.7, 2.8)].
5.2 Risk of Bleeding
Dabigatran increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue dabigatran etexilate capsules in patients with active pathological bleeding [see Dosage and Administration (2.4)].
Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). Dabigatran's anticoagulant activity and half-life are increased in patients with renal impairment [see Clinical Pharmacology (12.2)].
Reversal of Anticoagulant Effect:
In adults, a specific reversal agent (idarucizumab) for dabigatran is available when reversal of the anticoagulant effect of dabigatran is needed:
•For emergency surgery/urgent procedures
•In life-threatening or uncontrolled bleeding
In pediatric patients, the efficacy and safety of idarucizumab have not been established.
Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited [see Overdosage (10)]. Prothrombin complex concentrates, or recombinant Factor VIIa 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 where thrombocytopenia is present or long-acting antiplatelet drugs have been used.
5.3 Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].
To reduce the potential risk of bleeding associated with the concurrent use of dabigatran and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmaco*kinetic profile of dabigatran [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
5.4Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of dabigatran etexilate capsules in adult patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose-adjusted warfarin or 150 mg, 220 mg, or 300 mg of dabigatran etexilate capsules twice a day. RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) in the dabigatran etexilate capsules treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on dabigatran etexilate capsules postoperatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment. Therefore, the use of dabigatran is contraindicated in all patients with mechanical prosthetic valves [see Contraindications (4)].
The use of dabigatranfor the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of a bioprosthetic heart valve, has not been studied and is not recommended.
5.5 Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure
Theconcomitantuseofdabigatran withP-gpinducers(e.g.,rifampin)reducesexposuretodabigatranandshouldgenerallybeavoided[seeClinicalPharmacology (12.3)].
P-gp inhibitionandimpaired renalfunctionarethemajorindependentfactorsthatresultin increasedexposuretodabigatran[seeClinicalPharmacology(12.3)]. ConcomitantuseofP-gpinhibitorsinpatientswithrenalimpairmentisexpectedtoproduceincreasedexposureofdabigatrancomparedtothatseenwitheitherfactor alone.
ReductionofRiskofStrokeandSystemicEmbolisminNon-valvularAtrialFibrillation in Adult Patients
Reducethedosage ofdabigatran etexilate capsules to75mgtwicedailywhen dronedaroneorsystemicketoconazoleisco-administered with dabigatranetexilate capsules in patientswithmoderaterenal impairment(CrCl30 to 50mL/min).Avoiduseofdabigatran etexilate capsules andP-gpinhibitorsin patientswithsevererenalimpairment(CrCl15 to 30mL/min)[seeDrugInteractions (7.1) and Use in Specific Populations(8.6)].
TreatmentandReductioninthe RiskofRecurrenceof DeepVenousThrombosisandPulmonaryEmbolism in Adult Patients
Avoiduseofdabigatranetexilate capsules andconcomitantP-gpinhibitorsinpatientswithCrCl< 50mL/min[seeDrugInteractions(7.2)andUseinSpecificPopulations(8.6)].
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.
5.6Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome
Direct-acting oral anticoagulants (DOACs), including dabigatran, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple-positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
The followingclinically significantadverse 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 dabigatranwere related to bleeding[see Warnings and Precautions (5.2)].
6.1Clinical 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.
Table2Summary 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 dabigatranetexilate 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.
Table3Adjudicated Major Bleeding Events in Treated Patientsa
Event | Dabigatranetexilate capsules150 mg N = 6,059 n (%/yearb) | Warfarin N = 5,998 n (%/yearb) | Dabigatran etexilate capsules150 mgvs Warfarin HR (95% CI) |
Major Bleedingc | 350 (3.47) | 374 (3.58) | 0.97 (0.84, 1.12) |
Intracranial Hemorrhage (ICH)d | 23 (0.22) | 82 (0.77) | 0.29 (0.18, 0.46) |
Hemorrhagic Strokee | 6 (0.06) | 40 (0.37) | 0.16 (0.07, 0.37) |
Other ICH | 17 (0.17) | 46 (0.43) | 0.38 (0.22, 0.67) |
Gastrointestinal | 162 (1.59) | 111 (1.05) | 1.51 (1.19, 1.92) |
Fatal Bleedingf | 7 (0.07) | 16 (0.15) | 0.45 (0.19, 1.10) |
ICH | 3 (0.03) | 9 (0.08) | 0.35 (0.09, 1.28) |
Non-intracranialg | 4 (0.04) | 7 (0.07) | 0.59 (0.17, 2.02) |
aPatients 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.
bAnnual 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.
cDefined 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.
dIntracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
eOn-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14 Clinical Studies.
fFatal bleed: Adjudicated major bleed as defined above with investigator reported fatal outcome and adjudicated death with primary cause from bleeding.
gNon-intracranial fatal bleed: Adjudicated major bleed as defined above and adjudicated death with primary cause from bleeding but without symptomatic intracranial bleed based on investigator’s clinical assessment.
There was a higher rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg than in patients receiving warfarin (6.6% vs 4.2%, respectively).
The risk of major bleeds was similar with dabigatran etexilate capsules 150 mg and warfarin across major subgroups defined by baseline characteristics (see Figure 1), with the exception of age, where there was a trend toward a higher incidence of major bleeding on dabigatran etexilate capsules (hazard ratio 1.2, 95% CI: 1.0 to 1.5) for patients ≥75 years of age.
Figure 1 Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients
Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent hom*ogeneity or heterogeneity among groups should not be over-interpreted.
Gastrointestinal Adverse Reactions
Patients on dabigatran etexilate capsules 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).
Hypersensitivity Reactions
In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in < 0.1% of patients receiving dabigatran etexilate capsules.
Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
Dabigatranetexilate capsules was studied in 4,387 patients in 4 pivotal, parallel, randomized, double-blind trials. Three of these trials were active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY), and one study (RE-SONATE) was placebo-controlled. The demographic characteristics were similar among the 4 pivotal studies and between the treatment groups within these studies. Approximately 60% of the treated patients were male, with a mean age of 55.1 years. The majority of the patients were white (87.7%), 10.3% were Asian, and 1.9% were black with a mean CrCl of 105.6 mL/min.
Bleeding events for the 4 pivotal studies were classified as major bleeding events if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L or more, or leading to transfusion of 2 or more units of whole blood or red cells).
RE-COVER and RE-COVER II studies compared dabigatranetexilate capsules 150 mg twice daily and warfarin for the treatment of deep vein thrombosis and pulmonary embolism. Patients received 5-10 days of an approved parenteral anticoagulant therapy followed by 6 months, with mean exposure of 164 days, of oral only treatment; warfarin was overlapped with parenteral therapy. Table4 shows the number of patients experiencing bleeding events in the pooled analysis of RE-COVER and RE-COVER II studies during the full treatment including parenteral and oral only treatment periods after randomization.
Table4Bleeding Events in RE-COVER and RE-COVER II Treated Patients
Bleeding Events-Full Treatment Period Including Parenteral Treatment | |||
Dabigatranetexilate capsules 150 mg twice daily N (%) | Warfarin N (%) | Hazard Ratio (95% CI)c | |
Patients | N=2553 | N=2554 | |
Major bleeding eventa | 37 (1.4) | 51 (2.0) | 0.73 (0.48, 1.11) |
Fatal bleeding | 1 (0.04) | 2 (0.1) | |
Bleeding in a critical area or organ | 7 (0.3) | 15 (0.6) | |
Fall in hemoglobin ≥ 2 g/dL or transfusion≥ 2 units of whole blood or packed red blood cells | 32 (1.3) | 38 (1.5) | |
Bleeding sites for MBEb | |||
Intracranial | 2 (0.1) | 5 (0.2) | |
Retroperitoneal | 2 (0.1) | 1 (0.04) | |
Intraarticular | 2 (0.1) | 4 (0.2) | |
Intramuscular | 2 (0.1) | 6 (0.2) | |
Gastrointestinal | 15 (0.6) | 14 (0.5) | |
Urogenital | 7 (0.3) | 14 (0.5) | |
Other | 8 (0.3) | 8 (0.3) | |
Clinically relevant non-major bleeding | 101 (4.0) | 170 (6.7) | 0.58 (0.46, 0.75) |
Any bleeding | 411 (16.1) | 567 (22.7) | 0.70 (0.61, 0.79) |
Note: MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator assessment. Patients can have more than one site of bleeding.
cConfidence interval
The rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg in the full treatment period was 3.1% (2.4% on warfarin).
The RE-MEDY and RE-SONATE studies provided safety information on the use of dabigatranetexilate capsules for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism.
RE-MEDY was an active-controlled study (warfarin) in which 1,430 patients received dabigatran etexilate capsules 150 mg twice daily following 3 to 12 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-MEDY study had a combined treatment duration of up to more than 3 years, with mean exposure of 473 days. Table5 shows the number of patients experiencing bleeding events in the study.
Table5Bleeding Events in RE-MEDY Treated Patients
Dabigatran etexilate capsules 150 mg twice daily N (%) | Warfarin N (%) | Hazard Ratio (95% CI)c | |
Patients | N=1430 | N=1426 | |
Major bleeding eventa | 13 (0.9) | 25 (1.8) | 0.54 (0.25, 1.16) |
Fatal bleeding | 0 | 1 (0.1) | |
Bleeding in a critical area or organ | 7 (0.5) | 11 (0.8) | |
Fall in hemoglobin ≥ 2 g/dL or transfusion ≥ 2 units of whole blood or packed red blood cells | 7 (0.5) | 16 (1.1) | |
Bleeding sites for MBEb | |||
Intracranial | 2 (0.1) | 4 (0.3) | |
Intraocular | 4 (0.3) | 2 (0.1) | |
Retroperitoneal | 0 | 1 (0.1) | |
Intraarticular | 0 | 2 (0.1) | |
Intramuscular | 0 | 4 (0.3) | |
Gastrointestinal | 4 (0.3) | 8 (0.6) | |
Urogenital | 1 (0.1) | 1 (0.1) | |
Other | 2 (0.1) | 4 (0.3) | |
Clinically relevant non-major bleeding | 71 (5.0) | 125 (8.8) | 0.56 (0.42, 0.75) |
Any bleeding | 278 (19.4) | 373 (26.2) | 0.71 (0.61, 0.83) |
Note: MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator assessment. Patients can have more than one site of bleeding.
cConfidence interval
In the RE-MEDY study, the rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg was 3.1% (2.2% on warfarin).
RE-SONATE was a placebo-controlled study in which 684 patients received dabigatran etexilate capsules 150 mg twice daily following 6 to 18 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-SONATE study had combined treatment duration up to 9 months, with mean exposure of 165 days. Table6 shows the number of patients experiencing bleeding events in the study.
Table6Bleeding Events in RE-SONATE Treated Patients
Dabigatran etexilate capsules 150 mg twice daily N (%) | Placebo N (%) | Hazard Ratio (95% CI)c | |
Patients | N=684 | N=659 | |
Major bleeding eventa | 2 (0.3) | 0 | |
Bleeding in a critical area or organ | 0 | 0 | |
Gastrointestinalb | 2 (0.3) | 0 | |
Clinically relevant non-major bleeding | 34 (5.0) | 13 (2.0) | 2.54 (1.34, 4.82) |
Any bleeding | 72 (10.5) | 40 (6.1) | 1.77 (1.20, 2.61) |
Note: MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator assessment. Patients can have more than one site of bleeding.
cConfidence interval
In the RE-SONATE study, the rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg was 0.7% (0.3% on placebo).
Clinical Myocardial Infarction Events
In the active-controlled VTE studies, a higher rate of clinical myocardial infarction was reported in patients who received dabigatranetexilate capsules [20 (0.66 per 100 patient-years)] than in those who received warfarin [5 (0.17 per 100 patient-years)]. In the placebo-controlled study, a similar rate of non-fatal and fatal clinical myocardial infarction was reported in patients who received dabigatran etexilate capsules [1 (0.32 per 100 patient-years)] and in those who received placebo [1 (0.34 per 100 patient-years)].
Gastrointestinal Adverse Reactions
In the four pivotal studies, patients on dabigatran etexilate capsules 150 mg had a similar incidence of gastrointestinal adverse reactions (24.7% vs 22.7% on warfarin). Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred in patients on dabigatran etexilate capsules 7.5% vs 5.5% on warfarin, and gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage) occurred at 3.0% vs 1.7%, respectively.
Hypersensitivity Reactions
In the 4 pivotal studies, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in 0.1% of patients receiving dabigatran etexilate capsules.
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.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of dabigatran. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders:Agranulocytosis, neutropenia, thrombocytopenia
Gastrointestinal Disorders:Esophageal ulcer
Immune System Disorders:Angioedema
Renal and Urinary Disorders:Anticoagulant-related nephropathy
Skin and Subcutaneous Tissue Disorders:Alopecia
7.1Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients
The concomitant use of dabigatranwith 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 dabigatranto 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. 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 dabigatranand 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)].
7.2Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
Avoid use of dabigatranand 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)].
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.
8.1 Pregnancy
Risk Summary
The limited available data on dabigatranuse 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 vagin*l/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%-4% and 15%-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, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.2)].
Labor or delivery
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Dabigatranuse during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider discontinuation or use of shorter acting anticoagulant as delivery approaches [see Warnings and Precautions (5.2, 5.3)].
Data
Animal Data
Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at MRHD of300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vagin*l/uterine bleeding close to parturition.
Dabigatran administered to pregnant rats and rabbits during organogenesis up to maternally toxic doses of 200 mg/kg (8 and 13 times the human exposure, respectively, at a MRHD of 300 mg/day based on AUC comparisons) did not induce major malformations, but increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat.
Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).
8.2 Lactation
Risk Summary
There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with dabigatran.
8.3 Females and Males of Reproductive Potential
Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including dabigatran should be assessed in females of reproductive potential and those with abnormal uterine bleeding.
8.4 Pediatric Use
Safety and effectiveness of dabigatran etexilate capsules have not been established in pediatric patients with non-valvular atrial fibrillation or those 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.
8.5 Geriatric Use
Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions (5), Adverse Reactions (6.1), and Clinical Studies (14.1)].
8.6 Renal Impairment
Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients
No dose adjustment of dabigatran is recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3)]. Reduce the dose of dabigatranin patients with severe renal impairment (CrCl 15 to 30 mL/min) [see Dosage and Administration (2.2, 2.4) and Clinical Pharmacology (12.3)]. Dosing recommendations for patients with CrCl < 15 mL/min or on dialysis cannot be provided.
Adjust dose appropriately in patients with renal impairment receiving concomitant P-gp inhibitors [see Warnings and Precautions (5.5), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].
Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
Patients with severe renal impairment (CrCl ≤ 30 mL/min) were excluded from RE-COVER.
Dosing recommendations for patients with CrCl ≤ 30 mL/min or on dialysis cannot be provided. Avoid use of dabigatranwith concomitant P-gp inhibitors in patients with CrCl < 50 mL/min [see Warnings and Precautions (5.5), Drug Interactions (7.2), and Clinical Pharmacology (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.
Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with dabigatran, 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)].
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-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The molecular formula is C35H45N7O8S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is:
Dabigatran etexilate mesylate is a yellow-white to yellow powder. It is freely soluble in methanol, soluble in ethanol, and practically insoluble in ethyl acetate.
Dabigatran etexilate capsules are supplied in 75 mg, and 150 mg strengths for oral administration. Each capsule contains dabigatran etexilate mesylate as the active ingredient: 150 mg dabigatran etexilate (equivalent to 172.95 mg dabigatran etexilate mesylate), or 75 mg dabigatran etexilate (equivalent to 86.48 mg dabigatran etexilate mesylate)along with the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, magnesium stearate, talc, tartaric acid pellets. The capsule shell is composed of hypromellose, titanium dioxide. The imprinting ink contains black iron oxide, propylene glycol, potassium hydroxide and shellac.
12.1 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.
12.2 Pharmacodynamics
At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, TT, and dTT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.
Adults
The aPTT test provides an approximation of dabigatran ’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of dabigatranis not precisely known. In the RE-LY trial, the median (10th to 90th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.
Figure 2 Average Time Course for Effects of Dabigatran on aPTT, Following Approved Dabigatran Dosing Regimens in Adult Patients with Various Degrees of Renal Impairment*
*Simulations based on PK data from a study in subjects with renal impairment and PK/aPTT relationships derived from the RE-LY study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using PTT Reagent Roche Diagnostics GmbH, Mannheim, Germany. There may be quantitative differences between various established methods for aPTT assessment.
The degree of anticoagulant activity can also be assessed by the ecarin clotting time (ECT). This test is a more specific measure of the effect of dabigatran than activated partial thromboplastin time (aPTT). In the RE-LY trial, the median (10th to 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds.
Cardiac Electrophysiology
No prolongation of the QTc interval was observed with dabigatran etexilate at doses up to600 mg.
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.
12.3 Pharmaco*kinetics
Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmaco*kinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmaco*kinetics in healthy adult subjects and adult patients in the range of doses from 10 to 400 mg. Given twice daily, dabigatran’s accumulation factor in adults is approximately two.
Absorption
The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3% to 7%. Dabigatran etexilate is a substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilatein healthy volunteers, Cmax occurs at 1-hour post-administration in the fasted state. Coadministration of dabigatran with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran; Dabigatranmay be administered with or without food.
The oral bioavailability of dabigatran etexilateincreases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation based on a single-dose relative bioavailability study. Dabigatran etexilate capsules should therefore not be broken, chewed, or opened before administration.
Distribution
Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. The volume of distribution of dabigatran is 50 to 70 L.
Elimination
Dabigatran is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of total clearance after intravenous administration. After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces. The half-life of dabigatran in healthy adultsubjects is 12 to 17 hours.
Metabolism
After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation, forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.
Specific Populations
Renal Impairment
An open, parallel-group, single-center study compared dabigatran pharmaco*kinetics in healthy adult subjects and adult patients with mild to moderate renal impairment receiving a single dosages of dabigatranetexilate capsules 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 10). Similar findings were observed in the RE- LY, and RE-COVER trials.
Table10 Impact of Renal Impairment on Dabigatran Pharmaco*kinetics
Renal Function | CrCl (mL/min) | Increase in AUC | Increase in Cmax | t1/2 (h) |
Normal | ≥ 80 | 1x | 1x | 13 |
Mild | 50-80 | 1.5x | 1.1x | 15 |
Moderate | 30-50 | 3.2x | 1.7x | 18 |
Severe+ | 15-30 | 6.3x | 2.1x | 27 |
+Patients with severe renal impairment were not studied in RE-LY, and RE-COVER. Dosing recommendations in subjects with severe renal impairment are based on pharmaco*kinetic modeling [see Dosage and Administration (2.2, 2.4) and Use in Specific Populations (8.6)].
Hepatic Impairment
Administration of dabigatranetexilate capsules in adult patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics.
Drug Interactions
A summary of the effect of coadministered drugs on dabigatran exposure in healthy adult subjects is shown in Figures 3.1 and 3.2.
Figure 3.1 Effect of P-gp Inhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dosage and Dosage Frequency are given as well as the Time of Perpetrator Dosage in Relation to Dabigatran Etexilate Dosage (Time Difference)
Figure 3.2 Effect of Non-P-gp Inhibitor or Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dosage and Dosage Frequency are given as well as the Time of Perpetrator Dosage in Relation to Dabigatran Etexilate Dosage (Time Difference)
In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change the trough concentration of dabigatran.
Impact of Dabigatran on Other Drugs
In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alter the pharmaco*kinetics of amiodarone, atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine.
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.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Dabigatran was not carcinogenic when administered by oral gavage to mice and rats for up to 2 years. The highest doses tested (200 mg/kg/day) in mice and rats were approximately 3.6 and 6 times, respectively, the human exposure at MRHD of 300 mg/day based on AUC comparisons.
Dabigatran was not mutagenic in in vitro tests, including bacterial reversion tests, mouse lymphoma assay and chromosomal aberration assay in human lymphocytes, and the in vivo micronucleus assay in rats.
In the rat fertility study with oral gavage doses of 15, 70, and 200 mg/kg, males were treated for 29 days prior to mating, during mating up to scheduled termination, and females were treated 15 days prior to mating through gestation Day 6. No adverse effects on male or female fertility were observed at200 mg/kg or 9 to 12 times the human exposure at MRHD of 300 mg/day based on AUC comparisons. However, the number of implantations decreased in females receiving 70 mg/kg, or 3 times the human exposure at MRHD based on AUC comparisons.
14.1Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients
The clinical evidence for the efficacy of dabigatranetexilate capsules was derived from RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), a multi-center, multi-national, randomized, parallel group trial comparing two blinded dosages of dabigatranetexilate capsules (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors:
•Previous stroke, transient ischemic attack (TIA), or systemic embolism
•Left ventricular ejection fraction < 40%
•Symptomatic heart failure, ≥ New York Heart Association Class 2
•Age ≥ 75 years
•Age ≥ 65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension
The primary objective of this study was to determine if dabigatran etexilate capsuleswas non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. The study was designed to ensure that dabigatran etexilate capsules preserved more than 50% of warfarin’s effect as established by previous randomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.
A total of 18,113 patients were randomized and followed for a median of 2 years. The patients’ mean age was 71.5 years and the mean CHADS2 score was 2.1. The patient population was 64% male, 70% Caucasian, 16% Asian, and 1% black. Twenty percent of patients had a history of a stroke or TIA and 50% were vitamin K antagonist (VKA) naïve, defined as less than 2 months total lifetime exposure to a VKA. Thirty-two percent of the population had never been exposed to a VKA. Concomitant diseases of patients in this trial included hypertension 79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin and 6% were on clopidogrel. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2 to 3) was 64%.
Relative to warfarin and to dabigatran etexilate capsules 110 mg twice daily, dabigatran etexilate capsules 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism (see Table11 and Figure 4).
Table11First Occurrence of Stroke or Systemic Embolism in the RE-LY Study*
Dabigatran etexilate capsules 150 mg twice daily | Dabigatranetexilate capsules 110 mg twice daily | Warfarin | |
Patients randomized | 6,076 | 6,015 | 6,022 |
Patients (% per yr) with events | 135 (1.12%) | 183 (1.54%) | 203 (1.72%) |
Hazard ratio vs warfarin (95% CI) | 0.65 (0.52, 0.81) | 0.89 (0.73, 1.09) | |
P-value for superiority | 0.0001 | 0.27 | |
Hazard ratio vs dabigatran110 mg (95% CI) | 0.72 (0.58, 0.91) | ||
P-value for superiority | 0.005 |
* Randomized ITT
Figure 4Kaplan-Meier Curve Estimate of Time to First Stroke or Systemic Embolism
The contributions of the components of the composite endpoint, including stroke by subtype, are shown in Table 12. The treatment effect was primarily a reduction in stroke. Dabigatranetexilate capsules 150 mg twice daily was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.
Table 12 Strokes and Systemic Embolism in the RE-LY Study
Dabigatran etexilate capsules 150 mg twice daily | Warfarin | Hazard ratio vs warfarin (95% CI) | |
Patients randomized | 6076 | 6022 | |
Stroke | 123 | 187 | 0.64 (0.51, 0.81) |
Ischemic stroke | 104 | 134 | 0.76 (0.59, 0.98) |
Hemorrhagic stroke | 12 | 45 | 0.26 (0.14, 0.49) |
Systemic embolism | 13 | 21 | 0.61 (0.30, 1.21) |
In the RE-LY trial, the rate of all-cause mortality was lower on dabigatran etexilate capsules 150 mg than on warfarin (3.6% per year versus 4.1% per year). The rate of vascular death was lower on dabigatran etexilate capsules 150 mg compared to warfarin (2.3% per year versus 2.7% per year). Non-vascular death rates were similar in the treatment arms.
The efficacy of dabigatran etexilate capsules 150 mg twice daily was generally consistent across major subgroups (see Figure 5).
Figure 5 Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics*
* Randomized ITT
Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent hom*ogeneity or heterogeneity among groups should not be over-interpreted.
In RE-LY, a higher rate of clinical myocardial infarction was reported in patients who received dabigatranetexilate capsules (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).
14.2Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
In the randomized, parallel group, double-blind trials, RE-COVER and RE-COVER II, patients with deep vein thrombosis and pulmonary embolism received dabigatran etexilate capsules 150 mg twice daily or warfarin (dosed to target INR of 2 to 3) following initial treatment with an approved parenteral anticoagulant for 5 to 10 days.
In RE-COVER, the median treatment duration during the oral only treatment period was 174 days. A total of 2,539 patients (30.9% patients with symptomatic PE with or without DVT and 68.9% with symptomatic DVT only) were treated with a mean age of 54.7 years. The patient population was 58.4% male, 94.8% white, 2.6% Asian, and 2.6% black. The concomitant diseases of patients in this trial included hypertension (35.9%), diabetes mellitus (8.3%), coronary artery disease (6.5%), active cancer (4.8%), and gastric or duodenal ulcer (4.4%). Concomitant medications included agents acting on renin-angiotensin system (25.2%), vasodilators (28.4%), serum lipid-reducing agents (18.2%), NSAIDs (21%), beta-blockers (14.8%), calcium channel blockers (8.5%), ASA (8.6%), and platelet inhibitors excluding ASA (0.6%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 60% in RE-COVER study.
In RE-COVER II, the median treatment duration during the oral only treatment period was 174 days. A total of 2568 patients (31.8% patients with symptomatic PE with or without DVT and 68.1% with symptomatic DVT only) were treated with a mean age of 54.9 years. The patient population was 60.6% male, 77.6% white, 20.9% Asian, and 1.5% black. The concomitant diseases of patients in this trial included hypertension (35.1%), diabetes mellitus (9.8%), coronary artery disease (7.1%), active cancer (3.9%), and gastric or duodenal ulcer (3.8%). Concomitant medications included agents acting on renin-angiotensin system (24.2%), vasodilators (28.6%), serum lipid-reducing agents (20.0%), NSAIDs (22.3%), beta-blockers (14.8%), calcium channel blockers (10.8%), ASA (9.8%), and platelet inhibitors excluding ASA (0.8%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 57% in RE-COVER II study.
In studies RE-COVER and RE-COVER II, the protocol specified non-inferiority margin (2.75) for the hazard ratio was derived based on the upper limit of the 95% confidence interval of the historical warfarin effect. Dabigatran etexilate capsules was demonstrated to be non-inferior to warfarin (dosed to target INR of 2 to 3) (Table 13) based on the primary composite endpoint (fatal PE or symptomatic non-fatal PE and/or DVT) and retains at least 66.9% (RE-COVER) and 63.9% (RE-COVER II) of the historical warfarin effect, respectively.
Table 13 Primary Efficacy Endpoint for RE-COVER and RE-COVER II – Modified ITTa Population
Dabigatran etexilate capsules 150 mg twice daily N (%) | Warfarin N (%) | Hazard ratio vs warfarin (95% CI) | |
RE-COVER | N=1,274 | N=1,265 | |
Primary Composite Endpointb | 34 (2.7) | 32 (2.5) | 1.05 (0.65, 1.70) |
Fatal PEc | 1 (0.1) | 3 (0.2) | |
Symptomatic non-fatal PEc | 16 (1.3) | 8 (0.6) | |
Symptomatic recurrent DVTc | 17 (1.3) | 23 (1.8) | |
RE-COVER II | N=1,279 | N=1,289 | |
Primary Composite Endpointb | 34 (2.7) | 30 (2.3) | 1.13 (0.69, 1.85) |
Fatal PEc | 3 (0.2) | 0 | |
Symptomatic non-fatal PEc | 9 (0.7) | 15 (1.2) | |
Symptomatic recurrent DVTc | 30 (2.3) | 17 (1.3) |
aModified ITT analyses population consists of all randomized patients who received at least one dose of study medication.
bNumber of patients with one or more event.
cNumber of events. For patients with multiple events each event is counted independently.
In the randomized, parallel-group, double-blind, pivotal trial, RE-MEDY, patients received dabigatran etexilate capsules 150 mg twice daily or warfarin (dosed to target INR of 2 to 3) following 3 to 12 months of treatment with anticoagulation therapy for an acute VTE. The median treatment duration during the treatment period was 534 days. A total of 2,856 patients were treated with a mean age of 54.6 years. The patient population was 61% male, and 90.1% white, 7.9% Asian and 2.0% black. The concomitant diseases of patients in this trial included hypertension (38.6%), diabetes mellitus (9.0%), coronary artery disease (7.2%), active cancer (4.2%), and gastric or duodenal ulcer (3.8%). Concomitant medications included agents acting on renin-angiotensin system (27.9%), vasodilators (26.7%), serum lipid reducing agents (20.6%), NSAIDs (18.3%), beta-blockers (16.3%), calcium channel blockers (11.1%), aspirin (7.7%), and platelet inhibitors excluding ASA (0.9%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 62% in the study.
In study RE-MEDY, the protocol specified non-inferiority margin (2.85) for the hazard ratio was derived based on the point estimate of the historical warfarin effect. Dabigatranetexilate capsules was demonstrated to be non-inferior to warfarin (dosed to target INR of 2 to 3) (Table 14) based on the primary composite endpoint (fatal PE or symptomatic non-fatal PE and/or DVT) and retains at least 63.0% of the historical warfarin effect. If the non-inferiority margin was derived based on the 50% retention of the upper limit of the 95% confidence interval, dabigatran etexilate capsules was demonstrated to retain at least 33.4% of the historical warfarin effect based on the composite primary endpoint.
Table 14 Primary Efficacy Endpoint for RE-MEDY – Modified ITTa Population
Dabigatran etexilate capsules 150 mg twice daily N=1,430 N (%) | Warfarin N=1,426 N (%) | Hazard ratio vs warfarin (95% CI) | |
Primary Composite Endpointb | 26 (1.8) | 18 (1.3) | 1.44 (0.78, 2.64) |
Fatal PEc | 1 (0.07) | 1 (0.07) | |
Symptomatic non-fatal PEc | 10 (0.7) | 5 (0.4) | |
Symptomatic recurrent DVTc | 17 (1.2) | 13 (0.9) |
aModified ITT analyses population consists of all randomized patients who received at least one dose of studymedication.
bNumber of patients with one or more event.
cNumber of events. For patients with multiple events each event is counted independently.
In a randomized, parallel-group, double-blind, pivotal trial, RE-SONATE, patients received dabigatranetexilate capsules 150 mg twice daily or placebo following 6 to 18 months of treatment with anticoagulation therapy for an acute VTE. The median treatment duration was 182 days. A total of 1343 patients were treated with a mean age of 55.8 years. The patient population was 55.5% male, 89.0% white, 9.3% Asian, and 1.7% black. The concomitant diseases of patients in this trial included hypertension (38.8%), diabetes mellitus (8.0%), coronary artery disease (6.0%), history of cancer (6.0%), gastric or duodenal ulcer (4.5%), and heart failure (4.6%). Concomitant medications included agents acting on renin-angiotensin system (28.7%), vasodilators (19.4%), beta-blockers (18.5%), serum lipid reducing agents (17.9%), NSAIDs (12.1%), calcium channel blockers (8.9%), aspirin (8.3%), and platelet inhibitors excluding ASA (0.7%). Based on the outcome of the primary composite endpoint (fatal PE, unexplained death, or symptomatic non-fatal PE and/or DVT), dabigatranwas superior to placebo (Table 15).
Table 15 Primary Efficacy Endpoint for RE-SONATE – Modified ITTa Population
Dabigatran etexilate capsules 150 mg twice daily N=681 N (%) | Placebo N=662 N (%) | Hazard ratio vs placebo (95% CI) | |
Primary Composite Endpointb | 3 (0.4) | 37 (5.6) | 0.08 (0.02, 0.25) p-value <0.0001 |
Fatal PE and unexplained deathc | 0 | 2 (0.3) | |
Symptomatic non-fatal PEc | 1 (0.1) | 14 (2.1) | |
Symptomatic recurrent DVTc | 2 (0.3) | 23 (3.5) |
aModified ITT analyses population consists of all randomized patients who received at least one dose of study medication.
bNumber of patients with one or more events.
cNumber of events. For patients with multiple events each event is counted independently.
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.
Dabigatran etexilate capsules 75 mg capsules have a white to light yellow colored blend compressing granular powder, pellets in size “2” capsule having white opaque cap imprinted “MD” and white opaque body imprinted with “75” with black ink. The capsules are supplied in the packages listed:
•NDC 72205-202-60Unit of use bottle of 60 capsules
Dabigatran etexilate capsules 150 mg capsules have a white to light yellow colored blend compressing granular powder, pellets in size “0” capsule having white opaque cap imprinted “MD” and white opaque body imprinted with “150” with black ink. The capsules are supplied in the packages listed:
•NDC 72205-204-60Unit of use bottle of 60 capsules
Bottles
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° 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.
Keep out of the reach of children.
Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide).
Instructions for Patients
- Tell patients to take dabigatran etexilate capsules exactly as prescribed.
- Remind patients not to discontinue dabigatran etexilate capsules without talking to the healthcare provider who prescribed it.
- Keep dabigatran etexilate capsules in the original bottle to protect from moisture. Do not put dabigatran etexilate capsules in pill boxes or pill organizers.
- When more than one bottle is dispensed to the patient, instruct them to open only one bottle at a time.
- Instruct patient to remove only one capsule from the opened bottle at the time of use. The bottle should be immediately and tightly closed.
- Advise patients not to chew or break the capsules before swallowing them and not to open the capsules and take the pellets alone.
- Advise patients that the capsule should be taken with a full glass of water.
[ see Boxed Warning, Dosage and Administration (2.5)]
Bleeding
Inform patients that they may bleed more easily, may bleed longer, and should call their healthcare provider for any signs or symptoms of bleeding
[ see Warnings and Precautions (5.2)].
Instruct patients to seek emergency care right away if they have any of the following, which may be a sign or symptom of serious bleeding:
•Unusual bruising (bruises that appear without known cause or that get bigger)
•Pink or brown urine
•Red or black, tarry stools
•Coughing up blood
•Vomiting blood, or vomit that looks like coffee grounds
Instruct patients to call their healthcare provider or to get prompt medical attention if they experience any signs or symptoms of bleeding:
•Pain, swelling or discomfort in a joint
•Headaches, dizziness, or weakness
•Reoccurring nose bleeds
•Unusual bleeding from gums
•Bleeding from a cut that takes a long time to stop
•Menstrual bleeding or vagin*l bleeding that is heavier than normal
If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning].
Gastrointestinal Adverse Reactions
Instruct patients to call their healthcare provider if they experience any signs or symptoms of dyspepsia or gastritis:
- Dyspepsia (upset stomach), burning, or nausea
- Abdominal pain or discomfort
- Epigastric discomfort, GERD (gastric indigestion)
[ see Adverse Reactions (6.1)]
Invasive or Surgical Procedures
Instruct patients to inform their healthcare provider that they are taking dabigatranbefore any invasive procedure (including dental procedures) is scheduled [ see Dosage and Administration (2.8)].
Concomitant Medications
Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so their healthcare provider knows about other treatments that may affect bleeding risk (e.g., aspirin or NSAIDs) or dabigatran exposure (e.g., dronedarone or systemic ketoconazole) [ see Warnings and Precautions (5.2, 5.5)].
Prosthetic Heart Valves
Instruct patients to inform their healthcare provider if they will have or have had surgery to place a prosthetic heart valve [ see Warnings and Precautions ( 5.4)].
Allergic Reactions
Advise adult patients and caregivers that some adults taking dabigatran have developed symptoms of an allergic reaction. Advise adult patients or caregivers to inform their healthcare provider if theydevelop symptoms of an allergic reaction, such as hives, rash, or itching. Advise adult patients or caregivers to seek emergency medical attention if theydevelop chest pain or tightness, swelling of the face or tongue, trouble breathing or wheezing, or feeling dizzy or faint.
Pregnancy
Advise patients to inform their healthcare provider immediately if they become pregnant or intend to become pregnant during treatment with dabigatran [ see Use in Specific Populations (8.1)].
Lactation
Advise patients not to breastfeed if they are taking dabigatran etexilate capsules [ see Use in Specific Populations (8.2)].
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.
Manufactured by:
MSN Laboratories Private Limited
Telangana – 509 228,
INDIA
Distributed by:
Novadoz Pharmaceuticals LLC
Piscataway, NJ 08854 -3714
Issued on:
May 2024
Dabigatran etexilate(da’’ bi gat’ ran e tex’ i late) capsules |
This Medication Guide is for dabigatran etexilate capsules. Read this Medication Guide before you start taking dabigatran etexilate capsules and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. |
What is the most important information I should know about dabigatran etexilate capsules?
Dabigatran etexilate capsules may need to be stopped, if possible, before surgery or a medical or dental procedure. Ask the healthcare providerwho prescribed dabigatran etexilate capsules for you when you should stop taking it. Yourhealthcare provider will tell you when you may start taking dabigatran etexilate capsules again after your surgery or procedure. If you have to stop taking dabigatran etexilate capsules, your healthcare provider may prescribe another medicine to help prevent a blood clot from forming.
oit may take longer for any bleeding to stop Call your healthcare provider or get medical help right away if you have any of these signs or symptoms of bleeding: ounexpected bleeding or bleeding that lasts a long time, such as:
oyou take NSAIDs or a medicine to prevent blood from clotting oyou have a history of difficult or repeated epidural or spinal punctures oyou have a history of problems with your spine or have had surgery on your spine If you take dabigatran etexilate capsules and receive spinal anesthesia or have a spinal puncture, your healthcare provider should watch you closely for symptoms of spinal or epidural blood clots. Tell your healthcare provider right away if you have back pain, tingling, numbness, muscle weakness (especially in your legs and feet), loss of control of the bowels or bladder (incontinence). See “What are the possible side effects of dabigatran etexilate capsules?” for more information about side effects. |
What are dabigatran etexilate capsules? Dabigatran etexilate capsules areprescriptionmedicinethat isused to:
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Do not take dabigatran etexilate capsules if you:
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Before takingdabigatran etexilate capsules, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way dabigatran etexilate capsules works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about dabigatran etexilate capsules?” Especially tell your healthcare provider if you take a medicine that contains rifampin. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. |
How should I take dabigatran etexilate capsules?
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What are the possible side effects of dabigatran etexilate capsules? Dabigatran etexilate capsules can cause serious side effects . See “What is the most important information I should know about dabigatran etexilate capsules?”
otrouble breathing or wheezing oswelling of your face or tongue ofeeling dizzy or faint Common side effects of dabigatran etexilate capsules in adults include:
These are not all of the possible side effects of dabigatran etexilate capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
How should I store dabigatran etexilate capsules?
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General information about the safe and effective use of dabigatran etexilate capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use dabigatran etexilate capsules for a condition for which it was not prescribed. Do not give dabigatran etexilate capsules to other people, even if they have the same symptoms that you have.It may harm them. This Medication Guide summarizes the most important information about dabigatran etexilate capsules. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about dabigatran etexilate capsules that is written for health professionals. For more information about dabigatran etexilate capsules, including current prescribing information and Medication Guide, go to www.novadozpharma.com, or call Novadoz Pharmaceuticals LLC. at 1-855-668-2369. |
What are the ingredients in dabigatran etexilate capsules? Active ingredient: dabigatran etexilate mesylate Inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, magnesium sterate, talc, tartaric acid pellets. The capsule shell is composed of hypromellose, titanium dioxide. The imprinting ink contains black iron oxide, propylene glycol, potassium hydroxide and shellac. 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. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC. Piscataway, NJ 08854-3714 Issued on: May 2024 |
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Labeler -Novadoz Pharmaceuticals LLC(081109687)
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
MSN LABORATORIES PRIVATE LIMITED | 650786952 | ANALYSIS(72205-202, 72205-204) , MANUFACTURE(72205-202, 72205-204) |