Dabigatran Etexilate

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥ 75 years; heart failure (NYHA Class ≥ II); diabetes mellitus; hypertension.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. Treatment of venous thromboembolic events (VTE) and prevention of recurrent VTE in paediatric patients from the time the child is able to swallow soft food to less than 18 years of age.

2.

Posology Dabigatran etexilate Accord hard capsules can be used in adults and paediatric patients aged 8 years or older who are able to swallow the capsules whole. Other pharmaceutical forms may be more appropriate for administration to this population such as coated granules which can be used in children aged less than 12 years as soon as the child is able to swallow soft food.

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. 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 1.

Table 1:

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 dabigatran etexilate taken as one 150 mg capsule twice daily following treatment with a parenteral anticoagulant for at least 5 days Dose reduction recommended Patients aged ≥ 80 years Patients who receive concomitant verapamil daily dose of 220 mg dabigatran etexilate taken as one 110 mg capsule twice daily Dose reduction for consideration Patients between 75-80 years Patients with moderate renal impairment (CrCL 30-50 mL/min) Patients with gastritis, oesophagitis or gastroesophageal reflux Other patients at increased risk of bleeding daily dose of dabigatran etexilate of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding For DVT/PE the recommendation for the use of 220 mg dabigatran etexilate taken as one 110 mg capsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in this clinical setting.

2. In case of intolerability to dabigatran etexilate, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and systemic embolism associated with atrial fibrillation or for DVT/PE.

e. 2). g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products). 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.

Duration of use The duration of use of dabigatran etexilate in the indications SPAF, DVT and PE are shown in table 2.

Table 2:

Duration of use for SPAF and DVT/PE Indication Duration of use SPAF Therapy should be continued long term. 4). g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.

Missed dose A forgotten dabigatran etexilate dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted. 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).

Dabigatran etexilate treatment to Vitamin K antagonists (VKA):

The starting time of the VKA should be adjusted based on CrCL as follows: • CrCL ≥ 50 mL/min, VKA should be started 3 days before discontinuing dabigatran etexilate • CrCL ≥ 30-< 50 mL/min, VKA should be started 2 days before discontinuing dabigatran etexilate Because dabigatran etexilate can impact the International Normalised Ratio (INR), the INR will better reflect VKA’s effect only after dabigatran etexilate has been stopped for at least 2 days.

Until then, INR values should be interpreted with caution. VKA to dabigatran […]

Summary of the safety profile Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64000 patients; thereof approximately 35000 patients were treated with dabigatran etexilate. In total, 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 are provided in tables 12- 15 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 11 shows the adverse reactions identified studies and post-marketing data in the indications 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 (1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000) and not known (cannot be estimated from the available data).

Table 11:

Adverse reactions Frequency SOC / Preferred term Stroke and systemic embolism prevention in patients with atrial fibrillation DVT/PE treatment and DVT/PE prevention Blood and lymphatic system disorders Anaemia Common Uncommon Haemoglobin decreased Uncommon Not known Thrombocytopenia Uncommon Rare Haematocrit decreased Rare Not known Neutropenia Not known Not known Agranulocytosis Not known Not known Immune system disorder Drug hypersensitivity Uncommon Uncommon Rash Uncommon Uncommon Pruritus Uncommon Uncommon Anaphylactic reaction Rare Rare Angioedema Rare Rare Urticaria Rare Rare Bronchospasm Not known Not known Nervous system disorders Intracranial haemorrhage Uncommon Rare Vascular disorders Haematoma Uncommon Uncommon Haemorrhage Uncommon Uncommon Respiratory, thoracic and mediastinal disorders Epistaxis Common Common Haemoptysis Uncommon Uncommon Gastrointestinal disorders Gastrointestinal haemorrhage Common Common Abdominal pain Common Uncommon Diarrhoea Common Uncommon Dyspepsia Common Common Nausea Common Uncommon Rectal haemorrhage Uncommon Common Haemorrhoidal haemorrhage Uncommon Uncommon Gastrointestinal ulcer, including oesophageal ulcer Uncommon Uncommon Gastroesophagitis Uncommon Uncommon Gastroesophageal reflux disease Uncommon Uncommon Vomiting Uncommon Uncommon Dysphagia Uncommon Rare Hepatobiliary disorders Hepatic function abnormal / Liver function Test abnormal Uncommon Uncommon Alanine aminotransferase increased Uncommon Uncommon Aspartate aminotransferase increased Uncommon Uncommon Hepatic enzyme increased Rare Uncommon Hyperbilirubinaemia Rare Not known Skin and subcutaneous tissue disorder Skin haemorrhage Common Common Alopecia Not known Not known Musculoskeletal and connective tissue disorders Haemarthrosis Rare Uncommon Renal and urinary disorders Genitourological haemorrhage, including haematuria Common Common General disorders and administration site conditions Injection site haemorrhage Rare Rare Catheter site haemorrhage Rare Rare Injury, poisoning and procedural complications Traumatic haemorrhage Rare Uncommon Incision site haemorrhage Rare 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, 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). Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more risk factors (SPAF) Table 12 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation.

Table 12:

Bleeding events in a study testing […]

73 m2 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).

AND CLINICAL USE ........................................................................ 3 CONTRAINDICATIONS ............................................................................................ 3 WARNINGS AND PRECAUTIONS............................................................................

4 ADVERSE REACTIONS........................................................................................... 12 DRUG INTERACTIONS ........................................................................................... 22 DOSAGE AND ADMINISTRATION ........................................................................

27 OVERDOSAGE ........................................................................................................ 32 ACTION AND CLINICAL PHARMACOLOGY........................................................ 34 STORAGE AND STABILITY ...................................................................................

39 SPECIAL HANDLING INSTRUCTIONS .................................................................. 39 DOSAGE FORMS, COMPOSITION AND PACKAGING ......................................... 39 PART II: SCIENTIFIC INFORMATION .........................................................................

41 PHARMACEUTICAL INFORMATION .................................................................... 41 CLINICAL TRIALS .................................................................................................. 43 DETAILED PHARMACOLOGY...............................................................................

61 TOXICOLOGY ......................................................................................................... 62 PART III: CONSUMER INFORMATION........................................................................ 64 PRADAXA Product Monograph Page 3 of 68 Pr PRADAXA® Dabigatran Etexilate Capsules PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Nonmedicinal Ingredients Oral Capsules: 75 mg, 110 mg and 150 mg Acacia, carragenan, dimethicone, hydroxypropyl cellulose, hypromellose, indigo carmin, iron oxide black, potassium chloride, potassium hydroxide, propylene glycol, shellac, talc, tartaric acid, titanium dioxide.

INDICATIONS AND CLINICAL USE PRADAXA (dabigatran etexilate) is indicated for the: • prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement (THR) or total knee replacement (TKR) surgery • treatment of venous thromboembolism events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE • prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate Geriatrics (>65 years of age): Most older subjects demonstrate an increase in exposure to dabigatran, usually in association with age-related decline of renal function (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Renal Impairment).

Pediatrics (<18 years of age):

The safety and efficacy of PRADAXA have not been established in children <18 years of age. Therefore, PRADAXA is not indicated in this patient population. g. e. oral ketoconazole or oral glecaprevir/pibrentasvir (see WARNINGS AND PRECAUTIONS, P-gp inhibitors and DRUG INTERACTIONS) • Combination with any other anticoagulant, including o unfractionated heparin (UFH), except at doses used to maintain a patent central venous or arterial catheter, or during catheter ablation for atrial fibrillation, o low molecular weight heparins (LMWH), such as enoxaparin and dalteparin, o heparin derivatives, such as fondaparinux, o anti-thrombin agents, such as bivalirudin, and o oral anticoagulants, such as warfarin, rivaroxaban, apixaban, except under circumstances of switching therapy to or from PRADAXA.

• Patients with prosthetic heart valve(s) requiring anticoagulation due to valvular status itself (see WARNINGS AND PRECAUTIONS, Patients with Valvular Disease). • Patients with a known hypersensitivity to dabigatran or dabigatran etexilate or to any ingredient in the formulation or component of the container.

For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING. • Nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women). WARNINGS AND PRECAUTIONS PREMATURE DISCONTINUATION OF ANY ORAL ANTICOAGULANT, INCLUDING PRADAXA, INCREASES THE RISK OF THROMBOTIC EVENTS.

To reduce this risk, consider coverage with another anticoagulant if PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy. Bleeding As with all anticoagulants, PRADAXA (dabigatran etexilate) should be used with caution in circumstances associated with an increased risk of bleeding.

The possibility of a haemorrhage should be considered in evaluating the condition of any anticoagulated patient. Bleeding can occur at any site during therapy with PRADAXA. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site.

Patients with a known high risk of bleeding should not be prescribed PRADAXA (see CONTRAINDICATIONS). PRADAXA Product Monograph Page 5 of 68 Should severe bleeding occur, treatment with PRADAXA must be discontinued and the source of bleeding investigated promptly.

For situations of life-threatening or […]

The overall safety of PRADAXA (dabigatran etexilate) was evaluated in 23,393 patients who were treated with PRADAXA in 11 clinical trials. Prevention of VTE after THR or TKR surgery Out of the 6,684 patients treated with 150 mg or 220 mg PRADAXA once daily following major elective orthopedic surgery (short-term treatment up to 42 days) in 6 clinical trials, 9% of patients experienced adverse reactions; about 10% of patients treated with enoxaparin experienced adverse reactions.

Treatment of VTE and Prevention of Recurrent DVT and PE Out of the 2,553 patients treated with PRADAXA 150 mg bid in the acute DVT/PE treatment trials (RE-COVER, RE-COVER II) (long-term treatment of up to 6 months), 14% of patients experienced adverse reactions.

Out of the 2,114 patients treated with PRADAXA 150mg bid in the recurrent DVT/PE prevention trials (RE-MEDY, RE-SONATE) (long-term treatment up to 36 months), 15% of patients experienced adverse reactions. A total of 552 were rolled over from the RE-COVER trial (acute DVT/PE treatment) into the RE-MEDY trial and were counted in both the acute and recurrent patient totals.

Prevention of stroke and systemic embolism in AF patients – RE-LY trial:

Out of the 12,042 patients exposed to PRADAXA in RE-LY, 6,059 were treated with PRADAXA 150 mg bid, while 5,983 received doses of 110 mg bid. About 21% of AF patients treated with PRADAXA and about 16% of patients treated with warfarin (long-term treatment up to 3 years) experienced adverse events (AEs) considered related to treatment.

Bleeding Bleeding is the most relevant adverse reaction of PRADAXA. 4% of patients with acute DVT and/or PE. 5% (RE-SONATE) 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.

Since the patient populations treated with PRADAXA for different indications are not interchangeable, a summary description of major and total bleeding is provided by indication and/or trial in Table 3, Table 4, Table 5, Table 6, Table 7 and Table 8.

7) *Major Bleeding Events: Major bleeding was defined as clinically overt bleeding associated with ≥ 20 g/L fall in hemoglobin; clinically overt bleeding leading to transfusion of ≥ 2 units packed cells or whole blood; fatal, retroperitoneal, intracrani al, intraocular or intraspinal bleeding; bleeding warranting treatment cessation or leading to reoperation.

Major bleeding included those events occurring at the surgical site.

Treatment of VTE and Prevention of Recurrent DVT and PE Table 5:

Frequency of MBEs*, MBEs or CRBE(s) # and any bleeding event(s) in patients with acute DVT/PE in the RE-COVER and RE-COVER II (pooled data) Dabigatran etexilate 150 mg bid N (%) Warfarin N (%) Hazard ratio vs. 54) *The definition of major bleeding events (MBEs) in RE-COVER, RE-COVER II, RE-MEDY and RE-SONATE followed the recommendations of the International Society on Thrombosis and Hemostasis.

A bleeding event was categorised as an MBE if it fulfilled at least 1 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.

24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells #the definition of Clinically Relevant Bleeding Event (CRBE): In Studies RE-COVER II, RE-COVER, and RE-MEDY, a minor bleeding event was categorized as a CRBE if it fulfilled at least 1 of the following criteria: • Spontaneous skin hematoma ≥25 cm2 • Spontaneous nose bleed >5 minutes duration PRADAXA Product Monograph Page 14 of 68 • Macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting >24 hours • Spontaneous rectal bleeding (more than spotting on toilet paper) • Gingival bleeding >5 minutes • Bleeding leading to hospitalization and/or requiring surgical treatment • Bleeding leading to a transfusion of <2 units of whole blood or red cells • Any other bleeding […]

Primary prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Treatment of VTE and prevention of recurrent VTE in paediatric patients from the time the child is able to swallow soft food to less than 18 years of age.

2.

Posology Dabigatran etexilate Accord hard capsules can be used in adults and paediatric patients aged 8 years or older who are able to swallow the capsules whole. Other pharmaceutical forms may be more appropriate for administration to this population such as coated granules which can be used in children aged less than 12 years as soon as the child is able to swallow soft food.

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.

3 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 single capsule of 110 mg dabigatran etexilate 220 mg dabigatran etexilate once daily taken as 2 capsules of 110 mg 10 days Patients following elective hip replacement surgery 28-35 days Dose reduction recommended Patients with moderate renal impairment (creatinine clearance (CrCL) 30-50 mL/min) 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) Patients who receive concomitant verapamil*, amiodarone, quinidine Patients aged 75 or above *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.

Treatment of VTE and prevention of recurrent VTE in paediatric patients For the treatment of VTE in paediatric patients, treatment should be initiated following treatment with a parenteral anticoagulant for at least 5 days. For prevention of recurrent VTE, treatment should be initiated following previous treatment.

Dabigatran etexilate capsules should be taken twice daily, one dose in the morning and one dose in the evening, at approximately the same time every day. The dosing interval should be as close to 12 hours as possible. The recommended dose of dabigatran etexilate capsules is based on the patient’s weight and age as shown in table 2.

The dose […]

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 actively controlled VTE prevention trials 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 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 10 shows the adverse reactions ranked under headings of System Organ Class es (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).

16 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 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 Uncommon 17 haematuria 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 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, d yspnoea, 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 trials, according to dose.

4) Agranulocytosis and neutropenia Agranulocytosis and neutropenia have been reported very rarely during post approval use of 18 dabigatran etexilate. Because adverse reactions are reported in the postmarketing 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 […]

73 m2 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). 7

1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients Dabigatran etexilate capsules are indicated to reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation.

2 Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Dabigatran etexilate capsules are indicated for the treatment of deep venous thrombosis and pulmonary embolism in adult patients who have been treated with a parenteral anticoagulant for 5 to 10 days.

3 Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Dabigatran etexilate capsules are indicated to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in adult patients who have been previously treated.

4 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult PatientsFollowing Hip Replacement Surgery Dabigatran etexilate capsules are indicated for the prophylaxis of deep vein thrombosis and pulmonary embolism in adult patients who have undergone hip replacement surgery.

3)] . 3)] .

1 Important Dosage Information Dabigatran etexilate is available in different dosage forms and not all dosage forms are approved for the same indications and age groups. In addition, there are differences between the dosage forms with respect to dosing due to differences in bioavailability.

3)] . 2 Recommended Dabigatran Etexilate Capsules Dosage for Adults Indication Dosage Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF CrCl >30 mL/min: 150 mg twice daily CrCl 15 to 30 mL/min: 75 mg twice daily CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dosage to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.

CrCl <30 mL/min with concomitant use of P-gp inhibitors:

Avoid coadministration Treatment of DVT and PE Reduction in the Risk of Recurrence of DVT and PE CrCl >30 mL/min: 150 mg twice daily CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Prophylaxis of DVT and PE Following Hip Replacement Surgery CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily.

3)]. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided. Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily, after 5 to 10 days of parenteral anticoagulation.

3)]. Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily after previous treatment.

3)]. Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 110 mg taken orally 1 to 4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28 to 35 days.

If dabigatran etexilate capsules is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. 3)] . 3 Recommended Dabigatran Etexilate Capsules Dosage for Pediatrics Dabigatran etexilate capsules can be used in pediatric patients aged 8 to less than 18 years of age who are able to swallow the capsules whole.

Other age-appropriate pediatric dosage forms of dabigatran etexilate are available for pediatric patients less than 8 years of age. For the treatment of VTE in pediatric patients, initiate treatment following treatment with a parenteral anticoagulant for at least 5 days.

For reduction in risk of recurrence of VTE, initiate treatment following previous treatment. Dabigatran etexilate capsules are dosed orally twice daily, one dose in the morning and one dose in the evening, at approximately the same time every day.

The dosing interval should be as close to 12 hours as possible. The recommended dosage of dabigatran etexilate capsules for the treatment of or reducing the risk of VTE in pediatric patients 8 to less than 18 years of age is based on the patient’s actual weight as shown in Table 1 below.

Administer dabigatran etexilate capsules twice daily. 5)] . 4 Dosage Adjustments Adult patients with renal impairment Assess renal function prior to initiation of treatment with dabigatran etexilate capsules. , more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly.

Discontinue dabigatran etexilate capsules in patients who develop acute renal failure while on dabigatran etexilate and consider alternative anticoagulant therapy. Generally, in adult patients, the extent of anticoagulation does not need to be assessed.

2)] . Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation In patients with moderate renal impairment (CrCl 30 to 50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce dabigatran exposure similar to that observed in severe renal impairment.

3)] . Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism Dosing recommendations for patients with CrCl ≤30 mL/min cannot be provided. 3)] . Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery Dosing recommendations for patients with CrCl ≤30 mL/min or on dialysis cannot be provided.

3)] . 73 m 2 and the risk of increased exposure, avoid use of dabigatran etexilate capsules in these patients. 413 x height in cm) / serum creatinine in mg/dL. 3)] . 5 Administration Dabigatran etexilate capsules should be swallowed whole.

Dabigatran etexilate capsules should be taken with a full glass of water. 3)] . If a dose of dabigatran etexilate capsules are not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose.

The dose of dabigatran etexilate capsules should not be doubled to make up for a missed dose. Consider administration with food if gastrointestinal distress occurs with dabigatran etexilate capsules. 6 Converting from or to Warfarin When converting patients from warfarin therapy to dabigatran etexilate capsules, discontinue warfarin and start dabigatran etexilate capsules when the INR is below 2.

When converting from dabigatran etexilate capsules to warfarin, adjust the starting time of warfarin as follows: Adults For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing dabigatran etexilate capsules. For CrCl 30 to 50 mL/min, start warfarin 2 days before discontinuing dabigatran etexilate capsules.

For CrCl 15 to 30 mL/min, start warfarin 1 day before discontinuing dabigatran etexilate capsules. For CrCl <15 mL/min, no recommendations can be made. 73 m 2 , start warfarin 3 days before discontinuing dabigatran etexilate capsules.

73 m 2 have not been studied. Avoid use of dabigatran etexilate capsules in these patients. 2)]. , intravenous unfractionated heparin). 3)] . For pediatric patients currently taking dabigatran etexilate capsules, wait 12 hours after the last dose before switching to a parenteral anticoagulant.

8 Discontinuation for Surgery and Other Interventions If possible, discontinue dabigatran etexilate capsules in adults 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding.

3)] . 73 m 2 ). 73 m 2 have not been studied, avoid use of dabigatran etexilate capsules in these patients. 2)] . 3)] . Use a specific reversal agent (idarucizumab) in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is needed in adults.

2)] . Refer to the idarucizumab prescribing information for additional information. Restart dabigatran etexilate capsules as soon as medically appropriate.

2)]. gov/medwatch . 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

1)] . The numbers of patients and their exposures are described in Table 2. Limited information is presented on the 110 mg dosing arm because this dose is not approved. 3 Total patient-years 10,242 10,261 10,659 Drug Discontinuation in RE-LY The rates of adverse reactions leading to treatment discontinuation were 21% for dabigatran etexilate capsules 150 mg and 16% for warfarin.

, dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea). 2)] Table 3 shows the number of adjudicated major bleeding events during the treatment period in the RE-LY study, with the bleeding rate per 100 subject-years (%).

Major bleeding is defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells, bleeding at a critical site or with a fatal outcome. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

Table 3:

Adjudicated Major Bleeding Events in Treated Patients a Event Dabigatran Etexilate Capsules 150 mg N = 6,059 n (%/year b ) Warfarin N = 5,998 n (%/year b ) Dabigatran Etexilate Capsules 150 mg vs. 02) a Patients during treatment or within 2 days of stopping study treatment.

Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. b Annual event rate per 100 pt-years = 100 * number of subjects with event/subject-years.

25. In case of recurrent events of the same category, the first event was considered. c Defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site or with fatal outcome.

d Intracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. e On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14 Clinical Studies. f Fatal bleed: Adjudicated major bleed as defined above with investigator reported fatal outcome and adjudicated death with primary cause from bleeding.

g Non-intracranial fatal bleed: Adjudicated major bleed as defined above and adjudicated death with primary cause from bleeding but without symptomatic intracranial bleed based on investigator’s clinical assessment. 2%, respectively).

5) for patients ≥75 years of age.

Figure 1:

Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified.

The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Gastrointestinal Adverse Reactions Patients on dabigatran etexilate capsules 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).

1% of patients receiving dabigatran etexilate capsules. Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism Dabigatran etexilate capsules was studied in 4,387 patients in 4 pivotal, parallel, randomized, double-blind trials.

Three of these trials were active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY), and one study (RE-SONATE) was placebo-controlled. The demographic characteristics were similar among the 4 pivotal studies and between the treatment groups within these studies.

1 years. 6 mL/min. 24 mmol/L or more, or leading to transfusion of 2 or more units of whole blood or red cells). RE-COVER and RE-COVER II studies compared dabigatran etexilate capsules 150 mg twice daily and warfarin for the treatment of deep vein thrombosis and pulmonary embolism.

Patients received 5 to 10 days of an approved parenteral anticoagulant therapy followed by 6 months, with mean exposure of 164 days, of oral only treatment; warfarin was overlapped with parenteral therapy. Table 4 shows the number of patients experiencing bleeding events in the pooled analysis of RE-COVER and RE-COVER II studies during the full treatment including parenteral and oral only treatment periods after randomization.

79) Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding. 4% on warfarin). The RE-MEDY and RE-SONATE studies provided safety information on the use of dabigatran etexilate capsules for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism.

RE-MEDY was an active-controlled study (warfarin) in which 1,430 patients received dabigatran etexilate capsules 150 mg twice daily following 3 to 12 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-MEDY study had a combined treatment duration of up to more than 3 years, with mean exposure of 473 days.

Table 5 shows the number of patients experiencing bleeding events in the study. 83) Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding.

2% on warfarin). RE-SONATE was a placebo-controlled study in which 684 patients received dabigatran etexilate capsules 150 mg twice daily following 6 to 18 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-SONATE study had combined treatment duration up to 9 months, with mean exposure of 165 days.

Table 6 shows the number of patients experiencing bleeding events in the study. 61) Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding.

3% on placebo). 17 per 100 patient-years)]. 34 per 100 patient-years)]. 7% on warfarin). 7%, respectively. 1% of patients receiving dabigatran etexilate capsules. Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery Dabigatran etexilate capsules was studied in 5,476 patients, randomized and treated in two double-blind, active-controlled non-inferiority trials (RE-NOVATE and RE-NOVATE II).

The demographic characteristics were similar across the two studies and between the treatment groups within these studies. 2 years. 3% were black with a mean CrCl of 92 mL/min. 24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells, requiring treatment cessation or leading to re-operation.

The RE-NOVATE study compared dabigatran etexilate capsules 75 mg taken orally 1 to 4 hours after surgery followed by 150 mg once daily, dabigatran etexilate capsules 110 mg taken orally 1 to 4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery.

The RE-NOVATE II study compared dabigatran etexilate capsules 110 mg taken orally 1 to 4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery.

In the RE-NOVATE and RE-NOVATE II studies, patients received 28 to 35 days of dabigatran etexilate capsules or enoxaparin with median exposure of 33 days. Tables 7 and 8 show the number of patients experiencing bleeding events in the analysis of RE-NOVATE and RE-NOVATE II.

9% for enoxaparin. 5%, respectively. 1% vs. 6% vs 1%, respectively. 3% of patients receiving dabigatran etexilate capsules 220 mg. 3%) of patients who received enoxaparin. Pediatric Trials Treatment of VTE in Pediatric Patients The safety of dabigatran etexilate capsules in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY).

The DIVERSITY study was a randomized, open-label, active-controlled, parallel-group trial comparing dabigatran etexilate capsules with standard of care – SOC (vitamin K antagonists, low molecular weight heparin, or fondaparinux). There were 266 pediatric patients who received study treatment, 176 patients treated with dabigatran etexilate capsules and 90 patients treated with SOC.

Patients on dabigatran etexilate capsules received age- and weight-adjusted dosages of an age-appropriate formulation of dabigatran etexilate (capsules, pellets, or oral solution) twice daily. Patients had a median age of 14 years (range: 0 to 17 years), 92% were white, and half the patients were male (50%).

Following at least 5 days of parenteral anticoagulant therapy, the median duration of treatment with dabigatran etexilate capsules was 85 days (range: 1 to 105). 73m 2 were excluded from the trial. Bleeding Data on adjudicated major bleeding, clinically relevant non-major (CRNM) bleeding and minor bleeding events, for the dabigatran etexilate group and the SOC group in the DIVERSITY study, are reported in Table 9.

There was no statistically significant difference in the time to first major bleeding event. 24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells. 8% in SOC arm). Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions for patients on dabigatran etexilate capsules and SOC was 32% and 12%, respectively, with the following occurring in ≥ 5% of patients taking dabigatran etexilate capsules: dyspepsia (including term gastro-esophageal reflux disease, gastric pH decreased and esophagitis) in 9% (vs 2%), upper abdominal pain in 5% (vs 1%), vomiting in 8% (vs 2%), nausea 5% (vs 4%), and diarrhea 5% (vs 1%).

Reduction in Risk of Recurrence of VTE in Pediatric Patients The safety of dabigatran etexilate capsules in the reduction in the risk of recurrence of VTE in pediatric patients was studied in one open-label single-arm trial (Study 2).

Study 2 enrolled patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study and received dabigatran etexilate capsules until the clinical risk factor resolved, or up to a maximum of 12 months.

There were 213 pediatric patients treated with dabigatran etexilate capsules, in a similar fashion as in the DIVERSITY trial. Patients had a median age of 14 years (range: 0 to 18 years), 91% were white, and 55% of patients were male.

Patients previously enrolled on DIVERSITY accounted for 43% of patients enrolled on Study 2 (29% from dabigatran etexilate capsules arm and 14% from SOC arm). The median duration of treatment with dabigatran etexilate capsules in Study 2 was 42 weeks (range: 0 to 56 weeks), with 45% of patients completing the 12-month planned duration, 17% stopping due to resolution of VTE risk factors, 12% stopping due to failure to attain target dabigatran concentration and 6% had an adverse event leading to discontinuation.

4%) had a clinically relevant non-major bleeding event, and 44 patients (20%) had a minor bleeding event. 8%). The adverse reaction profile in pediatric patients was generally consistent with that of adult patients. 2 Postmarketing Experience The following adverse reactions have been identified during post approval use of dabigatran etexilate.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders :

Agranulocytosis, neutropenia, thrombocytopenia Gastrointestinal Disorders : Esophageal ulcer Immune System Disorders : Angioedema Renal and Urinary Disorders : Anticoagulant-related nephropathy Skin and Subcutaneous Tissue Disorders : Alopecia

4)] • Active pathological bleeding ( 4 ) • History of serious hypersensitivity reaction to dabigatran etexilate capsules ( 4 ) • Mechanical prosthetic heart valve ( 4 )