HETSOLID 110

Indications

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
• Treatment of deep vein thrombosis (DVT)
• Treatment of pulmonary embolism (PE)
• Prevention of recurrent DVT and PE

Dosage

Adults: Refer

Mechanism of action

Dabigatran and its acyl glucuronides act as competitive, direct inhibitors of thrombin, a serine protease crucial in the coagulation cascade. By inhibiting thrombin, dabigatran prevents the conversion of fibrinogen into fibrin, which is essential for clot formation. This action not only inhibits thrombin-induced platelet aggregation but also enhances fibrinolysis by affecting the viscoelastic properties of clots, leading to more permeable and less rigid fibrin structures, thereby promoting clot lysis.

Pharmacodynamics

Dabigatran's pharmacodynamic profile is characterized by its ability to provide rapid and predictable anticoagulation without the need for routine monitoring. The drug exhibits a dose-dependent effect on thrombin inhibition, leading to an anti-coagulant effect that is evident shortly after administration. Its effects are influenced by renal function, as dabigatran is primarily eliminated through the kidneys, and dosage adjustments may be necessary in patients with renal impairment.

Pharmacokinetics

Dabigatran has a bioavailability of approximately 3-7% when taken orally due to extensive first-pass metabolism. Peak plasma concentrations are achieved within 1-2 hours after administration. The drug is primarily excreted unchanged via the kidneys, with renal clearance being a significant pathway for its elimination. The half-life of dabigatran ranges from 12 to 17 hours in healthy individuals but can be prolonged in patients with renal impairment.

Contra-indications

• Active bleeding
• Severe renal impairment (creatinine clearance < 30 mL/min)
• Hypersensitivity to dabigatran or any of its excipients
• Mechanical prosthetic heart valves

Adverse effects

• Bleeding complications
• Gastrointestinal disturbances (e.g., dyspepsia, nausea)
• Increased liver enzymes
• Skin reactions (e.g., rash, pruritus)
• Anemia

Interactions

• Dronedarone - severe (increases exposure)
• Carbamazepine - severe (decreases exposure)
• Phenytoin - severe (decreases exposure)
• Ciclosporin - severe (increases exposure)
• Cobicistat - severe (increases exposure)
• Glecaprevir with pibrentasvir - severe (increases exposure)
• Ritonavir - severe (increases exposure)
• HIV-protease inhibitors boosted with ritonavir - severe (increases exposure)
• Letermovir - severe (decreases concentration)

Precautions

• Monitor renal function regularly
• Use with caution in patients with a history of gastrointestinal bleeding
• Discontinue prior to surgical procedures based on bleeding risk
• Consider the risk of bleeding in elderly patients

Pregnancy

Not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Not recommended as dabigatran may be excreted in breast milk.

Storage

Store in the original package to protect from moisture. Keep out of reach of children.

Formulations

• Capsules: 75 mg, 110 mg, 150 mg

Indications

• Prevention of venous thromboembolism in patients undergoing elective orthopedic surgery
• Treatment of venous thromboembolism
• Prevention of recurrent venous thromboembolism

Dosage

Children: Refer to the BNF for Children for appropriate dosages as paediatric dosing information is not provided here.

Adults: Refer to the relevant dosage guidelines in clinical practice or the BNF as dosing may vary based on indication and patient-specific factors.

Mechanism of action

Etexilate exerts its anticoagulant effect by selectively inhibiting Factor Xa, a key enzyme in the coagulation cascade that converts prothrombin to thrombin. By inhibiting Factor Xa, etexilate effectively prevents the conversion of fibrinogen to fibrin, thereby inhibiting clot formation and promoting anticoagulation.

Pharmacodynamics

The pharmacodynamic effects of etexilate include dose-dependent anticoagulation, measured by assays such as anti-factor Xa activity. The onset of action is typically rapid, with peak effects occurring within a few hours of administration. The anticoagulant response is maintained as long as the drug is present in the system, allowing for predictable dosing regimens without the need for routine monitoring of coagulation parameters in most patients.

Pharmacokinetics

Etexilate is well absorbed following oral administration, with bioavailability being influenced by food intake. It undergoes extensive first-pass metabolism to its active form. The elimination half-life is approximately 9-13 hours, allowing for once-daily dosing in most clinical scenarios. The drug is primarily excreted via the kidneys, necessitating dose adjustments in patients with renal impairment. Additionally, etexilate is metabolized by cytochrome P450 enzymes, which may lead to potential drug interactions.

Contra-indications

• Severe hypersensitivity to etexilate or any of its components
• Active bleeding disorders
• Severe hepatic impairment

Adverse effects

• Bleeding complications
• Thrombocytopenia
• Gastrointestinal disturbances such as nausea and diarrhea
• Headache
• Elevated liver enzymes

Interactions

• Anticoagulants may have additive effects leading to increased bleeding risk
• Strong CYP3A4 inducers may decrease the efficacy of etexilate
• Strong CYP3A4 inhibitors may increase the concentration and effects of etexilate

Precautions

• Use with caution in patients with a history of bleeding disorders
• Monitor liver function regularly in patients with pre-existing liver conditions
• Consider renal function when prescribing, as adjustments may be necessary

Pregnancy

Etexilate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines and clinical judgment.

Breast-feeding

Etexilate is excreted in breast milk. Caution should be exercised when administered to nursing mothers.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension

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. ... To evaluate the profibrinolytic effect of dabigatran, a new, direct thrombin inhibitor, using different in vitro models. The resistance of tissue factor-induced plasma clots to fibrinolysis by exogenous tissue-type plasminogen activator (t-PA) (turbidimetric method) was reduced by dabigatran in a concentration-dependent manner, with > or = 50% shortening of lysis time at clinically relevant concentrations (1-2 um). A similar effect was observed in the presence of low (0.1 and 1 nm) but not high (10 nm) concentrations of thrombomodulin. Acceleration of clot lysis by dabigatran was associated with a reduction in TAFI activation and thrombin generation, and was largely, although not completely, negated by an inhibitor of activated TAFI, potato tuber carboxypeptidase inhibitor. The assessment of the viscoelastic properties of clots showed that those generated in the presence of dabigatran were more permeable, were less rigid, and consisted of thicker fibers. The impact of these physical changes on fibrinolysis was investigated using a model under flow conditions, which demonstrated that dabigatran made the clots markedly more susceptible to flowing t-PA, by a mechanism that was largely TAFI-independent. Dabigatran, at clinically relevant concentrations, enhances the susceptibility of plasma clots to t-PA-induced lysis by reducing TAFI activation and by altering the clot structure. These mechanisms might contribute to the antithrombotic activity of the drug.