DABIGATRAN ETEXILATE ACCORD 150mg capsules medication leaflet

Dabigatran etexilate Accord 150 mg hard capsules

Each hard capsule contains dabigatran etexilate mesilate equivalent to 150 mg of dabigatran etexilate.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Size “0” (approx. 22 × 8 mm) capsule with a white opaque cap imprinted “MD” and white opaquebody imprinted “150” with black ink, containing a blend of white to light yellow coloured pellets andlight yellow coloured granulate.

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

Treatment of venous thromboembolic events (VTE) and prevention of recurrent VTE in paediatricpatients from the time the child is able to swallow soft food to less than 18 years of age.

For age appropriate dose forms, see section 4.2.

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

When changing between the formulations, the prescribed dose may need to be altered. The dose statedin the relevant dosing table of a formulation should be prescribed based on the weight and age of thechild.

Prevention of stroke and systemic embolism in adult patients with NVAF with one or more riskfactors (SPAF)

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

The recommended doses of dabigatran etexilate in the indications SPAF, DVT and PE are shown intable 1.

Table 1: Dose recommendations for SPAF, DVT and PE

Prevention of stroke and systemic embolism in300 mg dabigatran etexilate taken as one 150 mgadult patients with NVAF with one or more riskcapsule twice dailyfactors (SPAF)300 mg dabigatran etexilate taken as one 150 mg

Treatment of DVT and PE, and prevention ofcapsule twice daily following treatment with arecurrent DVT, and PE in adults (DVT/PE)parenteral anticoagulant for at least 5 days

Patients aged ≥ 80 years daily dose of 220 mg dabigatran etexilate takenas one 110 mg capsule twice daily

Patients who receive concomitant verapamil

Patients between 75-80 years

Patients with moderate renal impairment daily dose of dabigatran etexilate of 300 mg or(CrCL 30-50 mL/min) 220 mg should be selected based on anindividual assessment of the thromboembolic

Patients with gastritis, esophagitis orrisk and the risk of bleedinggastroesophageal reflux

Other patients at increased risk of bleeding

For DVT/PE the recommendation for the use of 220 mg dabigatran etexilate taken as one 110 mgcapsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and has not beenstudied in this clinical setting. See further down and sections 4.4, 4.5, 5.1 and 5.2.

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

In all patients and especially in the elderly (> 75 years), as renal impairment may be frequent in thisage group:

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

* Renal function should also be assessed when a decline in renal function is suspected duringtreatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinalproducts).

Additional requirements in patients with mild to moderate renal impairment and in patients aged over75 years:

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

The method to be used to estimate renal function (CrCL in mL/min) is the Cockcroft-Gault method

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

Table 2: Duration of use for SPAF and DVT/PE

Indication Duration of use

SPAF Therapy should be continued long term.

DVT/PE The duration of therapy should be individualised after careful assessment ofthe treatment benefit against the risk for bleeding (see section 4.4).

Short duration of therapy (at least 3 months) should be based on transient riskfactors (e.g. recent surgery, trauma, immobilisation) and longer durationsshould be based on permanent risk factors or idiopathic DVT or 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.

Dabigatran etexilate treatment should not be discontinued without medical advice. Patients should beinstructed to contact the treating physician if they develop gastrointestinal symptoms such as dyspepsia(see section 4.8).

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

The parenteral anticoagulant should be discontinued and dabigatran etexilate should be started0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time ofdiscontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (seesection 4.5).

The starting time of the VKA should be adjusted based on CrCL as follows:

* CrCL ≥ 50 mL/min, VKA should be started 3 days before discontinuing dabigatran etexilate

* CrCL ≥ 30-< 50 mL/min, VKA should be started 2 days before discontinuing dabigatranetexilate

Because dabigatran etexilate can impact the International Normalised Ratio (INR), the INR will betterreflect VKA’s effect only after dabigatran etexilate has been stopped for at least 2 days. Until then,

INR values should be interpreted with caution.

The VKA should be stopped. Dabigatran etexilate can be given as soon as the INR is < 2.0.

Patients can stay on dabigatran etexilate while being cardioverted.

Catheter ablation for atrial fibrillation (SPAF)

Catheter ablation can be conducted in patients on 150 mg twice daily dabigatran etexilate treatment.

Dabigatran etexilate treatment does not need to be interrupted (see section 5.1).

Percutaneous coronary intervention (PCI) with stenting (SPAF)

Patients with non valvular atrial fibrillation who undergo a PCI with stenting can be treated withdabigatran etexilate in combination with antiplatelets after haemostasis is achieved (see section 5.1).

For dose modifications in this population see table 1 above.

Patients with an increased bleeding risk (see sections 4.4, 4.5, 5.1 and 5.2) should be closely monitoredclinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at thediscretion of the physician, following assessment of the potential benefit and risk to an individualpatient (see table 2 above). A coagulation test (see section 4.4) may help to identify patients with anincreased bleeding risk caused by excessive dabigatran exposure. When excessive dabigatran exposureis identified in patients at high risk of bleeding, a reduced dose of 220 mg taken as one 110 mg capsuletwice daily is recommended. When clinically relevant bleeding occurs, treatment should beinterrupted.

For subjects with gastritis, esophagitis, or gastroesophageal reflux, a dose reduction may be considereddue to the elevated risk of major gastro-intestinal bleeding (see table 1 above and section 4.4).

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

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

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

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

Dose reductions are recommended for patients who receive concomitantly verapamil (see table 1above and sections 4.4 and 4.5). In this situation dabigatran etexilate and verapamil should be taken atthe same time.

Weight

No dose adjustment is necessary (see section 5.2), but close clinical surveillance is recommended inpatients with a body weight < 50 kg (see section 4.4).

No dose adjustment is necessary (see section 5.2).

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

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

Dabigatran etexilate capsules should be taken twice daily, one dose in the morning and one dose inthe evening, at approximately the same time every day. The dosing interval should be as close to12 hours as possible.

The recommended dose of dabigatran etexilate capsules is based on the patient’s weight and age asshown in table 3. The dose should be adjusted according to weight and age as treatment progresses.

For weight and age combinations not listed in the dosing table no dosing recommendation can beprovided.

Table 3: Single and total daily dabigatran etexilate doses in milligrams (mg) by weight inkilograms (kg) and age in years of the patient

Weight /age combinations Single dose Total daily dose

Weight in kg Age in years in mg in mg11 to < 13 8 to < 9 75 15013 to < 16 8 to < 11 110 22016 to < 21 8 to < 14 110 22021 to < 26 8 to < 16 150 30026 to < 31 8 to < 18 150 30031 to < 41 8 to < 18 185 37041 to < 51 8 to < 18 220 44051 to < 61 8 to < 18 260 52061 to < 71 8 to < 18 300 60071 to < 81 8 to < 18 300 600> 81 10 to < 18 300 600

Single doses requiring combinations of more than one capsule:300 mg: two 150 mg capsules orfour 75 mg capsules260 mg: one 110 mg plus one 150 mg capsule orone 110 mg plus two 75 mg capsules220 mg: two 110 mg capsules185 mg: one 75 mg plus one 110 mg capsule150 mg: one 150 mg capsule ortwo 75 mg capsules

Prior to the initiation of treatment, the estimated glomerular filtration rate (eGFR) should be estimatedusing the Schwartz formula (method used for creatinine assessment to be checked with local lab).

Treatment with dabigatran etexilate in paediatric patients with eGFR < 50 mL/min/1.73 m2 iscontraindicated (see section 4.3).

Patients with an eGFR ≥ 50 mL/min/1.73m2 should be treated with the dose according to table 3.

While on treatment, renal function should be assessed in certain clinical situations when it is suspectedthat the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certainco-medications, etc).

The duration of therapy should be individualised based on the benefit risk assessment.

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 onwards, the missed dose should be omitted.

A double dose to make up for missed individual doses must never be taken.

Dabigatran etexilate treatment should not be discontinued without medical advice. Patients or theircaregivers should be instructed to contact the treating physician if the patient develops gastrointestinalsymptoms such as dyspepsia (see section 4.8).

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

The parenteral anticoagulant should be discontinued and dabigatran etexilate should be started0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time ofdiscontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (seesection 4.5).

Patients should start VKA 3 days before discontinuing dabigatran etexilate.

Because dabigatran etexilate can impact the international normalised ratio (INR), the INR will betterreflect VKA’s effect only after dabigatran etexilate has been stopped for at least 2 days. Until then,

INR values should be interpreted with caution.

The VKA should be stopped. Dabigatran etexilate can be given as soon as the INR is < 2.0.

This medicinal product is for oral use.

The capsules can be taken with or without food. The capsules should be swallowed as a whole with aglass 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 (seesections 5.2 and 6.6).

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

* Severe renal impairment (CrCL < 30 mL/min) in adult patients

* eGFR < 50 mL/min/1.73 m2 in paediatric patients

* Active clinically significant bleeding

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

* Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), lowmolecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc),oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances.

These are switching anticoagulant therapy (see section 4.2), when UFH is given at dosesnecessary to maintain an open central venous or arterial catheter or when UFH is given duringcatheter ablation for atrial fibrillation (see section 4.5)

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

* Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole,cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir(see section 4.5)

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

Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding orwith concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation.

Bleeding can occur at any site during therapy. An unexplained fall in haemoglobin and/or haematocritor blood pressure should lead to a search for a bleeding site.

For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of theanticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available.

The efficacy and safety of idarucizumab have not been established in paediatric patients.

Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma,coagulation factor concentration (activated or non-activated), recombinant factor VIIa or plateletconcentrates are other possible options (see also section 4.9).

In clinical trials, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI)bleeding. An increased risk was seen in the elderly (≥ 75 years) for the 150 mg twice daily doseregimen. Further risk factors (see also table 4) comprise co-medication with platelet aggregationinhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs(NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux.

Table 4 summarises factors which may increase the haemorrhagic risk.

Table 4: Factors which may increase the haemorrhagic risk.

Risk factor

Pharmacodynamic and kinetic factors Age ≥ 75 years

Factors increasing dabigatran plasma levels Major:

* Moderate renal impairment in adultpatients (30-50 mL/min CrCL)

* Strong P-gp inhibitors (see section 4.3and 4.5)

* Mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, verapamil,quinidine and ticagrelor; see section 4.5)

Minor:

* Low body weight (< 50 kg) in adult patients

Pharmacodynamic interactions (see section 4.5) * ASA and other platelet aggregationinhibitors such as clopidogrel

* NSAIDs

* SSRIs or SNRIs

* Other medicinal products which mayimpair haemostasis

Diseases/procedures with special haemorrhagic * Congenital or acquired coagulationrisks disorders

* Thrombocytopenia or functional plateletdefects

* Recent biopsy, major trauma

* Bacterial endocarditis

* Esophagitis, gastritis or gastroesophagealreflux

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

The concomitant use of dabigatran etexilate with P-gp-inhibitors has not been studied in paediatricpatients but may increase the risk of bleeding (see section 4.5).

For the management of bleeding complications, see also section 4.9.

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 majorbleeding requires a careful benefit-risk assessment. Dabigatran etexilate should only be given if thebenefit outweighs bleeding risks.

Limited clinical data are available for paediatric patients with risk factors, including patients withactive meningitis, encephalitis and intracranial abscess (see section 5.1). In these patients, dabigatranetexilate should only be given if the expected benefit outweighs bleeding risks.

Close observation for signs of bleeding or anaemia is recommended throughout the treatment period,especially if risk factors are combined (see table 4 above). Particular caution should be exercised whendabigatran etexilate is co-administered with verapamil, amiodarone, quinidine or clarithromycin (P-gpinhibitors) and particularly in the occurrence of bleeding, notably in patients having a reduced renalfunction (see section 4.5).

Close observation for signs of bleeding is recommended in patients concomitantly treated with

NSAIDs (see section 4.5).

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

When severe bleedings occur, treatment must be discontinued, the source of bleeding investigated anduse of the specific reversal agent (idarucizumab) may be considered in adult patients. The efficacy andsafety of idarucizumab have not been established in paediatric patients. Haemodialysis can removedabigatran.

The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding. In caseof paediatric patients local labeling recommendations for proton pump inhibitors have to be followed.

Although this medicinal product does not in general require routine anticoagulant monitoring, themeasurement of dabigatran related anticoagulation may be helpful to detect excessive high exposure todabigatran in the presence of additional risk factors.

Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time(aPTT) may provide useful information, but results should be interpreted with caution due to inter-testvariability (see section 5.1).

The international normalised ratio (INR) test is unreliable in patients on dabigatran etexilate and falsepositive INR elevations have been reported. Therefore INR tests should not be performed.

Table 5 shows coagulation test thresholds at trough for adult patients that may be associated with anincreased risk of bleeding. Respective thresholds for paediatric patients are not known (see section 5.1)

Table 5: Coagulation test thresholds at trough for adult patients that may be associated with anincreased risk of bleeding.

Test (trough value) Indication

SPAF and DVT/PEdTT [ng/mL] > 200

ECT [x-fold upper limit of normal] > 3aPTT [x-fold upper limit of normal] > 2

INR Should not be performed

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

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

Patients can stay on dabigatran etexilate while being cardioverted. Dabigatran etexilate treatment(150 mg twice daily) does not need to be interrupted in patients undergoing catheter ablation for atrialfibrillation (see section 4.2).

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

Dabigatran etexilate should be temporarily discontinued. When rapid reversal of the anticoagulationeffect is required the specific reversal agent (idarucizumab) to dabigatran is available for adultpatients. The efficacy and safety of idarucizumab have not been established in paediatric patients.

Haemodialysis can remove dabigatran.

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 idarucizumab, if thepatient is clinically stable and adequate haemostasis has been achieved.

Dabigatran etexilate should be temporarily discontinued. A surgery/intervention should be delayed ifpossible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding maybe increased. This risk of bleeding should be weighed against the urgency of intervention.

If possible, dabigatran etexilate should be discontinued at least 24 hours before invasive or surgicalprocedures. In patients at higher risk of bleeding or in major surgery where complete haemostasis maybe required consider stopping dabigatran etexilate 2-4 days before surgery.

Table 6 summarises discontinuation rules before invasive or surgical procedures for adult patients.

Table 6: Discontinuation rules before invasive or surgical procedures for adult patients

Renal function Estimated half-life(CrCL in (hours) Dabigatran etexilate should be stopped before elective surgerymL/min) High risk of bleeding or major Standard risksurgery≥ 80 ~ 13 2 days before 24 hours before≥ 50-< 80 ~ 15 2-3 days before 1-2 days before≥ 30-< 50 ~ 18 4 days before 2-3 days before (> 48 hours)

Discontinuation rules before invasive or surgical procedures for paediatric patients are summarisedin table 7.

Table 7: Discontinuation rules before invasive or surgical procedures for paediatric patients

Renal function Stop dabigatran before elective surgery(eGFR in mL/min/1.73 m2)> 80 24 hours before50 - 80 2 days before< 50 These patients have not been studied (see section 4.3).

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 punctureand by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least2 hours should elapse before the administration of the first dose of dabigatran etexilate. These patientsrequire frequent observation for neurological signs and symptoms of spinal or epidural haematoma.

Dabigatran etexilate treatment should be resumed/started after the invasive procedure or surgicalintervention as soon as possible provided the clinical situation allows and adequate haemostasis hasbeen established.

Patients at risk for bleeding or patients at risk of overexposure, notably patients with reduced renalfunction (see also table 4), should be treated with caution (see sections 4.4 and 5.1).

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

Patients with elevated liver enzymes > 2 ULN were excluded in the main trials. No treatmentexperience is available for this subpopulation of patients, and therefore the use of dabigatran etexilateis not recommended in this population. Hepatic impairment or liver disease expected to have anyimpact on survival is contraindicated (see section 4.3).

Concomitant administration of P-gp inducers is expected to result in decreased dabigatran plasmaconcentrations, and should be avoided (see sections 4.5 and 5.2).

Direct acting Oral Anticoagulants (DOACs) including dabigatran etexilate are not recommended forpatients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particularfor patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta2glycoprotein I antibodies), treatment with DOACs could be associated with increased rates ofrecurrent thrombotic events compared with vitamin K antagonist therapy.

In the phase III study RE-LY (SPAF, see section 5.1) the overall rate of MI was 0.82, 0.81, and 0.64 %/ year for dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily andwarfarin, respectively, an increase in relative risk for dabigatran of 29 % and 27 % compared towarfarin. 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 orcoronary artery disease, patients with left ventricular ejection fraction < 40 %, and patients withmoderate renal dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly taking

ASA plus clopidogrel or clopidogrel alone.

In the three active controlled DVT/PE phase III studies, a higher rate of MI was reported in patientswho received dabigatran etexilate than in those who received warfarin: 0.4 % vs. 0.2 % in the shortterm RE-COVER 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.

The efficacy and safety have not been established for DVT/PE patients with active cancer. There islimited data on efficacy and safety for paediatric patients with active cancer.

For some very specific paediatric patients, e.g. patients with small bowel disease where absorptionmay be affected, use of an anticoagulant with parenteral route of administration should be considered.

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to sayessentially ‘sodium-free’

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gpinhibitors (see table 8) is expected to result in increased dabigatran plasma concentrations.

If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding oranaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductionsmay be required in combination with some P-gp inhibitors (see sections 4.2, pct. 4.3, pct. 4.4 and 5.1).

Table 8: Transporter interactions

Concomitant use contraindicated (see section 4.3)

Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 2.38-foldand 2.35-fold, respectively, after a single oral dose of 400 mg, and by

Ketoconazole2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400 mgketoconazole once daily.

When dabigatran etexilate and dronedarone were given at the same time totaldabigatran AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold,

Dronedaronerespectively, after multiple dosing of 400 mg dronedarone twice a day, andabout 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg.

Itraconazole, Based on in vitro results a similar effect as with ketoconazole may becyclosporine expected.

The concomitant use of dabigatran etexilate with the fixed-dose combination

Glecaprevir/pibrentasvir of the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increaseexposure of dabigatran and may increase the risk of bleeding.

Tacrolimus has been found in vitro to have a similar level of inhibitory effecton P gp as that seen with itraconazole and cyclosporine. Dabigatran etexilatehas not been clinically studied together with tacrolimus. However, limited

Tacrolimusclinical data with another P-gp substrate (everolimus) suggest that theinhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors.

Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4)

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

The greatest elevation of dabigatran exposure was observed with the first doseof an immediate release formulation of verapamil administered one hour priorto the dabigatran etexilate intake (increase of Cmax by about 2.8-fold and AUC

Verapamil by about 2.5-fold). The effect was progressively decreased with administrationof an extended release formulation (increase of Cmax by about 1.9-fold and

AUC by about 1.7-fold) or administration of multiple doses of verapamil(increase of Cmax by about 1.6-fold and AUC by about 1.5-fold).

There was no meaningful interaction observed when verapamil was given2 hours after dabigatran etexilate (increase of Cmax by about 1.1-fold and AUCby about 1.2-fold). This is explained by completed dabigatran absorption after2 hours.

When dabigatran etexilate was co-administered with a single oral dose of600 mg amiodarone, the extent and rate of absorption of amiodarone and itsactive metabolite DEA were essentially unchanged. The dabigatran AUC and

Amiodarone

Cmax were increased by about 1.6-fold and 1.5-fold, respectively. In view ofthe long half-life of amiodarone the potential for an interaction may exist forweeks after discontinuation of amiodarone (see sections 4.2 and 4.4).

Quinidine was given as 200 mg dose every 2nd hour up to a total dose of1 000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days,

Quinidine on the 3rd day either with or without quinidine. Dabigatran AUCτ,ss and Cmax,sswere increased on average by 1.53-fold and 1.56-fold, respectively withconcomitant quinidine (see sections 4.2 and 4.4).

When clarithromycin (500 mg twice daily) was administered together with

Clarithromycin dabigatran etexilate in healthy volunteers, increase of AUC by about 1.19-foldand Cmax by about 1.15-fold was observed.

When a single dose of 75 mg dabigatran etexilate was coadministeredsimultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUCand Cmax were increased by 1.73-fold and 1.95-fold, respectively. Aftermultiple doses of ticagrelor 90 mg twice a day the increase of dabigatranexposure is 1.56-fold and 1.46-fold for Cmax and AUC, respectively.

Concomitant administration of a loading dose of 180 mg ticagrelor and110 mg dabigatran etexilate (in steady state) increased the dabigatran AUCτ,ssand Cmax,ss by 1.49-fold and 1.65-fold, respectively, compared with dabigatranetexilate given alone. When a loading dose of 180 mg ticagrelor was given

Ticagrelor2 hours after 110 mg dabigatran etexilate (in steady state), the increase ofdabigatran AUCτ,ss and Cmax,ss was reduced to 1.27-fold and 1.23-fold,respectively, compared with dabigatran etexilate given alone. This staggeredintake is the recommended administration for start of ticagrelor with a loadingdose.

Concomitant administration of 90 mg ticagrelor twice a day (maintenancedose) with 110 mg dabigatran etexilate increased the adjusted dabigatran

AUCτ,ss and Cmax,ss 1.26-fold and 1.29-fold, respectively, compared withdabigatran etexilate given alone

Posaconazole also inhibits P-gp to some extent but has not been clinically

Posaconazole studied. Caution should be exercised when dabigatran etexilate is co-administered with posaconazole.

P-gp inducers

Concomitant use should be avoided .

Concomitant administration is expected to result in decreased dabigatranconcentrations.

e.g. rifampicin, St.

John’s wort (Hypericum Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily forperforatum), 7 days decreased total dabigatran peak and total exposure by 65.5 % andcarbamazepine, or 67 %, respectively. The inducing effect was diminished resulting in dabigatranphenytoin exposure close to the reference by day 7 after cessation of rifampicintreatment. No further increase in bioavailability was observed after another7 days.

Protease inhibitors such as ritonavir

Concomitant use not recommendede.g. ritonavir and its These affect P-gp (either as inhibitor or as inducer). They have not beencombinations with other studied and are therefore not recommended for concomitant treatment withprotease inhibitors dabigatran etexilate.

P-gp substrate

In a study performed with 24 healthy subjects, when dabigatran etexilate was

Digoxin co-administered with digoxin, no changes on digoxin and no clinicallyrelevant changes on dabigatran exposure have been observed.

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

From the data collected in the phase III study RE-LY (see section 5.1) it was observed that theconcomitant use of other oral or parenteral anticoagulants increases major bleeding rates with bothdabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations whenswitching from one anticoagulant to another (see section 4.3). Furthermore, concomitant use ofantiplatelets, ASA or clopidogrel approximately doubled major bleeding rates with both dabigatranetexilate and warfarin (see section 4.4).

UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter orduring catheter ablation for atrial fibrillation (see section 4.3).

Table 9: Interactions with anticoagulants and antiplatelet aggregation medicinal products

NSAIDs NSAIDs given for short-term analgesia have been shown not to be associated withincreased bleeding risk when given in conjunction with dabigatran etexilate. Withchronic use in the RE-LY study, NSAIDs increased the risk of bleeding byapproximately 50 % on both dabigatran etexilate and warfarin.

Clopidogrel In young healthy male volunteers, the concomitant administration of dabigatranetexilate and clopidogrel resulted in no further prolongation of capillary bleedingtimes compared to clopidogrel monotherapy. In addition, dabigatran AUC τ,ss and

Cmax,ss and the coagulation measures for dabigatran effect or the inhibition ofplatelet aggregation as measure of clopidogrel effect remained essentiallyunchanged comparing combined treatment and the respective mono-treatments.

With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUCτ,ss and

Cmax,s were increased by about 30-40 % (see section 4.4).

ASA Co-administration of ASA and 150 mg dabigatran etexilate twice daily mayincrease the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and325 mg ASA, respectively (see section 4.4).

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

Table 10: Other interactions

Selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptakeinhibitors (SNRIs)

SSRIs, SNRIs SSRIs and SNRIs increased the risk of bleeding in RE-LY in all treatment groups,

Substances influencing gastric pH

When dabigatran etexilate was co-administered with pantoprazole, a decrease inthe dabigatran AUC of approximately 30 % was observed. Pantoprazole and other

Pantoprazole proton-pump inhibitors (PPI) were co-administered with dabigatran etexilate inclinical trials, and concomitant PPI treatment did not appear to reduce the efficacyof dabigatran etexilate.

Ranitidine administration together with dabigatran etexilate had no clinically

Ranitidinerelevant effect on the extent of absorption of dabigatran.

Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have noin vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactionsare not expected with dabigatran.

Interaction studies have only been performed in adults.

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

There is limited amount of data from the use of dabigatran etexilate in pregnant women. Studies inanimals 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.

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

No human data available.

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

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

Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64 000 patients;thereof approximately 35 000 patients were treated with dabigatran etexilate.

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

The most commonly reported events are bleedings occurring in approximately 16.6 % in patients withatrial fibrillation treated long-term for the prevention of stroke and systemic embolism, and in 14.4 %of adult patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4 % of patients in the

DVT/PE prevention trial RE-MEDY (adult patients) and in 10.5 % of patients in the DVT/PEprevention trial RE-SONATE (adult patients).

Since the patient populations treated in the three indications are not comparable and bleeding eventsare distributed over several System Organ Classes (SOC), a summary description of major and anybleeding are broken down by indication and are provided in tables 12-15 below.

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

Table 11 shows the adverse reactions identified studies and post-marketing data in the indicationsprevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation,

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

Table 11: Adverse reactions

Frequency

Stroke and systemic embolism DVT/PE treatment and

SOC/Preferred term prevention in patients with atrial DVT/PE preventionfibrillation

Anaemia Common Uncommon

Haemoglobin decreased Uncommon Not known

Thrombocytopenia Uncommon Rare

Haematocrit decreased Rare Not known

Neutropenia Not known Not known

Agranulocytosis Not known Not known

Drug hypersensitivity Uncommon Uncommon

Rash Uncommon Uncommon

Pruritus Uncommon Uncommon

Anaphylactic reaction Rare Rare

Angioedema Rare Rare

Urticaria Rare Rare

Bronchospasm Not known Not known

Intracranial haemorrhage Uncommon Rare

Haematoma Uncommon Uncommon

Haemorrhage Uncommon Uncommon

Epistaxis Common Common

Haemoptysis Uncommon Uncommon

Gastrointestinal haemorrhage Common Common

Abdominal pain Common Uncommon

Diarrhoea Common Uncommon

Dyspepsia Common Common

Nausea Common Uncommon

Rectal haemorrhage Uncommon Common

Haemorrhoidal haemorrhage Uncommon Uncommon

Gastrointestinal ulcer, including

Uncommon Uncommonoesophageal ulcer

Gastroesophagitis Uncommon Uncommon

Gastroesophageal reflux disease Uncommon Uncommon

Vomiting Uncommon Uncommon

Dysphagia Uncommon Rare

Hepatic function abnormal/Liver

Uncommon Uncommonfunction Test abnormal

Alanine aminotransferase increased Uncommon Uncommon

Aspartate aminotransferase increased Uncommon Uncommon

Hepatic enzyme increased Rare Uncommon

Hyperbilirubinaemia Rare Not known

Skin and subcutaneous tissue disorder

Skin haemorrhage Common Common

Alopecia Not known Not known

Haemarthrosis Rare Uncommon

Genitourological haemorrhage, Common Commonincluding haematuria

Injection site haemorrhage Rare Rare

Catheter site haemorrhage Rare Rare

Traumatic haemorrhage Rare Uncommon

Incision site haemorrhage Rare Rare

Due to the pharmacological mode of action, the use of dabigatran etexilate may be associated with anincreased risk of occult or overt bleeding from any tissue or organ. The signs, symptoms, and severity(including fatal outcome) will vary according to the location and degree or extent of the bleedingand/or anaemia. In the clinical studies mucosal bleedings (e.g. gastrointestinal, genitourinary) wereseen more frequently during long term dabigatran etexilate treatment compared with VKA treatment.

Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit is ofvalue to detect occult bleeding. The risk of bleedings may be increased in certain patient groups e.g.those patients with moderate renal impairment and/or on concomitant treatment affecting haemostasisor strong P-gp inhibitors (see section 4.4 Haemorrhagic risk). Haemorrhagic complications maypresent as weakness, paleness, dizziness, headache or unexplained swelling, d yspnoea, andunexplained shock.

Known bleeding complications such as compartment syndrome and acute renal failure due tohypoperfusion and anticoagulant-related nephropathy in patients with predisposing risk factors havebeen reported for dabigatran etexilate. Therefore, the possibility of haemorrhage is to be considered inevaluating the condition in any anticoagulated patient. For adult patients a specific reversal agent fordabigatran, idarucizumab, is available in case of uncontrollable bleeding (see Section 4.9).

Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation withone or more risk factors (SPAF)

The table 12 shows bleeding events broken down to major and any bleeding in the pivotal study testingthe prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation.

Table 12: Bleeding events in a study testing the prevention of thromboembolic stroke andsystemic embolism in patients with atrial fibrillation

Dabigatran etexilate Dabigatran etexilate 150 mg Warfarin110 mg twice daily twice daily

Subjects randomised 6 015 6 076 6 022

Major bleeding 347 (2.92 %) 409 (3.40 %) 426 (3.61 %)

Intracranial bleeding 27 (0.23 %) 39 (0.32 %) 91 (0.77 %)

GI bleeding 134 (1.13 %) 192 (1.60 %) 128 (1.09 %)

Fatal bleeding 26 (0.22 %) 30 (0.25 %) 42 (0.36 %)

Minor bleeding 1 566 (13.16 %) 1 787 (14.85 %) 1 931 (16.37 %)

Any bleeding 1 759 (14.78 %) 1 997 (16.60 %) 2 169 (18.39 %)

Subjects randomised to dabigatran etexilate 110 mg twice daily or 150 mg twice daily had asignificantly 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 bleedrate. Subjects randomised to 110 mg dabigatran etexilate twice daily had a significantly lower risk formajor bleeds compared with warfarin (hazard ratio 0.81 [p = 0.0027]). Subjects randomised to 150 mgdabigatran etexilate twice daily had a significantly higher risk for major GI bleeds compared withwarfarin (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 systemic embolism prevention anddecreased risk of ICH compared to warfarin is preserved across individual subgroups, e.g. renalimpairment, age, concomitant medicinal product use such as anti-platelets or P-gp inhibitors. Whilecertain patient subgroups are at an increased risk of major bleeding when treated with ananticoagulant, the excess bleeding risk for dabigatran is due to GI bleeding, typically seen within thefirst 3-6 months following initiation of dabigatran etexilate therapy.

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

Table 13 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II testingthe treatment of DVT and 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 anominal alpha level of 5 %.

Table 13: Bleeding events in the studies RE-COVER and RE-COVER II testing the treatment of

DVT and PE

Dabigatran etexilate Warfarin Hazard ratio vs.150 mg twice daily warfarin (95 %confidence interval)

Patients included in safety 2 456 2 462analysis

Major bleeding events 24 (1.0 %) 40 (1.6 %) 0.60 (0.36, 0.99)

Intracranial Bleeding 2 (0.1 %) 4 (0.2 %) 0.50 (0.09, 2.74)

Major GI bleeding 10 (0.4 %) 12 (0.5 %) 0.83 (0.36, 1.93)

Life-threatening bleed 4 (0.2 %) 6 (0.2 %) 0.66 (0.19, 2.36)

Major bleeding 109 (4.4 %) 189 (7.7 %) 0.56 (0.45, 0.71)events/clinically relevantbleeds

Any bleeding 354 (14.4 %) 503 (20.4 %) 0.67 (0.59, 0.77)

Any GI bleeding 70 (2.9 %) 55 (2.2 %) 1.27 (0.90, 1.82)

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

Table 14 shows bleeding events in pivotal study RE-MEDY testing prevention of DVT and PE. Somebleeding events (MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of5 % in patients receiving dabigatran etexilate as compared with those receiving warfarin.

Table 14: Bleeding events in study RE-MEDY testing prevention of DVT and PE

Hazard ratio vs

Dabigatran etexilate

Warfarin warfarin (95 %150 mg twice daily

Confidence Interval)

Treated patients 1 430 1 426

Majory bleeding events 13 (0.9 %) 25 (1.8 %) 0.54 (0.25, 1.16)

Intracranial bleeding 2 (0.1 %) 4 (0.3 %) Not calculable*

Major GI bleeding 4 (0.3 %) 8 (0.5 %) Not calculable*

Life-threatening bleed 1 (0.1 %) 3 (0.2 %)) Not calculable*

Major bleeding event 80 (5.6 %) 145 (10.2 %) 0.55 (0.41, 0.72)/clinically relevant bleeds

Any bleeding 278 (19.4 %) 373 (26.2 %) 0.71 (0.61, 0.83)

Hazard ratio vs

Dabigatran etexilate

Warfarin warfarin (95 %150 mg twice daily

Confidence Interval)

Any GI bleeds 45 (3.1 %) 32 (2.2 %) 1.39 (0.87, 2.20)

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

Table 15 shows bleeding events in pivotal study RE-SONATE testing prevention of DVT and PE. Therate of the combination of MBEs/CRBEs and the rate of any bleeding was significantly lower at anominal alpha level of 5 % in patients receiving placebo as compared with those receiving dabigatranetexilate.

Table 15: Bleeding events in study RE-SONATE testing prevention of DVT and PE

Dabigatran etexilate Placebo Hazard ratio vs150 mg twice daily placebo (95 %confidence interval)

Treated patients 684 659

Major bleeding events 2 (0.3 %) 0 Not calculable*

Intracranial bleeding 0 0 Not calculable*

Major GI bleeding 2 (0.3 %) 0 Not calculable*

Life-threatening bleeds 0 0 Not calculable*

Major bleeding event/clinical 36 (5.3 %) 13 (2.0 %) 2.69 (1.43, 5.07)relevant bleeds

Any bleeding 72 (10.5 %) 40 (6.1 %) 1.77 (1.20, 2.61)

Any GI bleeds 5 (0.7 %) 2 (0.3 %) 2.38 (0.46, 12.27)

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

Agranulocytosis and neutropenia have been reported very rarely during post approval use ofdabigatran etexilate. Because adverse reactions are reported in the postmarketing surveillance settingfrom a population of uncertain size, it is not possible to reliably determine their frequency. Thereporting rate was estimated as 7 events per 1 million patient years for agranulocytosis and as 5 eventsper 1 million patient years for neutropenia.

The safety of dabigatran etexilate in the treatment of VTE and prevention of recurrent VTE inpaediatric patients was studied in two phase III trials (DIVERSITY and 1 160.108). In total,328 paediatric patients had been treated with dabigatran etexilate. The patients received age andweight adjusted doses of an age-appropriate formulation of dabigatran etexilate.

Overall, the safety profile in children is expected to be the same as in adults.

In total, 26 % of paediatric patients treated with dabigatran etexilate for VTE and for prevention ofrecurrent VTE experienced adverse reactions.

Table 16 shows the adverse reactions identified from the studies in the treatment of VTE andprevention of recurrent VTE in paediatric patients. They are ranked under headings of System Organ

Class (SOC) and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100to < 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 16: Adverse reactions

Frequency

SOC/Preferred term. treatment of VTE and prevention of recurrent VTE inpaediatric patients

Anaemia Common

Haemoglobin decreased Uncommon

Thrombocytopenia Common

Haematocrit decreased Uncommon

Neutropenia Uncommon

Agranulocytosis Not known

Drug hypersensitivity Uncommon

Rash Common

Pruritus Uncommon

Anaphylactic reaction Not known

Angioedema Not known

Urticaria Common

Bronchospasm Not known

Intracranial haemorrhage Uncommon

Haematoma Common

Haemorrhage Not known

Epistaxis Common

Haemoptysis Uncommon

Gastrointestinal haemorrhage Uncommon

Abdominal pain Uncommon

Diarrhoea Common

Dyspepsia Common

Nausea Common

Rectal haemorrhage Uncommon

Haemorrhoidal haemorrhage Not known

Gastrointestinal ulcer, including Not knownoesophageal ulcer

Gastroesophagitis Uncommon

Gastroesophageal reflux disease Common

Vomiting Common

Dysphagia Uncommon

Hepatic function abnormal/Not known

Liver function Test abnormal

Alanine aminotransferase increased Uncommon

Aspartate aminotransferase increased Uncommon

Hepatic enzyme increased Common

Hyperbilirubinaemia Uncommon

Skin and subcutaneous tissue disorder

Skin haemorrhage Uncommon

Alopecia Common

Haemarthrosis Not known

Genitourological haemorrhage, Uncommonincluding haematuria

Injection site haemorrhage Not known

Catheter site haemorrhage Not known

Traumatic haemorrhage Uncommon

Incision site haemorrhage Not known

In the two phase III trials in the indication treatment of VTE and prevention of recurrent VTE inpaediatric patients, a total of 7 patients (2.1 %) had a major bleeding event, 5 patients (1.5 %) aclinically relevant non-major bleeding event and 75 patients (22.9 %) a minor bleeding event. Thefrequency of bleeding events was overall higher in the oldest age group (12 to < 18 years: 28.6 %) thanin the younger age groups (birth to < 2 years: 23.3 %; 2 to < 12 years: 16.2 %). Major or severebleeding, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Dabigatran etexilate doses beyond those recommended, expose the patient to increased risk ofbleeding.

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

Excessive anticoagulation may require interruption of dabigatran etexilate treatment. Since dabigatranis excreted predominantly by the renal route adequate diuresis must be maintained. As protein bindingis low, dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of thisapproach in clinical studies (see section 5.2).

In the event of haemorrhagic complications, dabigatran etexilate treatment must be discontinued andthe source of bleeding investigated. Depending on the clinical situation appropriate supportivetreatment, such as surgical haemostasis and blood volume replacement, should be undertaken at theprescriber’s discretion.

For adult patients in situations when rapid reversal of the anticoagulant effect of dabigatran is requiredthe specific reversal agent (idarucizumab) antagonizing the pharmacodynamic effect of dabigatran isavailable. The efficacy and safety of idarucizumab have not been established in paediatric patients (seesection 4.4).

Coagulation factor concentrates (activated or non-activated) or recombinant Factor VIIa may be takeninto account. There is some experimental evidence to support the role of these medicinal products inreversing the anticoagulant effect of dabigatran, but data on their usefulness in clinical settings andalso on the possible risk of rebound thromboembolism is very limited. Coagulation tests may becomeunreliable following administration of suggested coagulation factor concentrates. Caution should beexercised when interpreting these tests. Consideration should also be given to administration ofplatelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet medicinalproducts have been used. All symptomatic treatment should be given according to the physician'sjudgement.

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

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

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 byesterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversibledirect thrombin inhibitor and is the main active principle in plasma.

Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during thecoagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits freethrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

In vivo and ex vivo animal studies have demonstrated antithrombotic efficacy and anticoagulantactivity of dabigatran after intravenous administration and of dabigatran etexilate after oraladministration in various animal models of thrombosis.

There is a clear correlation between plasma dabigatran concentration and degree of anticoagulanteffect 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 plasmaconcentration that can be compared to the expected dabigatran plasma concentrations. When thecalibrated dTT assay delivers a dabigatran plasma concentration resu lt at or below the limit ofquantification, 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 anticoagulationintensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitablefor precise quantification of anticoagulant effect, especially at high plasma concentrations ofdabigatran. Although high aPTT values should be interpreted with caution, a high aPTT valueindicates that the patient is anticoagulated.

In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatranlevels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90 th percentileof dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTTthresholds see section 4.4, table 5) is considered to be associated with an increased risk of bleeding.

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

Steady state geometric mean dabigatran peak plasma concentration, measured around 2 hours after150 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, measuredat trough in the morning, at the end of the dosing interval (i.e. 12 hours after the 150 mg dabigatranevening dose), was on average 91.0 ng/mL, with a range of 61.0-143 ng/mL (25th-75th percentilerange).

For patients with NVAF treated for prevention of stroke and systemic embolism with 150 mgdabigatran etexilate twice daily,

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

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

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

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

In patients treated for DVT and PE with 150 mg dabigatran etexilate twice daily, the dabigatrangeometric mean trough concentration, measured within 10-16 hours after dose, at the end of the dosinginterval (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 etexilate150 mg twice daily,

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

* an ECT at trough (10-16 hours after the previous dose), elevated approximately 2.3-foldcompared 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 twicedaily no pharmacokinetic data are available.

No clinically relevant ethnic differences among Caucasians, African-American, Hispanic, Japanese or

Chinese patients were observed.

Prevention of stroke and systemic embolism 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(Randomised Evaluation of Long-term anticoagulant therapy) a multi-centre, multi-national,randomised parallel group study of two blinded doses of dabigatran etexilate (110 mg and 150 mgtwice daily) compared to open-label warfarin in patients with atrial fibrillation at moderate to high riskof stroke and systemic embolism. The primary objective in this study was to determine if dabigatranetexilate was non-inferior to warfarin in reducing the occurrence of the composite endpoint stroke andsystemic embolism. Statistical superiority was also analysed.

In the RE-LY study, a total of 18 113 patients were randomised, with a mean age of 71.5 years and amean CHADS2 score of 2.1. The patient population was 64 % male, 70 % Caucasian and 16 % Asian.

For patients randomised to warfarin, the mean percentage of time in therapeutic range (TTR) (INR2-3) 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 systemic embolism in subjects with atrialfibrillation, with a reduced risk of ICH, total bleeding and major bleeding. The dose of 150 mg twicedaily reduces significantly the risk of ischemic and haemorrhagic stroke, vascular death, ICH and totalbleeding 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 and150 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 etexilatecompared to warfarin diminish.

Tables 17-19 display details of key results in the overall population:

Table 17: Analysis of first occurrence of stroke or systemic embolism (primary endpoint) duringthe study period in RE-LY.

Dabigatran etexilate Dabigatran etexilate Warfarin110 mg twice daily 150 mg twice daily

Subjects randomised 6 015 6 076 6 022

Stroke and/or systemic embolism

Incidences (%) 183 (1.54) 135 (1.12) 203 (1.72)

Hazard ratio over 0.89 (0.73, 1.09) 0.65 (0.52, 0.81)warfarin (95 % CI)p-value superiority p = 0.2721 p = 0.0001% refers to yearly event rate

Table 18: Analysis of first occurrence of ischemic or haemorrhagic strokes during the studyperiod in RE-LY

Dabigatran etexilate Dabigatran etexilate

Warfarin110 mg twice daily 150 mg twice daily

Subjects randomised 6 015 6 076 6 022

Stroke

Incidences (%) 171 (1.44) 123 (1.02) 187 (1.59)

Hazard ratio vs. 0.91 (0.74, 1.12) 0.64 (0.51, 0.81)warfarin (95 % CI)p-value 0.3553 0.0001

Systemic embolism

Incidences (%) 15 (0.13) 13 (0.11) 21 (0.18)

Hazard ratio vs. 0.71 (0.37, 1.38) 0.61 (0.30, 1.21)warfarin (95 % CI)p-value 0.3099 0.1582

Ischemic stroke

Incidences (%) 152 (1.28) 104 (0.86) 134 (1.14)

Hazard ratio vs. 1.13 (0.89, 1.42) 0.76 (0.59, 0.98)warfarin (95 % CI)p-value 0.3138 0.0351

Haemorrhagic stroke

Incidences (%) 14 (0.12) 12 (0.10) 45 (0.38)

Hazard ratio vs. 0.31 (0.17, 0.56) 0.26 (0.14, 0.49)warfarin (95 % CI)p-value 0.0001 < 0.0001% refers to yearly event rate

Table 19: Analysis of all cause and cardiovascular survival during the study period in RE-LY.

Dabigatran etexilate Dabigatran etexilate Warfarin110 mg twice daily 150 mg twice daily

Subjects randomised 6 015 6 076 6 022

All-cause mortality

Incidences (%) 446 (3.75) 438 (3.64) 487 (4.13)

Hazard ratio vs. 0.91 (0.80, 1.03) 0.88 (0.77, 1.00)warfarin (95 % CI)p-value 0.1308 0.0517

Vascular mortality

Incidences (%) 289 (2.43) 274 (2.28) 317 (2.69)

Hazard ratio vs. 0.90 (0.77, 1.06) 0.85 (0.72, 0.99)warfarin (95 % CI)p- value 0.2081 0.0430% refers to yearly event rate

Tables 20-21 display results of the primary efficacy and safety endpoint in relevant sub-populations:

For the primary endpoint, stroke and systemic embolism, no subgroups (i.e., age, weight, gender, renalfunction, ethnicity, etc.) were identified with a different risk ratio compared to warfarin.

Table 20: Hazard Ratio and 95 % CI for stroke/systemic embolism by subgroups

Dabigatran etexilate Dabigatran etexilate

Endpoint110 mg twice daily vs. warfarin 150 mg twice daily vs. warfarin

Age (years)< 65 1.10 (0.64, 1.87) 0.51 (0.26, 0.98)65 ≤ and < 75 0.86 (0.62, 1.19) 0.67 (0.47, 0.95)≥ 75 0.88 (0.66, 1.17) 0.68 (0.50, 0.92)≥ 80 0.68 (0.44, 1.05) 0.67 (0.44, 1.02)

CrCL(mL/min)30 ≤ and < 50 0.89 (0.61, 1.31) 0.48 (0.31, 0.76)50 ≤ and < 80 0.91 (0.68, 1.20) 0.65 (0.47, 0.88)≥ 80 0.81 (0.51, 1.28) 0.69 (0.43, 1.12)

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 riskwas highest in patients ≥ 75 years. The concomitant use of antiplatelets ASA or clopidogrelapproximately doubles MBE rates with both dabigatran etexilate and warfarin. There was nosignificant interaction of treatment effects with the subgroups of renal function and CHADS2 score.

Table 21: Hazard Ratio and 95 % CI for major bleeds by subgroups

Endpoint Dabigatran etexilate Dabigatran etexilate110 mg twice daily vs. warfarin 150 mg twice daily vs. warfarin

Age (years)< 65 0.32 (0.18, 0.57) 0.35 (0.20, 0.61)65 ≤ and < 75 0.71 (0.56, 0.89) 0.82 (0.66, 1.03)≥ 75 1.01 (0.84, 1.23) 1.19 (0.99, 1.43)≥ 80 1.14 (0.86, 1.51) 1.35 (1.03, 1.76)

CrCL(mL/min)30 ≤ and < 50 1.02 (0.79, 1.32) 0.94 (0.73, 1.22)50 ≤ and < 80 0.75 (0.61, 0.92) 0.90 (0.74, 1.09)≥ 80 0.59 (0.43, 0.82) 0.87 (0.65, 1.17)

ASA use 0.84 (0.69, 1.03) 0.97 (0.79, 1.18)

Clopidogrel use 0.89 (0.55, 1.45) 0.92 (0.57, 1.48)

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

The RE-LY extension study (RELY-ABLE) provided additional safety information for a cohort ofpatients which continued the same dose of dabigatran etexilate as assigned in the RE-LY trial. Patientswere eligible for the RELY-ABLE trial if they had not permanently discontinued study medicinalproduct at the time of their final RE-LY study visit. Enrolled patients continued to receive the samedouble-blind dabigatran etexilate dose randomly allocated in RE-LY, for up to 43 months of follow upafter RE-LY (total mean follow-up RE-LY + RELY-ABLE, 4.5 years). There were 5 897 patientsenrolled, representing 49 % of patients originally randomly assigned to receive dabigatran etexilate in

RE-LY and 86 % of RELY-ABLE-eligible patients.

During the additional 2.5 years of treatment in RELY-ABLE, with a maximum exposure of over6 years (total exposure in RELY + RELY-ABLE), the long-term safety profile of dabigatran etexilatewas confirmed for both test doses 110 mg twice a day and 150 mg twice a day. No new safety findingswere observed.

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

Data from non-interventional studies

A non-interventional study (GLORIA-AF) prospectively collected (in its second phase) safety andeffectiveness data in newly diagnosed NVAF patients on dabigatran etexilate in a real-world setting.

The study included 4 859 patients on dabigatran etexilate (55 % treated with 150 mg twice a day, 43 %treated with 110 mg twice a day, 2 % treated with 75 mg twice a day). Patients were followed-up for2 years. The mean CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. Mean on-therapyfollow-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 per100 patient-years and gastrointestinal bleeding in 0.60 per 100 patient-years. Stroke occurred in0.65 per 100 patient-years.

In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015 ;131 :157-164] in morethan 134 000 elderly patients with NVAF in the United States (contributing more than 37 500 patient-years of on-therapy follow-up time) dabigatran etexilate (84 % patients treated with 150 mg twice aday, 16 % patients treated with 75 mg twice a day) was associated with a reduced risk of ischemicstroke (hazard ratio 0.80, 95 % confidence interval [CI] 0.67 - 0.96), intracranial haemorrhage (hazardratio 0.34, CI 0.26 - 0.46), and mortality (hazard ratio 0.86, CI 0.77 - 0.96) and increased risk ofgastrointestinal bleeding (hazard ratio 1.28, CI 1.14 - 1.44) compared to warfarin. No difference wasfound for major bleeding (hazard ratio 0.97, CI 0.88 - 1.07).

These observations in real-world settings are consistent with the established safety and efficacy profilefor dabigatran etexilate in the RE-LY study in this indication.

Patients undergoing catheter ablation for atrial fibrillation

A prospective, randomised, open-label, multicenter, exploratory study with blinded, centrallyadjudicated endpoint evaluation (RE-CIRCUIT) was conducted in 704 patients who were under stableanticoagulant treatment. The study compared 150 mg twice daily uninterrupted dabigatran etexilatewith uninterrupted INR-adjusted warfarin in catheter ablation of paroxysmal or persistent atrialfibrillation. Of the 704 enrolled patients, 317 underwent atrial fibrillation ablation on uninterrupteddabigatran and 318 underwent atrial fibrillation ablation on uninterrupted warfarin. All patientsunderwent a Trans-oesophageal Echocardiography (TEE) prior to catheter ablation. The primaryoutcome (adjudicated major bleeding according to ISTH criteria) occurred in 5 (1.6 %) patients in thedabigatran 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 thedabigatran etexilate arm, and one event (TIA) in the warfarin arm from the time of ablation and until8 weeks post-ablation. This exploratory study showed that dabigatran etexilate was associated with asignificant reduction in MBE rate compared with INR-adjusted warfarin in the setting of ablation.

Patients who underwent percutaneous coronary intervention (PCI) with stenting

A prospective, randomised, open-label, blinded endpoint (PROBE) study (Phase IIIb) to evaluate dual-therapy with dabigatran etexilate (110 mg or 150 mg twice a day) plus clopidogrel or ticagrelor(P2Y12 antagonist) vs. triple-therapy with warfarin (adjusted to a INR 2.0 - 3.0) plus clopidogrel orticagrelor and ASA was conducted in 2 725 patients with non valvular atrial fibrillation whounderwent a PCI with stenting (RE-DUAL PCI). Patients were randomised to dabigatran etexilate110 mg twice a day dual-therapy, dabigatran etexilate 150 mg twice a day dual-therapy or warfarintriple-therapy. Elderly patients outside of the United States (≥ 80 years of age for all countries,≥ 70 years of age for Japan) were randomly assigned to the dabigatran etexilate 110 mg dual-therapygroup or the warfarin triple-therapy group. The primary endpoint was a combined endpoint of majorbleeds based on ISTH definition or clinically relevant non-major bleeding event.

The incidence of the primary endpoint was 15.4 % (151 patients) in the dabigatran etexilate 110 mgdual-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 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 and P = 0.002 for superiority). As part of the descriptive analysis, TIMI(Thrombolysis In Myocardial Infarction) major bleeding events was lower in both dabigatran etexilatedual-therapy groups than in the warfarin triple-therapy group: 14 events (1.4 %) in the dabigatranetexilate 110 mg dual-therapy group as compared with 37 events (3.8 %) in the warfarin triple-therapygroup (HR 0.37; 95 % CI 0.20, 0.68; P = 0.002) and 16 events (2.1 %) in the dabigatran etexilate150 mg dual-therapy group as compared with 30 events (3.9 %) in the corresponding warfarin triple-therapy group (HR 0.51; 95 % CI 0.28, 0.93; P = 0.03). Both dabigatran etexilate dual-therapy groupshad lower rates of intracranial hemorrhage than the corresponding warfarin triple -therapy group:3 events (0.3 %) in the 110 mg dabigatran etexilate dual-therapy group as compared with 10 events(1.0 %) in the warfarin triple-therapy group (HR 0.30; 95 % CI 0.08, 1.07; P = 0.06) and 1 event(0.1 %) in the 150 mg dabigatran etexilate dual-therapy group as compared with 8 events (1.0 %) inthe corresponding warfarin triple-therapy group (HR 0.12; 95 % CI 0.02, 0.98; P = 0.047). Theincidence 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).There were no statisticaldifferences in the individual components of the efficacy endpoints between either dabigatran etexilatedual-therapy groups and warfarin triple-therapy.

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

Treatment of DVT and 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 twice a day) with warfarin (target INR 2.0-3.0) in patients with acute DVT and/or PE. Theprimary objective of these studies was to determine if dabigatran etexilate was non-inferior to warfarinin 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 randomisedand 5 107 were treated.

The duration of treatment with fixed dose of dabigatran was 174.0 days without coagulationmonitoring. For patients randomised 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 non-inferiorto the treatment with warfarin (non-inferiority margin for RE-COVER, and RE-COVER II: 3.6 for riskdifference and 2.75 for hazard ratio).

Table 22: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of DVTand/or PE) until the end of post-treatment period for the pooled studies RECOVERand RE-COVER II

Dabigatran etexilate

Warfarin150 mg twice daily

Treated patients 2 553 2 554

Recurrent symptomatic VTEand VTE-related death 68 (2.7 %) 62 (2.4 %)

Hazard ratio vs warfarin (95 %confidence interval) 1.09 (0.77, 1.54)

Secondary efficacy endpoints

Recurrent symptomatic VTEand all-cause deaths 109 (4.3 %) 104 (4.1 %)95 % confidence interval 3.52, 5.13 3.34, 4.91

Symptomatic DVT 45 (1.8 %) 39 (1.5 %)95 % confidence interval 1.29, 2.35 1.09, 2.08

Symptomatic PE 27 (1.1 %) 26 (1.0 %)95 % confidence interval 0.70, 1.54 0.67, 1.49

VTE-related deaths 4 (0.2 %) 3 (0.1 %)95 % confidence interval 0.04, 0.40 0.02, 0.34

All-cause deaths 51 (2.0 %) 52 (2.0 %)95 % confidence interval 1.49, 2.62 1.52, 2.66

Prevention of recurrent DVT and PE in adults (DVT/PE prevention )

Two randomised, parallel group, double-blind studies were performed in patients previously treatedwith anticoagulation therapy. RE-MEDY, warfarin controlled study, enrolled patients already treatedfor 3 to 12 months with the need for further anticoagulant treatment and RE-SONATE, the placebocontrolled 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 dabigatranetexilate (150 mg twice a day) to warfarin (target INR 2.0-3.0) for the long-term treatment andprevention of recurrent, symptomatic DVT and/or PE. A total of 2 866 patients were randomised and2 856 patients were treated. Duration of dabigatran etexilate treatment ranged from 6 to 36 months(median 534.0 days). For patients randomised to warfarin, the median time in therapeutic range (INR2.0-3.0) was 64.9 %.

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

Table 23: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of DVTand/or PE) until the end of post-treatment period for the RE-MEDY study

Dabigatran etexilate Warfarin150 mg twice daily

Treated patients 1 430 1 426

Recurrent symptomatic VTE and26 (1.8 %) 18 (1.3 %)

VTE-related death

Hazard ratio vs warfarin (95 % 1.44 (0.78, 2.64)confidence interval)non-inferiority margin 2.85

Patients with event at 18 months 22 17

Cumulative risk at 18 months (%) 1.7 1.4

Risk difference vs. warfarin (%) 0.495 % confidence intervalnon-inferiority margin 2.8

Secondary efficacy endpoints

Recurrent symptomatic VTE and all-42 (2.9 %) 36 (2.5 %)cause deaths95 % confidence interval 2.12, 3.95 1.77, 3.48

Symptomatic DVT 17 (1.2 %) 13 (0.9 %)95 % confidence interval 0.69, 1.90 0.49, 1.55

Symptomatic PE 10 (0.7 %) 5 (0.4 %)95 % confidence interval 0.34, 1.28 0.11, 0.82

VTE-related deaths 1 (0.1 %) 1 (0.1 %)95 % confidence interval 0.00, 0.39 0.00, 0.39

All-cause deaths 17 (1.2 %) 19 (1.3 %)95 % confidence interval 0.69, 1.90 0.80, 2.07

The objective of the RE-SONATE study was to evaluate superiority of dabigatran etexilate versusplacebo for the prevention of recurrent symptomatic DVT and/or PE in patients who had alreadycompleted 6 to 18 months of treatment with VKA. The intended therapy was 6 months dabigatranetexilate 150 mg twice daily without need for monitoring.

RE-SONATE demonstrated dabigatran etexilate was superior to placebo for the prevention ofrecurrent 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 showedsuperiority of dabigatran etexilate over placebo.

The study included observational follow-up for 12 months after the conclusion of treatment. Afterdiscontinuation of study medicinal product 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 wasobserved. At the end of the follow-up VTE events in patients treated with dabigatran etexilate was6.9 % vs. 10.7 % among the placebo group (hazard ratio 0.61 (95 % CI 0.42, 0.88), p=0.0082).

Table 24: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of DVTand/or PE) until the end of post-treatment period for the RE-SONATE study.

Dabigatran etexilate Placebo150 mg twice daily

Treated patients 681 662

Recurrent symptomatic3 (0.4 %) 37 (5.6 %)

VTE and related deaths

Hazard Ratio vs placebo0.08 (0.02, 0.25)(95 % confidence interval)p-value for superiority < 0.0001

Secondary efficacyendpoints

Recurrent symptomatic3 (0.4 %) 37 (5.6 %)

VTE and all-cause deaths95 % confidence interval 0.09, 1.28 3.97, 7.62

Symptomatic DVT 2 (0.3 %) 23 (3.5 %)95 % confidence interval 0.04, 1.06 2.21, 5.17

Symptomatic PE 1 (0.1 %) 14 (2.1 %)95 % confidence interval 0.00, 0.82 1.16, 3.52

VTE-related deaths 0 (0) 0 (0)95 % confidence interval 0.00, 0.54 0.00, 0.56

Unexplained deaths 0 (0) 2 (0.3 %)95 % confidence interval 0.00, 0.54 0.04, 1.09

All-cause deaths 0 (0) 2 (0.3 %)95 % confidence interval 0.00, 0.54 0.04, 1.09

A phase II study examined dabigatran etexilate and warfarin in a total of 252 patients with recentmechanical valve replacement surgery (i.e. within the current hospital stay) and in patients whoreceived a mechanical heart valve replacement more than three months ago. More thromboembolicevents (mainly strokes and symptomatic/asymptomatic prosthetic valve thrombosis) and morebleeding events were observed with dabigatran etexilate than with warfarin. In the early post-operativepatients, major bleeding manifested predominantly as haemorrhagic pericardial effusions, specificallyin patients who started dabigatran etexilate early (i.e. on day 3) after heart valve replacement surgery(see section 4.3).

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

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing dabigatran etexilate in all subsets of the paediatric populationfor the indication of prevention of stroke and systemic embolism in patients with NVAF (seesection 4.2 for information on paediatric use).

The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilatecompared to standard of care (SOC) for the treatment of VTE in paediatric patients from birth to lessthan 18 years of age. The study was designed as an open-label, randomised, parallel-group,non-inferiority study. Patients enrolled were randomised according to a 2:1 scheme to either an age-appropriate formulation (capsules, coated granules or oral solution) of dabigatran etexilate (dosesadjusted for age and weight) or SOC comprised of low molecular weight heparins (LMWH) or vitamin

K antagonists (VKA) or fondaparinux (1 patient 12 years old). The primary endpoint was a compositeendpoint of patients with complete thrombus resolution, freedom from recurrent VTE, and freedomfrom mortality related to VTE. Exclusion criteria included active meningitis, encephalitis andintracranial abscess.

In total, 267 patients had been randomised. Of those, 176 patients were treated with dabigatranetexilate and 90 patients according to SOC (1 randomised patient was not treated). 168 patients were12 to less than 18 years old, 64 patients 2 to less than 12 years, and 35 patients were younger than2 years.

Of the 267 randomised patients, 81 patients (45.8 %) in the dabigatran etexilate group and 38 patients(42.2 %) in the SOC group met the criteria for the composite primary endpoint (complete thrombusresolution, freedom from recurrent VTE, and freedom from mortality -related VTE). Thecorresponding rate difference demonstrated non-inferiority of dabigatran etexilate to SOC. Consistentresults were also generally observed across subgroups: there were no significant differences in thetreatment effect for the subgroups by age, sex, region, and presence of certain risk factors. For the3 different age strata, the proportions of patients that met the primary efficacy endpoint in thedabigatran etexilate and SOC groups, respectively, were 13/22 (59.1 %) and 7/13 (53.8 %) for patientsfrom birth to < 2 years, 21/43 (48.8 %) and 12/21 (57.1 %) for patients aged 2 to < 12 years, and47/112 (42.0 %) and 19/56 (33.9 %) for patients aged 12 to < 18 years.

Adjudicated major bleeds were reported for 4 patients (2.3 %) in the dabigatran etexilate group and2 patients (2.2 %) in the SOC group. There was no statistically significant difference in the time to firstmajor bleeding event. Thirty-eight patients (21.6 %) in the dabigatran etexilate arm and 22 patients(24.4 %) in the SOC arm had any adjudicated bleeding event, most of them categorised as minor. Thecombined endpoint of adjudicated major bleeding event (MBE) or clinically relevant non -major(CRNM) bleeding (on treatment) was reported for 6 (3.4 %) patients in the dabigatran etexilate groupand 3 (3.3 %) patients in the SOC group.

An open label, single arm safety prospective cohort, multi-centre, phase III study (1160.108) wasconducted to assess the safety of dabigatran etexilate for the prevention of recurrent VTE in paediatricpatients from birth to less than 18 years. Patients who required further anticoagulation due to thepresence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least3 months) or after completing the DIVERSITY study were allowed to be included in the study.

Eligible patients received age and weight adjusted doses of an age-appropriate formulation (capsules,coated granules or oral solution) of dabigatran etexilate until the clinical risk factor resolved, or up to amaximum of 12 months. The primary endpoints of the study included the recurrence of VTE, majorand minor bleeding events and the mortality (overall and related to thrombotic or thromboembolicevents) at 6 and 12 months. Outcome events were adjudicated by an independent blinded adjudicationcommittee.

Overall, 214 patients entered the study; among them 162 patients in age stratum 1 (from 12 to less than18 years of age), 43 patients in age stratum 2 (from 2 to less than 12 years of age) and 9 patients in agestratum 3 (from birth to less than 2 years of age). During the on-treatment period, 3 patients (1.4 %)had an adjudication-confirmed recurrent VTE within the first 12 months after treatment start.

Adjudication-confirmed bleeding events during the on-treatment period were reported for 48 patients(22.5 %) within the first 12 months. The majority of the bleeding events were minor. In 3 patients(1.4 %), an adjudication-confirmed major bleeding event occurred within the first 12 months. For3 patients (1.4 %), adjudication-confirmed CRNM bleeding was reported within the first 12 months.

No on-treatment deaths occurred. During the on-treatment period, 3 patients (1.4 %) developedpost-thrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.

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. Theabsolute bioavailability of dabigatran following oral administration of dabigatran etexilate wasapproximately 6.5 %.

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

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 smoothplasma concentration-time profile without high peak plasma concentrations. Peak plasmaconcentrations are reached at 6 hours following administration in a postoperative period due tocontributing factors such as anaesthesia, gastrointestinal paresis, and surgical effects independent ofthe oral medicinal product formulation. It was demonstrated in a further study that slow and delayedabsorption is usually only present on the day of surgery. On subsequent days absorption of dabigatranis 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 plasmaconcentrations by 2 hours.

Cmax and AUC were dose proportional.

The oral bioavailability may be increased by 75 % after a single dose and 37 % at steady statecompared to the reference capsule formulation when the pellets are taken without the

Hydroxypropylmethylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsulesshould always be preserved in clinical use to avoid unintentionally increased bioavailability ofdabigatran etexilate (see section 4.2).

Low (34-35 %) concentration independent binding of dabigatran to human plasma proteins wasobserved. The volume of distribution of dabigatran of 60-70 L exceeded the volume of total bodywater indicating moderate tissue distribution of dabigatran.

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

Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Fourpositional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of totaldabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analyticalmethods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate ofapproximately 100 mL/min corresponding to the glomerular filtration rate.

Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half -life of11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours wasobserved. The half-life was independent of dose. Half-life is prolonged if renal function is impaired asshown in table 25.

In phase I studies the exposure (AUC) of dabigatran after the oral administration of dabigatranetexilate is approximately 2.7-fold higher in adult volunteers with moderate renal insufficiency (CrCLbetween 30 and 50 mL/min) than in those without renal insufficiency.

In a small number of adult volunteers with severe renal insufficiency (CrCL 10-30 mL/min), theexposure (AUC) to dabigatran was approximately 6 times higher and the half-life approximately2 times longer than that observed in a population without renal insufficiency (see sections 4.2, pct. 4.3and 4.4).

Table 25: Half-life of total dabigatran in healthy subjects and subjects with impaired renalfunction.

glomerular filtration rate gMean (gCV %; range)(CrCL,) half-life[mL/min] [h]> 80 13.4 (25.7 %; 11.0-21.6)> 50-≤ 80 15.3 (42.7 %; 11.7-34.1)> 30-≤ 50 18.4 (18.5 %; 13.3-23.0)≤ 30 27.2 (15.3 %; 21.6-35.0)

Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open labelrandomised pharmacokinetic study in NVAF patients with severe renal impairment (defined ascreatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate 75 mg twice daily. Thisregimen resulted in a geometric mean trough concentration of 155 ng/ml (gCV of 76.9 %), measuredimmediately before administration of the next dose and in a geometric mean peak concentration of202 ng/ml (gCV of 70.6 %) measured two hours after the administration of the last dose.

Clearance of dabigatran by haemodialysis was investigated in 7 adult patients with end-stage renaldisease (ESRD) without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flowrate, four hour duration and a blood flow rate of either 200 mL/min or 350-390 mL/min. This resultedin a removal of 50 % to 60 % of dabigatran concentrations, respectively. The amount of substancecleared by dialysis is proportional to the blood flow rate up to a blood flow rate of 300 mL/min. Theanticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PDrelationship 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 30-50 mL/min) hadon 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 100.3 mL/min. 21.7 % of patients had mild renalimpairment (CrCL > 50 -< 80 mL/min) and 4.5 % of patients had a moderate renal impairment (CrCLbetween 30 and 50 mL/min). Patients with mild and moderate renal impairment had at steady state anaverage 1.7-fold and 3.4-fold higher pre-dose dabigatran plasma concentrations compared withpatients 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 the RE-MEDY and RE-SONATE studies.

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 and 75 years (see sections 4.2 and 4.4).

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

The dabigatran trough concentrations were about 20 % lower in adult 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 inadult patients < 50 kg are available.

In atrial fibrillation patients females had on average 30 % higher trough and post-dose concentrations.

No dose adjustment is required (see section 4.2).

No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic,

Japanese or Chinese patients were observed regarding dabigatran pharmacokinetics andpharmacodynamics.

Oral administration of dabigatran etexilate according to the protocol defined dosing algorithm resultedin exposure within the range observed in adults with DVT/PE. Based on the pooled analysis ofpharmacokinetic data of studies DIVERSITY and 1 160.108, the observed geometric mean troughexposures were 53.9 ng/mL, 63.0 ng/mL and 99.1 ng/mL in 0 to < 2-year-old, 2 to < 12-year-old and12 to < 18-year-old paediatric VTE patients, respectively.

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

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

Effects observed in the repeated dose toxicity studies were due to the exaggerated pharmacodynamiceffect of dabigatran.

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

In a juvenile toxicity study conducted in Han Wistar rats, mortality was associated with bleedingevents at similar exposures, at which bleeding was seen in adult animals. In both adult and juvenilerats, mortality is considered to be related to the exaggerated pharmacological activity of dabigatran inassociation with the exertion of mechanical forces during dosing and handling. Data of the juveniletoxicity study did neither indicate an increased sensitivity in toxicity, nor any toxicity specific tojuvenile animals.

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

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

Tartaric acid (E334)

Hypromellose (E464)

Talc (E553b)

Hydroxypropylcellulose (E463)

Croscarmellose sodium (E468)

Magnesium stearate (E572)

Titanium dioxide (E171)

Hypromellose (E464)

Shellac (E904)

Propylene glycol (E1520)

Iron oxide black (E172)

Potassium hydroxide (E525)

Not applicable.

3 years

Bottle: After first opening: 60 days

Store below 30 °C.

OPA/Alu/desiccant PE-PET/Alu/PE blisters containing 10, 30, 60 and 180 hard capsules in a carton.

OPA/Alu/desiccant PE-PET/Alu/PE perforated unit dose blisters containing 10×1, 30×1, 60×1 and180×1 hard capsule in a carton.

Polypropylene bottle with child resistant closure containing 60 hard capsules in a carton.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in acco rdance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n,

Edifici Est, 6a Planta,

Barcelona, 08039

Spain

EU/1/22/1665/017

EU/1/22/1665/018

EU/1/22/1665/019

EU/1/22/1665/020

EU/1/22/1665/021

EU/1/22/1665/022

EU/1/22/1665/023

EU/1/22/1665/024

EU/1/22/1665/027

Date of first authorisation: 26 May 2023.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.