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Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery (pVTEp): In the primary VTE prevention trials after elective total hip replacement or total knee replacement surgery a total of 10,795 patients were treated in 6 controlled studies with at least one dose of dabigatran etexilate (150 mg qd, 220 mg qd, enoxaparin). 6,684 of the 10,795 patients were treated with 150 or 220 mg once daily of dabigatran etexilate. In total, about 9% of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days) experienced adverse reactions.
Reduction of the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF): In the RE-LY trial investigating the prevention of stroke and systemic embolism in patients with atrial fibrillation a total of 12,042 patients were treated with dabigatran etexilate. Of these 6,059 were treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily. 22% of patient with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years) experienced adverse reactions.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE): In the acute DVT/PE treatment trials (RE-COVER, RE-COVER II) a total of 2,553 patients were included in the safety analysis for dabigatran etexilate. All patients were treated with dabigatran etexilate 150 mg bid. 14% of patients treated for acute DVT/PE treatment (long-term treatment up to 6 months) experienced adverse reactions.
Prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE): In the recurrent DVT/PE prevention trials (RE-MEDY, RE-SONATE) a total of 2,114 patients were treated with dabigatran etexilate; 552 of the 2,114 patients were rolled over from the RE-COVER trial (acute DVT/PE treatment) into the RE-MEDY trial and are counted in both the acute and recurrent patient totals. All patients were treated with dabigatran etexilate 150 mg bid and 15% of patients treated for recurrent DVT/PE prevention (long-term treatment up to 36 months) experienced adverse reactions.
Bleeding: Bleeding is the most relevant adverse reaction of PRADAXA; dependent of the indication bleeding of any type or severity occurred in approximately 14 % of patients treated short-term for elective hip or knee replacement surgery, in long-term treatment in yearly 16.6 % of patient with atrial fibrillation treated for the prevention of stroke and systemic embolism and in 14.4% of patients with acute DVT and/or PE. In the recurrent DVT/PE trial RE-MEDY 19.4% and in the RE-SONATE trial 10.5% of patients experienced any bleeding.
Although rare 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.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery (pVTEp): Overall bleeding rates were similar between treatment groups and not significantly different.
Reduction of the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF): Major bleeding fulfilled one or more of the following criteria: Bleeding associated with a reduction in hemoglobin of at least 20 grams per liter or leading to a transfusion of at least 2 units of blood or packed cells;
Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding.
Major bleeds were classified as life-threatening if they fulfilled one or more of the following criteria: Fatal bleed; symptomatic intracranial bleed; reduction in hemoglobin of at least 50 grams per liter; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of intravenous inotropic agents; a bleed that necessitated surgical intervention.
Subjects randomized to dabigatran etexilate 110 mg twice daily and 150mg twice daily had a significantly lower risk for life-threatening bleeds, haemorrhagic stroke and intracranial bleeding compared to warfarin [p < 0.05]. Both dose strengths of dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomized to dabigatran etexilate 110mg twice daily had a signficantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81, p=0.0027).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE): The definition of major bleeding events (MBEs) followed the recommendations of the International Society on Thrombosis and Haemostasis. A bleeding event was categorised as an MBE if it fulfilled at least one of the following criteria: Fatal bleeding.
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial, or intramuscular with compartment syndrome. In order for bleeding in a critical area or organ to be classified as an MBE it had to be associated with a symptomatic clinical presentation.
Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells.
In a pooled analysis of the two pivotal trials (RE-COVER, RE-COVER II) in acute DVT/PE treatment, subjects randomized to dabigatran etexilate had lower rates of the following bleeding events, which were statistically significant: Major bleeding events (hazard ratio 0.60 (0.36, 0.99)); Major or clinically relevant bleeding events (CRBEs) (hazard ratio 0.56 (0.45, 0.71)); Any bleeding events (hazard ratio 0.67 (0.59, 0.77)).
All of which were superior vs. warfarin.
Bleeding events for both treatments are counted from the first intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events which occurred during dabigatran therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.
Prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE): The definition of MBEs followed the recommendations of the International Society on Thrombosis and Haemostasis. A bleeding in RE-MEDY event was categorised as an MBE if it fulfilled at least one of the following criteria: Fatal bleeding.
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial, or intramuscular with compartment syndrome. In order for bleeding in a critical area or organ to be classified as an MBE it had to be associated with a symptomatic clinical presentation.
Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells.
In RE-MEDY, patients randomized to dabigatran etexilate had significantly less bleeds compared to warfarin for the following categories: major bleeding events or clinically relevant bleeding events (hazard ratio 0.55 (0.41, 0.72), p<0.0001) and any bleeding events (hazard ratio 0.71 (0.61, 0.83), p<0.0001).
A bleeding event in RE-SONATE was categorised as an MBE if it fulfilled at least one of the following criteria: Fatal bleeding; Associated with a fall in haemoglobin of 2 g/dL or more; Led to the transfusion of ≥ 2 units packed cells or whole blood; Occurred in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal.
In RE-SONATE, the rates of MBE were low (2 patients with MBEs (0.3%) for dabigatran etexilate vs. 0 patients with MBE (0%) for placebo. The rate of major bleeding events or clinically relevant bleeding events were higher with dabigatran etexilate compared with placebo (5.3% vs. 2.0%).
Tabulated summary of adverse reactions: Adverse reactions classified by SOC and MedDRA preferred terms reported from any treatment group per population of all controlled studies are shown in the listings as follows.
Table 12 lists identified adverse reactions applicable to all indications.
Table 13 lists indication specific adverse reactions identified.
Adverse reactions are generally associated to the pharmacological mode of action of dabigatran etexilate and represent bleeding associated events that may occur in different anatomical regions and organs.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery (pVTEp): In patients treated for VTE prevention after hip or knee replacement surgery the observed incidences of adverse reactions of dabigatran etexilate were in the range of enoxaparin.
Reduction of the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF): The observed incidences of adverse reactions of dabigatran etexilate in patients treated for stroke prevention in patients with atrial fibrillation were in the range of warfarin except gastrointestinal disorders which appeared at a higher rate in the dabigatran etexilate arms.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE): The overall frequency of adverse reactions in patients receiving PRADAXA for acute DVT/PE treatment was lower for PRADAXA compared to warfarin (14.2% vs. 18.9%).
Prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE): The overall frequency of adverse reactions in patients treated for recurrent DVT/PE prevention was lower for PRADAXA compared to warfarin (14.6% vs. 19.6%); compared to placebo the frequency was higher (14.6% vs. 6.5%). (See Tables 12 and 13).
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