Dabigatran Etexilate Mesylate

Approved Indications:

1. Prevention of Stroke and Systemic Embolism:

• In patients with non-valvular atrial fibrillation (NVAF) at risk of stroke or systemic embolism.

2. Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE):

• For patients with acute DVT or PE following initial treatment with a parenteral anticoagulant for 5–10 days.

3. Secondary Prevention of DVT and PE:

• To reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

4. Thromboprophylaxis in Orthopedic Surgery:

• Prevention of venous thromboembolism (VTE) in patients undergoing hip replacement surgery.

Clinically Accepted Off-label Uses:

• Alternative to warfarin in some cases of mechanical heart valves (note: with caution; not routinely recommended).
• Use in cancer-associated thrombosis (CAT) in specific patients as part of individualized anticoagulation plans.

General Administration:

• Route: Oral
• Form: Capsules (usually 75 mg, 110 mg, and 150 mg)
• Must be swallowed whole with water. Do not chew, break, or open capsules.

A. Stroke Prevention in NVAF (Adults):

• Recommended Dose: 150 mg twice daily.
• Dose Adjustment (Age ≥75 or renal impairment): 110 mg twice daily may be considered.

B. DVT/PE Treatment:

• After 5–10 days of parenteral anticoagulant (e.g., enoxaparin): 150 mg twice daily.

C. Prevention of Recurrent DVT/PE:

• 150 mg twice daily.

D. VTE Prophylaxis Post-Hip Replacement Surgery:

• 110 mg on the first day (1–4 hours post-surgery), followed by 220 mg once daily for 28–35 days.

Special Populations:

Renal Impairment:

• CrCl ≥30 mL/min: No dose adjustment.
• CrCl 15–30 mL/min: Consider reduced dose (e.g., 75 mg twice daily; region-specific recommendation).
• CrCl <15 mL/min or on dialysis: Use is not recommended.

Hepatic Impairment:

• Avoid use in moderate to severe hepatic impairment (Child-Pugh B or C).

Elderly:

• Monitor renal function. Lower dose (110 mg BID) may be preferred in age >75 years.

Pediatrics:

• Approved for pediatric use in some regions with weight-based dosing (e.g., oral pellets or capsules); refer to specialized guidance.

Dabigatran etexilate mesylate is a direct thrombin inhibitor. It is a prodrug that is rapidly converted by esterases to dabigatran, its active form. Dabigatran selectively and reversibly binds to both free and clot-bound thrombin (Factor IIa), preventing the conversion of fibrinogen to fibrin, thereby inhibiting thrombus formation. Unlike warfarin, it acts independently of antithrombin III and does not affect other clotting factors, offering a more targeted anticoagulant effect. The inhibition of thrombin also prevents thrombin-induced platelet aggregation.

Absorption:

• Rapidly absorbed after oral administration.
• Bioavailability: ~6.5%.

Distribution:

• Plasma protein binding: ~35%.
• Volume of distribution: 50–70 L.

Metabolism:

• Dabigatran etexilate is a prodrug hydrolyzed by esterases to dabigatran.
• Not significantly metabolized by CYP450 enzymes.

Elimination:

• Primarily renal (~80% of active drug excreted unchanged in urine).
• Minor biliary/fecal elimination.

Half-life:

• ~12–17 hours in healthy adults.
• Prolonged in renal impairment.

Onset of Action:

• Peak plasma concentration reached within 1–2 hours.

Steady-State:

• Reached within 2–3 days of twice-daily dosing.

Pregnancy:

• FDA Category C (prior system).
• Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• No adequate human data; animal studies have shown reproductive toxicity at high doses.

Lactation:

• Unknown if dabigatran is excreted in human milk.
• Due to the potential for serious bleeding risks in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug.

Caution:

• Avoid use in pregnant and breastfeeding women unless clearly needed and under specialist care.

• Primary Class: Anticoagulant
• Subclass: Direct Oral Anticoagulant (DOAC)
• Generation: Direct Thrombin (Factor IIa) Inhibitor

• Hypersensitivity to dabigatran or any component of the formulation.
• Active pathological bleeding.
• Severe renal impairment (CrCl <15 mL/min).
• Prosthetic mechanical heart valves (due to increased thromboembolic and bleeding risk).
• Hepatic disease associated with coagulopathy and risk of bleeding.
• Recent major surgery or trauma with high bleeding risk.
• Concomitant treatment with other anticoagulants (e.g., heparin, warfarin) unless switching regimens or during bridging therapy.

• Bleeding Risk: Monitor closely for signs of bleeding; increased risk in elderly, renal impairment, and concurrent use with NSAIDs or antiplatelets.
• Spinal/Epidural Hematoma Risk: Avoid neuraxial anesthesia without appropriate interruption due to hematoma risk.
• Renal Function Monitoring: Required before initiation and periodically during treatment.
• GI Adverse Effects: Higher risk of dyspepsia and GI bleeding compared to other DOACs.
• Surgical Consideration: Discontinue dabigatran 1–2 days before surgery (3–5 days if high bleeding risk or impaired renal function).

Common Side Effects:

• Gastrointestinal:
• Dyspepsia
• Abdominal discomfort
• Gastritis-like symptoms
• Bleeding-Related:
• Bruising
• Epistaxis
• Hematuria
• Gingival bleeding
• Menorrhagia

Serious Adverse Effects:

• Major bleeding (e.g., intracranial, gastrointestinal, or retroperitoneal hemorrhage)
• Hypersensitivity reactions (rash, pruritus, anaphylaxis)
• Hepatic dysfunction (rare)
• Spinal or epidural hematoma (especially with neuraxial anesthesia)

Timing & Severity:

• Bleeding can occur at any time and is dose- and renal function-dependent.
• GI effects tend to appear early and may resolve with continued use or dose adjustment.

Major Drug-Drug Interactions:

• P-gp Inhibitors (e.g., amiodarone, verapamil, ketoconazole): May increase dabigatran levels; dose adjustment or avoidance may be needed.
• P-gp Inducers (e.g., rifampin, carbamazepine): May decrease effectiveness.
• Antiplatelet Agents (e.g., aspirin, clopidogrel): Increased bleeding risk.
• NSAIDs: Additive bleeding risk.
• Other Anticoagulants: Avoid concurrent use except when transitioning.

Drug-Food Interactions:

• No significant food interactions.
• Can be taken with or without meals.

Drug-Alcohol Interactions:

• Alcohol increases bleeding risk when combined with anticoagulants; limit or avoid concurrent use.

Enzyme System Involvement:

• Dabigatran is not metabolized by CYP450 but is a substrate of P-glycoprotein (P-gp) transport system.

• 2023–2025 Anticoagulation Guidelines: Dabigatran remains a first-line oral anticoagulant in non-valvular atrial fibrillation and VTE.
• FDA & EMA Advisory: Use in patients with mechanical prosthetic heart valves remains contraindicated due to thromboembolic and bleeding risks.
• Antidote Availability: Idarucizumab is an FDA- and EMA-approved reversal agent for dabigatran in emergency situations (e.g., life-threatening bleeding or urgent surgery).

• Temperature: Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F).
• Humidity Protection: Store in original packaging to protect from moisture.
• Light Protection: No special requirements.
• Handling Precautions:
• Do not open or crush capsules.
• Blister packs should be used immediately upon opening.
• Refrigeration/Reconstitution: Not required.