Dabigatran Etexilate: Package Insert and Label Information

DABIGATRAN ETEXILATE — dabigatran etexilate mesylate capsule
Camber Pharmaceuticals, Inc.

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 capsules, 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 capsules 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 etexilate capsules 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 INDICATIONS AND USAGE

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.

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 DOSAGE AND ADMINISTRATION

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 Dose for Adults

Indication Dosage
Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF CrCl >30 mL/min: CrCl 15 to 30 mL/min: CrCl <15 mL/min or on dialysis: 150 mg twice daily 75 mg twice daily Dosing recommendations cannot be provided
CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose 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: CrCl ≤30 mL/min or on dialysis: 150 mg twice 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 dose 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 dose of dabigatran etexilate capsules is 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 dose of dabigatran etexilate capsules is 150 mg taken orally, twice daily, after 5 to 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 is 150 mg taken orally, twice daily after previous treatment. 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)]. 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 dose 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 capsules 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 warfarin as 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 needed in 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.

3 DOSAGE FORMS AND STRENGTHS

150 mg capsules with a cream opaque cap / cream opaque body size ‘0’ HPMC capsules imprinted with ‘H’ on cap and ‘D11’ on body with black ink, filled with mixture of off white to yellowish white pellets.

75 mg capsules with a cream opaque cap / cream opaque body size ‘2’ HPMC capsules imprinted with ‘H’ on cap and ‘D10’ on body with black ink, filled with mixture of off white to yellowish white pellets.

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)]

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