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The safety of Pradaxa has been evaluated overall in 38,008 patients in 11 clinical trials; thereof 23,352 Pradaxa patients were investigated.
Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: In the primary VTE prevention trials after major orthopaedic surgery, a total of 10,795 patients were treated in 6 controlled-studies with at least 1 dose of dabigatran etexilate (enoxaparin 150 mg and 220 mg once daily). Of these, 6684 of the 10,795 were treated with dabigatran etexilate 150 mg or 220 mg once daily.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: 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 randomized to dabigatran etexilate. Of these, 6,059 were treated with dabigatran etexilate 150 mg twice daily, while 5,983 received doses of 110 mg twice daily.
Treatment of Acute DVT and/or PE and Prevention of Related Death: In the acute DVT/PE treatment trials (RE-COVER, RE-COVER II) a total of 2,456 patients were included in the safety analysis for dabigatran etexilate. All patients were treated with dabigatran etexilate 150 mg twice daily.
Prevention of Recurrent DVT and/or PE and Related Death: 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 twice daily.
In total, about 9% of the patients treated for elective hip or knee surgery (short-term treatment for up to 42 days) and 22% of the patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 yrs).
Fourteen percent (14%) of patients treated for acute DVT/PE treatment (long-term treatment up to 6 months) 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 side effect of Pradaxa; dependent of the indication, bleeding of any type or severity occurred in approximately 14% of the patients treated short-term for elective hip or knee-replacement surgery, and in long-term treatment in yearly 16.5% 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.
Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: Overall bleeding rates were similar between treatment groups and not significantly different.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: Major bleeding fulfilled ≥1 of the following criteria: Bleeding associated with a reduction in hemoglobin of at least 20 g/L 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 IM with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding.
Major bleeds were classified as life-threatening if they fulfilled ≥1 of the following criteria: Fatal bleed; symptomatic intracranial bleed; reduction in hemoglobin of at least 50 g/L; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of IV inotropic agents; a bleed that necessitated surgical interventions.
Subjects randomized to dabigatran etexilate 110 mg twice daily and 150 mg 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 also had a statistically significant lower total bleed rate. Subjects randomized to dabigatran etexilate 110 mg twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.8, p=0.0026).
Treatment of Acute DVT and/or PE and Prevention of Related Death: The definition of major bleeding events (MBEs) followed the recommendations of the International Society on thrombosis and haemostasis. A bleeding event was categorized as an MBE if it fulfilled at least 1 of the following criteria: Fatal bleeding; symptomatic bleeding in a critical area or organ eg, intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or IM 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 leading to transfusion of ≥2 units of whole blood or red cells.
In a pooled analysis of the 2 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 0.6 (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 versus warfarin.
Bleeding events for both treatments are counted from the 1st intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (only oral 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 DVT and/or PE and Related Death: The definition of MBEs followed the recommendations of the International Society on Thrombosis and Haemostasis. A bleeding in RE-MEDY event was categorized as an MBE if it fulfilled at least 1 of the following criteria: Fatal bleeding, symptomatic bleeding in a critical area or organ eg, intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or IM 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 leading to transfusion of ≥2 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 categorized as an MBE if it fulfilled at least 1 of the following criteria: Fatal bleeding associated with a fall in haemoglobin of ≥2 g/dL led to the transfusion of ≥2 units packed cells or whole blood.
Occurred in a critical site: Intracranial, intraspinal, intraocular, pericardial, intra-articular, IM 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%).
Adverse reactions classified by System Organ Class (SOC) and MedDRA preferred terms reported from any treatment group per population of all controlled studies are shown as follows. Side effects applicable to all 4 indications and additional lists of specific side effects are 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.
Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: 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.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: 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.
Treatment of Acute DVT and/or PE and Prevention of Related Death: 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%).
Prevention of Recurrent DVT and/or PE and Related Death: The overall frequency of side effects 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%).
Side Effects Identified From The Primary VTE Prevention Studies After Major Orthopaedic Surgery Program, The Prevention of Thromboembolic Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Treatment of Acute DVT and/or PE and Prevention of Related Death, and Prevention of Recurrent DVT and/or PE and Related Death: Blood and Lymphatic System Disorders: Anaemia, thrombocytopenia.
Immune System Disorders: Drug hypersensitivity including pruritus, rash and urticaria, bronchospasm, angioedema, anaphylactic reaction.
Nervous System Disorders: Intracranial haemorrhage.
Vascular Disorders: Haematoma, haemorrhage.
Respiratory, Thoracic and Mediastinal Disorders: Epistaxis, haemoptysis.
Gastrointestinal Disorders: Gastrointestinal haemorrhage, abdominal pain, diarrhoea, dyspepsia, nausea, gastrointestinal ulcer (including oesophageal ulcer), gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagia.
Hepatobiliary Disorders: Abnormal hepatic function.
Skin and Subcutaneous Tissue Disorders: Skin haemorrhage.
Musculoskeletal, Connective Tissue and Bone Disorders: Haemarthrosis.
Renal and Urinary Disorders: Urogenital haemorrhage.
General Disorders and Administration Site Conditions: Injection site haemorrhage, catheter-site haemorrhage.
Injury, Poisoning and Procedural Complications: Traumatic haemorrhage, incision-site haemorrhage.
Additional Specific Side Effects Identified Per Indication: Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: Vascular Disorders: Wound haemorrhage.
General Disorders and Administration Site Conditions: Bloody discharge.
Injury, Poisoning and Procedural Complications: Postprocedural haematoma, haemorrhage and discharge; postoperative anaemia, wound secretion.
Surgical and Medical Procedures: Wound drainage, postprocedural drainage.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: None.
Treatment and Prevention of Acute or Recurrent DVT and/or PE and Prevention of Related Death: None.
