Pharmacodynamic properties:-

Pharmacotherapeutic group:

Antithrombotic agents, direct thrombin inhibitors.
 

Mechanism of Action:-

Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma. Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.
 

Pharmacokinetic Properties:-

After oral administration, Dabigatran etexilate is rapidly and completely converted to Dabigatran, which is the active form in plasma. The cleavage of the prodrug Dabigatran etexilate by esterase-catalyzed hydrolysis to the active principle Dabigatran is the predominant metabolic reaction. The absolute bioavailability of Dabigatran following oral administration of Dabigatran was approximately 6.5 %after oral administration of Dabigatran in healthy volunteers, the pharmacokinetic profile of Dabigatran in plasma is characterized by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0 hours post administration.

• Absorption
  A study evaluating post-operative absorption of Dabigatran etexilate, 1-3 hours following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached at 6 hours following administration in a postoperative period due to contributing factors such as anesthesia, GI paresis, and surgical effects independent of the oral medicinal product formulation. It was demonstrated in a further study that slow and delayed absorption is usually only present on the day of surgery. On subsequent days absorption of Dabigatran is rapid with peak plasma concentrations attained 2 hours after medicinal product administration. Food does not affect the bioavailability of Dabigatran etexilate but delays the time to peak plasma concentrations by 2 hours. Cmax and AUC were dose proportional. The oral bioavailability may be increased by 75 % after a single dose and 37 % at steady state compared to the reference capsule formulation when the pellets are taken without the Hydroxypropyl methylcellulose (HPMC) capsule shell.
• Distribution
  Low (34-35 %) concentration independent binding of Dabigatran to human plasma proteins was observed. The volume of distribution of Dabigatran of 60-70 L exceeded the volume of total body water indicating moderate tissue distribution of Dabigatran.
• Biotransformation:
  After oral administration, Dabigatran etexilate is rapidly and completely converted to Dabigatran, which is the active form in plasma. The cleavage of the prodrug Dabigatran etexilate by esterase catalyzed hydrolysis to the active principle Dabigatran is the predominant metabolic reaction. Dabigatran is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10% of total Dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods.
• Elimination:
  Plasma concentrations of Dabigatran showed a bi exponential decline with a mean terminal half-life of 11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired.

• Aspirin, salicylates or other NSAID (anti-inflammatory) medicines
• Medicines used to thin your blood (such as warfarin, unfractionated heparins, heparin derivatives, low molecular weight heparins (enoxaparin), clopidogrel, tirofiban, bivalirudin, prasugrel, ticagrelor, eptifibatide, ticlopidine, dextran, sulfinpyrazone, rivaroxaban and apixaban).
• Amiodarone, dronedarone, medicines used to treat irregular heartbeats.
• Verapamil, a calcium channel blocker used to treat high blood pressure and angina
• Quinidine, a medicine used to treat malaria and irregular heartbeats
• Clarithromycin or rifampicin, medicines used to treat infections
• Lopinavir, nelfinavir, ritonavir, tipranavir or saquinavir, medicines used to treat HIV infections.
• Cyclosporine or tacrolimus, medicines used to help the body's immune system.
• Selective serotonin re-uptake inhibitors (SSRI) (e.g. citalopram, escitalopram, fluoxetine), selective serotonin norepinephrine re-uptake inhibitors (SNRI) (e.g. duloxetine, venlafaxine, desvenlafaxine), medicines used to treat mood disorders.
• Herbal medicines derived from St John's wort (Hypericum perforatum).
• Carbamazepine, a medicine used to treat fits or convulsions.
• Medicines used to treat reflux and stomach ulcers (such as pantoprazole and ranitidine).

• Prevention of venous thromboembolic events in adult patients who have undergone major orthopedic surgery of the lower limb (elective total hip or knee replacement).
• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke.
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and PE in adults.

Primary prevention of Venous Thromboembolism in orthopedic Surgery

Clinical Conditions	Dose recommendation
Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF)	Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF) 300 mg DABICLOT taken as one 150 mg capsule twice daily
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE)	300 mg t DABICLOT taken as one 150 mg capsule twice daily following treatment with a parenteral anticoagulant for at least 5 days
Dose reduction recommended
Patients aged ≥80 years	daily dose of 220 mg DABICLOT taken as one 110 mg capsule twice daily
Patients who receive concomitant verapamil	-
Dose reduction for consideration
Patients between 75-80 years	-
Patients with moderate renal impairment (CrCL 30-50 mL/min)	Daily dose of DABICLOT of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding.
Patients with gastritis, esophagitis or gastro esophageal reflux	-
Other patients at increased risk of bleeding	-

Duration of Use
The duration of use of DABICLOT in the indications SPAF, DVT and PE are shown in table

Indication Duration of Use
SPAF	Therapy should be continued long term.
DVT/PE	The duration of therapy should be individualized after careful assessment of the treatment benefit against the risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, and immobilization) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.

• Patients at risk of bleeding:
  Patients with an increased bleeding risk should be closely monitored clinically (looking for signs of bleeding or anemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient . A coagulation test may help to identify patients with an increased bleeding risk caused by excessive Dabigatran exposure. When excessive Dabigatran exposure is identified in patients at high risk of bleeding, a reduced dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted. For subjects with gastritis, esophagitis, or gastro esophageal reflux, a dose reduction may be considered due to the elevated risk of major gastro-intestinal bleeding.
• Renal impairment:
  Treatment with DABICLOT in patients with severe renal impairment (CrCL < 30 mL/min) is contraindicated .No dose adjustment is necessary in patients with mild renal impairment (CrCL 50- ≤ 80 mL/min). For patients with moderate renal impairment (CrCL 30-50 mL/min) the recommended dose of DABICLOT is also 300 mg taken as one 150 mg capsule twice daily. However, for patients with high risk of bleeding, a dose reduction of DABICLOT to 220 mg taken as one 110 mg capsule twice daily should be considered. Close clinical surveillance is recommended in patients with renal impairment.
• Concomitant use of DABICLOT with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. Amiodarone, quinidine or verapamil. No dose adjustment is necessary for concomitant use of Amiodarone or quinidine. Dose reductions are recommended for patients who receive concomitantly verapamil .In this situation DABICLOT and verapamil should be taken at the same time.
• Weight:
  No dose adjustment is necessary, but close clinical surveillance is recommended in patients with a body weight < 50 kg.
• Gender:
  No dose adjustment is necessary
• Pediatrics population
  There is no relevant use of DABICLOT in the Pediatric population for the indication of prevention of stroke and systemic embolism in patients with NVAF. For the indication DVT/PE, the safety and efficacy of DABICLOT in children from birth to less than 18 years of age have not yet been established.

DABICLOT is for oral use. The capsules can be taken with or without food. DABICLOT should be swallowed as a whole with a glass of water, to facilitate delivery to the stomach.

They are ranked under headings of System Organ Class (SOC) and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

	Frequency
SOC / Preferred term	Stroke and systemic embolism prevention in patients witd atrial fibrillation	DVT/PE treatment and DVT/PE prevention
Blood and lymphatic system disorders
Anemia	Common	-
Hemoglobin decreased	Uncommon	Not Known
Thrombocytopenia	Uncommon	Rare
Hematocrit decreased	Rare	Not Known
Immune system disorder
Drug hypersensitivity	Uncommon	Uncommon
Rash	Uncommon	Uncommon
Pruritus	Uncommon	Uncommon
Anaphylactic reaction	Rare	Rare
Urticaria	Rare	Rare
Angioedema	Rare	Rare
Bronchospasm	Not known	Not known
Nervous system disorders
Intracranial hemorrhage	Uncommon	Rare
Vascular disorders
Hematoma	Uncommon	Common
Respiratory, thoracic and mediastinal disorders Epistaxis	Common	Common
Hemoptysis	Uncommon	Uncommon
Gastrointestinal disorders
Gastrointestinal hemorrhage	Common	Common
Abdominal pain	Common	Uncommon
Diarrhea	Common	Uncommon
Dyspepsia	Common	Common
Nausea	Common	Uncommon
Rectal hemorrhage	Uncommon	Common
Rectal hemorrhage	Uncommon	Common
Haemorrhoidal hemorrhage	Uncommon	Uncommon
Gastrointestinal ulcer	Uncommon	Uncommon
Gastro esophagitis	Uncommon	Uncommon
Vomiting	Uncommon	Uncommon
Dysphagia	Uncommon	Uncommon
Gastro esophageal reflux disease	Uncommon	Rare
Hepatobiliary disorders
Hepatic function abnormal/ Liver function Test abnormal	Uncommon	Uncommon
Alanine aminotransferase increased	Uncommon	Uncommon
aspartate aminotransferase increased	Uncommon	Uncommon
Hepatic enzyme increased	Rare	Uncommon
Hyperbilirubinaemia	Rare	Not Known
Skin and subcutaneous tissue disorder
Skin hemorrhage	Common	Common
Musculoskeletal and connective tissue disorders
Haemarthrosis	Rare	Uncommon
Renal and urinary disorders
Genitourological hemorrhage, including hematuria	Common	Common
General disorders and administration site conditions
Injection site hemorrhage	Rare	Rare
Catheter site hemorrhage	Rare	Rare
Injury, poisoning and procedural complications
Traumatic hemorrhage	Rare	Uncommon
Incision site hemorrhage	Rare	Rare

Hemorrhagic risk

DABICLOT should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting hemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy with DABICLOT. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site. In clinical trials, DABICLOT was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (≥ 75 years) for the 150 mg twice daily dose regimen. Further risk factors comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non-steroidal anti-inflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastro esophageal reflux.
 

Women of childbearing potential

Women of childbearing potential should avoid pregnancy during treatment with Dabiclot.
 

Pregnancy

There is limited amount of data from the use of Dabiclot in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Dabiclot should not be used during pregnancy unless clearly necessary.
 

Breast-feeding

There are no clinical data of the effect of Dabigatran on infants during breast-feeding. Breast-feeding should be discontinued during treatment with Dabiclot.

• Hypersensitivity to the active substance or to any of the excipients
• Patients with severe renal impairment (CrCL < 30 mL/min)
• Active clinically significant bleeding
• Lesion or condition, if considered a significant risk factor for major bleeding.
• Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc.), heparin derivatives (fondaparinux etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban etc.) except under specific circumstances.
• Hepatic impairment or liver disease expected to have any impact on survival
• Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole and dronedarone
• Prosthetic heart valves requiring anticoagulant treatment.