Pradaxa 150 mg hard capsules

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

Excipients: Each hard capsule contains 4 micrograms sunset yellow (E110).

For a full list of excipients, see section 6.1.

Hard capsule

Imprinted capsules with light blue, opaque cap and cream-coloured, opaque body of size 0 filled with yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with "R150".

Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors:

• Previous stroke, transient ischemic attack, or systemic embolism (SEE)

• Left ventricular ejection fraction < 40 %

• Symptomatic heart failure, New York Heart Association (NYHA) Class 2

• Age 75 years

• Age 65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension

Posology

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

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

Elderly

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

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

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

Patients at risk of bleeding

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

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

Renal impairment

Treatment with Pradaxa in patients with severe renal impairment (creatinine clearance (CrCL) < 30 ml/min) is contraindicated (see section 4.3).

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

Renal function should be assessed by calculating the CrCL prior to initiation of treatment with Pradaxa to exclude patients with severe renal impairment (i.e. CrCL < 30 ml/min)].

While on treatment renal function should be assessed at least once a year or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc).

Concomitant use of Pradaxa with strong P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil

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

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

Weight

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

Gender

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

Hepatic impairment

Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in the study investigating the prevention of stroke and SEE associated with atrial fibrillation. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2).

Switching

Pradaxa treatment to parenteral anticoagulant

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

Parenteral anticoagulants to Pradaxa

Dabigatran etexilate should be given 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5).

Pradaxa treatment to Vitamin K antagonists (VKA)

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

• CrCL 50 ml/min, start VKA 3 days before discontinuing dabigatran etexilate

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

VKA to Pradaxa

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

Cardioversion

Patients can stay on dabigatran etexilate while being cardioverted.

Paediatric population

There is no relevant use of Pradaxa in the paediatric population in the indication: prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Pradaxa is not recommended for use in patients below 18 years due to lack of data on safety and efficacy.

Missed dose

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

No double dose should be taken to make up for missed individual doses.

Method of administration

Pradaxa should be swallowed as a whole with water, with or without food.

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

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

• Patients with severe renal impairment (CrCL < 30 ml/min)

• Active clinically significant bleeding

• Organic lesion at risk of bleeding

• Spontaneous or pharmacological impairment of haemostasis

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

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

Hepatic impairment

Patients with elevated liver enzymes > 2 ULN were excluded from the study investigating the prevention of stroke and SEE associated with atrial fibrillation. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population.

Haemorrhagic risk

As with all anticoagulants, dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding. Bleeding can occur at any site during therapy with dabigatran. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.

Factors, such as decreased renal function (30-50 ml/min CrCL), age 75 years, low body weight < 50 kg, or strong P-gp inhibitor co-medication (e.g. amiodarone, quinidine or verapamil) are associated with increased dabigatran plasma levels (see sections 4.2, 4.5 and 5.2).

In a study of prevention of stroke and SEE in adult patients with nonvalvular atrial fibrillation, Dabigatran was associated with higher rates of major gastrointestinal (GI) bleeding which was statistically significant for dabigatran etexilate 150 mg twice daily. This increased risk was seen in the elderly ( 75 years). Use of acetylsalicylic acid (ASA), clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux requiring proton pump inhibitors (PPI) or histamine 2 (H₂)-blocker treatment increase the risk of GI bleeding. In these atrial fibrillation patients a dosage of 220 mg dabigatran given as 110 mg capsule twice daily should be considered and posology recommendations in section 4.2 be followed. The administration of a PPI can be considered to prevent GI bleeding.

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

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

Table 1 summarises factors which may increase the haemorrhagic risk.

The measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.

The activated partial thromboplastin time (aPTT) test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding or at risk of bleeding, the aPTT test may be useful to assist in determining an excess of anticoagulant activity. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. High aPTT values should be interpreted with caution.

If required, more sensitive quantitative tests such as calibrated diluted Thrombin Time (dTT) should be performed (see section 5.1).

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

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

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

Agents that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Pradaxa (see section 4.5).

Use of fibrinolytic agents for the treatment of acute ischemic stroke

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

Interaction with P-gp inducers

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

Surgery and interventions

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

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

Preoperative phase

Table 2 summarizes discontinuation rules before invasive or surgical procedures.

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

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

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

Post-surgical patients with an increased risk for bleeding

Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 ml/min), should be treated with caution (see sections 4.4 and 5.1). Resume treatment after complete haemostasis is achieved.

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

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

Myocardial Infarction

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

Colorants

Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions.

Anticoagulants and antiplatelet aggregation agents

The following treatments have not been studied and may increase the risk of bleeding when used concomitantly with Pradaxa: UFH, low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, sulfinpyrazone, rivaroxaban, and vitamin K antagonists (see section 4.4).

UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter (see sections 4.2 and 4.4.)

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

ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA co-administration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively (see section 4.4). From the data collected in the phase III study RE-LY (see section 5.1), it was observed that ASA or clopidogrel co-medication with dabigatran etexilate at dosages of 110 mg or 150 mg twice daily may increase the risk of major bleeding (see section 4.4). The higher rate of bleeding events by ASA or clopidogrel co-medication was also observed for warfarin.

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

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

Interactions linked to dabigatran etexilate and dabigatran metabolic profile

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

Transporter interactions

P-gp inhibitors

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

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

Systemic ketoconazole, cyclosporine, itraconazole and tacrolimus are contraindicated (see section 4.3). Caution should be exercised with other strong P-gp inhibitors (e.g. amiodarone, quinidine or verapamil) (see sections 4.2 and 4.4).

Ketoconazole: Ketoconazole increased total dabigatran AUC_0- and C_max values by 138 % and 135 %, respectively, after a single oral dose of 400 mg , and 153 % and 149 %, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. The time to peak, terminal half-life and mean residence time were not affected by ketoconazole (see section 4.4). Concomitant treatment with systemic ketoconazole is contraindicated (see section 4.3).

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

Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3^rd day either with or without quinidine. Dabigatran AUC,ss and C_max,ss were increased on average by 53 % and 56 %, respectively with concomitant quinidine (see sections 4.2 and 4.4). Close clinical surveillance is recommended when dabigatran etexilate is combined with quinidine and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

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

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

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

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

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

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

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

Neither clinical nor in vitro test results are available for posaconazole which is not recommended for concomitant treatment with Pradaxa. Inadequate clinical data are available regarding the co-administration of Pradaxa and dronedarone, and their co-administration is not recommended (see section 4.4).

P-gp inducers

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

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

Other drugs affecting P-gp

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

P-gp substrate

Digoxin: In a study performed with 24 healthy subjects, when Pradaxa was co-administered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.

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

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

Gastric pH

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

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

Pregnancy

There are no adequate 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 is unknown.

Women of child-bearing potential should avoid pregnancy during treatment with dabigatran etexilate. Pradaxa should not be used during pregnancy unless clearly necessary.

Breast-feeding

There are no clinical data of the effect of dabigatran on infants during breast feeding.

Breast-feeding should be discontinued during treatment with Pradaxa.

Fertility

No human data available.

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

No studies on the effects on the ability to drive and use machines have been performed.

In the pivotal study investigating the prevention of stroke and SEE in patients with atrial fibrillation, a total of 12,091 patients were randomized. Of these 6,059 were treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily.

In total, 22 % of patient with atrial fibrillation treated for the prevention of stroke and SEE (long-term treatment for up to 3 years) experienced adverse reactions.

The most commonly reported adverse reactions are bleedings occurring in total in approximately 16,5 % in patients with atrial fibrillation treated for the prevention of stroke and SEE.

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

Adverse reactions

Table 3 shows the adverse reactions identified from the prevention of thromboembolic stroke and SEE in patients with atrial fibrillation program ranked under headings of System Organ Class (SOC) and frequency using the following convention: very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (can not be estimated from the available data).

Bleeding

The table 4 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and SEE in patients with atrial fibrillation.

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

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

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

Major bleeds were classified as life-threatening if they fulfilled one or more of the following criteria:

Fatal bleed; symptomatic intracranial bleed; reduction in haemoglobin of at least 50 g/l; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of intravenous inotropic agents; a bleed that necessitated surgical intervention.

Subjects randomized to dabigatran etexilate 110 mg twice daily or 150 mg twice daily had a significantly lower risk for life-threatening bleeds and intracranial bleeding compared to warfarin [p < 0.05]. Both dose strengths of dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomized to dabigatran etexilate 110 mg twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.80 [p=0.0026]). Subjects randomized to dabigatran etexilate 150 mg twice daily had a significantly higher risk for major GI bleeds compared with warfarin (hazard ratio 1.47 [p=0.0008]. This effect was seen primarily in patients 75 years.

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

Myocardial infarction

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

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

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

Excessive anticoagulation may require interruption of Pradaxa treatment. There is no specific antidote to dabigatran. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. Appropriate supportive treatment, such as surgical haemostasis and blood volume replacement, should be undertaken at the prescribers discretion.

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

Pharmacotherapeutic group: direct thrombine 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 by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.

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

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

There is a clear correlation between plasma dabigatran concentration and degree of anticoagulant effect based on phase II studies.

Steady state geometric mean dabigatran peak plasma concentration, measured around 2 hours after 150 mg dabigatran etexilate administration twice daily, was 175 ng/ml, with a range of 117-275 ng/ml (25^th-75^th percentile range). The dabigatran geometric mean trough concentration, measured at trough in the morning, at the end of the dosing interval (i.e. 12 hours after the 150 mg dabigatran evening dose), was on average 91.0 ng/ml, with a range of 61.0-143 ng/ml (25th-75th percentile range).

If the dTT is used, dabigatran concentrations above 200 ng/ml, measured at trough after150 mg twice daily dosing (10-16 hours after the previous dose), are associated with an increased risk of bleeding (see section 4.4 and 4.9).

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

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

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

Tables 5-7 display details of key results in the overall population:

Table 5: Analysis of first occurrence of stroke or SEE (primary endpoint) during the study period in RE-LY.

% refers to yearly event rate

Table 6: Analysis of first occurrence of ischemic or haemorrhagic strokes during the study period in RE-LY.

% refers to yearly event rate

Table 7: Analysis of all cause and cardiovascular survival during the study period in RE-LY.

% refers to yearly event rate

Tables 8-9 display results of the primary efficacy and safety endpoint in relevant sub-populations:

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

Table 8: Hazard Ratio and 95 % CI for stroke/SEE by subgroups

For the primary safety endpoint of major bleeding there was an interaction of treatment effect and age. The relative risk of bleeding with dabigatran compared to warfarin increased with age. Relative risk was highest in patients 75 years. There was no significant interaction of treatment effects with the subgroups of renal function and CHADS₂ score.

Table 9: Hazard Ratio and 95 % CI for major bleeds by subgroups

Paediatric population

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

Ethnic origin

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

After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. The cleavage of the prodrug dabigatran etexilate by esterase-catalysed hydrolysis to the active principle dabigatran is the predominant metabolic reaction. The absolute bioavailability of dabigatran following oral administration of Pradaxa was approximately 6.5 %.

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

Absorption

A study evaluating post-operative absorption of dabigatran etexilate, 1-3 hours following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached at 6 hours following administration in a postoperative period due to contributing factors such as anaesthesia, GI paresis, and surgical effects independent of the oral medicinal product formulation. It was demonstrated in a further study that slow and delayed absorption is usually only present on the day of surgery. On subsequent days absorption of dabigatran is rapid with peak plasma concentrations attained 2 hours after medicinal product administration.

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

The oral bioavailability may be increased by 75 % compared to the reference capsule formulation when the pellets are taken without the Hydroxypropylmethylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsules should always be preserved in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate. Therefore, patients should be advised not to open the capsules and taking the pellets alone (e.g. sprinkled over food or into beverages) (see section 4.2).

Distribution

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

C_max and the area under the plasma concentration-time curve were dose proportional. Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as shown in table 10.

Metabolism and elimination

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

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

Special populations

Renal insufficiency

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

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

Table 10: Half-life of total dabigatran in healthy subjects and subjects with impaired renal function.

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

Elderly patients

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

Hepatic insufficiency

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

Body weight

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

Gender

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

Ethnic origin

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

Pharmacokinetic interactions

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

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

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

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

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

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

Capsule fill

Capsule shell

Black printing ink

Not applicable.

Blister and bottle: 3 years

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

Blister

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

Bottle

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

Cartons containing 1, 3, or 6 blister strips (10 x 1, 30 x 1, 60 x 1) and a multipack containing 3 packs of 60 x 1 hard capsules (180 hard capsules) in perforated aluminium unit dose blisters. The blister consists of an aluminium lidding foil coated with polyvinylchloride-polyvinylacetate copolymer-acrylate (PVCAC acrylate) in contact with the product and an aluminium bottom foil with polyvinylchloride (PVC) in contact with the product.

Polypropylene bottle with a screw cap containing 60 hard capsules.

Not all pack sizes may be marketed.

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

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

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

Boehringer Ingelheim International GmbH

Binger Str. 173

D-55216 Ingelheim am Rhein

Germany

EU/1/08/442/009

EU/1/08/442/010

EU/1/08/442/011

EU/1/08/442/012

EU/1/08/442/013

Date of first authorisation: 01 August 2011

04/2012

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.