DABIGATRAN ETEXILATE ACCORD 75mg capsules medication leaflet

Dabigatran etexilate Accord 75 mg hard capsules

Each hard capsule contains dabigatran etexilate mesilate equivalent to 75 mg of dabigatran etexilate.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Size “2” (approx. 18 × 6 mm) capsule with a white opaque cap imprinted “MD” and white opaquebody imprinted “75” with black ink, containing a blend of white to light yellow coloured pellets andlight yellow coloured granulate.

Primary prevention of venous thromboembolic events (VTE) in adult patients who have undergoneelective total hip replacement surgery or total knee replacement surgery.

Treatment of VTE and prevention of recurrent VTE in paediatric patients from the time the child isable 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.

The recommended doses of dabigatran etexilate and the duration of therapy for primary prevention of

VTE in orthopaedic surgery are shown in table 1.

Table 1: Dose recommendations and duration of therapy for primary prevention of VTE inorthopaedic surgery

Treatment initiation Maintenance Duration ofon the day of surgery dose starting on maintenance1-4 hours after the first day dosecompleted surgery after surgery

Patients following elective knee 220 mg10 daysreplacement surgery dabigatransingle capsule ofetexilate once110 mg dabigatran

Patients following elective hip daily taken asetexilatereplacement surgery 2 capsules of 28-35 days110 mg

Patients with moderate renal150 mg 10 days (kneeimpairment (creatinine clearancedabigatran replacement(CrCL) 30-50 mL/min)single capsule of 75 mg etexilate once surgery) or

Patients who receivedabigatran etexilate daily taken as 28-35 days (hipconcomitant verapamil*,2 capsules of replacementamiodarone, quinidine75 mg surgery)

Patients aged 75 or above

*For patients with moderate renal impairment concomitantly treated with verapamil see Specialpopulations

For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatmentis not started on the day of surgery then treatment should be initiated with 2 capsules once daily.

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 to initiationof 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).

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

It is recommended to continue with the remaining daily doses of dabigatran etexilate at the same timeof the next day.

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 24 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).

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

In patients with moderate renal impairment (CrCL 30-50 mL/min), a dose reduction is recommended(see table 1 above and sections 4.4 and 5.1).

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

Dosing should be reduced as indicated in table 1 (see also sections 4.4 and 4.5). In this situationdabigatran etexilate and these medicinal products should be taken at the same time.

In patients with moderate renal impairment and concomitantly treated with verapamil, a dose reductionof dabigatran etexilate to 75 mg daily should be considered (see sections 4.4 and 4.5).

For elderly patients > 75 years, a dose reduction is recommended (see table 1 above and sections 4.4and 5.1).

Weight

There is very limited clinical experience in patients with a body weight < 50 kg or > 110 kg at therecommended posology. Given the available clinical and kinetic data no adjustment is necessary (seesection 5.2), but close clinical surveillance is recommended (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 ofprimary prevention of VTE in patients who have undergone elective total hip replacement surgery ortotal knee replacement surgery.

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 2. 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 2: 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/1.73 m2 should be treated with the dose according to table 2.

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).

Use of platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or nonsteroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis orgastroesophageal reflux increase the risk of GI bleeding.

Table 3 summarises factors which may increase the haemorrhagic risk.

Table 3: 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 adult patients(30-50 mL/min CrCL)

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

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

Minor:

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

Pharmacodynamic interactions (see * ASA and other platelet aggregation inhibitorssection 4.5) such as clopidogrel

* NSAIDs

* SSRIs or SNRIs

* Other medicinal products which may impairhaemostasis

Diseases/procedures with special * Congenital or acquired coagulation disordershaemorrhagic risks * 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 3 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 4 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 4: Coagulation test thresholds at trough for adult patients that may be associated with anincreased risk of bleeding.

Test (trough value) ThresholddTT [ng/mL] > 67

ECT [x-fold upper limit of normal] No dataaPTT [x-fold upper limit of normal] > 1.3

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.

Caution should be exercised when treatment is temporarily discontinued for interventions andanticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficien cymay 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 5 summarises discontinuation rules before invasive or surgical procedures for adult patients.

Table 5: Discontinuation rules before invasive or surgical procedures for adult patients

Renal function Estimated half-life Dabigatran etexilate should be stopped before elective(CrCL in (hours) surgerymL/min) High risk of bleeding or Standard riskmajor surgery≥ 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 summarised intable 6.

Table 6: 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 should be restarted after the invasive procedure or surgical intervention as soon aspossible provided the clinical situation allows and adequate haemostasis has been established.

Patients at risk for bleeding or patients at risk of overexposure, notably patients with reduced renalfunction (see also table 3), 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.

There is no data on the use of dabigatran etexilate in patients undergoing hip fracture surgery.

Therefore treatment is not recommended.

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-beta2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates ofrecurrent thrombotic events compared with vitamin K antagonist therapy.

There is limited 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 7) 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 7: 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 2.53-fold

Ketoconazoleand 2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazoleonce 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 be expected.

cyclosporine

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

Glecaprevir/pibrentasvir 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

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 of thelong half-life of amiodarone the potential for an interaction may exist for weeksafter 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 and 110 mg

Ticagrelor dabigatran etexilate (in steady state) increased the dabigatran AUCτ,ss and Cmax,ssby 1.49-fold and 1.65-fold, respectively, compared with dabigatran etexilategiven alone. When a loading dose of 180 mg ticagrelor was given 2 hours after110 mg dabigatran etexilate (in steady state), the increase of dabigatran AUCτ,ssand Cmax,ss was reduced to 1.27-fold and 1.23-fold, respectively, compared withdabigatran etexilate given alone. This staggered intake is the recommendedadministration for start of ticagrelor with a loading dose.

Concomitant administration of 90 mg ticagrelor twice a day (maintenance dose)with 110 mg dabigatran etexilate increased the adjusted dabigatran AUCτ,ss and

Cmax,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilategiven 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 % and 67 %,carbamazepine, orrespectively. The inducing effect was diminished resulting in dabigatranphenytoinexposure close to the reference by day 7 after cessation of rifampicin treatment.

No further increase in bioavailability was observed after another 7 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 been studiedcombinations with other and are therefore not recommended for concomitant treatment with dabigatranprotease inhibitors 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 clinically relevantchanges 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 o ralanticoagulants (see section 4.3), and antiplatelet aggregation medicinal products such as GPIIb/IIIareceptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (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 8: 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 a phase III clinical trial comparing dabigatran to warfarin for strokeprevention in atrial fibrillation patients (RE-LY), NSAIDs increased the risk ofbleeding by approximately 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 9: Other interactions

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

SSRIs and SNRIs increased the risk of bleeding in all treatment groups of a

SSRIs, SNRIs phase III clinical trial comparing dabigatran to warfarin for stroke prevention inatrial fibrillation patients (RE-LY).

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

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-feeding should 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 actively controlled VTE prevention trials 6 684 patients were treated with 150 mg or 220 mgdabigatran etexilate daily.

The most commonly reported events are bleedings occurring in approximately 14 % of patients; thefrequency of major bleeds (including wound site bleedings) is less than 2 %.

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

Table 10 shows the adverse reactions ranked under headings of System Organ Classes (SOC) andfrequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10),uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known(cannot be estimated from the available data).

Table 10: Adverse reactions

SOC/Preferred term Frequency

Haemoglobin decreased Common

Anaemia Uncommon

Haematocrit decreased Uncommon

Thrombocytopenia Rare

Neutropenia Not known

Agranulocytosis Not known

Drug hypersensitivity Uncommon

Anaphylactic reaction Rare

Angioedema Rare

Urticaria Rare

Rash Rare

Pruritus Rare

Bronchospasm Not known

Intracranial haemorrhage Rare

Haematoma Uncommon

Wound haemorrhage Uncommon

Haemorrhage Rare

Epistaxis Uncommon

Haemoptysis Rare

Gastrointestinal haemorrhage Uncommon

Rectal haemorrhage Uncommon

Haemorrhoidal haemorrhage Uncommon

Diarrhoea Uncommon

Nausea Uncommon

Vomiting Uncommon

Gastrointestinal ulcer, including

Rareoesophageal ulcer

Gastroesophagitis Rare

Gastroesophageal reflux disease Rare

Abdominal pain Rare

Dyspepsia Rare

Dysphagia Rare

Hepatic function abnormal/Liver

Commonfunction Test abnormal

Alanine aminotransferase increased Uncommon

Aspartate aminotransferase increased Uncommon

Hepatic enzyme increased Uncommon

Hyperbilirubinaemia Uncommon

Skin and subcutaneous tissue disorder

Skin haemorrhage Uncommon

Alopecia Not known

Haemarthrosis Uncommon

Genitourological haemorrhage, including Uncommonhaematuria

Injection site haemorrhage Rare

Catheter site haemorrhage Rare

Bloody discharge Rare

Traumatic haemorrhage Uncommon

Post procedural haematoma Uncommon

Post procedural haemorrhage Uncommon

Post procedural discharge Uncommon

Wound secretion Uncommon

Incision site haemorrhage Rare

Anaemia postoperative Rare

Surgical and medical procedures

Wound drainage Rare

Post procedural drainage Rare

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).

The table 11 shows the number (%) of patients experiencing the adverse reaction bleeding during thetreatment period in the indication primary VTE prevention after hip or knee replacement surgery in thetwo pivotal clinical trials, according to dose.

Table 11: Number (%) of patients experiencing the adverse reaction bleeding

Dabigatran etexilate Dabigatran etexilate

Enoxaparin150 mg 220 mg

N (%)

N (%) N (%)

Treated 1 866 (100.0) 1 825 (100.0) 1 848 (100.0)

Major bleeding 24 (1.3) 33 (1.8) 27 (1.5)

Any bleeding 258 (13.8) 251 (13.8) 247 (13.4)

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, 328paediatric patients had been treated with dabigatran etexilate. The patients received age and weightadjusted 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 12 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 12: 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 4) is considered to be associated with an increased risk of bleeding.

Steady state (after day 3) geometric mean dabigatran peak plasma concentration, measured around2 hours after 220 mg dabigatran etexilate administration, was 70.8 ng/mL, with a range of35.2-162 ng/mL (25th-75th percentile range).The dabigatran geometric mean trough concentration,measured at the end of the dosing interval (i.e. 24 hours after a 220 mg dabigatran dose), was onaverage 22.0 ng/mL, with a range of 13.0-35.7 ng/mL (25th-75th percentile range).

In a dedicated study exclusively in patients with moderate renal impairment (creatinine clearance,

CrCL 30-50 mL/min) treated with dabigatran etexilate 150 mg QD, the dabigatran geometric meantrough concentration, measured at the end of the dosing interval, was on average 47.5 ng/mL, with arange of 29.6-72.2 ng/mL (25th-75th percentile range).

In patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mgdabigatran etexilate once daily,

* the 90th percentile of dabigatran plasma concentrations was 67 ng/mL, measured at trough(20-28 hours after the previous dose) (see section 4.4 and 4.9),

* the 90th percentile of aPTT at trough (20-28 hours after the previous dose) was 51 seconds,which would be 1.3-fold upper limit of normal.

The ECT was not measured in patients treated for prevention of VTEs after hip or knee replacementsurgery with 220 mg dabigatran etexilate once daily.

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

Chinese patients were observed.

In 2 large randomised, parallel group, double-blind, dose-confirmatory trials, patients undergoingelective major orthopaedic surgery (one for knee replacement surgery and one for hip replacementsurgery) received 75 mg or 110 mg dabigatran etexilate within 1-4 hours of surgery followed by150 mg or 220 mg once daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on theday prior to surgery and daily thereafter.

In the RE-MODEL trial (knee replacement) treatment was for 6-10 days and in the RE-NOVATE trial(hip replacement) for 28-35 days. Totals of 2 076 patients (knee) and 3 494 (hip) were treatedrespectively.

Composite of total VTE (including pulmonary embolism (PE), proximal and distal deep veinthrombosis (DVT), whatever symptomatic or asymptomatic detected by routine venography) and all-cause mortality constituted the primary end-point for both studies. Composite of major VTE (including

PE and proximal DVT, whatever symptomatic or asymptomatic detected by routine venography) and

VTE-related mortality constituted a secondary end-point and is considered of better clinical relevance.

Results of both studies showed that the antithrombotic effect of 220 mg and 150 mg dabigatranetexilate were statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. Thepoint estimate for incidence of major VTE and VTE related mortality for the 150 mg dose was slightlyworse than enoxaparin (table 13). Better results were seen with the 220 mg dose where the pointestimate of Major VTE was slightly better than enoxaparin (table 13).

The clinical studies have been conducted in a patient population with a mean age > 65 years.

There were no differences in the phase 3 clinical studies for efficacy and safety data between men andwomen.

In the studied patient population of RE-MODEL and RE-NOVATE (5 539 patients treated), 51 %suffered from concomitant hypertension, 9 % from concomitant diabetes, 9 % from concomitantcoronary artery disease and 20 % had a history of venous insufficiency. None of these diseases showedan impact on the effects of dabigatran on VTE-prevention or bleeding rates.

Data for the major VTE and VTE-related mortality endpoint were homogeneous with regards to theprimary efficacy endpoint and are shown in table 13.

Data for the total VTE and all cause mortality endpoint are shown in table 14.

Data for adjudicated major bleeding endpoints are shown in table 15 below.

Table 13: Analysis of major VTE and VTE-related mortality during the treatment period in the

RE-MODEL and the RE-NOVATE orthopaedic surgery studies

Trial Dabigatran etexilate Dabigatran etexilate Enoxaparin220 mg 150 mg 40 mg

RE-NOVATE (hip)

N 909 888 917

Incidences (%) 28 (3.1) 38 (4.3) 36 (3.9)

Risk ratio over enoxaparin 0.78 1.0995 % CI 0.48, 1.27 0.70, 1.70

RE-MODEL (knee)

N 506 527 511

Incidences (%) 13 (2.6) 20 (3.8) 18 (3.5)

Risk ratio over enoxaparin 0.73 1.0895 % CI 0.36, 1.47 0.58, 2.01

Table 14: Analysis of total VTE and all cause mortality during the treatment period in the

RE-NOVATE and the RE-MODEL orthopaedic surgery studies

Trial Dabigatran etexilate Dabigatran etexilate Enoxaparin220 mg 150 mg 40 mg

RE-NOVATE (hip)

N 880 874 897

Incidences (%) 53 (6.0) 75 (8.6) 60 (6.7)

Risk ratio over enoxaparin 0.9 1.2895 % CI (0.63, 1.29) (0.93, 1.78)

RE-MODEL (knee)

N 503 526 512

Incidences (%) 183 (36.4) 213 (40.5) 193 (37.5)

Risk ratio over enoxaparin 0.97 1.0795 % CI 0.82, 1.13 0.92, 1.25

Table 15: Major bleeding events by treatment in the individual RE-MODEL and the

RE-NOVATE studies

Trial Dabigatran etexilate Dabigatran etexilate Enoxaparin220 mg 150 mg 40 mg

RE-NOVATE (hip)

Treated patients N 1 146 1 163 1 154

Number of MBE N (%) 23 (2.0) 15 (1.3) 18 (1.6)

RE-MODEL (knee)

Treated patients N 679 703 694

Number of MBE N (%) 10 (1.5) 9 (1.3) 9 (1.3)

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).

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 populationin prevention of thromboembolic events for the indication of primary prevention of VTE in patientswho have undergone elective total hip replacement surgery or total knee replacement surgery (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 anage-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 (1 160.108) 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 16.

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 16: 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.

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.

Active substance exposure in the primary VTE prevention studies was about 40 % to 50 % higher infemale patients and no dose adjustment is recommended.

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 and 60 hard capsules in a carton.

OPA/Alu/desiccant PE-PET/Alu/PE perforated unit dose blisters containing 10x1, 30x1 and 60x1hard 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/1/22/1665/001

EU/1/22/1665/002

EU/1/22/1665/003

EU/1/22/1665/004

EU/1/22/1665/005

EU/1/22/1665/006

EU/1/22/1665/025

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/.