Dabigatran etexilate

Dabigatran etexilate Uses, Dosage, Side Effects, Food Interaction and all others data.

Dabigatran etexilate is an inactive pro-drug that is converted to dabigatran, the active form, by esterase-catalyzed hydrolysis in the plasma and liver. Dabigatran, the main active principle in plasma, is a rapid-acting competitive and reversible direct inhibitor of thrombin. Thrombin, a serine protease, is responsible for the conversion of fibrinogen to fibrin in the coagulation cascade. Inhibition of thrombin consequently prevents thrombus development. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

Dabigatran etexilate is a double prodrug that is hydrolyzed to the active dabigatran by intestinal and hepatic carboxylesterases. Dabigatran is a reversible competitive thrombin inhibitor that directly inhibits the conversion by thrombin of fibrinogen to fibrin, impairing the clotting process and acting as an anticoagulant. Dabigatran use prolongs coagulation markers such as the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), thrombin time (TT), and dilute thrombin time (dTT), but not the international normalized ratio (INR), which cannot be used in this context as it can in warfarin monitoring.

As with all anticoagulant therapies, dabigatran carries a risk of bleeding, which may increase with concomitant use of antiplatelet agents, fibrinolytic therapy, heparins, or chronic NSAID use, and should be monitored for. Premature discontinuation of dabigatran, in the absence of an alternative anticoagulant, also carries an increased risk of thromboembolic events. Due to the risk of an epidural or spinal hematoma, dabigatran should generally not be used in the context of neuraxial anesthesia or spinal puncture; if such use is unavoidable, careful monitoring should be employed. Dabigatran should not be used in patients with prosthetic heart valves due to an increased occurrence of major bleeding and thromboembolic events. Dabigatran is a substrate of the P-gp transporter and should generally not be administered together with P-gp inhibitors or inducers, especially in patients with impaired renal function. Lastly, dabigatran or any other direct-acting oral anticoagulant should not be administered in patients with triple-positive antiphospholipid syndrome (APS) due to an increased risk of recurrent thrombotic events. In case of the need for emergency reversal, idarucizumab is available for use in adult patients; the safety and efficacy of idarucizumab has not been established in pediatric patients yet, for whom reversal may be achieved through hemodialysis, prothrombin complex concentrates, or recombinant FVIIa. However, none of these have been sufficiently evaluated in clinical trials.

Dabigatran etexilate
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Dabigatran etexilate
Generic	Dabigatran etexilate
Dabigatran etexilate Other Names	Dabigatran etexilate
Type
Formula	C₃₄H₄₁N₇O₅
Weight	Average: 627.7332 Monoisotopic: 627.316917457
Protein binding	Dabigatran is ~35% bound to plasma proteins, including human serum albumin.
Groups	Approved
Therapeutic Class	Anti-coagulants, Anti-platelet drugs, Fibrinolytics (Thrombolytics)
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

Uses

Reduction Of Risk Of Stroke And Systemic Embolism In Non-valvular Atrial Fibrillation: Dabigatran is used to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

Treatment Of Deep Venous Thrombosis and Pulmonary Embolism: Dabigatran is used for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days.

Reduction In The Risk Of Recurrence Of Deep Venous Thrombosis And Pulmonary Embolism: Dabigatran is used to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated.

Prophylaxis Of Deep Vein Thrombosis And Pulmonary Embolism Following Hip Replacement Surgery: Dabigatran is used for the prophylaxis of deep vein thrombosis and pulmonary embolism, in patients who have undergone hip replacement surgery.

Dabigatran etexilate is also used to associated treatment for these conditions: Deep Vein Thrombosis, Deep vein thrombosis recurrent, Pulmonary Embolism, Recurrent pulmonary embolism, Stroke, Systemic Embolism, Venous Thromboembolism

How Dabigatran etexilate works

Hemostasis is a complex process that balances coagulation to prevent excessive thrombus formation or excessive bleeding. Central to the coagulation process is the serine protease thrombin (FIIa), which is synthesized as inactive prothrombin (FII) and subsequently activated by FXa/FVa, leading to a positive feedback loop and the production of large quantities of thrombin; once enough thrombin is formed, it cleaves soluble fibrinogen to form insoluble fibrin fibres that, together with aggregated platelets, form a clot. Although beneficial in wound healing, aberrant thrombus formation can lead to serious health consequences.

Dabigatran is a univalent reversible direct thrombin inhibitor (DTI) that competitively inhibits thrombin with a K_i of 4.5 ± 0.2 nmol/L. Furthermore, the reversible nature of the inhibition is believed to allow for some normal physiological thrombin function, which may help alleviate some adverse effects associated with anticoagulation therapy. In addition, dabigatran has several glucuronidated metabolites, all of which have been shown to possess in vitro activity similar to the parent compound.

In addition to a direct effect on thrombin activity, dabigatran has also been shown to inhibit platelet aggregation, another step in the coagulation pathway. However, the mechanism remains unclear as dabigatran inhibits platelet aggregation stimulated by thrombin and von Willebrand factor (vWF), but not by other pathways such as ADP- or thromboxane A2-induced aggregation.

Dosage

Dabigatran etexilate dosage

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: For patients with creatinine clearance >30 mL/min, the recommended dose of Dabigatran is 150 mg taken orally, twice daily. For patients with severe renal impairment 15-30 mL/min, the recommended dose of Dabigatran is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or ondialysiscannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran is 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

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran 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

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran is 110 mg taken orally 1-4 hours after surgery and afterhemostasishas been achieved, then 220 mg taken once daily for 28-35 days. If Dabigatran is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided

May be taken with or without food. Swallow whole, do not chew or crush.

Side Effects

The following serious adverse reactions are observed:

Increased Risk of Thrombotic Events after Premature Discontinuation
Risk of Bleeding
Spinal/Epidural Anesthesia or Puncture
Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The most serious adverse reactions reported with Dabigatran were related to bleeding

Toxicity

No human studies involving pregnancy, labor and delivery, nursing, or pediatrics. Geriatric patients are at higher risk of adverse effects than younger patients but the risk to benefit ratio is generally still favourable for older patients. Patients with a creatinine clearance of 15-30mL/min should have their doses of dabigatran etexilate reduced, and no data is available for patients with a creatinine clearance below 15mL/min.

In animal studies, dabigatran increases the rates of dead offspring and causes uterine and vaginal bleeding close to birth. Dabigatran may or may not be excreted in breast milk so the risk and benefit of stopping the drug or stopping breast feeding must be considered.

Precaution

Hepatic impairment; hemorrhagic risk; spinal or epidural anesth, lumbar puncture. Pregnancy & lactation. Childn <18 yr.

Interaction

Vit K antagonist, amiodarone, verapamil, quinidine, clarithromycin, ketoconazole, rifampicin, St. John's wort, carbamazepine.

Food Interaction

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
Avoid St. John's Wort. This herb induces PGP which may reduce the serum levels of dabigatran.
Take with a full glass of water.
Take with or without food.

Volume of Distribution

Dabigatran has a volume of distribution of 50-70L.

Elimination Route

Oral dabigatran has a bioavailability of 3-7%, although the relative bioavailability of dabigatran pellets is 37% higher than that for capsules and the bioavailability increases to 75% when the capsule shell is removed; dabigatran capsules should not be tampered with in any way prior to administration. The C_max is achieved by one hour following oral dosing, which is extended to two hours if accompanied by a high-fat meal. Dabigatran can be taken with or without food. Dabigatran pharmacokinetics are approximately linear over a range of 10-400 mg in healthy adults and adult patients and it has an accumulation factor of two in adult and pediatric patients.

Half Life

Dabigatran has a half-life of 12-17 hours in adult patients and 12-14 hours in pediatric patients.

Clearance

Following intravenous administration, renal clearance constitutes ~80% of total dabigatran clearance.

Elimination Route

Dabigatran is primarily eliminated in the urine. Following oral administration of radiolabeled dabigatran, 7% of the radioactivity is recovered in urine and 86% is recovered in feces.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Safety and effectiveness of Dabigatran during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using Dabigatran in this setting. It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Dabigatran , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Severe renal impairment (CrCl <30 mL/min). Haemorrhagic manifestations, bleeding diathesis, spontaneous or pharmacological impairment of haemostatis. Organ lesions at risk of clinically significant bleeding, indwelling spinal or epidural catheter & during the 1st hr after removal. Concomitant treatment with systemic ketoconazole.

Special Warning

Pediatric Use: Safety and effectiveness of Dabigatran in pediatric patients have not been established.

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