DABIGATRAN ETEXILATE 150 MG HARD CAPSULES - summary of medicine characteristics

Dabigatran etexilate 150 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 150 mg of dabigatran etexilate (as mesilate).

3 PHARMACEUTICAL FORM

Hard capsule

Capsules with pink opaque cap and body of size ‘0el’ of approximately 24 mm, filled with a mixture of tartaric acid pellets and a granulate which contains dabigatran etexilate and excipients. Capsules are printed with “E102”.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults

4.2 Posology and method of administration

Prevention of stroke and SEE in adult patients with NVAF with one or more risk  factors (SPAF)

The recommended daily dose of Dabigatran etexilate is 300 mg taken as one 150 mg capsule twice daily. Therapy should be continued long term.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE)

The recommended daily dose of Dabigatran etexilate is 300 mg taken as one 150 mg capsule twice daily following treatment with a parenteral anticoagulant for at least 5 days. The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.

SPAF, DVT/PE

For the following groups the recommended daily dose of Dabigatran etexilate is 220 mg taken as one 110 mg capsule twice daily:

Patients aged 80 years or above

Patients who receive concomitant verapamil

For the following groups the daily dose of Dabigatran etexilate of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding:

Patients between 75–80 years

Patients with moderate renal impairment

Patients with gastritis, esophagitis or gastroesophage­al reflux

Other patients at increased risk of bleeding

For DVT/PE the recommendation for the use of Dabigatran etexilate 220 mg taken as one 110 mg capsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in this clinical setting.

See further down and sections 4.4, 4.5, 5.1 and 5.2.

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

Patients between 75–80 years should be treated with a daily dose of 300 mg taken as one 150 mg capsule twice daily. A dose of 220 mg taken as one 110 mg capsule twice daily can be individually considered, at the discretion of the physician, when the thromboembolic risk is low and the bleeding risk is high (see section 4.4).

Patients aged 80 years or above should be treated with a daily dose of 220 mg taken as one 110 mg capsule twice daily due to the increased risk of bleeding in this population.

As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating the CrCL prior to initiation of treatment with Dabigatran etexilate to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min ). The renal function should also be assessed at least once a year in patients treated with Dabigatran etexilate or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc) (see sections 4.3, 4.4 and 5.2).

Patients at risk of bleeding (SPAF, DVT/PE)

Patients with an increased bleeding risk (see sections 4.4, 4.5, 5.1 and 5.2) should be closely monitored clinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient. A coagulation test (see section 4.4) may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. When excessive dabigatran exposure is identified in patients at high risk of bleeding, a dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted.

For subjects with gastritis, esophagitis, or gastroesophageal reflux, the dose of 220 mg taken as one 110 mg capsule twice daily may be considered due to the elevated risk of major gastro-intestinal bleeding (see section 4.4).

Assessment of renal function (SPAF, DVT/PE) In all patients:

Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Dabigatran etexilate to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min) (see sections 4.3, 4.4 and 5.2). Dabigatran etexilate is contraindicated in patients with severe renal impairment

Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products)

Additional requirements in patients with mild to moderate renal impairment and in patients aged over 75 years:

Renal function should be assessed during treatment with Dabigatran etexilate at least once a year or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (e.g. hypovolaemia, dehydration, and in case of concomitant us of certain medicinal products)

The method used to estimate renal function (CrCL in mL/min) during the clinical development of Dabigatran etexilate was the Cockgroft-Gault method (see section 4.2 Dabigatran etexilate 75 mg).

Special populations

Renal impairment SPAF, DVT/PE

Treatment with Dabigatran etexilate in patients with severe renal impairment (CrCL < 30 mL/min) is contraindicated (see section 4.3).

No dose adjustment is necessary in patients with mild renal impairment (CrCL 50– < 80 mL/min). For patients with moderate renal impairment (CrCL 30–50 mL/min) the recommended dose of Dabigatran etexilate is also 300 mg taken as one 150 mg capsule twice daily. However, for patients with high risk of bleeding, a dose reduction of Dabigatran etexilate to 220 mg taken as one 110 mg capsule twice daily should be considered (see sections 4.4 and 5.2). Close clinical surveillance is recommended in patients with renal impairment.

Concomitant use of Dabigatran etexilate with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil (SPAFDVT/PE)

No dose adjustment is necessary for concomitant use of amiodarone or quinidine (see sections 4.4, 4.5 and 5.2).

Dosing should be reduced to 220 mg taken as one 110 mg capsule twice daily in patients who receive concomitantly dabigatran etexilate and verapamil (see sections 4.4 and 4.5). In this situation Dabigatran etexilate and verapamil should be taken at the same time.

Weight (SPAF, DVT/PE)

Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2), but close clinical surveillance is recommended in patients with a body weight < 50 kg (see section 4.4).

Gender (SPAF, DVT/PE)

Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2).

Hepatic impairment (SPAF, DVT/PE)

Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded inthe main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Dabigatran etexilate is not recommended in this population (see sections 4.4 and 5.2). Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see section 4.3).

Switching (SPAF, DVT/PE)

Dabigatran etexilate treatment to parenteral anticoagulant

It is recommended to wait 12 hours after the last dose before switching from dabigatran etexilate to a parenteral anticoagulant (see section 4.5).

Parenteral anticoagulants to Dabigatran etexilate

Discontinue the parenteral anticoagulant and start dabigatran etexilate 0–2 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)) (see section 4.5).

Dabigatran etexilate treatment to Vitamin K antagonists (VKA)

Adjust the starting time of the VKA based on CrCL as follows:

CrCL > 50 mL/min, start VKA 3 days before discontinuing dabigatran etexilate

CrCL > 30-< 50 mL/min, start VKA 2 days before discontinuing dabigatran etexilate

Because Dabigatran etexilate can increase INR, the INR will better reflect VKA’s effect only after Dabigatran etexilate has been stopped for at least 2 days. Until then, INR values should be interpreted with caution.

VKA to Dabigatran etexilate

The VKA should be stopped. Dabigatran etexilate can be given as soon as the International Normalized Ratio (INR) is < 2.0.

Cardioversion (SPAF, DVT/PE)

Patients can stay on dabigatran etexilate while being cardioverted.

Paediatric population (SPAF)

There is no relevant use of Dabigatran etexilate for the paediatric population in the indication: prevention of stroke and systemic embolism in patients with NVAF.

Paediatric population (DVT/PE)

The safety and efficacy of Dabigatran etexilate for children from birth to less than 18 years of age have not yet been established. Currently available data are described in section 4.8 and 5.1, but no recommendation on a posology can be made.

Missed dose (SPAFDVT/PE)

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

No double dose should be taken to make up for missed individual doses. Method of administration (SPAFDVT/PE)

Dabigatran etexilate can be taken with or without food. Dabigatran etexilate should be swallowed as a whole with a glass of water, to facilitate delivery to the stomach.

Patients should be instructed not to open the capsule as this may increase the risk of bleeding (see sections 5.2 and 6.6).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Patients with severe renal impairment (CrCL < 30 mL/min) (see section 4.2)

Active clinically significant bleeding

Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5)

Hepatic impairment or liver disease expected to have any impact on survival

Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and dronedarone (see section 4.5)

Prosthetic heart valves requiring anticoagulant treatment (see section 5.1).

4.4 Special warnings and precautions for use

Hepatic impairment

Patients with elevated liver enzymes > 2 ULN were excluded from the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Dabigatran etexilate is not recommended in this population.

Haemorrhagic risk

Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding and in situations with concomitant use of drugs affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy with dabigatran etexilate. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.

For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent (Praxbind, idarucizumab) is available (see section 4.9).

Factors, such as decreased renal function (30–50 mL/min CrCL), age > 75 years, low body weight

< 50 kg, or mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, quinidine or verapamil) are associated with increased dabigatran plasma levels (see sections 4.2, 4.5 and 5.2).

The concomitant use of ticagrelor increases the exposure to dabigatran and may show pharmacodynamic interaction, which may result in an increased risk of bleeding (see section 4.5).

In a study of prevention of stroke and SEE in adult patients with NVAF, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding which was statistically significant for dabigatran etexilate 150 mg twice daily. This increased risk was seen in the elderly (> 75 years). Use of acetylsalicylic acid (ASA), clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux requiring increase the risk of GI bleeding. In these atrial fibrillationpa­tients a dosage of 220 mg dabigatran given as 110 mg capsule twice daily should be considered and posology recommendations in section 4.2 be followed. The administration of a PPI can be considered to prevent GI bleeding.

Bleeding risk may be increased in patients concomitantly treated with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs) (see section 4.5).

Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined (see section 5.1).

Table 1 summarises factors which may increase the haemorrhagic risk. Please also refer to contraindications in section 4.3.

Table 1: Factors which may increase the haemorrhagic risk.

The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see section 4.5), which significantly increase the risk of major bleeding requires a careful benefit-risk assessment. Dabigatran etexilate should only be given if the benefit outweighs bleeding risks.

Dabigatran etexilate does not in general require routine anticoagulant monitoring. However, the measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors. The INR test is unreliable in patients on Dabigatran etexilate and false positive INR elevations have been reported.

Therefore INR tests should not be performed. Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but the tests are not standardised, and results should be interpreted with caution (see section 5.1).

Table 2 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see section 5.1)

Table 2: Coagulation test thresholds at trough that may be associated with an increased risk of bleeding.

Patients who develop acute renal failure must discontinue Dabigatran etexilate (see section 4.3).

Limited data is available in patients < 50 kg (see section 5.2).

When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see section 4.9).

Medicinal products that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Dabigatran etexilate (see section 4.5).

Use of fibrinolytic medicinal products for the treatment of acute ischemic stroke

The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient presents with a dTT, ECT or aPTT not exceeding the ULN according to the local reference range.

Interaction with P-gp inducers

Concomitant administration of P-gp inducers (such as rifampicin, St. John's wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran plasma concentrations, and should be avoided (see sections 4.5 and 5.2).

Surgery and interventions

Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of dabigatran etexilate.

Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see section 5.2). This should be considered in advance of any procedures. In such cases a coagulation test (see sections 4.4 and 5.1) may help to determine whether haemostasis is still impaired.

Emergency surgery or urgent procedures

Dabigatran etexilate should be temporarily discontinued. When rapid reversal of the anticoagulation effect is required the specific reversal agen (Praxbind, idarucizumab) to Dabigatran etexilate is available.

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

Subacute surgery/inter­ventions

Dabigatran etexilate should be temporarily discontinued. A surgery / intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention (for cardioversion see section 4.2).

Elective surgery

If possible, Dabigatran etexilate should be discontinued at least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding or in major surgery where complete haemostasis may be required consider stopping Dabigatran etexilate 2–4 days before surgery. Clearance of dabigatran in patients with renal insufficiency may take longer. This should be considered in advance of any procedures.

Table 3 summarises discontinuation rules before invasive or surgical procedures.

Table 3: Discontinuation rules before invasive or surgical procedures

If an acute intervention is required, dabigatran etexilate should be temporarily discontinued. A surgery/ intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against theurgency of intervention (for cardioversion see section 4.2).

Spinal anaesthesia/e­pidural anaesthesia/lumbar , puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of dabigatran etexilate. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.

Postoperative , phase

Dabigatran etexilate should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.

Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30–50 mL/min), should be treated with caution (see sections 4.4 and 5.1).

Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic e­vents

There are limited efficacy and safety data for dabigatran available in these patients and therefore they should be treated with caution.

Myocardial Infarction (SPAF)

In the phase III study RE-LY (see section 5.1.) the overall rate of myocardial infarction (MI) was 0.82, 0.81, and 0.64 % / year for dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase in relative risk for dabigatran of 29 % and 27 % compared to warfarin. Irrespective of therapy, the highest absolute risk of MI was seen in the following subgroups, with similar relative risk: patients with previous MI, patients > 65 years with either diabetes or coronary artery disease, patients with left ventricular ejection fraction < 40 %, and patients with moderate renal dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly taking ASA plus clopidogrel or clopidogrel alone.

Myocardial Infarction (DVT/PE)

In the three active controlled studies, a higher rate of MI was reported in patients who received dabigatran etexilate than in those who received warfarin: 0.4% vs. 0.2% in the short-term RECOVER and RE-COVER II studies; and 0.8% vs. 0.1% in the long-term RE-MEDY trial. The increase was statistically significant in this study (p=0.022).

In the RE-SONATE study, which compared dabigatran etexilate to placebo, the rate of MI was 0.1% for patients who received dabigatran etexilate and 0.2% for patients who received placebo

Active Cancer Patients (DVT/PE)

The efficacy and safety have not been fully-established for DVT/PE patients with active cancer.

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 therapy.

4.5 Interaction with other medicinal products and other forms of interaction

Anticoagulants and antiplatelet aggregation medicinal products

There is no or only limited experience with the following treatments which may increase the risk of bleeding when used concomitantly with Dabigatran etexilate: anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic medicinal products, and vitamin K antagonists, rivaroxaban or other oral anticoagulants (see section 4.3), and platelet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see section 4.4).

From the limited data collected in the phase III study RE LY in patients with atrial fibrillation it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both dabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another (see section 4.3).

UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter (see sections 4.3).

From the data collected in the phase III study RE-LY in patients with atrial fibrillation (see section 5.1), it was observed that the concomitant use of antiplatelets ASA or clopidogrel approximately doubles major bleeding rates with both dabigatran etexilate and warfarin (see section 4.4).

Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUCYss and Cmax,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUCYss and Cmax,ss were increased by about 30–40 % (see section 4.4) (see also subsection on ASA below).

ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA co-administration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively (see section 4.4).

NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use in the RE-LY study, NSAIDs increased the risk of bleeding by approximately 50% on both dabigatran etexilate and warfarin. Therefore, due to the risk of haemorrhage, notably with NSAIDs with elimination half-lives > 12 hours, close observation for signs of bleeding is recommended (see section 4.4).

LMWH: The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin.

Interactions linked to dabigatran etexilate and dabigatran metabolic profile

Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran.

Transporter interactions

P-gp inhibitors

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole, dronedarone, clarithromycin and ticagrelor) is expected to result in increased dabigatran plasma concentrations.

If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure (see sections 4.2, 4.4 and 5.1).

The following strong P-gp inhibitors are contraindicated: systemic ketoconazole, cyclosporine, itraconazole and dronedarone (see section 4.3). Concomitant treatment with tacrolimus is not recommended. Caution should be exercised with mild to moderate P-gp inhibitors (e.g. amiodarone, posaconazole, quinidine, verapamil and ticagrelor) (see sections 4.2 and 4.4).

Ketoconazole: Ketoconazole increased total dabigatran AUC0-co and Cmax values by 138 % and 135 %, respectively, after a single oral dose of 400 mg, and 153 % and 149 %, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. The time to peak, terminal halflife and mean residence time were not affected by ketoconazole (see section 4.4). Concomitant treatment with systemic ketoconazole is contraindicated (see section 4.3).

Dronedarone: When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC0-co and Cmax values increased by about 2.4-fold and 2.3-fold (+136 % and 125 %), respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold (+114 % and 87 %), respectively, after a single dose of 400 mg. The terminal half-life and renal clearance of dabigatran were not affected by dronedarone. When single and multiple doses of dronedarone were given 2 h after dabigatran etexilate, the increases in dabigatran AUC0-co were 1.3-fold and 1.6-fold, respectively. Concomitant treatment with dronedarone is contraindicated.

Amiodarone: When Dabigatran etexilate was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 60 % and 50 %, respectively. The mechanism of the interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4 Close clinical surveillance is recommended when dabigatran etexilate is combined with amiodarone and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1,000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUCYss and Cmax,ss were increased on average by 53 % and 56 %, respectively with concomitant quinidine (see sections 4.2 and 4.4). Close clinical surveillance is recommended when dabigatran etexilate is combined with quinidine and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Verapamil: When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on timing of administration and formulation of verapamil (see sections 4.2 and 4.4).

The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of Cmax by about 180 % and AUC by about 150 %). The effect was progressively decreased with administration of an extended release formulation (increased of Cmax by about 90 % and AUC by about 70 %) or administration of multiple doses of verapamil (increased of Cmax by about 60 % and AUC by about 50 %).

Patients concomitantly receiving dabigatran etexilate and verapamil, the dose of Dabigatran etexilate should be reduced to 220 mg taken as one 110 mg capsule twice daily (see section 4.2).Close clinical surveillance is recommended when dabigatran etexilate is combined with verapamil and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increased of Cmax by about 10 % and AUC by about 20 %). This is explained by completed dabigatran absorption after 2 hours (see section 4.4).

Clarithromycin: When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 19 % and Cmax by about 15 % was observed without any clinical safety concern. However, in patients receiving dabigatran, a clinically relevant interaction cannot be excluded when combined with clarithromycin. Therefore, a close monitoring should be exercised when dabigatran etexilate is combined with clarithromycin and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Ticagrelor: When a single dose of 75mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and Cmaxwere increased by 1.73-fold and 1.95-fold (+73% and 95 %), respectively. After multipledoses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is 1.56-fold and 1.46-fold (+56% and 46%) for Cmax and AUC, respectively.

Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUCYss and Cmax,ss by 1.49-fold and 1.65-fold (+49% and 65%), respectively, compared with dabigatran etexilate given alone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mg dabigatran etexilate (in steady state), the increase of dabigatran AUCYss and Cmax,ss was reduced to 1.27-fold and 1.23-fold (+27% and 23%), respectively, compared with dabigatran etexilate given alone. This staggered intake is the recommended administration for start of ticagrelor with a loading dose.

Concomitant administration of 90 mg ticagrelor BID (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUCYss and Cmax,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate given alone.

The following potent P-gp inhibitors have not been clinically studied but from in vitro results a similar effect as with ketoconazole may be expected:

Itraconazole and cyclosporine, which are contra-indicated (see section 4.3).

Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors. Based on these data concomitant treatment with tacrolimus is not recommended.

Posaconazole also inhibits P-gp to some extent but has not been clinically studied. Caution should be exercised when Dabigatran etexilate is co-administered with posaconazole.

P-gp inducers

Concomitant administration of a P-gp inducer (such as rifampicin, St. John's wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be avoided (see sections 4.4 and 5.2).

Rifampicin: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5 and 67 %, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.

Other medicinal products affecting P-gp

Protease inhibitors including ritonavir and its combinations with other protease inhibitors affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with Dabigatran etexilate.

P-gp substrate

Digoxin: In a study performed with 24 healthy subjects, when Dabigatran etexilate was coadministered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.

Co-medication with selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs)

SSRIs and SNRIs increased the risk of bleeding in RE-LY in all treatment groups. Gastric pH

Pantoprazole: When Dabigatran etexilate was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Dabigatran etexilate in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Dabigatran etexilate.

Ranitidine: Ranitidine administration together with Dabigatran etexilate had no clinically relevant effect on the extent of absorption of dabigatran.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should avoid pregnancy during treatment with dabigatran etexilate.

Pregnancy

There are limited amount of data from the use of dabigatran etexilate in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Dabigatran etexilate should not be used during pregnancy unless clearly necessary.

Breast-feeding

There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breastfeeding should be discontinued during treatment with Dabigatran etexilate.

Fertility

No human data available.

In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5– to 10-fold higher plasma exposure level to patients), a decrease in fetal body weight and embryofetal viability along with an increase in fetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in fetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).

4.7 Effects on ability to drive and use machines

Dabigatran etexilate has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

In the pivotal study investigating the prevention of stroke and SEE in patients with atrial fibrillation, a total of 12,042 patients were treated with dabigatran etexilate. Of these 6,059 were treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily.

In the 2 active controlled DVT/PE treatment trials, RE-COVER and RE-COVER II, a total of 2,553 patients were included in the safety analysis for dabigatran etexilate. All patients received doses of 150 mg twice daily of dabigatran etexilate. Adverse drug reactions for both treatments, dabigatran etexilate and warfarin, are counted from the first intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all adverse drug reactions which occurred during dabigatran therapy. All adverse drug reactions, which occurred during warfarin therapy, are included except for those during the overlap period between warfarin and parenteral therapy.

A total of 2,114 patients were treated in the active controlled DVT/PE prevention trial, REMEDY, and in the placebo-controlled DVT/PE prevention trial, RE-SONATE. All patients received doses of 150 mg twice daily of dabigatran etexilate.

In total, 22 % of patient with atrial fibrillation treated for the prevention of stroke and SEE (long-term treatment for up to 3 years) , 14 % of patients treated for DVT/PE and 15 % of patients treated for DVT/PE preventionexpe­rienced adverse reactions.

The most commonly reported adverse reactions are bleedings occurring in total in approximately 16,6 % in patients with atrial fibrillation treated long-term for the prevention of stroke and SEE and in 14,4 % of patients treated for DVT/PE. Furthermore, bleedings occured in 19.4 % of patients in the DVT/PE prevention trial RE-MEDY and in 10,5 % of patients in the DVT/PE trial RE-SONATE.

Since the patient population treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and are provided in tables 5, 6, 7 and 8 below.

Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.

Tabulated list of adverse reactions

Table 4 shows the adverse reactions identified from the study in prevention of thromboembolic stroke and SEE in patients with atrial fibrillation, the studies in DVT/PE treatment and in

DVT/PE prevention. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention.very common (01/10), common (01 /100 to <1 /10), uncommon (□ 1/1,000 to <1 /100), rare (□ 1 /10,000 to <1 /1,000), very rare (<1 /10,000), not known (cannot be estimated from the available data).

Table 4: Adverse reactions

Bleeding

Prevention of stroke and SEE in adult patients with nonvalvular atrial fibrillation with one or more risk factors (SPAF)

The table 5 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and SEE in patients with atrial fibrillation.

Table 5: Bleeding events in a study testing the prevention of thromboembolic stroke and SEE in patients with atrial fibrillation

Major bleeding was defined to fulfil one or more of the following criteria:

Bleeding associated with a reduction in haemoglobin of at least 20 g/L or leading to a transfusion of at least 2 units of blood or packed cells.

Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding.

Major bleeds were classified as life-threatening if they fulfilled one or more of the following criteria: Fatal bleed; symptomatic intracranial bleed; reduction in haemoglobin of at least 50 g/L; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of intravenous inotropic medicinal products; a bleed that necessitated surgical intervention.

Subjects randomized to dabigatran etexilate 110 mg twice daily or 150 mg twice daily had a significantly lower risk for life-threatening bleeds and intracranial bleeding compared to warfarin [p< 0.05]. Both dose strengths of dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomized to dabigatran etexilate 110 mg twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81 [p=0.0027]). Subjects randomized to dabigatran etexilate 150 mg twice daily had a significantly higher risk for major GI bleeds compared with warfarin (hazard ratio 1.48 [p=0.0005]. This effect was seen primarily in patients > 75 years.

The clinical benefit of dabigatran with regard to stroke and SEE prevention and decreased risk of ICH compared to warfarin is preserved across individual subgroups, e.g. renal impairment, age, concomitant medication use such as anti-platelets or P-gp inhibitors. While certain patient subgroups are at an increased risk of major bleeding when treated with an anticoagulant, the excess bleeding risk for dabigatran is due to GI bleeding, typically seen within the first 3–6 months following initiation of dabigatran etexilate therapy.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (DVT/PE) treatment

Table 6 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). In the pooled studies the primary safety endpoints of major bleeding, major or clinically relevant bleeding and any bleeding were significantly lower than warfarin at a nominal alpha level of 5 %.

Table 6: Bleeding events in the studies RE-COVER and RE-COVER II testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)

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

The definition of major bleeding events (MBEs) followed the recommendations of the International Society on Thrombosis and Haemostasis. A bleeding event was categorised as an MBE if it fulfilled at least one of the following criteria:

Fatal bleeding

Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial, or intramuscular with compartment syndrome. In order for bleeding in a critical area or organ to be classified as a MBE it had to be associated with a symptomatic clinical presentation

Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells

Table 7 shows bleeding events in pivotal study RE-MEDY testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). Some bleeding events (MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of 5% in patients receiving dabigatran etexilate as compared with those receiving warfarin.

Table 7: Bleeding events in study RE-MEDY testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE)

HR not estimable as there is no event in either one cohort/treatment

The definition of MBEs followed the recommendations of the International Society on Thrombosis and Haemostasis as described under RE-COVER and RE-COVER II.

Table 8 shows bleeding events in pivotal study RE-SONATE testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE),. The rate of the combination of MBEs/CRBEs and the rate of any bleeding was significantly lower at a nominal alpha level of 5 % in patients receiving placebo as compared with those receiving dabigatran etexilate.

Table 8: Bleeding events in study RE-SONATE testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE)

*HR not estimable as there is no event in either one treatment

The definition of MBEs followed the recommendations of the International Society on Thrombosis and Haemostasis as described under RE-COVER and RE-COVER II.

Myocardial infarction

Prevention of stroke and SEE in adult patients with nonvalvular atrial fibrillation with one or more risk factors (SPAF)

In the RE-LY study, in comparison to warfarin the annual myocardial infarction rate for dabigatran etexilate was increased from 0.64 % (warfarin) to 0.82 % (dabigatran etexilate 110 mg twice daily) / 0.81 % (dabigatran etexilate 150 mg twice daily) (see section 5.1).

Treatment of DVT and PE, and prevention of recurrent DVT and PE in adults (DVT/PE)

In the three active controlled studies, a higher rate of MI was reported in patients who received dabigatran etexilate than in those who received warfarin: 0.4% vs. 0.2% in the short-term RECOVER and RECOVER II studies; and 0.8% vs. 0.1% in the long-term RE-MEDY trial. The increase was statistically significant in this study (p=0.022).

In the RE-SONATE study, which compared dabigatran etexilate to placebo, the rate of MI was 0.1 % for patients who received dabigatran etexilate and 0.2 %for patients who received placebo (see section 4.4.).

Paediatric population (DVT/PE)

In the clinical study 1160.88 in total, 9 adolescent patients (age 12 to < 18 years) with diagnosis of primary VTE received an initial oral dose of dabigatran etexilate of 1.71 (± 10 %) mg/kg bodyweight.

Based on dabigatran concentrations as determined by the diluted thrombin time test and clinical assessment, the dose was adjusted to the target dose of 2.14 (± 10%) mg/kg bodyweight of dabigatran etexilate On treatment 2 (22.1 %) patients experienced mild related adverse events (gastrooesophageal reflux / abdominal pain; abdominal discomfort) and 1 (11.1 %) patient experienced a not related serious adverse event (recurrent VTE of the leg) in the post treatment period > 3 days after stop of dabigatran etexilate.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Doses of dabigatran etexilate beyond those recommended, expose the patient to increased risk of bleeding.

In case of an overdose suspicion, coagulation tests can help to determine a bleeding risk (see sections 4.4 and 5.1). A calibrated quantitative (dTT) test or repetitive dTT measurements allow prediction of the time by when certain dabigatran levels will be reached (see section 5.1), also in case additional measures e.g. dialysis have been initiated.

Excessive anticoagulation may require interruption of Dabigatran etexilate treatment. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. Depending on the clinical situation appropriate supportive treatment, such as surgical haemostasis and blood volume replacement, should be undertaken at the prescribers discretion.

For situations when rapid reversal of the anticoagulant effect of Dabigatran etexilate is required the specific reversal agent (Praxbind, idarucizumab) antagonizing the pharmacodynamics effect of Dabigatran etexilate is available (see section 4.4).

Coagulation factor concentrates (activated or non-activated) or recombinant Factor VIIa may be taken into account. There is some experimental evidence to support the role of these medicinal products in reversing the anticoagulant effect of dabigatran, but data on their usefulness in clinical settings and also on the possible risk of rebound thromboembolism is very limited. Coagulation tests may become unreliable following adminstration of suggested coagulation factor concentrates. Caution should be exercised when interpreting these tests. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet drugs have been used. All symptomatic treatment should be given according to the physician's jud­gement.

Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.

As protein binding is low, dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies (see section 5.2).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic, direct thrombin inhibitors, ATC code: B01AE07.

Mechanism of action

Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, 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.

Pharmacodynamic effects

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

There is a clear correlation between plasma dabigatran concentration and degree of anticoagulant effect based on phase II studies. Dabigatran prolongs the thrombin time (TT), ECT, and aPTT.

The calibrated quantitative diluted TT (dTT) test provides an estimation of dabigatran plasma concentration that can be compared to the expected dabigatran plasma concentrations. When the calibrated dTT assay delivers a dabigatran plasma concentration result at or below the limit of quantification, an additional coagulation assay such as TT, ECT or aPTT should be considered.

The ECT can provide a direct measure of the activity of direct thrombin inhibitors.

The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. Although Hhigh aPTT values should be interpreted with caution, a high aPTT value indicates that the patient is anticoagulated.

In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see section 4.4, table 2) is considered to be associated with an increased risk of bleeding. Steady state geometric mean dabigatran peak plasma concentration, measured around 2 hours after 150 mg dabigatran etexilate administration twice daily, was 175 ng/mL, with a range of 117–275 ng/mL (25th-75th percentile range). The dabigatran geometric mean trough concentration, measured at trough in the morning, at the end of the dosing interval (i.e. 12 hours after the 150 mg dabigatran evening dose), was on average 91.0 ng/mL, with a range of 61.0–143 ng/mL (25th- 75th percentile range).

For patients with NVAF treated for prevention of stroke and SEE with 150 mg dabigatran etexilate twice daily,

the 90th percentile of dabigatran plasma concentrations measured at trough (10–16 hours after the previous dose) was about 200 ng/mL,

an ECT at trough (10–16 hours after the previous doshe), elevated approximately 3fold upper limit of normal refers to the observed 90th percentile of ECT prolongation of 103 seconds,

an aPTT ratio greater than 2-fold upper limit of normal (aPTT prolongathion of about 80 seconds), at trough (10–16 hours after the previous dose) reflects the 90th percentile of observations.

In patients treated for DVT and PE with 150 mg dabigatran etexilate twice daily, the dabigatran geometric mean trough concentration, measured within 10–16 hours after dose, at the end of the dosing interval (i.e. 12 hours after the 150 mg dabigatran evening dose), was 59.7 ng/ml, with a range of 38.6 – 94.5 ng/ml (25th-75th percentile range). For treatment of DVT and PE, with dabigatran etexilate 150 mg twice daily,

the 90th percentile of dabigatran plasma concentrations measured at trough (10–16 hours after the previous dose) was about 146 ng/ml,

an ECT at trough (10–16 hours after the previous dose), elevated approximately 2.3-fold compared to baseline refers to the observed 90th percentile of ECT prolongation of 74 seconds,

the 90th percentile of aPTT at trough (10–16 hours after the previous dose) was 62 seconds, which would be 1.8-fold compared to baseline.

In patients treated for prevention of recurrent of DVT and PE with 150 mg dabigatran etexilate twice daily no pharmacokinetic data are available.

Clinical efficacy and safety (SPAF)

Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors

The clinical evidence for the efficacy of dabigatran etexilate is derived from the RE-LY study (Randomized Evaluation of Long -term anticoagulant therapy) a multi-centre, multi-national, randomized parallel group study of two blinded doses of dabigatran etexilate (110 mg and 150 mg twice daily) compared to open-label warfarin in patients with atrial fibrillation at moderate to high risk of stroke and SEE. The primary objective in this study was to determine if dabigatran etexilate was non-inferior to warfarin in reducing the occurrence of the composite endpoint stroke and SEE. Statistical superiority was also analyzed.

In the RE-LY study, a total of 18,113 patients were randomized, with a mean age of 71.5 years and a mean CHADS2 score of 2.1. The patient population was 64 % male, 70 % Caucasian and 16 % Asian. For patients randomized to warfarin, the mean percentage within time in therapeutic range (TTR) (INR 2–3) was 64.4 % (median TTR 67 %).

The RE-LY study demonstrated that dabigatran etexilate, at a dose of 110 mg twice daily, is non-inferior to warfarin in the prevention of stroke and SEE in subjects with atrial fibrillation, with a reduced risk of ICH, total bleeding and major bleeding. The dose of 150 mg twice daily, reduces significantly the risk of ischemic and haemorrhagic stroke, vascular death, ICH and total bleeding compared to warfarin. Major bleeding rates with this dose were comparable to warfarin. Myocardial infarction rates were slightly increased with dabigatran etexilate 110 mg twice daily and 150 mg twice daily compared to warfarin (hazard ratio 1.29; p=0.0929 and hazard ratio 1.27; p=0.1240, respectively). With improving monitoring of INR the observed benefits of dabigatran etexilate compared to warfarin diminish.

Tables 9–11 display details of key results in the overall population:

Table 9: Analysis of first occurrence of stroke or SEE (primary endpoint) during the study period in RE-LY.

% refers to yearly event rate

Table 10: Analysis of first occurrence of ischemic or haemorrhagic strokes during the study period in RE-LY.

% refers to yearly event rate

Table 11:     Analysis of all cause and cardiovascular survival during the study period in RE

LY.

% refers to yearly event rate

Tables 12–13 display results of the primary efficacy and safety endpoint in relevant subpopulations: For the primary endpoint, stroke and SEE, no subgroups (i.e., age, weight, gender, renal function, ethnicity, etc.) were identified with a different risk ratio compared to warfarin.

Table 12:    Hazard Ratio and 95 % CI for stroke/SEE by subgroups

For the primary safety endpoint of major bleeding there was an interaction of treatment effect and age. The relative risk of bleeding with dabigatran compared to warfarin increased with age. Relative risk was highest in patients > 75 years. The concomitant use of antiplatelets ASA or clopidogrel approximately doubles MBE rates with both dabigatran and warfarin. There was no significant interaction of treatment effects with the subgroups of renal function and CHADS2 score.

Table 13:     Hazard Ratio and 95 % CI for major bleeds by subgroups

RELY-ABLE (Long term multi-center extension of dabigatran treatment in patients with atrial fibrillation who completed the RE-LY trial)

The RE-LY extension study (RELY-ABLE) provided additional safety information for a cohort of patients which continued the same dose of dabigatran etexilate as assigned in the RE-LY trial. Patients were eligible for the RELY-ABLE trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the same double-blind dabigatran etexilate dose randomly allocated in RE-LY, for up to 43 months of follow up after RE-LY (total mean follow-up RE-LY + RELY-ABLE, 4.5 years). There were 5897 patients enrolled, representing 49 % of patients originally randomly assigned to receive dabigatran etexilate in RE-LY and 86 % of RELYABLE-eligible patients.

During the additional 2.5 years of treatment in RELY-ABLE, with a maximum exposure of over

6 years (total exposure in RELY + RELY-ABLE), the long-term safety profile of dabigatran etexilate was confirmed for both test doses 110 mg b.i.d. and 150 mg b.i.d.. No new safety findings were observed.

The rates of outcome events including, major bleed and other bleeding events were consistent with those seen in RE-LY.

Paediatric population (SPAF)

The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing dabigatran etexilate in all subsets of the paediatric population in prevention of thromboembolic events in the granted indication (see section 4.2 for information on paediatric use).

Ethnic origin (SPAF)

No clinically relevant ethnic differences among Caucasians, African-American, Hispanic, Japanese or Chinese patients were observed.

Clinical efficacy and safety (DVT/PE treatment)

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE treatment

The efficacy and safety was investigated in two multi-center, randomised, double blind, parallel- group, replicate studies RE-COVER and RE-COVER II. These studies compared dabigatran etexilate (150 mg bid) with warfarin (target INR 2.0–3.0) in patients with acute DVT and/or PE. The primary objective of these studies was to determine if dabigatran etexilate 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 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.

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 %.

The trials, demonstrated that treatment with dabigatran etexilate 150 mg twice daily was noninferior to the treatment with warfarin ( non-inferiority margin for RE-COVER and RECOVER II: 3.6 for risk difference and 2.75 for hazard ratio).

Table 14: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of DVT and/or PE) until the end of post-treatment period for the pooled studies RE-COVER and RE-COVER II

Ethnic orgin (DVT/PE treatment)

No clinically relevant ethnic differences among Caucasians, Afrian-American, Hispanic, Japanese or Chinese patients were observed.

Paediatric population (DVT/PE treatment)

The European Medicines Agency has deferred the obligation to submit the results of studies with with the reference medicinal product containing dabigatran etexilate in all subsets of the paediatric population in DVT/PE treatment (see section 4.2 for information on paediatric use).

The pharmacokinetics and pharmacodynamics of dabigatran etexilate administered twice daily for three consecutive days (total 6 doses) at the end of standard anticoagulant therapy were assessed in an open-label safety and tolerability study in 9 stable adolescents (12 to < 18 years). All patients received an initial oral dose of 1.71 (± 10%) mg/kg of dabigatran etexilate (80 % of the adult dose of 150 mg/70 kg adjusted for the patient’s weight). Based on dabigatran concentrations and clinical assessment, the dose was subsequently modified to a target dose of 2.14 (± 10 %) mg/kg of dabigatran etexilate (100 % of the adult dose adjusted for the patient’s weight). In this small number of adolescents, dabigatran etexilate capsules were apparently tolerated with only three mild and transient gastrointestinal adverse events reported by two patients. According to the relatively low exposure, coagulation at 72 hrs (presumed dabigatran trough level at steady state or close to steady state conditions) was only slightly prolonged with aPTT at maximum 1.60 fold, ECT 1.86 fold, and Hemoclot® TT (Anti-FIIa) 1.36 fold, respectively. Dabigatran plasma concentrations observed at 72 hrs were relatively low, between 32.9 ng/mL and 97.2 ng/mL at final doses between 100 mg and 150 mg (gMean dose normalized total dabigatran plasma concentration of 0.493 ng/mL/mg).

Clinical efficacy and safety (DVT/PE prevention)

Prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE prevention)

Two randomized, parallel group, double-blind studies were performed in patients previously treated with anticagulation therapy. RE-MEDY, warfarin controlled study, enrolled patients already treated for 3 to 12 months with the need for further anticoagulant treatment and RE-SONATE, the placebo controlled study, enrolled patients already treated for 6 to 18 months with Vitamin K inhibitors.

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 2.0–3.0) 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. Duration of dabigatran exilate treatment ranged from 6 to 36 months (median 534.0 days). For patients randomized to warfarin, the median time in therapeutic range (INR 2.0–3.0) was 64.9 %.

RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily – was non-inferior to warfarin (non-inferiority margin 2.85 for hazard ratio and 2.8 for risk difference).

Table 15: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of DVT and/or PE) until the end of post-treatment period for the RE-MEDY 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 VKA. The intended therapy was 6 months dabigatran etexilate 150 mg twice daily without need for monitoring.

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 from 5.6 % to 0.4 % (relative risk reduction 92 % based on hazard ratio) 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 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 (95% CI 0.42, 0.88), p=0.0082).

Table 16:      Analysis of the primary and secondary efficacy endpoints (VTE is a

composite of DVT and/or PE) until the end of post-treatment period for the RE-SONATE study.

Ethnic origin (DVT/PE prevention)

No clinically relevant ethnic differences among Caucasians, African-American, Hispanic, Japanese or Chinese patients were observed.

Paediatric population (DVT/PE prevention)

The European Medicines Agency has deferred the obligation to submit the results of studies with the reference medicinal product containing dabigatran etexilate in all subsets of the paediatric population in DVT/PE prevention (see section 4.2 for information on paediatric use).

Clinical trials for the prevention of thromboembolism in patients with prosthetic heart valves

A phase II study examined 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 heart valve replacement more than three months ago. More thromboembolic events (mainly strokes and symptomatic/a­symptomatic prosthetic valve thrombosis) and more bleeding events were observed with dabigatran etexilate than with warfarin. In the early post-operative patients, major bleeding manifested predominantly as haemorrhagic pericardial effusions, specifically in patients who started dabigatran etexilate early (i.e. on Day 3) after heart valve replacement surgery (see section 4.3).

5.2 Pharmacokinetic properties

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.

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

After oral administration of Dabigatran etexilate in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0 hours post administration.

Absorption

A study evaluating post-operative absorption of dabigatran etexilate, 1–3 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 in a postoperative period due to contributing factors such as anaesthesia, GI paresis, and surgical effects independent of the oral medicinal product formulation. 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 medicinal product administration.

Food does not affect the bioavailability of dabigatran etexilate but delays the time to peak plasma concentrations by 2 hours.

The oral bioavailability may be increased by 75 % after a single dose and 37 % at steady state compared to the reference capsule formulation when the pellets are taken without the Hydroxypropyl­methylcellulo­se (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 taking the pellets alone (e.g. sprinkled over food or into beverages) (see section 4.2).

Distribution

Low (34–35 %) concentration independent binding of dabigatran to human plasma proteins was observed. The volume of distribution of dabigatran of 60–70 L exceeded the volume of total body water indicating moderate tissue distribution of dabigatran.

Cmax and the area under the plasma concentration-time curve were dose proportional. Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12–14 hours was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as shown in table 17.

Biotransformation

Metabolism and excretion of dabigatran were studied following a single intravenous dose of radiolabeled dabigatran in healthy male subjects. After an intravenous 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 88–94 % of the administered dose by 168 hours post dose.

Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of total dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods. 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

Renal insufficiency

In phase I studies the exposure (AUC) of dabigatran after the oral administration of Dabigatran etexilate is approximately 2.7-fold higher in volunteers with moderate renal insufficiency (CrCL between 30– 50 mL/min) than in those without renal insufficiency.

In a small number of volunteers with severe renal insufficiency (CrCL 10–30 mL/min), the exposure (AUC) to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer than that observed in a population without renal insufficiency (see sections 4.2, 4.3 and 4.4).

Table 17:       Half-life of total dabigatran in healthy subjects and subjects with impaired renal

function.

Clearance of dabigatran by haemodialysis was investigated in 7 patients with end-stage renal disease (ESRD) without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flow rate, four hour duration and a blood flow rate of either 200 mL/min or 350–390 mL/min. This resulted in a removal of 50 % to 60 % of dabigatran concentrations, respectively. The amount of drug cleared by dialysis is proportional to the blood flow rate up to a blood flow rate of 300 mL/min. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PD relationship was not affected by the procedure.

The median CrCL in RE-LY was 68.4 mL/min. Almost half (45.8 %) of the RE-LY patients had a CrCL > 50-< 80 mL/min. Patients with moderate renal impairment (CrCL between 30 and 50 mL/min) had on average 2.29-fold and 1.81-fold higher pre- and post-dose dabigatran plasma concentrations, respectively, when compared with patients without renal impairment (CrCL > 80 mL/min).

The median CrCL in the RE-COVER study was 100.4 mL/min. 21.7 % of patients had mild renal impairment (CrCL > 50 – < 80 mL/min) and 4.5% of patients had a moderate renal impairment (CrCL between 30 and 50 mL/min). Patients with mild and moderate renal impairment had at steady state an average 1.8-fold and 3.6-fold higher pre-dosedabigatran plasma concentrations compared with patients with CrCL > 80 mL/min, respectively. Similar values for CrCL were found in RE-COVER II.

The median CrCL in the RE-MEDY and RE-SONATE studies were 99.0 mL/min and 99.7 mL/min, respectively. 22.9 % and 22.5 % of the patients had a CrCL > 50-< 80 mL/min, and 4.1 % and 4.8 % had a CrCL between 30 and 50 mL/min in in the RE-MEDY and RE-SONATE studies.

Elderly patients

Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60 % in the AUC and of more than 25 % in Cmax compared to young subjects.

The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31 % higher trough concentration for subjects > 75 years and by about 22 % lower trough level for subjects < 65 years compared to subjects between 65 and75 years (see sections 4.2 and 4.4).

Hepatic impairment

No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls (see sections 4.2 and 4.4).

Body weight

The dabigatran trough concentrations were about 20 % lower in patients with a body weight > 100 kg compared with 50–100 kg. The majority (80.8 %) of the subjects were in the > 50 kg and < 100 kg category with no clear difference detected (see sections 4.2 and 4.4). Limited clinical data in patients < 50 kg are available.

Gender

In atrial fibrillation patients females had on average 30 % higher trough and post-dose concentrations. No dose adjustment is recommended (see section 4.2).

Ethnic origin

No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding dabigatran pharmacokinetics and pharmacodynamics.

Pharmacokinetic interactions

The pro-drug dabigatran etexilate but not dabigatran is a substrate of the efflux transporter P-gp. Therefore concomitant use of P-gp transporter inhibitors (amiodarone, verapamil, clarithromycin, quinidine, dronedarone, ticagrelor and ketoconazole) and inducers (rifampicin) had been investigated (see sections 4.2, 4.4 and 4.5).

In vitro interaction studies did not show any inhibition or induction of the principal isoenzymes of cytochrome P450. This has been confirmed by in vivo studies with healthy volunteers, who did not show any interaction between this treatment and the following active substances: atorvastatin (CYP3A4), digoxin (P-gp transporter interaction) and diclofenac (CYP2C9).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Effects observed in the repeat-dose toxicity studies were due to the exaggerated pharmacodynamic effect of dabigatran.

An effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (5-fold the plasma exposure level in patients). At doses that were toxic to the mothers (5– to 10-fold the plasma exposure level in patients), a decrease in fetal body weight and viability along with an increase in fetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in fetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).

In lifetime toxicology studies in rats and mice, there was no evidence for a tumorigenic potential of dabigatran up to maximum doses of 200 mg/kg.

Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in the environment.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule fill

Cellulose microcrystalline

Croscarmellose sodium

Crospovidone

Tartaric acid pellets

Hydroxypropyl­cellulose

Mannitol (E-421)

Magnesium stearate

Talc

Capsule shell

Red iron oxide (E-172)

Titanium dioxide (E-171)

Hypromellose

Black printing ink Shellac

Propylene glycol

Strong ammonia solution Black iron oxide (E-172) Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister and bottle: 2 years

Once the bottle is opened, the medicinal product must be used within 4 months.

6.4 Special precautions for storage

Blister

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

Bottle

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

6.5 Nature and contents of container

Cartons containing 10, 30 or 60 hard capsules, a multipack containing 3 packs of 60 hard capsules (180 hard capsules) and a multipack containing 2 packs of 50 hard capsules (100 hard capsules) in perforated peelable aluminium blisters with desiccant.

White polyethylene bottle containing a desiccant together with a filler, and a white polypropylene cap with 60 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

When taking Dabigatran etexilate capsules out of the blister pack, the following instructions should be followed:

The hard capsules should be taken out of the blister card by peeling off the backing foil.

The hard capsules should not be pushed through the blister foil.

The blister foil should only be peeled off, when a hard capsule is required.

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

7. MARKETING AUTHORISATION HOLDER

TOWA Pharmaceutical Europe, S.L., C/ de Sant Marti, 75–97, Martorelles, 08107 Barcelo­na, Spai.

8 MARKETING AUTHORISATION NUMBER(S)

PL 52226/0003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

10/01/2019