DABIGATRAN ETEXILATE 75 MG HARD CAPSULES - summary of medicine characteristics

Dabigatran etexilate 75 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 75 mg of dabigatran etexilate (as mesilate).

Hard capsule

Capsules with pink opaque cap and body of size ‘2’ of 18 mm approximately, filled with a mixture of tartaric acid pellets and a granulate which contains dabigatran etexilate and excipients. Capsules are printed with “E100”.

4.1 Therapeutic indications

Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

4.2 Posology and method of administration

Posology

Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery (pVTEp orthopaedic surgery)

Patients following elective knee replacement surgery

The recommended dose of Dabigatran etexilate is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1–4 hours of completed surgery with a single of 110 mg capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.

Patients following elective hip replacement surgery

The recommended dose of Dabigatran etexilate is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1–4 hours of completed surgery with a single capsule of 110 mg and continuing with 2 capsules once daily thereafter for a total of 28–35 days.

For the following groups the recommended daily dose of Dabigatran etexilate is 150 mg taken once daily as 2 capsules of 75 mg.

Treatment should be initiated orally within 1–4 hours of completed surgery with a single capsule of 75 mg and continuing with 2 capsules once daily thereafter for a total of 10 days (knee replacement surgery) or 28–35 days (hip replacement surgery):

Patients with moderate renal impairment (creatinine clearance, CrCL 30–50 mL/min) [see Renal impairment (pVTEp orthopaedic surgery )]

Patients who receive concomitant verapamil, amiodarone, quinidine [see Concomitant use of Dabigatran etexilate with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amidarone, quinidine or verapamil (pVTEp orthopaedic surgery)]

Patients aged 75 or above [see Elderly (pVTEp orthopaedic surgery)]

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

Assessment of renal function (pVTEp orthopaedic surgery): In all patients:

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

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

The method used to estimate renal function (CrCL in mL/min) during the clinical development of Dabigatran etexilate was the Cockgroft-Gault method. The formula is as follows:

For creatinine in Dmol/L:

1.23 D(140-age [years]) Dweight [kg] (D0.85 if female) serum creatinine [Dmol/L]

For creatinine in mg/dL:

(140-age [years]) Dweight [kg] (D0.85 if female) 72 □ serum creatinine [mg/dL]

This method is recommended when assessing patients’ CrCL prior to and during Dabigatran etexilate treatment.

Special populations

Renal impairment pVTEp orthopaedic surgery)

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

In patients with moderate renal impairment (CrCL 30–50 mL/min), there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections 4.4 and 5.1).

Concomitant use of Dabigatran etexilate with mild to moderate P – glycoprotein (P – gp) inhibitors, i.e. amiodarone, quinidine or verapamil (pVTEp orthopaedic surgery)

Dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Dabigatran etexilate in patients who receive concomitantly dabigatran etexilate and amiodarone, quinidine or verapamil (see sections 4.4 and 4.5). In this situation Dabigatran etexilate and these medicinal products should be taken at the same time.

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

Elderly(pVTEp orthopaedic surgery)

In elderly patients (> 75 years) there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections 4.4 and 5.1).

As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating the CrCL prior to initiation of treatment with Dabigatran etexilate to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min). While on treatment the renal function should also be assessed 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).

Hepatic impairment (pVTEp orthopaedic surgery)

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

Weight (pVTEp orthopaedic surgery)

There is very limited clinical experience in patients with a body weight < 50 kg or > 110 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see section 5.2), but close clinical surveillance is recommended (see section 4.4).

Gender (pVTEp orthopaedic surgery)

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

Switching (pVTEp orthopaedic surgery)

Dabigatran etexilate treatment to parenteral anticoagulant

It is recommended to wait 24 hours after the last dose before switching from Dabigatran etexilate to a parenteral anticoagulant (see section 4.5).

Parenteral anticoagulants to Dabigatran etexilate

Discontinue the parenteral andticoagulant and start dabigatran etexilate 0–2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5).

Paediatric population (pVTEp orthopaedic surgery)

There is no relevant use of Dabigatran etexilate for the paediatric population in the indication: primary prevention of venous thromboembolic events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

Missed dose (pVTEp orthopaedic surgery)

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

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

Method of administration (pVTEp orthopaedic surgery)

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

Patients should be instructed not to open the capsule as this may increase the risk of bleeding (see

sections 5.2 and 6.6).

4.3 Contraindications

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

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

Active clinically significant bleeding

Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent

intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

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

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

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

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

4.4 Special warnings and precautions for use

Hepatic impairment

Patients with elevated liver enzymes > 2 ULN were excluded in controlled clinical trials investigating the VTE prevention following elective hip or knee replacement surgery. No treatment experience is available for this subpopulation of patients, and therefore the use of Dabigatran etexilate is not recommended in this population.

Haemorrhagic risk

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

For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent (Praxbind, idarucizumab) is available (see section 4.9). Dabigatran etexilate is not intended to be used as a kit.

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

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

Use of acetylsalicylic acid (ASA), clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux increase the risk of GI bleeding. 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. Please also refer to contraindications in section 4.3.

Table 1: Factors which may increase the haemorrhagic risk.

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

Dabigatran etexilate does not in general require routine anticoagulant monitoring. However, the measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors. The INR test is unreliable in patients on Dabigatran etexilate and false positive INR elevations have been reported. Therefore INR tests should not be performed. Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but the tests are not standardised, and results should be interpreted with caution (see section 5.1).

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

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

Test (trough value)

Patients who develop acute renal failure must discontinue Dabigatran etexilate (see section 4.3). Limited data is available in patients < 50 kg (see section 5.2).

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

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

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

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

Interaction with P-gp inducers

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

Surgery and interventions

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

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

Emergency surgery or urgent , procedures

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

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

Subacute surgery/inter­ventions

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

Elective surgery

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

Table 3 summarises discontinuation rules before invasive or surgical procedures.

Table 3: Discontinuation rules before invasive or surgical procedures

Spinal anaesthesia/e­pidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

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

Postoperative phase

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

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

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

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

Hip fracture surgery

There is no data on the use of Dabigatran etexilate in patients undergoing hip fracture surgery. Therefore treatment is not recommended.

Patients with antiphospholipid syndrome

Direct acting Oral Anticoagulants (DOACs) including dabigatran etexilate are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

4.5 Interaction with other medicinal products and other forms of interaction

Anticoagulants and antiplatelet aggregation medicinal products

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

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

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 AUCr,ss and Cmax,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUCr,ss and Cmax,ss were increased by about 30–40 % (see section 4.4).

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

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

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

Interactions linked to dabigatran etexilate and dabigatran metabolic profile

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

Transporter interactions

P-gp inhibitors

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

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

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

Ketoconazole: Ketoconazole increased total dabigatran AUC0-co and Cmax values by 138 % and 135 %, respectively, after a single oral dose of 400 mg, and 153 % and

149 %, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. The time to peak, terminal 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).

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

Amiodarone: When Dabigatran etexilate was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 60 % and 50 %, respectively. The mechanism of the interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4).

Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Dabigatran etexilate if they receive concomitantly dabigatran etexilate and amiodarone (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with amiodarone and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1,000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUCYss and Cmax,ss were increased on average by 53 % and 56 %, respectively with concomitant quinidine (see sections 4.2 and 4.4).

Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Dabigatran etexilate if they receive concomitantly dabigatran etexilate and quinidine (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with quinidine and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

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

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

Therefore, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with verapamil. In patients with normal renal function after the hip or knee replacement surgery, receiving dabigatran etexilate and verapamil concomitantly, the dose of Dabigatran etexilate should be reduced to 150 mg taken once daily as 2 capsules of 75 mg. In patients with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Dabigatran etexilate to 75 mg daily should be considered (see sections 4.2 and 4.4). Close clinical surveillance is recommended when dabigatran etexilate is combined with verapamil and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

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

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

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

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

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

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

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

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

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

P – g pinducers

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

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

Other medicinal products affecting P-gp

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

P-gp substrate

Digoxin: In a study performed with 24 healthy subjects, when Dabigatran etexilate was 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 Dabigatran etexilate was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Dabigatran etexilate in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Dabigatran etexilate.

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

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

Pregnancy

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

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

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

Breast-feeding

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

Fertility

No human data available.

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

A total of 10,795 patients were treated in 6 actively controlled VTE prevention trials with at least one dose of the medicinal product. Of these 6,684 were treated with 150 mg or 220 mg daily of Dabigatran etexilate.

The most commonly reported adverse reactions are bleedings occurring in total in approximately 14 % of patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %.

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

Tabulated list of adverse reactions

Table 4 shows the adverse reactions ranked under headings of System Organ Classes (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 4: Adverse reactions

Bleeding

The table 5 shows the number (%) of patients experiencing the adverse reaction bleeding during the treatment period in the VTE prevention in the two pivotal clinical trials, according to dose.

Table 5: Number (%) of patients experiencing the adverse reaction bleeding

The definition of the adverse reaction major bleeding in the RE-NOVATE and REMODEL studies were as follows:

fatal bleeding

clinically overt bleeding in excess of what was expected and associated with > 20 g/L (corresponds to 1.24 mmol/L) fall in haemoglobin in excess of what was expected

clinically overt bleeding in excess of what was expected and leading to transfusion of > 2 units packed cells or whole blood in excess of what was expected

symptomatic retroperitoneal, intracranial, intraocular or intraspinal bleeding

bleeding requiring treatment cessation

bleeding leading to re-operation

Objective testing was required for a retroperitoneal bleed (ultrasound or Computer Tomography (CT) scan) and for an intracranial and intraspinal bleed (CT scan or Magnetic Resonance Imaging).

Reporting of suspected adverse reactions

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

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity.

After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.

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

Pharmacodynamic effects

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

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

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

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

In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see section 4.4, table 2) is considered to be associated with an increased risk of bleeding.

Steady state (after day 3) geometric mean dabigatran peak plasma concentration, measured around 2 hours after 220 mg dabigatran etexilate administration, was 70.8 ng/mL, with a range of 35.2–162 ng/mL (25th-75th percentile range).The dabigatran geometric mean trough concentration, measured at the end of the dosing interval (i.e. 24 hours after a 220 mg dabigatran dose), was on average 22.0 ng/mL, with a range of 13.0–35.7 ng/mL (25th-75th percentile range).

In a dedicated study exclusively in patients with moderate renal impairment (creatinine clearance, CrCL 30–50 mL/min) treated with dabigatran etexilate 150 mg QD, the dabigatran geometric mean trough concentration, measured at the end of the dosing interval, was on average 47.5 ng/mL, with a range of 29.6 – 72.2 ng/mL (25th-75th percentile range).

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

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

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

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

Clinical efficacy and safety

Ethnic origin

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

Clinical trials in Venous Thromboembolism (VTE) prophylaxis following major joint replacement surgery

In 2 large randomized, parallel group, double-blind, dose-confirmatory trials, patients undergoing elective major orthopaedic surgery (one for knee replacement surgery and one for hip replacement surgery) received Dabigatran etexilate 75 mg or 110 mg within 1–4 hours of surgery followed by 150 mg or 220 mg daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery and daily thereafter.

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

Composite of total VTE (including PE, proximal and distal DVT, whatever symptomatic or asymptomatic detected by routine venography) and all-cause mortality constituted the primary end-point for both studies. Composite of major VTE (including PE and proximal DVT, whatever symptomatic or asymptomatic detected by routine venography) and VTE-related mortality constituted a secondary end-point and is considered of better clinical relevance.

Results of both studies showed that the antithrombotic effect of Dabigatran etexilate 220 mg and 150 mg were statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The point estimate for incidence of major VTE and VTE related mortality for the 150 mg dose was slightly worse than enoxaparin (table 6). Better results were seen with the 220 mg dose where the point estimate of Major VTE was slightly better than enoxaparin (table 6).

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

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

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

Data for the major VTE and VTE-related mortality endpoint were homogeneous with regards to the primary efficacy endpoint and are shown in table 6.

Data for the total VTE and all cause mortality endpoint are shown in table 7. Data for adjudicated major bleeding endpoints are shown in table 8 below.

Table 6: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and the RE-NOVATE orthopaedic surgery studies

Table 7: Analysis of total VTE and all cause mortality during the treatment period in the RE-NOVATE and the RE-MODEL orthopaedic surgery studies

Table 8: Major bleeding events by treatment in the individual RE-MODEL and the RE-NOVATE studies

Paediatric population

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

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

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

5.2 Pharmacokinetic properties

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

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

Absorption

A study evaluating post-operative absorption of dabigatran etexilate, 1–3 hours following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached at 6 hours following administration in a postoperative period due to contributing factors such as anaesthesia, gastrointestinal paresis, and surgical effects independent of the oral medicinal product formulation. It was demonstrated in a further study that slow and delayed absorption is usually only present on the day of surgery. On subsequent days absorption of dabigatran is rapid with peak plasma concentrations attained 2 hours after medicinal product administration. Food does not affect the bioavailability of dabigatran etexilate but delays the time to peak plasma concentrations by 2 hours.

The oral bioavailability may be increased by 75 % after a single dose and 37 % at steady state compared to the reference capsule formulation when the pellets are taken without the Hydroxypropyl­methylcellulo­se (HPMC) capsule shell. Hence, the integrity of the HPMC capsules should always be preserved in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate. Therefore, patients should be advised not to open the capsules and taking the pellets alone (e.g. sprinkled over food or into beverages) (see section 4.2).

Distribution

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

Cmax and the area under the plasma concentration-time curve were dose proportional. Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12–14 hours was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as shown in table 9.

Biotransformation

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

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

Special populations

Renal insufficiency

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

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

Table 9: Half-life of total dabigatran in healthy subjects and subjects with impaired renal function.

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

Elderly patients

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

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

Hepatic impairment

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

Body weight

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

Gender

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

Ethnic origin

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

Pharmacokinetic interactions

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

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

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule fill

Cellulose microcrystalline

Croscarmellose sodium

Crospovidone

Tartaric acid pellets

Hydroxypropyl cellulose

Mannitol (E-421)

Magnesium stearate

Talc

Capsule shell

Red iron oxide (E-172)

Titanium dioxide (E-171)

Hypromellose

Black printing ink

Shellac

Propylene glycol

Strong ammonia solution

Black iron oxide (E-172)

Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister and bottle: 2 years

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

6.4 Special precautions for storage

Blister

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

Bottle

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

6.5 Nature and contents of container

Blister

Cartons containing 10, 30 or 60 hard capsules in perforated peelable aluminium blisters with desiccant.

Bottle

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

Not all pack sizes may be marketed.