DABIGATRAN ETEXILATE

Posology Dabigatran etexilate capsules can be used in adults and paediatric patients aged 8 years or older who are able to swallow the capsules whole. Dabigatran etexilate coated granules can be used in children aged less than 12 years as soon as the child is able to swallow soft food.

Dabigatran etexilate is only available as hard capsules. For paediatric patients aged less than 8 years please refer to other products. When changing between the formulations, the prescribed dose may need to be altered. The dose stated in the relevant dosing table of a formulation should be prescribed based on the weight and age of the child.

Primary prevention of VTE in orthopaedic surgery The recommended doses of dabigatran etexilate and the duration of therapy for primary prevention of VTE in orthopaedic surgery are shown in table 1.

Table 1:

Dose recommendations and duration of therapy for primary prevention of VTE in orthopaedic surgery Treatment initiation on the day of surgery 1-4 hours after completed surgery Maintenance dose starting on the first day after surgery Duration of maintenance dose Patients following elective knee replacement surgery 10 days Patients following elective hip replacement surgery single capsule of 110 mg dabigatran etexilate 220 mg dabigatran etexilate once daily taken as 2 capsules of 110 mg 28-35 days Dose reduction recommended Patients with moderate renal impairment (creatinine clearance (CrCL) 30-50 mL/min) Patients who receive concomitant verapamil*, amiodarone, quinidine Patients aged 75 or above single capsule of 75 mg dabigatran etexilate 150 mg dabigatran etexilate once daily taken as 2 capsules of 75 mg 10 days (knee replacement surgery) or 28- 35 days (hip replacement surgery) *For patients with moderate renal impairment concomitantly treated with verapamil see Special populations For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed.

If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily. e. 2). g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products). The method to be used to estimate renal function (CrCL in mL/min) is the Cockcroft- Gault method.

Missed dose It is recommended to continue with the remaining daily doses of dabigatran etexilate at the same time of the next day. No double dose should be taken to make up for missed individual doses. Discontinuation of dabigatran etexilate Dabigatran etexilate treatment should not be discontinued without medical advice.

8). 5). g. 5). 3). 1). e. 5). In this situation dabigatran etexilate and these medicinal products should be taken at the same time. 5). 1). Weight There is very limited clinical experience in patients with a body weight <50 kg or >110 kg at the recommended posology.

4). 2). Paediatric population There is no relevant use of dabigatran etexilate in the paediatric population for the indication of primary prevention of VTE in patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF) Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (DVT/PE) The recommended doses of dabigatran etexilate in the indications SPAF, DVT and PE are shown in table 2 Table 2: Dose recommendations for SPAF, DVT and PE Dose recommendation Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF) 300 mg dabigatran etexilate taken as one 150 mg capsule twice daily Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (DVT/PE) 300 mg […]

Summary of the safety profile Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; thereof approximately 35,000 patients were treated with dabigatran etexilate. In total, about 9% of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days), 22% of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14% of patients treated for DVT/PE and 15% of patients treated for DVT/PE prevention experienced adverse reactions.

4% of adult patients treated for DVT/PE. 5% of patients in the DVT/PE prevention trial RE-SONATE (adult patients). Since the patient populations treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and provided in tables 13-17 below.

Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes. Tabulated list of adverse reactions Table 12 shows the adverse reactions identified from studies and post-marketing data in the indications primary VTE prevention after hip or knee replacement surgery, prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation, DVT/PE treatment and DVT/PE prevention.

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).

Table 12:

Adverse reactions Frequency SOC / Preferred term. Primary VTE prevention after hip or knee replacement surgery Stroke and systemic embolism prevention in patients with atrial fibrillation DVT/PE treatment and DVT/PE prevention Blood and lymphatic system disorders Anaemia Uncommon Common Uncommon Haemoglobin decreased Common Uncommon Not known Thrombocytopenia Rare Uncommon Rare Haematocrit decreased Uncommon Rare Not known Neutropenia Not known Not known Not known Agranulocytosis Not known Not known Not known Immune system disorder Drug hypersensitivity Uncommon Uncommon Uncommon Rash Rare Uncommon Uncommon Pruritus Rare Uncommon Uncommon Anaphylactic reaction Rare Rare Rare Angioedema Rare Rare Rare Urticaria Rare Rare Rare Bronchospasm Not known Not known Not known Nervous system disorders Intracranial haemorrhage Rare Uncommon Rare Vascular disorders Haematoma Uncommon Uncommon Uncommon Haemorrhage Rare Uncommon Uncommon Wound haemorrhage Uncommon - Respiratory, thoracic and mediastinal disorders Epistaxis Uncommon Common Common Haemoptysis Rare Uncommon Uncommon Gastrointestinal disorders Gastrointestinal Haemorrhage Uncommon Common Common Abdominal pain Rare Common Uncommon Diarrhoea Uncommon Common Uncommon Dyspepsia Rare Common Common Nausea Uncommon Common Uncommon Rectal haemorrhage Uncommon Uncommon Common Haemorrhoidal haemorrhage Uncommon Uncommon Uncommon Gastrointestinal ulcer, including oesophageal ulcer Rare Uncommon Uncommon Gastroesophagitis Rare Uncommon Uncommon Gastroesophageal reflux Disease Rare Uncommon Uncommon Vomiting Uncommon Uncommon Uncommon Dysphagia Rare Uncommon Rare Hepatobiliary disorders Hepatic function abnormal/ Liver function Test abnormal Common Uncommon Uncommon Alanine aminotransferase Increased Uncommon Uncommon Uncrommon Aspartate aminotransferase Increased Uncommon Uncommon Uncommon Hepatic enzyme increased Uncommon Rare Uncommon Hyperbilirubinaemia Uncommon Rare Not known Skin and subcutaneous tissue disorder Skin haemorrhage Uncommon Common Common Alopecia Not known Not known Not known Musculoskeletal and connective tissue disorders Haemarthrosis Uncommon Rare Uncommon Renal and urinary disorders Genitourological haemorrhage, including haematuria Uncommon Common Common General disorders and administration site conditions Injection site haemorrhage Rare Rare Rare Catheter site haemorrhage Rare Rare Rare Bloody discharge Rare - Injury, poisoning and procedural complications Traumatic haemorrhage Uncommon Rare Uncommon Incision site haemorrhage Rare Rare Rare Post procedural haematoma Uncommon - - Post procedural Haemorrhage Uncommon - Anaemia postoperative Rare - - Post procedural discharge Uncommon - - Wound secretion Uncommon - - Surgical and medical procedures Wound drainage Rare - - Post procedural drainage Rare - .

Description of selected adverse reactions Bleeding reactions Due to the pharmacological mode of action, the use of dabigatran etexilate may be associated with an increased risk of occult or overt bleeding from any tissue or organ. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia.

g. gastrointestinal, genitourinary) were seen more frequently during long term dabigatran etexilate treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit is of value to detect occult bleeding.

g. 4 Haemorrhagic risk). Haemorrhagic complications may present as weakness, paleness, […]

Haemorrhagic risk Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy.

An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available.

The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran. 9). In clinical trials, dabigatran etexilate 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 (see also table 5) comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux.

Risk factors Table 5 summarises factors which may increase the haemorrhagic risk.

Table 5:

Factors which may increase the haemorrhagic risk. g. 2). 5). 9. 5), which significantly increase the risk of major bleeding requires a careful benefit-risk assessment. Dabigatran etexilate should only be given if the benefit outweighs bleeding risks.

1). In these patients, dabigatran etexilate should only be given if the expected benefit outweighs bleeding risks. Close clinical surveillance Close observation for signs of bleeding or anaemia is recommended throughout the treatment period, especially if risk factors are combined (see table 5 above).

5). 5). 3). When severe bleedings occur, treatment must be discontinued, the source of bleeding investigated and use of the specific reversal agent (idarucizumab) may be considered in adult patients. The efficacy and safety of idarucizumab have not been established in paediatric patients.

Haemodialysis can remove dabigatran. Use of proton-pump inhibitors The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding. In case of paediatric patients local labeling recommendations for proton pump inhibitors have to be followed.

Laboratory coagulation parameters Although this medicinal product does not in general require routine anticoagulant monitoring, the measurement of dabigatran related anticoagulation may be helpful to detect excessive high exposure to dabigatran in the presence of additional risk factors.

1). The international normalised ratio (INR) test is unreliable in patients on dabigatran etexilate and false positive INR elevations have been reported. Therefore, INR tests should not be performed. Table 6 shows coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding.

1).

Table 6:

Coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding. 3 >2 INR Should not be […]

73m2 in paediatric patients • Active clinically significant bleeding • Lesion or condition, if considered a significant risk factor for major bleeding. 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.

1).