Dabigatran Etexilate

Registered South African indications:

• Treatment of acute and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE)
• To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation
• Prevention of venous thromboembolic events in patients who have undergone hip and knee replacement surgery

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients
• Severe renal impairment (CrCI <30ml/min)
• Haemorrhagic manifestations, patients with a bleeding diathesis, or patients with spontaneous or pharmacological impairment of haemostasis
• Moderate to severe hepatic impairment (Child-Pugh B/C)
• Organ lesions at risk of clinically significant bleeding, including haemorrhagic stroke within the last 6 months
• Patients with an indwelling spinal or epidural catheter and during the first hour after removal
• Prolonged co-administration with heparins or warfarin
• Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir
• The following treatments should not be administered concomitantly with dabigatran etexilate: unfractionated heparins and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic medicines, GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, ticagrelor, dextran, sulfinpyrazone and Vitamin K antagonists. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter and that dabigatran etexilate and Vitamin K antagonists (e.g., warfarin) can be administered together, but only for a few days during switching from dabigatran etexilate to Vitamin K antagonist treatment
• Suspected infective endocarditis
• Prosthetic heart valve replacement

Cautions

• Pregnancy
• Breastfeeding
• Females of reproductive potential
• Moderate renal impairment
• Mild hepatic impairment
• Elderly
• Risk factors for haemorrhage
• Antiphospholipid syndrome
• Surgery or invasive procedures 
• High surgical mortality risk, with intrinsic risk factors for thromboembolic events
• Spinal anaesthesia
• Epidural anesthesia
• Lumbar puncture
• Risk for thromboembolic events
• Congenital or acquired coagulation disorders
• Thrombocytopenia
• Major trauma
• Bacterial endocarditis
• Active malignancy
• Weight <50kg
• Functional platelet defects
• Recent biopsy
• Oesophagitis
• Gastritis
• Gastroesophageal reflux

Forms avail. in SA and covered in this monograph: cap

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
Prevention of recurrent DVT and PE

• Oral (cap): 150mg, 12hrly

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5 days of parenteral anticoagulation required before initiation with dabigatran

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Duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding

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Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE

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Treatment therapy should be continued for up to 6 months and prevention therapy could be continued life-long depending on individual patient's risk factors

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Prevention of systemic embolism and stroke in patients with nonvalvular atrial fibrillation with one or more risk factors
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation

• Oral (cap): 150mg, 12hrly

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Therapy should be continued life-long

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Patients can stay on dabigatran while being cardioverted

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Catheter ablation for atrial fibrillation can be conducted at the above dose without interrupting dabigatran treatment

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Patients with nonvalvular atrial fibrillation who undergo a percutaneous coronary intervention with stenting can be treated with dabigatran in combination with antiplatelets after haemostasis is achieved

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Prevention of venous thromboembolic events in patients who have undergone knee replacement surgery

• Oral (cap): Initial: 110mg, as a single dose 1-4hrs after surgery; Maintenance: 220mg, daily; Treatment duration: 10 days

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Initiate once haemostasis has been established

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If treatment is not started on the day of surgery then initiate with 220mg, daily

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Prevention of venous thromboembolic events in patients who have undergone hip replacement surgery 

• Oral (cap): Initial: 110mg, as a single dose 1-4 hrs after surgery; Maintenance: 220mg, daily; Treatment duration: 28 days

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Initiate once haemostasis has been established

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If treatment is not started on the day of surgery then initiate with 220mg, daily

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For all indications, dose adjustment may be necessary for the elderly, moderate renal impairment, gastritis, oesophagitis or GORD or patients at high risk of bleeding

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Administration directions
Dabigatran etexilate can be taken with or without food. Dabigatran etexilate should be taken with a glass of water, to facilitate delivery to the stomach. Do not open the capsule. If gastrointestinal symptoms develop it is recommended to take dabigatran etexilate with a meal and/or a proton pump inhibitor such as pantoprazole

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See Additional Prescribing Points 

Not established for use in children below 18 years

Pregnancy

• Caution
• There is limited amount of data from the use of dabigatran etexilate in pregnant women.  Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown
• Women of childbearing potential should avoid pregnancy during treatment with dabigatran etexilate
• Dabigatran etexilate should not be used during pregnancy unless clearly necessary

Breastfeeding

• Caution; not recommended
• There are no clinical data of the effect of dabigatran on infants during breastfeeding
• Breastfeeding should be discontinued during treatment with dabigatran etexilate

Fertility

• No human data available
• Until safety data are available, adequate contraception is recommended during dabigatran therapy for females of childbearing potential. Women planning a pregnancy should be switched to alternative anticoagulants prior to conception
• In animal studies, an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed
• There was no influence on male fertility in animal studies

Renal Impairment

• Mild (CrCl 50-≤80ml/min): No dose adjustment recommended
• Moderate (CrCl 30-50ml/min): Caution; no dose adjustment recommended
  Consider dose adjustment for the following:
  High bleeding risk
  Oral (cap): 110-150mg, 12hrly; Consider dose adjustment based on individual assessment of the thromboembolic risk and the risk of bleeding
  For prevention of venous thromboembolic events in patients who have undergone hip or knee replacement surgery
  Oral (cap): 150mg, daily
• Severe (CrCl <30ml/min): Contraindicated

Hepatic Impairment

• Mild (Child-Pugh Class A): Caution; no information available
• Moderate to severe (Child-Pugh Classes B & C): Contraindicated

Elderly

• Caution; dose adjustment recommended
  75-80 years
  Oral (cap): 110-150mg, 12hrly; Consider dose adjustment based on individual assessment of the thromboembolic risk and the risk of bleeding
  ≥80 years
  Oral (cap): 110mg; 12hrly

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders 

• Intracranial haemorrhage

Respiratory Disorders 

• Haemoptysis
• Epistaxis
• Bronchospasm

Gastrointestinal Disorders 

• Gastrointestinal haemorrhage
• Haemorrhoidal haemorrhage
• Rectal haemorrhage
• Abdominal pain
• Nausea and vomiting
• Diarrhoea
• Dyspepsia
• Gastrointestinal ulcer
• Oesophageal ulcer
• Gastroesophageal reflux disease
• Gastroesophagitis
• Dysphagia

Hepatobiliary disorders

• Increased hepatic enzymes
• Hyperbilirubinaemia
• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Abnormal liver function tests
• Abnormal liver function

Genitourinary Disorders 

• Genitourological haemorrhage
• Haematuria

Musculoskeletal Disorders 

• Haemarthrosis

Skin and subcutaneous tissue disorder

• Skin haemorrhage
• Rash
• Pruritis
• Urticaria
• Injection site haemorrhage
• Aloplecia

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Decreased haemoglobin
• Thrombocytopenia
• Decreased haematocrit
• Neutropenia
• Agranulocytosis
• Hypersensitivity reactions
• Anaphylactic reactions
• Angioedema
• Haematoma
• Haemorrhage
• Post operative anaemia

Others

• Post procedural haematoma
• Post procedural haemorrhage
• Incision site haemorrhage
• Traumatic haemorrhage
• Catheter site haemorrhage
• Post procedural discharge
• Wound secretion

• Anticoagulants
• Unfractionated heparin
• Low molecular weight heparins
• Enoxaparin
• Dalteparin
• Heparin derivatives
• Fondaparinux
• Desirudin
• Warfarin
• Rivaroxaban
• Apixaban
• Vitamin K antagonists
• Antiplatelet aggregation agents
• GPIIb/IIIa antagonists
• Clopidogrel
• Ticlopidine
• Prasugrel
• Ticagrelor
• Dextran
• Sulfinpyrazone
• Thrombolytic agents
• Aspirin
• Non-steroidal anti-inflammatory agents
• P-glycoprotein inhibitors
• Ketoconazole
• Dronedarone
• Itraconazole
• Cyclosporine
• Glecaprevir
• Pibrentasvir
• Glecaprevir/pibrentasvir
• P-glycoprotein inducers
• Selective serotonin re-uptake inhibitors
• Selective serotonin norepinephrine re-uptake inhibitors
• Tacrolimus
• Verapamil
• Amiodarone
• Qunidine
• Clarithromycin
• Posaconazole
• Rifampicin
• Carbamazepine
• Phenytoin
• Protease inhibitors
• Ritonavir
• St. John's wort

• Renal function
• Full blood count
• Hepatic function

Specific cases may require

• Coagulation tests

Missed dose 

• Prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery: No double dose should be taken to make up for missed individual doses
• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; Treatment of deep vein thrombosis and pulmonary embolism: Missed dose may still be taken up to 6hrs prior to the next scheduled dose. No double dose should be taken to make up for missed individual doses

Switching to parenteral treatment

• Prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery: Wait 24hrs after the last dose before switching to parenteral treatment
• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; Treatment of deep vein thrombosis and pulmonary embolism: Wait 12hrs after the last dose before switching to parenteral treatment

Switching from other anticoagulants to dabigatran 

• Parenteral treatment: Give dabigatran within 2hrs prior to the time that the next dose of the parenteral treatment would be due or at discontinuation in the case of continuous treatment
• Vitamin K antagonists: Stop vit K antagonists; Dabigatran can be given as soon as the INR <2.0

Coagulation tests

• Dabigatran cannot be therapeutically monitored by coagulation tests
• The INR test is unreliable in patients on dabigatran and false positive INR elevations have been reported. Therefore INR tests should not be performed
• Tests of anticoagulant activity such as thrombin time (TT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) are available to detect excessive dabigatran activity
• Dabigatran related anticoagulation can be assessed by ECT or TT. If ECT or TT is not available, the aPTT test provides an approximation of dabigatran's anticoagulant activity. However, in patients who are bleeding aPTT tests may help determine an excess of anticoagulant activity

Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. 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.

Capsule 75mg

• Pradaxa  (Ingelheim) originator

Capsule 110mg

• Pradaxa  (Ingelheim) originator

Capsule 150mg

• Pradaxa (Ingelheim) originator