PRADAXA 20mg dried pellets medication leaflet

Pradaxa 20 mg coated granules

Pradaxa 30 mg coated granules

Pradaxa 40 mg coated granules

Pradaxa 50 mg coated granules

Pradaxa 110 mg coated granules

Pradaxa 150 mg coated granules

Each sachet contains coated granules with 20 mg dabigatran etexilate (as mesilate).

Each sachet contains coated granules with 30 mg dabigatran etexilate (as mesilate).

Each sachet contains coated granules with 40 mg dabigatran etexilate (as mesilate).

Each sachet contains coated granules with 50 mg dabigatran etexilate (as mesilate).

Each sachet contains coated granules with 110 mg dabigatran etexilate (as mesilate).

Each sachet contains coated granules with 150 mg dabigatran etexilate (as mesilate).

For the full list of excipients, see section 6.1.

Coated granules.

Yellowish coated granules.

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.

Pradaxa coated granules can be used in children aged less than 12 years as soon as the child is able toswallow soft food. Pradaxa capsules can be used in adults and paediatric patients aged 8 years or olderwho are able to swallow the capsules whole.

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.

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 coated granules should be taken twice daily, one dose in the morning and onedose in the evening, at approximately the same time every day. The dosing interval should be as closeto 12 hours as possible.

The recommended dose of dabigatran etexilate coated granules is based on the patient’s weight andage as shown in tables 1 and 2. The dose should be adjusted according to weight and age as treatmentprogresses.

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

Table 1: Single and total daily dabigatran etexilate doses in milligrams (mg) for patients agedless than 12 months. The doses depend on weight in kilograms (kg) and age inmonths of the patient.

Weight/age combinations Single dose Total daily dose

Weight in kg Age in MONTHS in mg in mg2.5 to < 3 4 to < 5 20 403 to < 4 3 to < 6 20 404 to < 5 1 to < 3 20 403 to < 8 30 608 to < 10 40 805 to < 7 0 to < 1 20 401 to < 5 30 605 to < 8 40 808 to < 12 50 1007 to < 9 3 to < 4 40 804 to < 9 50 1009 to < 12 60 1209 to < 11 5 to < 6 50 1006 to < 11 60 12011 to < 12 70 14011 to < 13 8 to < 10 70 14010 to < 12 80 16013 to < 16 10 to < 11 80 16011 to < 12 100 200

Convenient sachet combinations to achieve the single doses recommended in the dosing table areprovided below. Other combinations are possible.20 mg: One 20 mg sachet 60 mg: Two 30 mg sachets30 mg: One 30 mg sachet 70 mg: One 30 mg plus one 40 mg sachet40 mg: One 40 mg sachet 80 mg: Two 40 mg sachets50 mg: One 50 mg sachet 100 mg: Two 50 mg sachets

Table 2: Single and total daily dabigatran etexilate doses in milligrams (mg) for patients aged1 year to less than 12 years. The doses depend on weight in kilograms (kg) and agein years of the patient.

Weight/age combinations Single dose Total daily dose

Weight in kg Age in YEARS in mg in mg5 to < 7 1 to < 2 50 1007 to < 9 1 to < 2 60 1202 to < 4 70 1409 to < 11 1 to < 1.5 70 1401.5 to < 7 80 16011 to < 13 1 to < 1.5 80 1601.5 to < 2.5 100 2002.5 to < 9 110 22013 to < 16 1 to < 1.5 100 2001.5 to < 2 110 2202 to < 12 140 28016 to < 21 1 to < 2 110 2202 to < 12 140 28021 to < 26 1.5 to < 2 140 2802 to < 12 180 36026 to < 31 2.5 to < 12 180 36031 to < 41 2.5 to < 12 220 44041 to < 51 4 to < 12 260 52051 to < 61 5 to < 12 300 60061 to < 71 6 to < 12 300 60071 to < 81 7 to < 12 300 600> 81 10 to < 12 300 600

Convenient sachet combinations to achieve the single doses recommended in the dosing table areprovided below. Other combinations are possible.50 mg: One 50 mg sachet 140 mg: One 30 mg plus one 110 mg sachet60 mg: Two 30 mg sachets 180 mg: One 30 mg plus one 150 mg sachet70 mg: One 30 mg plus one 40 mg sachet 220 mg: Two 110 mg sachets80 mg: Two 40 mg sachets 260 mg: One 110 mg plus one 150 mg sachet100 mg: Two 50 mg sachets 300 mg: Two 150 mg sachets110 mg: One 110 mg sachet

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 tables 1 and2.

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. If a dose has only beentaken partially, there should be no attempt to administer a second dose at that time-point, and the nextdose should be taken as scheduled approximately 12 hours later.

Dabigatran etexilate treatment should not be discontinued without medical advice. Caregivers shouldbe instructed to contact the treating physician if their treated child develops gastrointestinal symptomssuch 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 coated granules should be mixed with food prior to intake and only be used with apple juice or thesoft foods mentioned in the instructions for administration. After mixing with food or apple juice, themedicinal product has to be administered within 30 minutes. The coated granules are not compatiblewith milk or milk products.

This medicinal product is not compatible with feeding tubes.

Detailed instructions for the use of this medicinal product are provided in ‘Instructions foradministration’ in the package leaflet.

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

- 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) or when UFH is given at dosesnecessary to maintain an open central venous or arterial catheter (see section 4.5).

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

- Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole,cyclosporine, itraconazole, dronedarone and the fixed-dose combinationglecaprevir/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 plateletaggregation. Bleeding can occur at any site during therapy. An unexplained fall in haemoglobin and/orhaematocrit or blood pressure should lead to a search for a bleeding site.

The efficacy and safety of the specific reversal agent idarucizumab used for adult patients in situationsof life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect ofdabigatran is required, have not been established in paediatric patients. Haemodialysis can removedabigatran. For adult patients, fresh whole blood or fresh frozen plasma, coagulation factorconcentration (activated or non-activated), recombinant factor VIIa or platelet concentrates are otherpossible 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: Risk factors which may increase the haemorrhagic risk.

Risk factor

Factors increasing dabigatran Major:plasma levels - Strong P-gp inhibitors (see section 4.3 and 4.5)

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

Pharmacodynamic interactions (see - ASA and other platelet aggregation inhibitors such assection 4.5) clopidogrel

- NSAIDs

- SSRIs or SNRIs

- Other medicinal products which may impair haemostasis

Diseases/procedures with special - Congenital or acquired coagulation disordershaemorrhagic risks - Thrombocytopenia or functional platelet defects

- Recent biopsy, major trauma

- Bacterial endocarditis

- Esophagitis, gastritis or gastroesophageal reflux

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.

When severe bleedings occur, treatment must be discontinued and the source of bleeding investigated.

The efficacy and safety of the specific reversal agent (idarucizumab) to dabigatran have not beenestablished in paediatric patients. Haemodialysis can remove dabigatran.

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.

Coagulation test thresholds at trough for paediatric patients that may be associated with an increasedrisk of bleeding are not known.

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 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.

The efficacy and safety of the specific reversal agent (idarucizumab) to dabigatran have not beenestablished in paediatric patients. Haemodialysis can remove dabigatran.

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 bleedingmay be 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.

Discontinuation rules before invasive or surgical procedures for paediatric patients are summarised intable 4.

Table 4: 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 (see table 3) should be treated withcaution (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-beta2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates ofrecurrent thrombotic events compared with vitamin K antagonist therapy.

Active cancer patients

There is limited data on efficacy and safety for paediatric patients with active cancer.

Very specific paediatric population

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.

Interaction studies have only been performed in adults.

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gpinhibitors (see table 5) 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. See alsosections pct. 4.3, pct. 4.4 and 5.1).

Table 5: Transporter interactions

Concomitant use contraindicated (see section 4.3)

Ketoconazole Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 2.38-fold and2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazole oncedaily.

Dronedarone 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,respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-foldand 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

Glecaprevir/The concomitant use of dabigatran etexilate with the fixed-dose combination of thepibrentasvir P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure ofdabigatran and may increase the risk of bleeding.

Tacrolimus Tacrolimus has been found in vitro to have a similar level of inhibitory effect on

P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has notbeen clinically studied together with tacrolimus. However, limited clinical data withanother P-gp substrate (everolimus) suggest that the inhibition of P-gp withtacrolimus is weaker than that observed with strong P-gp inhibitors.

Cautions to be exercised in case concomitant use (see section 4.4)

Verapamil When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the

Cmax and AUC of dabigatran were increased but the magnitude of this changediffers depending on timing of administration and formulation of verapamil (seesection 4.4).

The greatest elevation of dabigatran exposure was observed with the first dose ofan immediate release formulation of verapamil administered one hour prior to thedabigatran etexilate intake (increase of Cmax by about 2.8-fold and AUC by about2.5-fold). The effect was progressively decreased with administration of anextended release formulation (increase of Cmax by about 1.9-fold and AUC byabout 1.7-fold) or administration of multiple doses of verapamil (increase of Cmaxby about 1.6-fold and AUC by about 1.5-fold).

There was no meaningful interaction observed when verapamil was given 2 hoursafter dabigatran etexilate (increase of Cmax by about 1.1-fold and AUC by about1.2-fold). This is explained by completed dabigatran absorption after 2 hours.

Amiodarone When dabigatran etexilate was co-administered with a single oral dose of 600 mgamiodarone, the extent and rate of absorption of amiodarone and its activemetabolite DEA were essentially unchanged. The dabigatran AUC and Cmax wereincreased by about 1.6-fold and 1.5-fold, respectively. In view of the long half-lifeof amiodarone the potential for an interaction may exist for weeks afterdiscontinuation of amiodarone (see section 4.4).

Quinidine 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, onthe 3rd day either with or without quinidine. Dabigatran AUCτ,ss and Cmax,ss wereincreased on average by 1.53-fold and 1.56-fold, respectively with concomitantquinidine (see section 4.4).

Clarithromycin When clarithromycin (500 mg twice daily) was administered together withdabigatran etexilate in healthy volunteers, increase of AUC by about 1.19-foldand Cmax by about 1.15-fold was observed.

Ticagrelor When a single dose of 75 mg dabigatran etexilate was coadministeredsimultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and

Cmax were increased by 1.73-fold and 1.95-fold, respectively. After multiple dosesof ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is 1.56-fold and1.46-fold for Cmax and AUC, respectively.

Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mgdabigatran etexilate (in steady state) increased the dabigatran AUCτ,ss and Cmax,ssby 1.49-fold and 1.65-fold, respectively, compared with dabigatran etexilate givenalone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mgdabigatran etexilate (in steady state), the increase of dabigatran AUCτ,ss and Cmax,sswas reduced to 1.27-fold and 1.23-fold, respectively, compared with dabigatranetexilate given alone. This staggered intake is the recommended administrationfor start of ticagrelor with a loading dose.

Concomitant administration of 90 mg ticagrelor b.i.d. (maintenance dose) with110 mg dabigatran etexilate increased the adjusted dabigatran AUCτ,ss and Cmax,ss1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate givenalone.

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

Caution should be exercised when dabigatran etexilate is co-administered withposaconazole.

P-gp inducers

Concomitant use should be avoided.

e.g. rifampicin, Concomitant administration is expected to result in decreased dabigatran

St. John´s wort concentrations.(Hypericumperforatum), Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily forcarbamazepine, 7 days decreased total dabigatran peak and total exposure by 65.5 % and 67 %,or phenytoin respectively. The inducing effect was diminished resulting in dabigatran exposureclose to the reference by day 7 after cessation of rifampicin treatment. No furtherincrease in bioavailability was observed after another 7 days.

Protease inhibitors such as ritonavir

Concomitant use not recommendede.g. ritonavir and These affect P-gp (either as inhibitor or as inducer). They have not been studiedits combinations and are therefore not recommended for concomitant treatment with dabigatranwith other etexilate.proteaseinhibitors

P-gp substrate

Digoxin In a study performed with 24 healthy subjects, when dabigatran etexilate wasco-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 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).

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

Table 6: 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 of bleedingby 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 bleeding timescompared to clopidogrel monotherapy. In addition, dabigatran AUCτ,ss and Cmax,ss andthe coagulation measures for dabigatran effect or the inhibition of platelet aggregationas measure of clopidogrel effect remained essentially unchanged comparing combinedtreatment and the respective mono-treatments. With a loading dose of 300 mg or600 mg clopidogrel, dabigatran AUCτ,ss and Cmax,ss were increased by about 30-40 %(see section 4.4).

ASA Co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase therisk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA,respectively (see section 4.4).

LMWH The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has notbeen specifically investigated. After switching from 3-day treatment of once daily40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure todabigatran was slightly lower than that after administration of dabigatran etexilate(single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed afterdabigatran etexilate administration with enoxaparin pre-treatment compared to that aftertreatment with dabigatran etexilate alone. This is considered to be due to the carry-overeffect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatranrelated anti-coagulation tests were not changed significantly by the pre-treatment ofenoxaparin.

Table 7: 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 all treatment groups of a phase IIIclinical trial comparing dabigatran to warfarin for stroke prevention in atrialfibrillation patients (RE-LY).

Substances influencing gastric pH

Pantoprazole When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran

AUC of approximately 30 % was observed. Pantoprazole and other proton-pumpinhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant

PPI treatment did not appear to reduce the efficacy of Pradaxa.

Ranitidine Ranitidine administration together with dabigatran etexilate had no clinicallyrelevant 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.

Women of childbearing potential should avoid pregnancy during treatment with Pradaxa.

There is limited amount of data from the use of Pradaxa in pregnant women.

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

Pradaxa 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 Pradaxa.

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 (see section 5.3).

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. The safety of dabigatranetexilate in the treatment of VTE and prevention of recurrent VTE in paediatric patients was studied intwo phase III trials (DIVERSITY and 1160.108). In total, 328 paediatric patients had been treated withdabigatran etexilate. The patients received age and weight adjusted doses of an age-appropriateformulation 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 8 shows the adverse reactions identified from the studies in the treatment of VTE and preventionof 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 ( 1/100 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 8: 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/Liver Not knownfunction 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

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, dyspnoea, 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.

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 %)than in 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.

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 adminstration 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 result 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.

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) orvitamin K antagonists (VKA) or fondaparinux (1 patient 12 years old). The primary endpoint was acomposite endpoint of patients with complete thrombus resolution, freedom from recurrent VTE, andfreedom from 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 the 3different age strata, the proportions of patients that met the primary efficacy endpoint in the dabigatranetexilate and SOC groups, respectively, were 13/22 (59.1 %) and 7/13 (53.8 %) for patients from birthto < 2 years, 21/43 (48.8 %) and 12/21 (57.1 %) for patients aged 2 to < 12 years, and 47/112 (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 tofirst major bleeding event. Thirty-eight patients (21.6 %) in the dabigatran etexilate arm and22 patients (24.4 %) in the SOC arm had any adjudicated bleeding event, most of them categorised asminor. The combined 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 etexilategroup and 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 lessthan 18 years of age), 43 patients in age stratum 2 (from 2 to less than 12 years of age) and 9 patientsin age stratum 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 %) developed post-thrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.

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 1160.108, 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.

Experience from adults

The absolute bioavailability of dabigatran following oral administration of Pradaxa capsules wasapproximately 6.5 %.

After oral administration of Pradaxa in healthy volunteers, the pharmacokinetic profile of dabigatranin plasma is characterised by a rapid increase in plasma concentrations with Cmax attained within 0.5and 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, GI paresis, and surgical effects independent of the oralmedicinal 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. Pradaxa coated granules are not compatible with milk or milk products (seesection 4.5).

Cmax and AUC were dose proportional.

In adults, low (34-35 %) concentration independent binding of dabigatran to human plasma proteinswas observed. The volume of distribution of dabigatran of 60-70 L exceeded the volume of total bodywater indicating moderate tissue distribution of dabigatran.

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 byesterase-catalysed hydrolysis to the active principle dabigatran is the predominant metabolic reaction.

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 9.

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 4.3 and 4.4).

Table 9: Half-life of total dabigatran in healthy subjects and subjects with impaired renalfunction (adults).

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 non-valvular atrial fibrillation (NVAF) patients with severerenal impairment (defined as creatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate75 mg twice daily.

This regimen resulted in a geometric mean trough concentration of 155 ng/mL (gCV of 76.9 %),measured immediately before administration of the next dose and in a geometric mean peakconcentration of 202 ng/mL (gCV of 70.6 %) measured two hours after the administration of the lastdose.

Clearance of dabigatran by haemodialysis was investigated in 7 patients with end-stage renal disease(ESRD) without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flow rate,four hour duration and a blood flow rate of either 200 mL/min or 350-390 mL/min. This resulted in aremoval of 50 % to 60 % of dabigatran concentrations, respectively. The amount of substance clearedby 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.

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

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

No dose adjustment is recommended (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.

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

Acacia

Hypromellose

Dimeticone 350

Talc

Hydroxypropylcellulose

Not applicable.

3 years

After first opening of the aluminium bag

Once the aluminium bag containing the sachets with the coated granules and the desiccant is opened,the medicinal product must be used within 6 months.

After first opening of the sachet

The opened sachet cannot be stored and must be used immediately after opening.

After preparation

After mixing with soft food or apple juice, the medicinal product has to be administered within30 minutes.

The aluminium bag containing the sachets with the coated granules should only be openedimmediately prior to use of the first sachet in order to protect from moisture.

After opening of the aluminium bag, the individual sachets should be kept unopened until immediatelyprior to use in order to protect from moisture.

Aluminium bag containing 60 silver-coloured PET/Alu/LDPE sachets with the coated granules andone desiccant (labelled “DO NOT EAT” including pictogram and “SILICA GEL”).

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

Boehringer Ingelheim International GmbH

Binger Str. 17355216 Ingelheim am Rhein

Germany

EU/1/08/442/025

EU/1/08/442/026

EU/1/08/442/027

EU/1/08/442/028

EU/1/08/442/029

EU/1/08/442/030

Date of first authorisation: 18 March 2008

Date of latest renewal: 08 January 2018

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

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