Apo-Dabigatran Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

APO-DABIGATRAN (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 dabigatran etexilate have not been established in children <18 years of age. Therefore, APO-DABIGATRAN is not indicated in this patient population.

CONTRAINDICATIONS

APO-DABIGATRAN is contraindicated in:

• Patients with severe renal impairment (eCrCl < 30 mL/min).
• Patients with haemorrhagic manifestations, clinically significant active bleeding, including gastrointestinal bleeding, bleeding diathesis, spontaneous or pharmacological impairment of hemostasis
• Patients with lesions at risk of clinically significant bleeding, e.g. extensive cerebral infarction (haemorrhagic or ischemic) within the last 6 months, active peptic ulcer disease with recent bleeding
• Combination with strong P-glycoprotein (P-gp) inhibitors, i.e. oral ketoconazole or oral glecaprevir/pibrentasvir (see WARNINGS AND PRECAUTIONS, P-gp inhibitors and DRUG INTERACTIONS)

• Combination with any other anticoagulant, including

  • unfractionated heparin (UFH), except at doses used to maintain a patent central venous or arterial catheter, or during catheter ablation for atrial fibrillation,
  • low molecular weight heparins (LMWH), such as enoxaparin and dalteparin,
  • heparin derivatives, such as fondaparinux,
  • anti-thrombin agents, such as bivalirudin, and
  • oral anticoagulants, such as warfarin, rivaroxaban, apixaban, except under circumstances of switching therapy to or from APO-DABIGATRAN.
• 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 APO-DABIGATRAN, INCREASES THE RISK OF THROMBOTIC EVENTS.

To reduce this risk, consider coverage with another anticoagulant if APO-DABIGATRAN is discontinued for a reason other than pathological bleeding or completion of a course of therapy.

Bleeding

As with all anticoagulants, APO-DABIGATRAN (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 APO-DABIGATRAN. 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 APO-DABIGATRAN (see CONTRAINDICATIONS).

Should severe bleeding occur, treatment with APO-DABIGATRAN must be discontinued and the source of bleeding investigated promptly.

For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effects of dabigatran is required, the specific reversal agent, PRAXBIND (idarucizumab), may be used (see Surgery/Procedural Interventions, below, and OVERDOSAGE).

Close clinical surveillance is recommended throughout the treatment period, i.e., looking for signs of bleeding or anaemia, by testing for occult blood in the stool or ruling out a significant drop in serum hemoglobin, especially if risk factors which increase bleeding risk are combined (see Table 1 below and DRUG INTERACTIONS, Drug-Drug Interactions, Table 14).

Table 1: Factors which increase haemorrhagic risk, as identified in clinical studies

The measurement of dabigatran-related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additiosnal risk factors (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Antiplatelet agents:

Prasugrel and ticagrelor: The ADP receptor inhibitors prasugrel and ticagrelor have not been studied with dabigatran etexilate in the prevention of stroke in patients with atrial fibrillation (AF), and are not recommended as concomitant therapy. Note that the concomitant use of ticagrelor increases exposure to dabigatran (see DRUG INTERACTIONS, Table 14, Ticagrelor).

NSAIDs, ASA or clopidogrel: Concomitant use of ASA or other antiplatelet agents, such as clopidogrel, based on medical need to prevent myocardial infarction, should be undertaken with caution. Close clinical surveillance is recommended.

In AF patients in the RE-LY trial, concomitant use of ASA or clopidogrel with dabigatran etexilate approximately doubled the risk of major bleed, irrespective of the dose of dabigatran etexilate used. However, there was little improvement in stroke and systemic embolic events. A similar increase in the risk of major bleed was noted with concomitant use with the study comparator, warfarin. Concomitant use of dabigatran etexilate with an antithrombotic is not recommended for prevention of cardiogenic thromboembolic stroke in AF patients.

P-gp Inhibitors: Concomitant treatment with strong P-gp inhibitors, i.e. oral ketoconazole or oral glecaprevir/pibrentasvir is contraindicated (see CONTRAINDICATIONS).

APO-DABIGATRAN should not be used with dronedarone (see DRUG INTERACTIONS, Drug-Drug Interactions, Table 14).

Thrombolytic agents: Since there is very limited experience with the use of thrombolytic agents in conjunction with dabigatran etexilate, a careful risk-benefit assessment is required before instituting thrombolytics due to potential increased risk of major bleeding. Thrombolytic agents for treatment of acute myocardial infarction or acute ischemic stroke in conjunction with dabigatran etexilate may be considered, if thrombin time (TT), ecarin clotting time (ECT), or activated thromboplastin time (aPTT), not exceeding the upper limit of normal (ULN) have been obtained (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Patients with atrial fibrillation and another cardiovascular condition: In patients with atrial fibrillation and having another cardiovascular condition that warrants single or dual antiplatelet therapy, a careful assessment of the potential risks against potential benefits should be made before combining this therapy with APO-DABIGATRAN.

Specifically, co-administration of oral antiplatelet drugs, including ASA, clopidogrel or NSAIDs, or P-gp inhibitors in patients aged ≥75 years increases the risk of major bleeding, including gastrointestinal bleeding, by about 2-fold.

Cardiovascular

Acute myocardial infarction (AMI)

Discontinuation of APO-DABIGATRAN in the setting of AMI should be considered if the MI treatment involves invasive procedures, such as percutaneous coronary revascularization, or coronary artery bypass surgery. Similar consideration should be given if thrombolytic therapy is to be initiated, because bleeding risk may be expected to increase. Patients with AMI should be treated according to current clinical guidelines for that disorder. In this setting, APO-DABIGATRAN may be resumed for the prevention of stroke and systemic embolism upon completion of these revascularization procedures.

Cardioversion

Patients can be maintained on APO-DABIGATRAN while being cardioverted (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Cardioversion).

Catheter ablation for atrial fibrillation

Catheter ablation can be conducted in patients on 150 mg twice daily APO-DABIGATRAN treatment. APO-DABIGATRAN treatment does not need to be interrupted.

Percutaneous coronary intervention (PCI) with stenting

Patients with nonvalvular atrial fibrillation who undergo a PCI with stenting can be treated with APO-DABIGATRAN in combination with antiplatelets after hemostasis is achieved.

Patients with Valvular Disease

Safety and efficacy of dabigatran etexilate have not been studied in patients with prosthetic heart valves, or those with hemodynamically significant rheumatic heart disease, especially mitral stenosis, with or without atrial fibrillation. Occasional reports of thromboembolism in association with mechanical valves have been received. Therefore, the use of APO-DABIGATRAN is not recommended in this setting.

A Phase II study examined the effects of dabigatran etexilate and warfarin in a total of 252 patients with recent mechanical valve replacement surgery (i.e. within the current hospital stay), and in patients who received a mechanical valve replacement more than 3 months earlier. More thromboembolic events (mainly strokes and symptomatic prosthetic valve thrombosis) and more bleeding events were observed with dabigatran etexilate than with warfarin (see CONTRAINDICATIONS).

Of note, in the pivotal Phase III RE-LY trial in atrial fibrillation, about 22% of patients had other valvular disease including aortic stenosis, aortic regurgitation, and/or mitral regurgitation. About 17% had mitral regurgitation.

Patients with Antiphospholipid Syndrome

Direct acting Oral Anticoagulants (DOACs) including dabigatran etexilate are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist (VKA) therapy.

Hepatic

No treatment experience is available for patients with severe hepatic impairment (Child-Pugh classification C), acute liver disease or with elevated liver enzymes ≥2 upper limit of normal (ULN). Therefore, the use of APO-DABIGATRAN is not recommended in these populations.

Pulmonary

Acute Pulmonary Embolus in haemodynamically unstable patients, or in those requiring thrombolysis or pulmonary embolectomy.

Safety and efficacy of dabigatran etexilate have not been established for the treatment of VTE in patients with pulmonary embolus who are haemodynamically unstable, or who may receive thrombolysis or pulmonary embolectomy. In these patients the initial anticoagulation therapy should exclude the use of APO-DABIGATRAN (see DOSAGE AND ADMINISTRATION).

Other Surgery / Procedural Interventions

As with any anticoagulant, patients on APO-DABIGATRAN who undergo surgery or invasive procedures are at increased risk for bleeding. In these circumstances, temporary discontinuation of APO-DABIGATRAN may be required (see DOSAGE AND ADMINISTRATION – Cardioversion and catheter ablation for atrial fibrillation).

In case of necessary emergency surgery or urgent procedures, when rapid reversal of the anticoagulation effect is required, the specific reversal agent, PRAXBIND (idarucizumab), may be used.

Pre-Operative Phase

Elective Surgery/Intervention: APO-DABIGATRAN should be stopped at least 24 hours before the intervention, if possible, based on the clinical judgement of the physician.

Patients at higher risk of bleeding (see DOSAGE AND ADMINISTRATION) or in major surgery where complete hemostasis may be required: Consider stopping APO-DABIGATRAN 2 to 4 days before surgery.

Patients with renal insufficiency: Clearance of dabigatran in patients with renal insufficiency may take longer (see DOSAGE AND ADMINISTRATION, Renal Impairment). This should be considered in advance of any procedures, see Table 2 below.

Table 2: Discontinuation rules before invasive or surgical procedures

*for more details, see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Table 20

Patients with acute renal failure: APO-DABIGATRAN is contraindicated in patients with severe renal dysfunction (eCrCl <30 mL/min) (see CONTRAINDICATIONS). If acute renal failure occurs before surgery is required, APO-DABIGATRAN should generally be stopped at least 5 days before major surgery.

In cases of acute intervention: If acute intervention is required, APO-DABIGATRAN should be temporarily discontinued, due to increased risk of bleeding. Acute surgical or procedural interventions should be delayed if possible at least 12 hours after the last dose of APO-DABIGATRAN, with risk of bleeding weighed against the urgency of the needed intervention (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Peri-Operative Spinal/Epidural Anaesthesia, Lumbar Puncture

Procedures such as spinal anaesthesia may require complete hemostatic function. In patients treated with APO-DABIGATRAN for VTE prevention following major orthopedic surgery and who undergo spinal or epidural anaesthesia, or in whom lumbar puncture is performed in follow-up to surgery, the formation of spinal or epidural haematomas that may result in long-term or permanent paralysis cannot be excluded.

In the case of these peri-spinal procedures, administration of the 1^st dose of APO-DABIGATRAN should occur after hemostasis has been obtained and no sooner than 2 hours following puncture or removal of catheters related to these procedures.

The risk of these rare events may be higher with post-operative use of indwelling epidural catheters or the concomitant use of other products affecting hemostasis. Accordingly, the use of APO-DABIGATRAN is not recommended in patients undergoing anesthesia with post-operative indwelling epidural catheters.

Post-Procedural Period

Resume/start treatment with APO-DABIGATRAN as soon as complete hemostasis is achieved and the clinical situation allows.

Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. APO-DABIGATRAN treatment can be re-initiated 24 hours after administration of PRAXBIND (idarucizumab), if the patient is clinically stable and adequate hemostasis has been achieved.

Renal

Determine estimated creatinine clearance (eCrCl) in all patients before instituting APO-DABIGATRAN, and monitor renal function during APO-DABIGATRAN treatment, as clinically appropriate (see DOSAGE AND ADMINISTRATION).

APO-DABIGATRAN is contraindicated in cases of severe renal impairment (eCrCl < 30 mL/min) (see CONTRAINDICATIONS). APO-DABIGATRAN should be discontinued in patients who develop acute renal failure.

Anticoagulant-related nephropathy

There have been post-marketing reports of anticoagulant-related nephropathy (ARN) following dabigatran etexilate capsules use, presenting as acute kidney injury. Close monitoring including renal function evaluation is advised in patients with excessive anticoagulation, compromised renal function and hematuria.

Special Populations

Pregnant Women: There are no studies of dabigatran etexilate in pregnant women and therefore, the potential risk in these patients is unknown. Women should avoid pregnancy during treatment with APO-DABIGATRAN and when pregnant, should not be treated with APO-DABIGATRAN unless the expected benefit is greater than the risk.

Animal Data: Dabigatran decreased the number of implantations when male and female rats were treated at dosages about 2.6 to 3.0x the human exposure at maximum recommended human dose (MRHD) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits.

Labour and Delivery: Safety and effectiveness of dabigatran etexilate during labor and delivery have not been studied in clinical trials. Consider the risks vs the benefits in using dabigatran etexilate in this setting.

Animal Data: Death of offspring and mother rats during labour in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at doses about 2.6x the human exposure at MRHD.

Nursing Women: There are no clinical data available on the excretion of dabigatran into breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dabigatran etexilate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see CONTRAINDICATIONS).

Geriatrics (> 65 years of age): Most older subjects demonstrate an increase in drug exposure; especially in those patients 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 dabigatran etexilate have not been established in children <18 years of age. Therefore, APO-DABIGATRAN is not indicated in this patient population.

Patients of low body weight (< 50 kg): Use dabigatran etexilate with caution since limited data are available in these patients.

Monitoring and Laboratory Tests

Although there is no need to monitor anticoagulation effect of APO-DABIGATRAN during routine clinical practice, in certain infrequent situations such as overdosage, acute bleeding, urgent surgery, in cases of suspected non-compliance, or in other unusual circumstances, assessment of the anticoagulant effect of dabigatran may be appropriate.

At recommended doses of APO-DABIGATRAN, dabigatran prolongs coagulation time as measured by the:

• activated partial thromboplastin time (aPTT),
• thrombin time (TT) and
• ecarin clotting time (ECT).

In patients who are bleeding due to excess activity of dabigatran, these coagulation assays would be expected to be elevated and may be helpful in assessing anticoagulant activity of dabigatran.

The preferred assays are the calibrated Hemoclot TT assay and the ECT assay, but if they are not available, the aPTT assay is widely available and provides an approximation of dabigatran etexilate’s anticoagulant activity. The aPTT assay is generally less sensitive to anticoagulant activity than either the TT or ECT assay.

Prothrombin time (PT) (INR) tests should not be performed in patients taking dabigatran etexilate. The PT (INR) assay is unreliable and false-positive INR elevations have been reported.

Assays sensitivity and precision with varying dabigatran plasma concentrations: aPTT assay: A curvilinear relationship was shown between dabigatran plasma concentrations and aPTT. The aPTT assay shows low sensitivity at dabigatran plasma concentrations >100 ng/mL and well within the range observed following effective oral doses.

TT assay: The TT assay exhibited a linear relationship with plasma concentration. The TT assay shows a high level of sensitivity and may be too sensitive to dabigatran plasma concentrations in the clinically relevant plasma concentration range; for example, at dabigatran concentrations >600 ng/mL, TT frequently exceeded the maximum measurement time of the coagulometer. Therefore, the TT assay may serve as a sensitive method for determining if any dabigatran is present. However, since reagents used for determining TT at different laboratories are not standardised, the calibrated Hemoclot^® thrombin inhibitor assay (a diluted TT assay) with dabigatran standards should be used to calculate dabigatran concentration.

ECT assay: The ECT assay displayed a linear relationship with drug plasma concentrations in the clinically-relevant drug concentration range and exhibited adequate sensitivity and precision. However, given the lack of uniform standardisation of this assay, the clinical utility of this test remains to be established.

Results of coagulation tests indicating an increased risk of bleeding

TT assay: A TT measure with the calibrated Hemoclot^® thrombin inhibitor assay (Hyphen BioMed, Neuvillesur-Oise, France), indicating >200 ng/mL dabigatran plasma concentration (approximately > 65 seconds), taken just prior to the next dose of dabigatran etexilate after 150 mg bid dosing (at trough, i.e., 10 to 16 hours after the previous dose), is associated with a higher risk of bleeding.

aPTT assay: AF patients treated with dabigatran etexilate 150 mg bid, having an aPTT >2.0 to 3.0-fold of normal range at trough, were seen to have an increased risk of bleeding.

Results of coagulation tests indicating a lack of efficacy

aPTT assay: An aPTT assay in the normal range in patients deemed to have been anticoagulated with dabigratran etexilate, indicates no meaningful ongoing anticoagulant effect so planned surgery entailing high risk of bleeding could then proceed, if required.

ADVERSE REACTIONS

The overall safety of dabigatran etexilate was evaluated in 23,393 patients who were treated with dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate in RE-LY, 6,059 were treated with dabigatran etexilate 150 mg bid, while 5,983 received doses of 110 mg bid. About 21% of AF patients treated with dabigatran etexilate 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 dabigatran etexilate. Bleeding of any type or severity occurred in approximately 14 % of patients treated short-term for elective hip- or knee- replacement surgery; in 16.6% of AF patients treated long-term 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 trials 19.4% (RE-MEDY) and 10.5% (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 dabigatran etexilate 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.

Prevention of VTE after THR or TKR surgery

Table 3: Number (%) of patients experiencing bleeding events during the treatment period for VTE prevention in the REMODEL and RENOVATE trials, according to dose

Table 4: Number (%) of patients experiencing bleeding events during the treatment period for VTE prevention in the REMOBILIZE trial, according to dose

*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, intracranial, 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)

*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. 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

^#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
• 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 event considered clinically relevant by the investigator

^& Statistically significant, superior vs. warfarin

Bleeding events for both treatments were counted from the first intake of dabigatran etexilate or warfarin after the parenteral therapy had been discontinued (oral only treatment period). This included all bleeding events which occurred during dabigatran therapy. All bleeding events which occurred during warfarin therapy were included except for those during the overlap period between warfarin and parenteral therapy.

Table 6: Frequency event rate (%) of bleeding events from MBEs*, MBEs or CRBE(s)^# and any bleeding event(s) in patients the RE-MEDY study includes events that occurred between first intake of active study drug and 6 days after last intake of study drug:

^{* #} see footnotes under Table 5

^& Statistically significant

Table 7: Frequency event rate (%) of bleeding events from MBEs, MBEs or CRBE(s) and any bleeding event(s) in the RE-SONATE study includes events that occurred between first intake of active study drug and 6 days after last intake of study drug

*In RE-SONATE, CRBEs were defined as investigator-reported, overt bleeding not meeting the criteria for an MBE, but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment, or associated with discomfort such as pain, or impairment of activities of daily life.

Prevention of stroke and systemic embolism in AF patients - the RE-LY trial In Table 8, the category of major bleeds includes both life-threatening and non-life threatening bleeds. Intracranial bleeds is a subcategory of life-threatening bleeds. Intracranial bleeds include intracerebral (haemorrhagic stroke), subarachnoid and subdural bleeds. For this reason, these events may be counted in multiple categories.

Table 8: Frequency and annualized event rate (%) of bleeding events in patients with atrial fibrillation treated for prevention of stroke and systemic embolism in the RE-LY trial

* Adjudicated Bleeds

** Dose-adjusted warfarin to an INR of 2.0 – 3.0

⁺ICH consists of adjudicated haemorrhagic stroke and subdural and/or subarachnoid haemorrhage a Investigator-reported bleeding events

Major bleeding fulfilled ≥1 of the following criteria:

• Bleeding associated with a reduction in hemoglobin of ≥20 g/L or leading to a transfusion of ≥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 ≥1 of the following criteria:
• Fatal bleed; symptomatic intracranial bleed; reduction in hemoglobin of ≥50 g/L; transfusion of ≥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.

Patients >75 years of age

AF patients >75 years of age taking an anticoagulant are known to be at increased risk of having a stroke, serious and non-serious bleeding events and death compared to those <75 years of age. This risk is even higher in patients who are also receiving concomitant ASA or an antiplatelet agent compared to those not receiving ASA or an antiplatelet agent (see Table 9 below).

Table 9: Annualized rates of key safety outcomes in the RE-LY trial in patients > 75 years with or without antiplatelets (AP) or P-glycoprotein inhibitors (Pgp-inh.):

>75 years without

*Dabigatran etexilate 110 mg bid

** Dabigatran etexilate 150 mg bid

⁺dose adjusted, INR 2.0 – 3.0

^# Stroke/SEE and Ischemic Stroke outcomes are provided for comparative purpose only

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Prevention of VTE after THR or TKR surgery

Table 10: Common Adverse Reactions observed in ≥ 1% of dabigatran-treated patients in active - controlled VTE prevention trials

a Based on N = 2,716

b Enoxaparin 40mg QD or 30 mg BID

Treatment of VTE and Prevention of Recurrent DVT and PE

Table 11: Common Adverse Reactions observed in ≥ 1% of dabigatran-treated patients for acute DVT/PE in the RE-COVER and RE-COVER II trials (pooled data) and of dabigatran-treated patients for recurrent DVT/PE prevention in the RE-MEDY and RE-SONATE trials

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

Table 12: Common Adverse Reactions observed in ≥ 1% of dabigatran-treated patients with atrial fibrillation in the active- controlled trial, RE-LY

*Aggregate incidence presented for all adverse reactions within the body system, including those reactions occurring < 1% and not listed in the Table 12 above.

Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort), or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric haemorrhage, haemorrhagic gastritis, haemorrhagic erosive gastritis, gastrointestinal ulcer).

Gastrointestinal (GI) haemorrhage occurred at a higher frequency with dabigratran etexilate 150 mg bid, compared to warfarin (see Table 12 above). GI-adjudicated major bleeds were reported at 1.1%, 1.6%, and 1.1% (annualized rates) in the DE 110 mg, DE 150 mg and warfarin groups, respectively. GI life-threatening bleeds occurred with a frequency of 0.6%, 0.8% and 0.5% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. Any GI bleeds occurred with frequency of 5.4%, 5.7% and 3.9% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. The underlying mechanism of the increased rate of GI bleeding has not been established (see CLINICAL TRIALS, Prevention of stoke and systemic embolism in patients with atrial fibrillation).

Allergic reactions or drug hypersensitivity including angioedema, urticaria, bronchospasm, rash and pruritus have been reported in patients who received dabigatran etexilate. Rare cases of anaphylactic reactions have also been reported.

Liver Function Tests

In the long-term RE-LY study, observed abnormalities of liver function tests (LFTs) are presented below in Table 13.

Table 13: Liver Function Tests in the RE-LY trial

In the active controlled studies RE-COVER, RE-COVER II and RE-MEDY, potential abnormalities of LFTs occurred with a comparable or lower incidence in dabigatran etexilate vs. warfarin treated patients. In RE-SONATE, there was no marked difference between the dabigatran and placebo groups with regard to possible clinically significant abnormal LFT values.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

• Prevention of VTE after THR or TKR surgery (dabigatran 150 mg and 220 mg /day)

  Blood and lymphatic system: thrombocytopenia, neutropenia, agranulocytosis Gastrointestinal disorders: haemorrhoidal haemorrhage, rectal haemorrhage General: bloody discharge, catheter site haemorrhage

  Hepatobiliary disorders: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hepatic function abnormal/liver function test abnormal, transaminases increased

  Injury, poisoning and procedural complications: incision site haemorrhage Laboratory Investigations: blood urine present, hematocrit decrease, occult blood positive Musculoskeletal and cumulative tissue disorders: hemarthrosis

  Respiratory and thoracic system: epistaxis

  Skin and sub-cutaneous tissue: ecchymosis

  Surgical and medical procedures: post-procedural drainage, wound drainage Vascular disorders: haemorrhage

• Treatment of VTE and Prevention of Recurrent DVT and PE (dabigatran 150 mg bid)

  Blood and lymphatic system disorders: anaemia, thrombocytopenia, neutropenia, agranulocytosis

  Vascular disorders: haematoma, haemorrhage

  Gastrointestinal disorders: diarrhoea, dysphagia, gastrointestinal ulcer (including esophageal ulcer), gastro-esophagitis, gastro-esophageal reflux disease, nausea, vomiting Hepatobiliary disorders: hepatic function abnormal

  Musculoskeletal and connective tissue and bone disorders: hemarthrosis General disorders and administration site conditions: catheter site haemorrhage, injection site haemorrhage

  Injury, poisoning and procedural complications: incision site haemorrhage, traumatic haemorrhage

  Immune system disorder: anaphylaxis*, angioedema, drug hypersensitivity (bronchospasm*, pruritus, rash, urticaria)

  Respiratory disorders: hemoptysis

  Nervous system disorders: intracranial haemorrhage

  * These side effects were not reported in clinical trials as ADRs (AEs only); therefore, a frequency could not be calculated.

• Prevention of stroke and systemic embolism in AF patients - the RE-LY trial (dabigatran 110 mg bid and 150 mg bid)

  Blood and lymphatic system disorders: thrombocytopenia, neutropenia, agranulocytosis Vascular disorders: haematoma, haemorrhage

  Gastrointestinal disorders: dysphagia, gastrointestinal ulcer (including esophageal ulcer), gastro-esophagitis, gastro-esophageal reflux disease, vomiting

  Hepatobiliary disorders: hepatic enzyme increased, hepatic function abnormal / liver function test abnormal

  Musculoskeletal and connective tissue and bone disorders: hemarthrosis Renal and urinary disorders: urogenital haemorrhage

  General disorders and administration site conditions: catheter site haemorrhage, injection site haemorrhage

  Injury, poisoning and procedural complications: incision site hematoma, incision site haemorrhage, traumatic haemorrhage, traumatic hematoma

  Immune system disorder: anaphylaxis, drug hypersensitivity (bronchospasm*, pruritus, rash, urticaria)

  Respiratory disorders: hemoptysis

  Nervous system disorders: intracranial haemorrhage

  *These side effects were not reported in clinical trials as ADRs (AEs only)

Long-term experience in AF patients

RELY-ABLE, the open-label extension study of RE-LY (see CLINICAL TRIALS), assessed the long-term safety of two doses of dabigatran etexilate (110 mg bid and 150 mg bid) in patients with AF who had not permanently discontinued study medication at the time of their final RE-LY study visit. Patients enrolled in RELY-ABLE continued to receive the same dose of dabigatran etexilate as assigned in RE-LY for an additional 2.5 years. There were 5,851 patients enrolled in RELY-ABLE, representing 49% of patients originally randomized to receive dabigatran etexilate in RE-LY and 86% of RELY-ABLE-eligible patients. In this open-label study, the investigator-reported rates of outcome events (thromboembolic events, major bleed and other bleeding events) were consistent with event rates observed in RE-LY, including lower frequencies of bleeding events with the 110 mg bid dose compared with the 150 mg bid dose. The results of RELY-ABLE indicated that the long-term safety profile of dabigatran etexilate remained favourable for both test doses. No new safety findings were observed.

Post-Marketing Experience

The following additional 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. Decisions to include these reactions in labeling are typically based on ≥1 of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to dabigatran etexilate.

Renal and urinary disorders: Anticoagulant-related nephropathy (ARN)

Rare cases of angioedema and anaphylactic reaction have been reported in patients receiving dabigatran etexilate. Occasional reports of haemorrhagic pericardial effusion have been received.

Severe liver injury adverse events including cases of acute liver failure have been reported in patients treated with dabigatran etexilate irrespective of indication. A causal relationship with dabigatran etexilate has not been established.

Cases of alopecia were observed post marketing.

Cases of neutropenia and agranulocytosis have been observed. Neutropenia and agranulocytosis may manifest with symptoms such as frequent infection with fever, sore throat or mouth ulcers.

In addition to the Phase III RE-LY trial, an international, observational study (GLORIA-AF), prospectively collected (in its second phase) safety and effectiveness data in newly diagnosed NVAF patients on dabigatran etexilate in a real-world setting. Outcomes were reported as observed (unadjudicated). The study included 4,859 patients on dabigatran etexilate (dosages according to local clinical practice and local label; 55% treated with 150 mg bid, 43% treated with 110 mg bid, 2% treated with 75 mg bid). Patients were followed-up for 2 years. The mean CHADS₂ and HAS-BLED scores were 1.9 and 1.2, respectively, compared to a mean CHADS₂ and HAS-BLED score of 2.1 and 1.3 in RE-LY, respectively. Mean on-therapy follow-up time was 18.3 months. Major bleeding occurred in 0.97 per 100 patient-years. Life-threatening bleeding was reported in 0.46 per 100 patient-years, intracranial haemorrhage in 0.17 per 100 patient-years and gastrointestinal bleeding in 0.60 per 100 patient-years. Stroke occurred in 0.65 per 100 patient-years. Furthermore, in an obervational study in more than 134,000 elderly patients (≥65 years) with nonvalvular atrial fibrillation (NVAF) in the United States (contributing more than 37,500 patient-years of follow-up time), patients were treated with either dabigatran etexilate or warfarin, under real-world conditions between October 2010 and December 2012. Dabigatran etexilate (84% patients treated with 150 mg bid, 16% patients treated with 75 mg bid) was associated with a statistically significant reduced risk of ischemic stroke (hazard ratio 0.80, 95% confidence interval [CI] 0.67 - 0.96), intracranial hemorrhage (hazard ratio 0.34, CI 0.26 - 0.46), and mortality (hazard ratio 0.86, CI 0.77 - 0.96) and increased risk of gastrointestinal bleeding (hazard ratio 1.28, CI 1.14 - 1.44) compared to warfarin. No significant difference was found for major bleeding (hazard ratio 0.97, CI 0.88 – 1.07).

In both these studies, the observations in real-world settings were consistent with the established safety and efficacy profile for dabigatran etexilate in this indication.

DRUG INTERACTIONS

Overview

Concomitant use of APO-DABIGATRAN with other anticoagulants is contraindicated (see CONTRAINDICATIONS). Concomitant use with antiplatelet agents is not recommended (see WARNINGS AND PRECAUTIONS, Bleeding).

CYP P450 System

Based on in vitro evaluations, neither dabigatran etexilate nor its active moiety, dabigatran, are metabolised by the human cytochrome P450 system, nor do they exhibit effects on human CYP P450 isozymes.

Transporter interactions

Dabigatran etexilate, but not dabigatran, is a substrate with moderate affinity for the efflux P-glycoprotein (P-gp) transporter. Therefore, potent P-gp inducers or inhibitors may be expected to impact exposure to dabigatran.

P- glycoprotein inhibitors: Concomitant treatment with strong P-gp inhibitors, such oral ketoconazole is contraindicated (see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS, Bleeding).

For other P-gp inhibitors, such as amiodarone, quinidine and verapamil, see Table 14 below and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Patients taking the P-gp inhibitor verapamil).

P-gp inhibitors such as but not limited to cyclosporine, itraconazole, nelfinavir, posaconazole, ritonavir, saquinavir, tacrolimus and tipranavir may be expected to increase systemic exposure to dabigatran and should be used with caution.

The concomitant use of APO-DABIGATRAN with the fixed-dose combination of the P-gp inhibitors glecaprevir/pibrentasvir has been shown a 2.05 and 2.38-fold increase of dabigatran C_max and AUC and may increase the risk of bleeding. Concomitant use of dabigatran and strong P-glycoprotein (P-gp) inhibitors, i.e. oral ketoconazole or oral glecaprevir/pibrentasvir is contraindicated (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, P-gp inhibitors).

P- glycoprotein inducers: Potent P-gp inducers such as the anticonvulsants carbamazepine, phenytoin and Saint John’s Wort are expected to reduce dabigatran systemic exposure. Co-administration with APO-DABIGATRAN is not recommended. Caution is advised when co-administering these drug products.

P-glycoprotein substrates: Dabigatran etexilate is not expected to have a clinically meaningful interaction with P-gp substrates that do not also act as inhibitors or inducers of P-gp.

Drug-Drug Interactions

Table 14: Summary of Pharmacokinetic Drug-Drug Interactions

* C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

Food does not affect the bioavailability of APO-DABIGATRAN but delays the time-to-peak plasma concentrations by 2 hours.

Drug-Herb Interactions

Drug-herb interactions have not been investigated. Potent P-gp inducers such as Saint John’s Wort (Hypericum perforatum) may be expected to reduce systemic exposure of dabigatran. Co-administration of these products is not recommended.

Drug-Laboratory Interactions

Drug-laboratory interactions have not been investigated.

Drug-Lifestyle Interactions

Alcohol: No direct interaction between dabigatran etexilate and alcohol was demonstrated in animal models or has been hypothesized.

Ability to drive and use machine: The effect of dabigatran etexilate on the ability to drive, cycle and use machines has not been investigated. However, no such interaction is to be expected.

DOSAGE AND ADMINISTRATION

As for any non-vitamin K antagonist oral anticoagulant (NOAC) drug, before initiating APO-DABIGATRAN (dabigatran etexilate), ensure that the patient understands and is prepared to accept adherence to NOAC therapy, as directed.

APO-DABIGATRAN (dabigatran etexilate) should be taken orally with the entire capsule to be swallowed whole. The capsule should not be chewed, broken, or opened.

APO-DABIGATRAN should be taken regularly, as prescribed, to ensure optimal effectiveness. All temporary discontinuations should be avoided, unless medically indicated.

Monitoring renal function:

Before starting APO-DABIGATRAN: Determine estimated creatinine clearance (eCrCl) in all patients.

During APO-DABIGATRAN treatment: Monitor renal function as clinically appropriate.

Determination of renal function by eCrCl should occur at least once per year, and especially during circumstances when renal function may be expected to be compromised, i.e., acute myocardial infarction (AMI), acute decompensated heart failure (AHF), increased use of diuretics, use of certain co-medications, dehydration, hypovolemia, etc. Clinically relevant deterioration of renal function may require dosage adjustment or discontinuation of APO-DABIGATRAN (see Renal Impairment).

Glomerular filtration rate may be estimated by calculating eCrCl, using the following formula:

eCrCl (mL/min) =

in males: (140-age) (years) x weight (kg) x 1.23 or, (140-age) (yrs) x weight (kg) serum creatinine (mcmol/L) 72 x serum creatinine (mg/100 mL)

in females: (140-age) (years) x weight (kg) x 1.04 or, (140-age) (yrs) x weight (kg) x 0.85 serum creatinine (mcmol/L) 72 x serum creatinine (mg/100mL)

Elderly: As with any anticoagulant, caution is required when prescribing APO-DABIGATRAN to the elderly (see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS, Bleeding). Renal impairment may be frequent in the elderly (>75 years of age).

Renal impairment: APO-DABIGATRAN is contraindicated in patients with severe renal impairment (eCrCl <30 mL/min) (see CONTRAINDICATIONS).

Patients taking the P-glycoprotein (P-gp) inhibitor verapamil (see DRUG INTERACTIONS): Simultaneous initiation of treatment with APO-DABIGATRAN and verapamil should be avoided at any time. In all cases, to minimize potential interaction, APO-DABIGATRAN should be given at least 2 hours before verapamil.

Patients at higher risk of bleeding: As for any anticoagulant, APO-DABIGATRAN is NOT indicated in patients at excessive risk of bleeding (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Patient Body Weight: Population PK modelling showed that patients with a body weight of about 120 kg have about 20% lower drug exposure. Patients with a body weight of about 48 kg have about 25% higher drug exposure compared to patients with average weight. No dose adjustment is deemed necessary.

Recommended Dose and Dosage Adjustment

VTE prevention following elective hip- or knee-replacement surgery

General: Treatment should normally be initiated within 1 to 4 hours of completed surgery once hemostasis is secured. If hemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery for whatever reason, then treatment should be initiated with 2 capsules at once.

Table 15: Recommended dose and dosage adjustment for VTE prevention following elective hip-or knee-replacement surgery

Patients taking the P-gp inhibitor verapamil: Treatment initiation with verapamil should be avoided in patients following orthopedic surgery who are already treated with APO-DABIGATRAN.

Patients taking antacids, including aluminium compounds, sodium bicarbonate, calcium and/or magnesium compounds, or combinations of these (see DRUG INTERACTIONS):

• Co-administration of an antacid with APO-DABIGATRAN should be avoided within 24 hours after orthopedic surgery.
• APO-DABIGATRAN should be administered at least 2 hours before taking an antacid.

Treatment and prevention of DVT and PE

General: Start treatment with APO-DABIGATRAN following treatment with a parenteral anticoagulant for 5 to 10 days. The duration of therapy should be individualized after careful assessment of the treatment benefit against the risk of bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. surgery, trauma, immobilisation) and extended duration should be based on permanent risk factors or idiopathic DVT or PE.

Table 16: Recommended dose and dosage adjustment for the treatment and prevention of

DVT and PE

Elderly: The information of dose adjustment in this patient population has been extrapolated based on the PK/PD analysis of darbigatrin etexilate and has not been studied in this clinical setting.

Renal impairment: A dose reduction from 150 mg bid to 110 mg bid in the prevention or treatment of DVT/PE in patients with moderate renal impairment (eCrCl 30 to 50 mL/min) has not been studied and cannot be recommended. The dose selected should be based on the risk/benefit assessment of a given patient.

Patients at higher risk of bleeding: There are limited clinical data available for patients with multiple risk factors for bleeding. In these patients, APO-DABIGATRAN should only be given if the expected benefit outweighs bleeding risks.

Prevention of stroke and systemic embolism in patients with atrial fibrillation

Table 17: Recommended dose and dosage adjustment for the prevention of stroke and systemic embolism in patients with atrial fibrillation

Elderly:

• Patients ≥80 years of age: Alternate dosing may be considered for other geriatric patients

  (see CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Table 38 and Table 39).

• Patients >75 years of age with ≥1 risk factor for bleeding (see WARNINGS AND

  PRECAUTIONS, Bleeding, Table 1). The dosing may also be considered for patients taking concomitant anti-platelet agents or P-gp inhibitors (see ADVERSE REACTIONS, Bleeding, Table 9). The effectiveness of stroke prevention may be expected to be lessened with this dosage regimen, compared to that of the usual 1 capsule of 150 mg APO-DABIGATRAN twice daily.

Renal impairment: No dose adjustment is generally needed in patients with moderate renal impairment (eCrCl 30 to 50 mL/min). (see CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Table 40 and Table 41).

Switching treatment

Switching from parenteral anticoagulants treatment to APO-DABIGATRAN: Treatment with APO-DABIGATRAN should be initiated 0 to 2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment [e.g. intravenous unfractionated heparin, (UFH)].

Switching from APO-DABIGATRAN treatment to parenteral anticoagulant:

• VTE prevention following hip- or knee-replacement surgery: Wait 24 hours after the last dose of APO-DABIGATRAN before switching to a parenteral anticoagulant.

• Treatment and prevention of DVT and PE: wait 12 hours after the last dose of APO-

  DABIGATRAN before switching to a parenteral anticoagulant.

• Prevention of stroke and systemic embolism in patients with atrial fibrillation: Wait 12 hours after the last dose of APO-DABIGATRAN before switching to a parenteral anticoagulant.

Switching from Vitamin K antagonists (VKAs) to APO-DABIGATRAN: APO-DABIGATRAN should only be started after VKAs have been discontinued, and the patient’s INR found to be <2.0.

Switching from APO-DABIGATRAN to VKAs: As with any short-acting anticoagulant, there is a potential for inadequate anticoagulation when transitioning from APO-DABIGATRAN to a VKA. It is important to maintain an adequate level of anticoagulation when transitioning patients from one anticoagulant to another.

The starting time of the VKA should be adjusted according to the patient’s calculated creatinine clearance (eCrCl) as follows:

• eCrCl ≥ 50 mL/min, start VKA 3 days before discontinuing APO-DABIGATRAN

• eCrCl ≥ 30 to < 50 mL/min, start VKA 2 days before discontinuing APO-

  DABIGATRAN

In general, after starting VKA therapy, its clinically relevant anticoagulant effect is not readily apparent for at least 2 days, while the full therapeutic effect is achieved in about 5 to 7 days.

Note that when converting a patient from APO-DABIGATRAN to VKA therapy, the INR will not reliably reflect the anticoagulant effect of VKA until at least 2 days after discontinuation of APO-DABIGATRAN. In switching from APO-DABIGATRAN to VKA, the INR should only be used to assess the anticoagulant effect of the VKA.

The INR is only calibrated and validated for VKA and should not be used for any other anticoagulant, including APO-DABIGATRAN.

Cardioversion and catheter ablation for atrial fibrillation

Patients can stay on APO-DABIGATRAN while being cardioverted (see WARNINGS AND PRECAUTIONS, Cardiovascular, Cardioversion).

Catheter ablation can be conducted in patients on 150 mg twice daily APO-DABIGATRAN treatment. APO-DABIGATRAN treatment does not need to be interrupted (see WARNINGS AND PRECAUTIONS, Cardiovascular, Catheter ablation for atrial fibrillation).

Missed Dose

In all cases, patients should not take a double dose to make up for missed individual doses.

• Prevention of venous thromboembolism in patients following orthopaedic surgery:

  Patients can continue with their remaining daily doses of APO-DABIGATRAN at the scheduled time of the next day.

• Treatment and prevention of DVT and PE: A forgotten APO-DABIGATRAN 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.
• Prevention of stroke and systemic embolism in patients with atrial fibrillation: If the prescribed dose of APO-DABIGATRAN is not taken at the scheduled time, the dose should be taken as soon as possible on the same day. A forgotten APO-DABIGATRAN 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. For optimal effect and safety, it is important to take APO-DABIGATRAN regularly twice a day, at approximately 12 hour intervals.

Administration

APO-DABIGATRAN should be taken with a full glass of water to facilitate delivery to the stomach. APO-DABIGATRAN may be taken with food, or on an empty stomach. Patients experiencing dyspepsia should take APO-DABIGATRAN with meals. Based on clinical judgment, treatment with a proton-pump inhibitor may be considered in patients still experiencing dyspepsia despite taking APO-DABIGATRAN with or within 30 minutes after meals.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Doses of APO-DABIGATRAN beyond those recommended expose the patient to increased risk of bleeding. Excessive anticoagulation may require discontinuation of APO-DABIGATRAN.

The use of activated charcoal to reduce absorption in case of APO-DABIGATRAN overdose may be considered.

In case of complications such as bleeding or need for urgent required surgical procedures, associated with an overdose with APO-DABIGATRAN, when rapid reversal of the anticoagulation effect is required use of the specific reversal agent, PRAXBIND (idarucizumab), should be considered.

Management of Bleeding

In the event of haemorrhagic complications in a patient receiving APO-DABIGATRAN, treatment must be discontinued, and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route, adequate diuresis must be maintained. Appropriate standard treatment, e.g. surgical hemostasis as indicated and blood volume replacement, should be undertaken. In addition, consideration may be given to the use of fresh whole blood or the transfusion of fresh frozen plasma.

For a list of assays to assess anticoagulant activity of dabigatran, see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests.

For situations of life-threatening or uncontrolled bleeding in the setting of dabigatran etexilate overdose, when rapid reversal of the anticoagulation effects of dabigatran is required, use of the specific reversal agent, PRAXBIND, should be considered (see WARNINGS AND PRECAUTIONS, Bleeding).

In rare circumstances when mandated clinically, combined or overlapping use of PRAXBIND with one of the following procoagulants may be considered:

• activated prothrombin complex concentrates (aPCC), e.g., FEIBA
• recombinant Factor-VIIa (rFVIIa)
• prothrombin complex concentrate (PCC)

There is some experimental evidence to support the role of these procoagulant agents in reversing the anticoagulant effect of dabigatran but their usefulness in clinical settings has not yet been clearly demonstrated. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet drugs have been used.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of APO-DABIGATRAN and should not be used for this specific reason.

Hemodialysis

As protein binding is low, dabigatran can be dialysed, although there is limited clinical experience in using dialysis in this setting.

Clearance of dabigatran by hemodialysis was investigated in patients with end-stage renal disease (ESRD), without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flow rate, four hour duration, a blood flow rate of either 200 ml/min or 350 to 390 ml/min. This resulted in a removal of 50% or 60% of total dabigatran concentrations, respectively, depending on the blood-flow rate. The amount of drug cleared by dialysis was proportional to the blood flow rate. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PD relationship was not affected by the procedure.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Dabigatran etexilate is a prodrug which does not exhibit anticoagulant activity itself. Following oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver.

Dabigatran is a competitive, reversible direct thrombin inhibitor and is the main active principle in plasma. Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

In vivo and ex vivo animal studies have demonstrated antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate following oral administration in various animal models of thrombosis.

Pharmacodynamics

There is a clear correlation between plasma dabigatran concentration and degree of anticoagulant effect. The maximum effect (E_max) of dabigatran on pharmacodynamic (PD) parameters occurred at the same time as C_max, indicating that thrombin inhibition by dabigatran is a direct effect, linked to the central plasma compartment.

Table 18 below shows peak and trough dabigatran plasma concentrations at steady-state in the RE-LY trial following administration of dabigatran etexilate 110 mg and 150 mg bid in patients with atrial fibrillation, expressed as median values (10^th to 90^th percentiles):

Table 18:

*C_2h,ss = dabigatran plasma concentration measured at steady-state 2 hours (deemed peak) after the last dose

^#C_pre,ss = dabigatran plasma concentration measured at steady-state 10 to 16 hours (deemed trough) after the last dose

Pharmacokinetics

After oral administration of dabigatran etexilate in healthy volunteers, the pharmacokinetic (PK) profile of dabigatran in plasma is characterised by a rapid increase in plasma concentrations with C_max attained 0.5 to 2.0 hours post-administration. After C_max, plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of approximately 11 hours in healthy elderly subjects. Following administration of multiple doses, a terminal half-life of about 12 to 14 hours was observed, with the half-life independent of dose. C_max and AUC were dose-proportional.

Half-life is prolonged if renal function is impaired as shown in Table 19.

Table 19: Half-life of total dabigatran in relation to renal function

The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate was approximately 6.5 %.

Table 20: Summary of PK parameters after single and repeated oral administration in humans

The oral bioavailability may be increased by 75% (about 1.8 -fold) compared to the reference capsule formulation when the pellets are taken without the HPMC capsule shell. Hence, the integrity of the HPMC capsules should always be preserved in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate. Therefore, patients should be advised NOT to open the capsules and take the pellets alone, e.g. sprinkled over food or into beverages (see DOSAGE AND ADMINISTRATION, Administration).

Absorption: A study evaluating post-operative absorption of dabigatran etexilate, 1 to 3 hours following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached at 6 hours following administration, or at 7 to 9 hours following surgery. It is noted however that contributing factors such as anaesthesia, gastrointestinal paresis, and surgical effects will mean that a proportion of patients will experience absorption delay independent of the oral drug formulation. Although this study did not predict whether impaired absorption persists with subsequent doses, it was demonstrated in a further study, that slow and delayed absorption is usually only present on the day of surgery. On subsequent days, absorption of dabigatran is rapid with peak plasma concentrations attained 2 hours after drug administration.

Distribution: Low concentration-independent binding of dabigatran to human plasma proteins (about 35%) was observed. The volume of distribution of dabigatran of 60 to 70 L exceeded the volume of total body water, indicating moderate tissue distribution of dabigatran.

Metabolism: After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. The cleavage of the prodrug dabigatran etexilate by esterase-catalysed hydrolysis to the active principle dabigatran is the predominant metabolic reaction. Dabigatran is metabolised in the liver by conjugation with activated glucuronic acid forming pharmacologically active acylglucuronides. Four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounting for <10% of total dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods. CYP 450 metabolic enzymes are not involved in dabigatran metabolism.

Excretion: Metabolism and excretion of dabigatran were studied following a single intravenous (iv) dose of radiolabeled dabigatran in healthy male subjects. After an iv dose, the dabigatran-derived radioactivity was eliminated primarily in the urine (85%). Faecal excretion accounted for 6% of the administered dose. Recovery of the total radioactivity ranged from 88 to 94 % of the administered dose by 168 hours post dose.

Hepatic elimination via the bile represents a minor elimination pathway (approximately 20% of the administered dose).

Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 mL/min corresponding to the glomerular filtration rate.

Special Populations

Geriatrics: Elderly subjects showed an increase of 40 to 60% (1.4 to 1.6-fold) in the AUC and about 25% (1.3-fold) in C_max, compared to young subjects.

Patients >65 years of age: The AUCτ,ss and C_max,ss in elderly females were approximately 1.9-fold and 1.6-fold higher, respectively, than in younger females. In elderly males, the AUCτ,ss and C_max,ss were 2.2-fold and 2.0-fold higher, respectively, than in male subjects aged 18 to 40 years.

The observed increase of dabigatran exposure correlated with the age-related reduction in creatinine clearance.

Patient ≥75 years

In AF patients in RE-LY, compared to subjects aged 65 to 75 years, subjects ≥75 years of age showed about 31% (about 1.3-fold) increase in through concentration, while subjects <65 years of age showed about 22% lower through concentration.

Gender:

Primary VTE prevention studies: Drug exposure was about 40 to 50% higher (1.4 to 1.5-fold) in female patients than in male patients.

Atrial fibrillation patients: Females had on average 30 % higher (1.3-fold) trough and post-dose concentrations.

Race: The PK of dabigatran were investigated in Caucasian and Japanese volunteers after single and multiple doses. Ethnic origin did not affect the PK of dabigatran in a clinically relevant manner. Only limited PK data in patients from African descent are available.

Hepatic Insufficiency: No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls.

Renal Insufficiency: Following oral dosing with dabigatran etexilate, there is a direct correlation of systemic exposure to dabigatran with degree of renal impairment. Severe renal insufficiency (eCrCl < 30 mL/min) increased exposure to dabigatran 6-fold (see CONTRAINDICATIONS) while moderate renal impairment (eCrCl 30 to 50 mL/min) increased exposure 2.7-fold.

In the RE-LY trial, compared to patients without renal impairment (eCrCl ≥80 mL/min), patients with moderate renal impairment (eCrCl 30 to 50 mL/min) had on average 2.2-fold and 1.8-fold higher pre- and post-dose dabigatran plasma concentrations with 150 mg bid dosing, and 2.4-fold and 1.8-fold higher pre- and post-dose dabigatran concentrations with 110 mg bid.

In RE-COVER, patients with mild (CrCl > 50 mL/min but < 80 mL/min) and moderate (CrCl between 30 to 50 mL/min). renal impairment had on average 1.7-fold and 3.4-fold higher steady state dabigatran trough concentrations compared with patients with CrCl > 80 mL/min.

Hemodialysis: As protein binding is low, dabigatran can be dialysed, although there is limited clinical experience in using dialysis in this setting (see Management of Bleeding).

Body weight: The dabigatran trough concentrations were about 20% lower in patients with a body weight > 100 kg, compared with 50 to 100 kg. The majority (80.8%) of patients in the RELY trial were in the ≥ 50 kg and < 100 kg category with no clear difference detected. Limited data in patients ≤ 50 kg are available.

Cardioversion: A total of 1,255 subjects had cardioversions performed during the RE-LY study, 409 (6.8%), 415 (6.8%) and 431 (7.2%) in the dabigatran etexilate 110 mg, dabigatran etexilate 150 mg, and warfarin treatment groups, respectively. The rate of stroke occurring within 30 days of cardioversion was low and similar across all treatment groups, i.e., dabigatran etexilate 110 mg (0.03%), dabigatran etexilate 150 mg (0.03%) and warfarin (0.02%) (see WARNINGS AND PRECAUTIONS, Cardiovascular, Cardioversion).

Catheter Ablation for Atrial Fibrillation:

A prospective, randomized, open-label, multicenter, exploratory study with blinded, centrally adjudicated endpoint evaluation (RE-CIRCUIT) was conducted in patients who were under stable anticoagulant and eligible for dabigatran 150 mg twice daily treatment. The study compared 150 mg twice daily uninterrupted dabigatran etexilate with uninterrupted INR-adjusted warfarin in patients with paroxysmal or persistent atrial fibrillation who underwent catheter ablation. Of the 704 enrolled patients, 635 patients underwent catheter ablation procedure (317 on uninterrupted dabigatran and 318 on uninterrupted warfarin). All patients underwent a Trans-oesophageal Echocardiography (TEE) prior to catheter ablation. The primary outcome , adjudicated major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) criteria, occurred in 5 (1.6 %) patients in the dabigatran etexilate group and 22 (6.9 %) patients in the warfarin group (risk difference −5.3%; 95% CI −8.4, −2.2; P=0.0009). There was no stroke/systemic embolism/TIA (composite) event in the dabigatran etexilate arm, and one event (TIA) in the warfarin arm from the time of ablation until 8 weeks post-ablation. This study demonstrated that dabigatran etexilate was associated with a significant reduction in major bleeding event (MBE) rate compared with INR-adjusted warfarin, in the setting of ablation.

Patients who underwent Percutaneous coronary intervention (PCI) with stenting: A prospective, randomized, open-label, blinded endpoint (PROBE) study (Phase IIIb) to evaluate dual-therapy with dabigatran etexilate (110 mg or 150 mg bid) plus clopidogrel or ticagrelor (P2Y₁₂ antagonist) vs. triple-therapy with warfarin (adjusted to a INR 2.0 to 3.0) plus clopidogrel or ticagrelor and aspirin was conducted in patients with nonvalvular atrial fibrillation who underwent a PCI with stenting (RE-DUAL PCI). Patients (n=2725) were randomized to dabigatran etexilate 110 mg bid dual-therapy, dabigatran etexilate 150 mg bid dual-therapy or warfarin triple-therapy. In the triple-therapy group, aspirin was discontinued after 1 month in patients in whom a bare metal stent was implanted and after 3 months in patients in whom a drug-eluting stent was implanted. Elderly patients outside of the United States (≥70 years of age for Japan, ≥80 years of age for all other countries) were randomly assigned to the dabigatran etexilate 110 mg dual-therapy group or the warfarin triple-therapy group. The primary endpoint was time to first major or clinically relevant non-major bleeding event, as defined by ISTH.

The incidence of the primary endpoint was 15.4 % (151 patients) in the dabigatran etexilate 110 mg dual-therapy group as compared with 26.9 % (264 patients) in the warfarin triple-therapy group (HR 0.52; 95% CI 0.42, 0.63; P<0.0001 for non-inferiority and P<0.0001 for superiority) and in 20.2 % (154 patients) in the dabigatran etexilate 150 mg dual-therapy group as compared with 25.7 % (196 patients) in the corresponding warfarin triple-therapy group (HR 0.72; 95% CI 0.58, 0.88; P<0.0001 for non-inferiority Both dabigatran etexilate dual-therapy groups had lower rates of intracranial hemorrhage than the corresponding warfarin triple-therapy group: 0.3% (3 patients) in the 110 mg dabigatran etexilate dual-therapy group as compared with 1.0% (10 patients) in the warfarin triple-therapy group (HR 0.30; 95% CI 0.08, 1.07; P=0.064) and 0.1% (1 patient) in the 150 mg dabigatran etexilate dual-therapy group as compared with 1.0% (8 patients) in the corresponding warfarin triple-therapy group (HR 0.12; 95% CI 0.02, 0.98; P=0.047). The incidence of the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, or systemic embolism) or unplanned revascularization in the two dabigatran etexilate dual-therapy groups combined was non-inferior to the warfarin triple-therapy group (13.7% vs. 13.4% respectively; HR 1.04; 95% CI: 0.84, 1.29; P=0.0047 for non-inferiority).

This study demonstrated that dual-therapy, with dabigatran etexilate and a P2Y₁₂ antagonist, significantly reduced the risk of bleeding vs. warfarin triple-therapy, with non-inferiority for composite of thromboembolic events, in patients with atrial fibrillation who underwent a PCI with stenting.

STORAGE AND STABILITY

Blister: Store at 15˚C - 30˚C. Store in original package to protect from moisture.

Bottle: Store at 15˚C - 30˚C. Store in original package to protect from moisture. Once opened, the product must be used within 4 months. Keep the bottle tightly closed.

SPECIAL HANDLING INSTRUCTIONS

Store in a safe place out of the reach and sight of children.

To remove a capsule from the blister, push the capsule through the blister foil.

When taking a capsule out of the bottle, please note the following instructions:

• The cap opens by pushing and turning.
• After removing the capsule, place the cap back on the bottle and tightly close the bottle right away after you take your dose.

Store in the original package in order to protect from moisture.

Do not put the capsules in pill boxes or pill organizers, unless capsules can be maintained in the original package.

Any unused product or waste material should be disposed in accordance with local requirements.

DOSAGE FORMS, COMPOSITION AND PACKAGING

HPMC (hydroxypropylmethylcellulose) Capsules of 75 mg, 110 mg and 150 mg.

APO-DABIGATRAN 75 mg capsule (Dabigatran Etexilate):

Hypromellose capsule shells with buff opaque body, light blue opaque cap, imprinted “APO” on cap and “D75” on body in black ink. Filled with light yellow to yellow colored powder.

APO-DABIGATRAN 110 mg capsule (Dabigatran Etexilate):

Hypromellose capsule shells with buff opaque body, light blue opaque cap, imprinted “APO” on cap and “D110” on body in black ink. Filled with light yellow to yellow colored powder.

APO-DABIGATRAN 150 mg capsule (Dabigatran Etexilate):

Hypromellose capsule shells with buff opaque body, light blue opaque cap, imprinted “APO” on cap and “D150” on body in black ink. Filled with light yellow to yellow colored powder.

Non-medicinal ingredients:

Colloidal silicon dioxide, croscarmellose sodium, fumaric acid, magnesium stearate, and mannitol.

HPMC capsule shell contains:

Black printing ink, FD&C Blue #1, hypromellose, iron oxide red, iron oxide yellow, and titanium dioxide.

Printing ink contains:

Iron oxide black, potassium hydroxide, propylene glycol, shellac and strong ammonia solution

Packaging:

Blisters of 30s (3x10s, 5x6s) for 75 mg and 60s (6x10s, 10x6s) for 110 mg and 150 mg Bottles of 30s for 75 mg and 60s for 110 mg and 150 mg

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Chemical name:

Molecular Formula:

Molecular weight:

Structural formula:

Dabigatran etexilate (INN).

The pro-drug dabigatran etexilate is used in its salt form dabigatran etexilate mesylate (BIBR 1048 MS).

(INN) - Ethyl 3-[[[2-[[[4-

[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1- methyl-1H- benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino] propanoate.

(IUPAC) - Ethyl N-{[2-({[4-((E)-

amino{[(hexyloxy)carbonyl]imino}

methyl)phenyl]amino}methyl)-1-methyl-1H-benzimidazol-5-yl] carbonyl}-N-pyridin-2-yl-β-alaninate methanesulfonate.

(CAS name) - beta-Alanine, N-[[2-[[[4-

[[[(hexyloxy)carbonyl]amino]

iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate.

C₃₄H₄₁N₇O₅-CH₄SO₃

723.86 g/mol (salt) and 627.75 g/mol (free base)

Physicochemical properties

Chirality:

Physical Appearance:

Melting Point:

Dissociation Constants:

Apparent Partition Coefficient:

Hygroscopicity:

pH-Solubility Profile:

Dabigatran etexilate mesylate has no chiral centres and therefore does not form enantiomers. Geometric isomers (tautomers) are possible.

Yellow-white powder.

Dabigatran Etexilate mesylate shows two endothermic peaks at 155.08°C and 184.49 °C.

pKa1 = 4.0 ± 0.1

pKa2 = 6.7 ± 0.1

The partition coefficient of the neutral form (free base) is log P = 3.8

Dabigatran Etexilate Mesylate is slightly hygroscopic.

Solubility is strongly pH dependent with increased solubility at acidic pH. Highest dose of Dabigatran Etexilate Mesylate is 172.95 mg. Calculated dose solubility volume is (172.95 mg / 0.0003 mg/ml) 576500 ml which is more than 250 ml.

Table 21: Solubility in Organic Solvents of Dabigatran etexilate mesylate:

CLINICAL TRIALS

Comparative Bioavailability Studies

A randomized, single dose, double-blinded, two-treatment, two-sequence, four-period, fully-replicated, four-way crossover comparative bioavailability study of APO-DABIGATRAN 150 mg capsules (Apotex Inc.) and PRADAXA^® 150 mg capsules [Boehringer Ingelheim (Canada) Ltd.] was conducted in 49 healthy, adult, male subjects under fasting conditions. Comparative bioavailability data, based on the active metabolite of dabigatran etexilate (i.e. dabigatran) from the 42 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ APO-DABIGATRAN (dabigatran etexilate as dabigatran etexilate mesylate) capsules, 150 mg (Apotex Inc.) ² PRADAXA^® (dabigatran etexilate as dabigatran etexilate mesylate) capsules, 150 mg [Boehringer Ingelheim (Canada) Ltd.]

³ Expressed as median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

Prevention of VTE after THR or TKR surgery

Table 22: Summary of patient demographics for Phase III clinical trials in primary prevention of VTE following major orthopaedic surgery

* Dabigatran etexilate dose - 220 mg q.d., and 150 mg q.d., each initiated with a half dose on the day of surgery Enoxaparin dose – 40 mg qd, beginning the night prior to surgery; 30 mg bid beginning 12-24 hours post-operatively

**D220 – Dabigatran etexilate 220 mg

D150 – Dabigatran etexilate 150 mg

E – Enoxaparin

The clinical trials inclusion and exclusion criteria were uniform across the Phase III programme - the mean age was >65 years, about 60% were female, and the mean BMI was >29. Some important patient subgroups excluded by protocol were: patients with known hepatic disease with potential impact on survival or with baseline elevation of liver function tests above 2 x ULN, patients with severe renal insufficiency (eCrCl <30 mL/min), patients who were or had the potential to become pregnant during the study period, and patients under 40 kg.

All the Phase III trials were non-inferiority studies. The pre-specified primary efficacy endpoint was total VTE and all-cause mortality. A pre-specified meta-analysis of the composite endpoint major VTE and VTE-related death including all the 3 Phase III studies showed that there were no clinically relevant differences with regard to this endpoint between any of the 3 treatment regimens tested in this programme.

Table 23: Analysis of total VTE and all-cause mortality during treatment period for FAS* in Phase III orthopaedic surgery studies

+ DE = Dabigatran Etexilate, Enox = Enoxaparin.

* Full analysis set

^a Probability for testing difference vs. enoxaparin > Minimum Important Difference (MID) ^b Calculated as [lower bound (placebo-enoxaparin) - upper bound (dabigatran-enoxaparin)] / lower bound (placebo-enoxaparin)

^c MID was defined to preserve 2/3 of the enoxaparin effect size based on the lower bound of the 95% confidence interval. MID was 9.2% for RE-MODEL, 7.7% for RE-NOVATE, and 9.2% for RE-MOBILIZE

Pre-specified secondary endpoints of each of the Phase III trials were the composite of major VTE and VTE-related death, as well as each of the individual components of the 2 composite endpoints, total VTE and all-cause mortality, and major VTE and VTE-related mortality.

Table 24: Analysis of major VTE and VTE-related mortality during treatment period in risk ratio scale for FAS-major in Phase III orthopaedic surgery studies and summary of individual components contributing to major VTE and VTE related mortality during treatment period for FAS-major in Phase III orthopaedic surgery studies

⁺ DE = Dabigatran Etexilate, Enox = Enoxaparin

^* Full analysis set – major

^# Patients were counted only one in the most severe category in order of death > PE > proximal DVT

Table 25: Major bleeding events (MBE) and any bleeding events by treatment in the Phase

III trials (RE-MODEL, RE-NOVATE and RE-MOBILIZE)

* Enoxaparin dose 40 mg OD

** Enoxaparin dose 30 mg bid

Treatment of VTE and prevention of recurrent DVT and PE

Table 26: Summary of clinical trials in the acute DVT/PE treatment

¹ Number of patients who took at least 1 dose of any study medication (i.e., patients in the full analysis set [FAS]

DE – Dabigatran Etexilate

W – warfarin (target INR 2.0-3.0)

Clinical evidence has demonstrated dabigatran etexilate to be an effective and safe treatment for DVT and/or PE. Two multi-center, randomised, double-blind, parallel-group, replicate studies, RE-COVER and RE-COVER II, compared dabigatran etexilate (150 mg bid) with warfarin (target INR 2.0 to 3.0) in patients with acute DVT and/or PE. The primary objective of these studies was to determine if dabigatran was non-inferior to warfarin in reducing the occurrence of the primary endpoint which was the composite of recurrent symptomatic DVT and/or PE and related deaths within the 6 month acute treatment period.

In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were randomized and 5,107 were treated. Patients were mostly Caucasian (86.1%).

Table 27: Characteristics of the Patients According to Study and Assigned Study Drug

The duration of treatment with fixed dose of dabigatran was 174.0 days without coagulation monitoring. For patients randomized to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) was 60.6%. Concomitant medications included vasodilators 28.5%, agents acting on the renin-angiotensin system 24.7%, lipids lowering agents 19.1%, beta-blockers 14.8%, calcium channel blockers 9.7%, NSAIDs 21.7%, aspirin 9.2%, antiplatelet agents 0.7%, P-gp inhibitors 2.0% (verapamil 1.2% and amiodarone 0.4%).

RE-COVER and RE-COVER II demonstrated that in patients presenting with acute DVT and/or PE treated initially for ≥ 5 days of parenteral therapy, treatment with dabigatran etexilate 150 mg twice daily was non-inferior to the treatment with warfarin (p values for non-inferiority: RE-COVER p<0.0001, RE-COVER II p=0.0002). Bleeding events (MBEs, MBE or CRBEs and any bleeding) were significantly lower in patients receiving dabigatran etexilate 150 mg twice daily as compared with those receiving warfarin.

Figure 1 Time to first adjudicated VTE and VTE-related death until the end of post-treatment period for the RE-COVER and RE-COVER II pooled

Table 28: Analysis of the primary and secondary efficacy endpoints for the RE-COVER and RE-COVER II (pooled) [FAS]

*VTE is a composite of DVT and/or PE Events were taken into account until the end of the post-treatment period

Table 29: Summary of all clinical trials supporting the indication for the prevention of recurrent DVT/PE

¹ Number of patients who took at least 1 dose of any study medication (i.e., patients in the full analysis set [FAS] DE – Dabigatran Etexilate

W – warfarin (target INR 2.0-3.0)

P- placebo

Clinical evidence has demonstrated dabigatran etexilate to be an effective and safe treatment for recurrent DVT and/or PE. Two randomized, parallel group, double-blind studies, RE-MEDY and RE-SONATE, were performed in patients previously treated with anticoagulation therapy.

Table 30: Characteristics of the Patients According to Study and Assigned Study Drug

‡ Creatinine clearance was

estimated according to the Cockcroft–Gault method

^& P = 0.02 for the difference between the dabigatran group and the warfarin group, chi-square test ^** P = 0.007 for the difference between the dabigatran group and the warfarin group, chi-square test

RE-MEDY was a warfarin-controlled study, which enrolled patients already treated for 3 to 12 months with the need for further anticoagulant treatment. The objective of the RE-MEDY study was to compare the safety and efficacy of oral dabigatran etexilate (150 mg bid) to warfarin (target INR 2.0 to 3.0) for the long-term treatment and prevention of recurrent, symptomatic DVT and/or PE. A total of 2,866 patients were randomized and 2,856 patients were treated. Patients were mostly Caucasian (90.1%). Concomitant medications: agents acting on the renin-angiotensin system 27.9 %, vasodilators 26.7, lipid lowering agents 20.6%, NSAIDs 18.3 %, beta-blockers 16.3 %, calcium channel blockers 11.1 %, aspirin 7.7 %, P-gp inhibitors 2.7% (verapamil 1.2% and amiodarone 0.7%), antiplatelets 0.9 %. Duration of dabigatran etexilate treatment ranged from 6 to 36 months (median - 534.0 days). For patients randomized to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) was 64.9%.

Patients who completed the acute DVT/PE treatment studies (RE-COVER OR RE-COVER II) were also eligible to roll-over into RE-MEDY.

In RE-MEDY concomitant use of P-gp inhibitors was reported by few patients (2.7%); verapamil (1.2%) and amiodarone (0.7%) were the most frequent.

Figure 2: Time to first adjudicated VTE and VTE-related death until the end of the planned treatment period for the RE-MEDY study

RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (p=0.0135 for non-inferiority). Bleeding events (MBEs or CRBEs; any bleeding) were significantly lower in patients receiving dabigatran etexilate as compared with those receiving warfarin.

Table 31: Analysis of the primary and secondary efficacy endpoints in RE-MEDY [FAS]:

*VTE is a composite of DVT and/or PE

Events were taken into account until the end of the post-treatment period

RE-SONATE was a placebo-controlled study.

The objective of the RE-SONATE study was to evaluate superiority of dabigatran etexilate versus placebo for the prevention of recurrent symptomatic DVT and/or PE in patients who had already completed 6 to 18 months of treatment with vitamin K antagonist (VKA). The intended therapy was 6 months dabigatran etexilate 150 mg twice daily without need for monitoring.

The index events at baseline: DVT 64.5%, PE 27.8%, PE and DVT 7.7%. A total of 1,353 patients were randomized and 1,343 patients treated. Patients’ baseline characteristics: mean age 55.8 years, males 55.5%, Caucasian 89.0%, Asian 9.3%, blacks 1.7%. Concomitant medications: agents acting on the renin-angiotensin system 28.7%, vasodilators 19.4%, lipid lowering agents 17.9%, beta-blockers 18.5%, calcium channel blockers 8.9%, NSAIDs 12.1%, aspirin 8.3%, antiplatelets 0.7% and P-gp inhibitors 1.7% (verapamil 1.0% and amiodarone 0.3%).

Patients who had completed the VTE treatment studies were also eligible to roll-over into this study, if the risk and benefit of further anticoagulation therapy were considered at equipoise.

Figure 3: Time to first adjudicated VTE and VTE-related death until the end of the planned treatment period for the RE-SONATE study

RE-SONATE demonstrated dabigatran etexilate was superior to placebo for the prevention of recurrent symptomatic DVT/PE events including unexplained deaths, with a risk reduction of 92% during the treatment period (p<0.0001). All secondary and sensitivity analyses of the primary endpoint and all secondary endpoints showed superiority of dabigatran etexilate over placebo. The rates of MBEs and the combination of MBEs/CRBEs were significantly higher in patients receiving dabigatran etexilate as compared with those receiving placebo.

The study included observational follow-up for 12 months after the conclusion of treatment. After discontinuation of study medication the effect was maintained until the end of the follow-up, indicating that the initial treatment effect of dabigatran etexilate was sustained. No rebound effect was observed. At the end of the follow-up VTE events in patients treated with dabigatran etexilate was 6.9% vs. 10.7% among the placebo group (hazard ratio 0.61 (0.42, 0.88), p=0.0082).

Table 32: Analysis of the primary and secondary efficacy endpoints for RE-SONATE [FAS]

*VTE is a composite of DVT and/or PE

#including unexplained deaths

Events were taken into account until the end of the post-treatment period

Myocardial infarction (MI) occurred at a low frequency in all 4 of the VTE studies for all treatment groups. Cardiac death occurred in 1 patient in the warfarin treatment group.

In the 3 active controlled studies, a higher rate of MI was reported in patients who received dabigatran etexilate (20; 0.5%) than in those who received warfarin (5; 0.1%).

In the RE-SONATE study, which compared dabigatran etexilate to placebo, there was 1 MI event in each of the treatment groups, resulting in MI rates with dabigatran equal to MI rates with placebo.

Prevention of stroke and systemic embolism in patients with atrial fibrillation

Table 33: Summary of patient demographics for RE-LY, a Phase III clinical trial in atrial fibrillation

**DE110– Dabigatran etexilate 110 mg bid

DE150 – Dabigatran etexilate 150 mg bid

The primary clinical evidence for the effectiveness of dabigatran etexilate in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) is derived from the RE-LY study (Randomised Evaluation of Long–term anticoagulant therapy). This was a multi-center, multi-national, randomised parallel-group study of 2 blinded doses of dabigatran (110 mg bid and 150 mg bid), compared to open-label warfarin in AF patients at moderate to high risk of stroke or systemic embolism. The primary objective was to determine if dabigatran was non-inferior to warfarin in reducing the occurrence of the composite endpoint, total stroke and systemic embolic events (SEE).

In the RE-LY study, a total of 18,113 patients were randomised, with a mean age of 71.5 years and a mean CHADS₂ score of 2.1. The population had approximately equal proportions of patients with CHADS₂ score 1, 2 and ≥ 3. The patient population was 64% male, 70% Caucasian and 16% Asian. RE-LY had a median treatment of 20 months with dabigatran etexilate given as fixed dose without coagulation monitoring. In addition to documented (AF) i.e., paroxysmal, persistent or permanent AF, patients had 1 of the following additional risk factors for stroke:

• Previous stroke, transient ischemic attack, or systemic embolism
• Left ventricular ejection fraction <40 %
• Symptomatic heart failure, ≥ NYHA Class 2
• Age ≥ 75 years
• Age ≥ 65 years associated with one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension

Patients with prosthetic heart valves, or those with hemodynamically significant rheumatic heart disease, especially mitral stenosis, were excluded from the RE-LY trial, and thus were not evaluated. The RE-LY trial results do not apply to these patients, with or without atrial fibrillation (see WARNINGS AND PRECAUTIONS, Cardiovascular, Patients with Valvular Disease).

The concomitant diseases of patients in this trial included hypertension (79%), diabetes mellitus (23%), valvular disease (not meeting study exclusion criteria, see paragraph just above) (22%), and CAD (28%). 50% of the patient population was VKA naïve defined as <2 months total lifetime exposure; 32% had never been exposed to a VKA. For those patients randomised to warfarin, the time in therapeutic range (INR 2 to 3) for the trial was a median of 67%.

Concomitant medications during the study included aspirin (25% of patients used ASA ≥50% of the time in study), clopidogrel (3.6%), ASA+clopidogrel (2%), NSAIDs (6.3%), beta-blockers (63.4%), diuretics (53.9%), statins (46.4%), ACE-inhibitors (44.6%), angiotensin receptor

blockers (ARBs) (26.1%), oral hypoglycemics (17.5%), insulin (5.2%), digoxin (29.4%), amiodarone (11.3%), diltiazem (8.9%), verapamil (5.4%), and proton pump inhibitors (17.8%).

This study demonstrated that dabigatran etexilate, at a dose of 110 mg bid was non-inferior to warfarin in the prevention of stroke and systemic embolism in AF patients. The dose of 150 mg bid was shown to be superior to warfarin with respect to stroke and systemic embolism. The dose of 110 mg dabigatran demonstrated a significantly lower risk of major bleeding compared to warfarin.

Table 34: Analysis of first occurrence of stroke or systemic embolism (primary endpoint) during the study period in the RE-LY study

^*% refers to yearly event rate ^**SEE: systemic embolic event ⁺dose adjusted, INR 2.0- 3.0

Figure 4: Kaplan-Mayer curve of time to first stroke or systemic embolism in the RE-LY trial

Table 35: Analysis of first occurrence of ischemic or haemorrhagic strokes during the study period in the RE-LY study

⁺ dose adjusted, INR 2.0- 3.0

% refers to yearly event rate

Table 36: Analysis of all cause mortality and cardiovascular mortality during the study period in the RE-LY study

⁺ dose adjusted, INR 2.0- 3.0

% refers to yearly event rate

^*vascular mortality: cardiac death (includes sudden and non-sudden cardiac death, e.g. pump failure), and mortality due to stroke, pulmonary embolus, peripheral embolus, aortic dissection/rupture, haemorrhage and deaths of unknown cause

The frequencies of major bleeding events (MBEs) and fatal bleeding were similar between dabigatran etexilate 150 mg bid and warfarin. However, the frequencies of life-threatening MBEs, intracranial haemorrhage (ICH) and any bleeding event were lower with dabigatran etexilate 150 mg bid than with warfarin. Frequencies for all bleeding events were lower with dabigatran etexilate 110 mg bid than with warfarin (see ADVERSE REACTIONS, Bleeding, Table 8).

Abnormalities in liver function tests (LFTs) (ALT or AST >3xULN or >5xULN or >3xULN + Bilirubin >2xULN) were similar among patients treated with dabigatran etexilate 110 mg bid and 150 mg bid, and warfarin (see ADVERSE REACTIONS, Liver Function Tests, Table 13).

Table 37: Other Measures Evaluated in the RE-LY study

% refers to yearly event rate

^*myocardial infarction including silent MI

For the randomised set, there was an imbalance in adjudicated MI with an increased frequency observed in the dabigatran etexilate (DE) treatment groups compared to the warfarin treatment group. The all-MI hazard ratios for DE110 BID and DE150 BID vs. warfarin were 1.29 (p=0.0929) and 1.27 (p=0.1240), respectively, with confidence intervals that included unity. The increased hazard was not dose-related and did not reach statistical significance. The imbalance could not be explained by differences in baseline risk factors or concomitant treatments. Almost 1/5 (21%) of all MI occurred off study drug. Most of those patients were receiving a non-study drug anticoagulant, either orally or parenterally, at the visit prior to their infarct event. It should be noted that, in the RE-LY trial, treatment with dabigatran etexilate or warfarin in patients that sustained MI, was discontinued as per protocol. Given the different half-life of these drugs, differential anticoagulant effect cannot be ruled out within a period of about 72 hours after discontinuation.

The event rates for efficacy and safety outcomes stratified by age groups are presented in Table 38 and Table 39.

Table 38: Efficacy outcomes by age group in the RE-LY trial during the study period

(randomised set)

n: Number of patients with event; N: total number of patients

Hazard ratio (95% CI) and p-value are from Cox proportional hazard ratio with treatment as a covariate P-value: two sided for superiority

Warfarin – dose adjusted INR 2.0-3.0

^* vascular mortality: cardiac death (includes sudden and non-sudden cardiac death, e.g. pump failure), and mortality due to stroke, pulmonary embolus, peripheral embolus, aortic dissection/rupture, haemorrhage and deaths of unknown cause.

Table 39: Safety outcomes by age group in the RE-LY trial during the study period

(randomised set)

n: Number of patients with event; N: total number of patients

Hazard ratio (95% CI) and p-value are from Cox proportional hazard ratio with treatment as a covariate P-value: two sided for superiority

^# adjudicated bleeds

⁺ICH consists of adjudicated haemorrhagic stroke and subdural and/or subarachnoid haemorrhage. ^a Investigator-reported bleeding events

The event rates for efficacy and safety outcomes stratified by renal function are presented in Table 40 and Table 41.

Table 40: Efficacy outcomes by renal function (eCrCL) in the RE-LY trial during the study period (randomised set)

n: Number of patients with event; N: total number of patients

Hazard ratio (95% CI) and p-value are from Cox proportional hazard ratio with treatment as a covariate P-value: two sided for superiority

Patients with missing baseline creatinine clearance or baseline creatinine clearance < 30 ml/Min are not included in the analyses.

Warfarin – dose adjusted INR 2.0-3.0

* vascular mortality: cardiac death (includes sudden and non-sudden cardiac death, e.g. pump failure), and mortality due to stroke, pulmonary embolus, peripheral embolus, aortic dissection/rupture, haemorrhage and deaths of unknown cause.

Table 41: Safety outcomes by renal function (eCrCl) in the RE-LY trial during the study period (randomised set)

n: Number of patients with event; N: total number of patients

Hazard ratio (95% CI) and p-value are from Cox proportional hazard ratio with treatment as a covariate P-value: two sided for superiority

Patients with missing baseline creatinine clearance or baseline creatinine clearance < 30 ml/Min are not included in the analyses.

Warfarin – dose adjusted INR 2.0-3.0

P-value: two sided for superiority

^# adjudicated bleeds

⁺ICH consists of adjudicated haemorrhagic stroke and subdural and/or subarachnoid haemorrhage. ^a Investigator-reported bleeding events

DETAILED PHARMACOLOGY

Intravenous administration of BIBR 953 ZW (dabigatran) and oral administration of BIBR 1048 MS (dabigatran mesilate) result in potent antithrombotic activity in animal models of thrombosis.

BIBR 953 ZW inhibits purified thrombin in vitro with a Ki of 4.5 nM. Its selectivity is apparent through the lack of effect on other serine proteases involved in coagulation. It is active in coagulation assays that simulate intrinsic, extrinsic and common pathway activation, not only in human plasma, but in other species as well. Platelet aggregation is not affected by BIBR 953 ZW, unless the aggregation stimulus is thrombin.

Anticoagulant activity ex vivo is prolonged in a dose-dependent manner in mice (investigated only in toxicology studies), rats, rabbits and Rhesus monkeys and the aPTT is a particularly sensitive assay. Anticoagulation after oral administration of higher doses of BIBR 1048 could be detected ≤5 hrs p.a. Antithrombotic activity in venous stasis models in both rats and rabbits showed 50% reduction of thrombus formation with 33 and 66 mcg/kg BIBR 953 after i.v. dosing. There was a good correlation between reduction of clot size and increasing aPTT. Similar effects could be shown after oral dosing with BIBR 1048, with maximal thrombus inhibition 30 min and 2 hrs post dosing in rats and rabbits, respectively.

BIBR 953 ZW had no effect on hERG-mediated potassium current at concentrations ≤30 mcM. In addition, there was no effect on the action potential configuration in guinea pig papillary muscle at concentrations ≤10 mcM. In vivo studies were performed in pigs and Rhesus monkeys, with no effect on any ECG parameter. Thus these data suggest that the risk for proarrhythmic events is very low.

Cardiovascular studies in rats, rabbits and Rhesus monkeys, after both i.v. and p.o. routes of administration showed very little effect.

There was no effect on locomotor activity. Further testing in rats at doses ≤300 mg/kg p.o. showed no effect except for a slight reduction in body temperature at the highest dose. At doses >100 mg/kg in mice, there was a dose-dependent increase in the number of deaths due to bleeding.

Effects on the GI tract were minimal. There was no effect on gastrointestinal transit with either i.v. or p.o. routes of administration.

TOXICOLOGY

Acute toxicity

Acute oral toxicity studies were conducted in rats and mice. In both species, the approximate lethal dose after single oral administration was >2000 mg/kg. In dogs and Rhesus monkeys, oral administration of 600 mg/kg (dabigatran etexilate) did not induce any toxicologically meaningful changes.

Chronic toxicity

In repeat-dose toxicity studies over a maximum of 26 weeks in rats and 52 weeks in Rhesus monkeys, dosages ≤300 mg/kg (free base equivalent) were used. Generally, these doses were tolerated remarkably well by both rats and Rhesus monkeys. Bleeding problems were observed in association with traumata (e.g. blood sampling) within the first 4 – 6 hours after administration and were directly related to the pharmacodynamic activity of dabigatran.

Reproductive toxicity

Teratology studies were performed with ≤200 mg/kg (free base equivalent) in rats and rabbits. A slight effect on the morphogenesis of foetuses was observed in rats at 200 mg/kg (free base equivalent). No teratogenic effects were noted in rabbits.

In the fertility study in rats, no toxicologically remarkable parental findings were noted. With respect to litter parameters, a slight decrease in corpora lutea and an increase in pre-implantation loss led to a decrease in the mean number of implantations in the 200 mg/kg (free base equivalent) dose group.

Carcinogenicity / mutagenicity

Comprehensive in vitro and in vivo studies revealed no evidence of a mutagenic potential of dabigatran etexilate.

Two-year carcinogenicity studies were conducted in male and female mice and rats given oral doses of dabigatran etexilate of 30, 100, and 200 mg/kg/day. In both studies, no evidence for carcinogenic potential of dabigatran etexilate was observed.

REFERENCES

1. 1. Product Monograph –PRADAXA^® (as Dabigatran Etexilate Mesilate) Capsules 75 mg, 110 mg and 150 mg; Boehringer Ingelheim Canada Ltd., Submission Control No.: 292587, Date of Revision: APR 22, 2025.