Dabigatran: uses, appearance and warnings

Dabigatran Etexilate Capsules is 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 to 10 days ( 1.2 ) To reduce the risk of recurrence of DVT and PE in adult patients who have been previously treated ( 1.3 ) For the prophylaxis of DVT and PE in adult patients who have undergone hip replacement surgery ( 1.4 ) For the treatment of venous thromboembolic events (VTE) in pediatric patients 8 to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days ( 1.5 ) To reduce the risk of recurrence of VTE in pediatric patients 8 to less than 18 years of age who have been previously treated ( 1.6 ) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients Dabigatran Etexilate Capsules is 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 is 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 is indicated to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in adult patients who have been previously treated. 1.4 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery Dabigatran Etexilate Capsules is indicated for the prophylaxis of deep vein thrombosis and pulmonary embolism in adult patients who have undergone hip replacement surgery. 1.5 Treatment of Venous Thromboembolic Events in Pediatric Patients Dabigatran Etexilate Capsules is indicated for the treatment of venous thromboembolic events (VET) in pediatric patients 8 to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days [see Dosage and Administration (2.3)]. 1.6 Reduction in the Risk of Recurrence of Venous Thromboembolic Events in Pediatric Patients Dabigatran Etexilate Capsules is indicated to reduce the risk of recurrence of VTE in pediatric patients 8 to less than 18 years of age who have been previously treated [see Dosage and Administration (2.3)].

150 mg capsules with a white to pale yellow pellets filled in HPMC capsule size “0EL” light navy blue opaque cap and light cream opaque body imprinted with “150” on body and “DAB” on cap in black ink. 110 mg capsules with a white to pale yellow pellets filled in HPMC capsule size "0" light blue opaque body and light blue opaque cap imprinted with "110" on body and "Dab" on cap in black ink. 75 mg capsules with a white to pale yellow pellets filled in HPMC capsule size “1” light cream opaque cap and light cream opaque body imprinted with “DAB” on cap and “75” on body in black ink. Capsules: 75 mg, 110 mg and 150 mg ( 3 )

Dabigatran Etexilate Capsules 75 mg capsules have a light cream opaque cap and light cream opaque body imprinted with “DAB” on cap and “75” on body in black ink. The capsules are supplied in the packages listed: • NDC 67877-474-60 Unit of use bottle of 60 capsules • NDC 67877-474-31 Blister package containing 60 capsules (6 x 10 Unit-dose) Dabigatran Etexilate Capsules 110 mg capsules have a light blue opaque body and light blue opaque cap imprinted with "110" on body and "Dab" on cap in black ink. The capsules are supplied in the packages listed: • NDC 67877-624-60 Unit of use bottle of 60 capsules • NDC 67877-624-31 Blister package containing 60 (10 x 6) Unit-dose Capsules Dabigatran Etexilate Capsules 150 mg capsules have a light navy blue opaque cap and light cream opaque body imprinted with “150” on body and “DAB” on cap in black ink. The capsules are supplied in the packages listed: • NDC 67877-475-60 Unit of use bottle of 60 capsules • NDC 67877-475-31 Blister package containing 60 capsules (6 x 10 Unit-dose) Bottles Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Once opened, the product must be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect from moisture. Blisters Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original package to protect from moisture. Keep out of the reach of children.

Dabigatran Etexilate Capsules is contraindicated in patients with: • Active pathological bleeding [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] • History of a serious hypersensitivity reaction to dabigatran, dabigatran etexilate, or to one of the excipients of the product (e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions ( 6.1 )] • Mechanical prosthetic heart valve [see Warnings and Precautions ( 5.4 )] • Active pathological bleeding ( 4) • History of serious hypersensitivity reaction to Dabigatran Etexilate Capsules ( 4 ) • Mechanical prosthetic heart valve ( 4 )

• Bleeding: Dabigatran Etexilate Capsules can cause serious and fatal bleeding ( 5.2 ) • Bioprosthetic heart valves: Dabigatran Etexilate Capsules use not recommended ( 5.4 ) • Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate Capsules use not recommended ( 5.6 ) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including Dabigatran Etexilate Capsules, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If Dabigatran Etexilate Capsules is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart Dabigatran Etexilate Capsules as soon as medically appropriate [see Dosage and Administration (2.6, 2.7, 2.8)]. 5.2 Risk of Bleeding Dabigatran Etexilate Capsules 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 Etexilate Capsules’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 Etexilate Capsules 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 Etexilate Capsules and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic 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. 5.4 Thromboembolic 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 Etexilate Capsules is contraindicated in all patients with mechanical prosthetic valves [see Contraindications (4)]. The use of Dabigatran Etexilate Capsules for 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 The concomitant use of Dabigatran Etexilate Capsules with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3)] . …

The following clinically significant adverse reactions are described elsewhere in the labeling: Increased Risk of Thrombotic Events after Premature Discontinuation [see Warnings and Precautions (5.1)] Risk of Bleeding [see Warnings and Precautions (5.2)] Spinal/Epidural Anesthesia or Puncture [see Warnings and Precautions (5.3)] Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves [see Warnings and Precautions (5.4)] Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome [see Warnings and Precautions (5.6)] The most serious adverse reactions reported with Dabigatran Etexilate Capsules were related to bleeding [see Warnings and Precautions (5.2)] . …

P-gp inducers: Avoid coadministration with Dabigatran Etexilate Capsules ( 5.5 ) P-gp inhibitors in adult patients with CrCl 30 to 50 mL/min: Reduce dosage or avoid ( 7 ) P-gp inhibitors in adult patients with CrCl <30 mL/min: Not recommended ( 7 ) 7.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients The concomitant use of Dabigatran Etexilate Capsules with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3)] . P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3)] . Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. …