Dabigatran Etexilate Teva (Previously Dabigatran Etexilate Leon Farma)

Summary of the safety profile Dabigatran etexilate has been evaluated in clinical studies overall in approximately 64 000 patients; thereof approximately 35 000 patients were treated with dabigatran etexilate. In actively controlled VTE prevention studies 6 684 patients were treated with 150 mg or 220 mg dabigatran etexilate daily.

The most commonly reported events are bleedings occurring in approximately 14 % of patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %. Although rare in frequency in clinical studies, 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 10 shows the adverse reactions ranked under headings of System Organ Classes (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 10:

Adverse reactions. SOC / Preferred term Frequency Blood and lymphatic system disorders Haemoglobin decreased Common Anaemia Uncommon Haematocrit decreased Uncommon Thrombocytopenia Rare Neutropenia Not known Agranulocytosis Not known Immune system disorder Drug hypersensitivity Uncommon Anaphylactic reaction Rare Angioedema Rare Urticaria Rare Rash Rare 16 Pruritus Rare Bronchospasm Not known Nervous system disorders Intracranial haemorrhage Rare Vascular disorders Haematoma Uncommon Wound haemorrhage Uncommon Haemorrhage Rare Respiratory, thoracic and mediastinal disorders Epistaxis Uncommon Haemoptysis Rare Gastrointestinal disorders Gastrointestinal haemorrhage Uncommon Rectal haemorrhage Uncommon Haemorrhoidal haemorrhage Uncommon Diarrhoea Uncommon Nausea Uncommon Vomiting Uncommon Gastrointestinal ulcer, including oesophageal ulcer Rare Gastroesophagitis Rare Gastroesophageal reflux disease Rare Abdominal pain Rare Dyspepsia Rare Dysphagia Rare Hepatobiliary disorders Hepatic function abnormal/ Liver function Test abnormal Common Alanine aminotransferase increased Uncommon Aspartate aminotransferase increased Uncommon Hepatic enzyme increased Uncommon Hyperbilirubinaemia Uncommon Skin and subcutaneous tissue disorder Skin haemorrhage Uncommon Alopecia Not known Musculoskeletal and connective tissue disorders Haemarthrosis Uncommon Renal and urinary disorders Genitourological haemorrhage, including haematuria Uncommon General disorders and administration site conditions Injection site haemorrhage Rare Catheter site haemorrhage Rare Bloody discharge Rare Injury, poisoning and procedural complications Traumatic haemorrhage Uncommon Post procedural haematoma Uncommon Post procedural haemorrhage Uncommon Post procedural discharge Uncommon Wound secretion Uncommon Incision site haemorrhage Rare Anaemia postoperative Rare Surgical and medical procedures Wound drainage Rare Post procedural drainage Rare 17 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, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock.

Known bleeding complications such as compartment syndrome and acute renal failure due to hypoperfusion and anticoagulant-related nephropathy in patients with predisposing risk factors have been reported for dabigatran etexilate. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

9). The table 11 shows the number (%) of patients experiencing the adverse reaction bleeding during the treatment period in the indication primary VTE prevention after hip or knee replacement surgery in the two pivotal clinical studies, according to dose.

Table 11:

Number (%) of patients experiencing the adverse reaction bleeding. 4) Agranulocytosis and neutropenia Agranulocytosis and neutropenia have been reported very rarely during post approval use of dabigatran etexilate. Because adverse reactions are reported in the post-marketing surveillance setting from a population of uncertain size, it is not possible to reliably determine their frequency.

The reporting rate was estimated as 7 events per 1 million patient years for agranulocytosis and as 5 events per 1 million patient years for neutropenia. 108). In total, 328 paediatric patients had been treated with dabigatran etexilate.

The patients received age and weight adjusted doses of an age-appropriate formulation of dabigatran etexilate. Overall, the safety […]

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). Use of 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 increase the risk of GI bleeding.

Risk factors Table 3 summarises factors which may increase the haemorrhagic risk.

Table 3:

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 3 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. 1) 9 Table 4: Coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding.

3 INR Should not be performed Use of fibrinolytic medicinal products for the treatment of acute ischemic stroke The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient presents with a dTT, ECT or aPTT not exceeding the upper limit of normal (ULN) according to the local reference range.

Surgery and […]

73m2 in paediatric patients • Active clinically significant bleeding • Lesion or condition, if considered a significant risk factor for major bleeding. g. 1). 7