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In the primary VTE prevention trials after have undergone elective total hip replacement surgery 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, while 522 received doses less than 150 mg once daily and 1168 received doses in excess of 220 mg daily.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): 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 randomized to 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.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (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.
Adverse drug reaction for both treatments, dabigatran etexilate and warfarin, are counted from the first intake of dabigatran etexilate of warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all adverse drug reactions which occurred during dabigatran therapy. All adverse drug reactions, which occurred during warfarin therapy, are included except for those during the overlap period between warfarin and parenteral therapy.
In total, about 9 % of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days) and 22 % of patient 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 acute DVT/PE treatment (long-term treatment up to 6 months), experienced adverse reactions.
Bleeding: Bleeding is the most relevant side effect of PRADAXA; dependant 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 and 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.
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.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery: Overall bleeding rates were similar between treatment groups and not significantly different.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): 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.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (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.
Table 11 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II Testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). In the pooled studies the primary safety endpoints of major bleeding, major or clinically relevant bleeding and any bleeding were significantly lower than warfarin at a nominal alpha level of 5% (see Table 11).
Click on icon to see table/diagram/imageBleeding 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.
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 significantly lower risk for major bleeds compared with warfarin (hazard ration 0.81, p= 0.0027) (see Table 12).
Click on icon to see table/diagram/imagePrimary VTE prevention studies after have undergone elective total hip and total knee surgery : Overall bleeding rates were similar between treatment groups and not significantly different.
Table 13 as follows, shows the number (%) of patients experiencing bleeding events during the treatment period in the VTE prevention in the two pivotal clinical trials, according to dose (see Table 13).
Click on icon to see table/diagram/imageAdverse reactions classified by SOC and MedDRA preferred terms reported from any treatment group per population of all controlled studies are shown in the listings below. Table 14 and 15 lists identified side effects applicable to all indications. Table 16 lists indication specific side effects identified.
Side effects 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.
In patients treated for VTE prevention after hip or knee replacement surgery the observed incidences of side effects of dabigatran etexilate were in the range of enoxaparin.
The observed incidences of side effects 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.
The overall frequency of side effects in patients receiving PRADAXA for acute DVT/PE treatment was lower for PRADAXA compared to warfarin (14.2% vs. 18.9%).
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare ((≥1/10,000, <1/1000); very rare (<1/10,000) (see Table 14, Table 15 and Table 16).
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