4.1. Therapeutic indications

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

Treatment of VTE and prevention of recurrent VTE in paediatric patients from the time the child is able to swallow soft food to less than 18 years of age.

For age appropriate dose forms, see section 4.2.

4.2. Posology and method of administration

Posology Dabigatran capsules can be used in adults and paediatric patients aged 8 years or older who are able to swallow the capsules whole. Dabigatran coated granules can be used in children aged less than 12 years as soon as the child is able to swallow soft food. When changing between the formulations, the prescribed dose may need to be altered. The dose stated in the relevant dosing table of a formulation should be prescribed based on the weight and age of the child. Primary prevention of VTE in orthopaedic surgery The recommended doses of dabigatran etexilate and the duration of therapy for primary prevention of VTE in orthopaedic surgery are shown in table 1. Table 1: Dose recommendations and duration of therapy for primary prevention of VTE in orthopaedic surgery Treatment initiation on the day of surgery 1-4 hours after completed surgery Maintenance dose starting on the first day after surgery Duration of maintenance dose Patients following elective knee replacement surgery single capsule of 110 mg dabigatran etexilate 220 mg dabigatran etexilate once daily taken as 2 capsules of 110 mg 10 days Patients following elective hip replacement surgery 28-35 days Dose reduction recommended Patients with moderate renal impairment (creatinine clearance (CrCL 30-50 mL/min) single capsule of 75 mg dabigatran etexilate 150 mg dabigatran etexilate once daily taken as 2 capsules of 75 mg 10 days (knee replacement surgery) or 28-35 days (hip replacement surgery) Patients who receive concomitant verapamil*, amiodarone, quinidine Patients aged 75 or above *For patients with moderate renal impairment concomitantly treated with verapamil see Special populations 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 prior to and during dabigatran etexilate treatment In all patients and especially in the elderly (> 75 years), as renal impairment may be frequent in this age group: • Renal function should be assessed by calculating the creatinine 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). • 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 to be used to estimate renal function (CrCL in mL/min) is the Cockcroft-Gault method. Missed dose 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. Discontinuation of dabigatran etexilate Dabigatran etexilate treatment should not be discontinued without medical advice. Patients should be instructed to contact the treating physician if they develop gastrointestinal symptoms such as dyspepsia (see section 4.8). Switching 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: The parenteral anticoagulant should be discontinued and dabigatran etexilate should be started 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). Special populations Renal impairment 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), a dose reduction is recommended (see table 1 above and sections 4.4 and 5.1). Concomitant use of dabigatran etexilate with mild to moderate P - glycoprotein (P - gp) inhibitors, i.e. amiodarone, quinidine or verapamil Dosing should be reduced as indicated in table 1 (see also sections 4.4 and 4.5). In this situation dabigatran etexilate and these medicinal products should be taken at the same time. In patients with moderate renal impairment and concomitantly treated with verapamil, a dose reduction of dabigatran etexilate to 75 mg daily should be considered (see sections 4.4 and 4.5). Elderly For elderly patients > 75 years, a dose reduction is recommended (see table 1 above and sections 4.4 and 5.1). Weight 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 No dose adjustment is necessary (see section 5.2). Paediatric population There is no relevant use of dabigatran etexilate in the paediatric population for the indication of primary prevention of VTE in patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Treatment of VTE and prevention of recurrent VTE in paediatric patients For the treatment of VTE in paediatric patients, treatment should be initiated following treatment with a parenteral anticoagulant for at least 5 days. For prevention of recurrent VTE, treatment should be initiated following previous treatment. Dabigatran etexilate capsules should be taken twice daily , one dose in the morning and one dose in the evening, at approximately the same time every day. The dosing interval should be as close to 12 hours as possible. The recommended dose of dabigatran etexilate capsules is based on the patient's weight and age as shown in table 2. The dose should be adjusted according to weight and age as treatment progresses. For weight and age combinations not listed in the dosing table no dosing recommendation can be provided. Table 2: Single and total daily dabigatran etexilate doses in milligrams (mg) by weight in kilograms (kg) and age in years of the patient Weight / age combinations Single dose in mg Total daily dose in mg Weight in kg Age in years 11 to < 13 8 to < 9 75 150 13 to < 16 8 to < 11 110 220 16 to < 21 8 to < 14 110 220 21 to < 26 8 to < 16 150 300 26 to < 31 8 to < 18 150 300 31 to < 41 8 to < 18 185 370 41 to < 51 8 to < 18 220 440 51 to < 61 8 to < 18 260 520 61 to < 71 8 to < 18 300 600 71 to < 81 8 to < 18 300 600 > 81 10 to < 18 300 600 Single doses requiring combinations of more than one capsule: 300 mg: two 150 mg capsules or four 75 mg capsules 260 mg: one 110 mg plus one 150 mg capsule or one 110 mg plus two 75 mg capsules 220 mg: 185 mg: two 110 mg capsules one 75 mg plus one 110 mg capsule 150 mg: one 150 mg capsule or two 75 mg capsules Assessment of renal function prior to and during treatment Prior to the initiation of treatment, the estimated glomerular filtration rate (eGFR) should be estimated using the Schwartz formula (method used for creatinine assessment to be checked with local lab). Treatment with dabigatran etexilate in paediatric patients with eGFR < 50 mL/min/1.73m 2 is contraindicated (see section 4.3). Patients with an eGFR ≥50 mL/min/1.73m 2 should be treated with the dose according to table 2. While on treatment, renal function should be assessed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain co- medications, etc). Duration of use The duration of therapy should be individualised based on the benefit risk assessment. 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 onwards, the missed dose should be omitted. A double dose to make up for missed individual doses must never be taken. Discontinuation of dabigatran etexilate Dabigatran etexilate treatment should not be discontinued without medical advice. Patients or their caregivers should be instructed to contact the treating physician if the patient develops gastrointestinal symptoms such as dyspepsia (see section 4.8). Switching Dabigatran etexilate 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 dabigatran etexilate: The parenteral anticoagulant should be discontinued and dabigatran etexilate should be started 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). Dabigatran etexilate treatment to Vitamin K antagonists (VKA): Patients should start VKA 3 days before discontinuing dabigatran etexilate. Because dabigatran etexilate can impact the International Normalised Ratio (INR), the INR will better reflect VKA's effect only after dabigatran etexilate has been stopped for at least 2 days. Until then, INR values should be interpreted with caution. VKA to dabigatran etexilate: The VKA should be stopped. Dabigatran etexilate can be given as soon as the INR is < 2.0. Method of administration This medicinal product is for oral use. The capsules can be taken with or without food. The capsules should be swallowed as a whole with 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). <summary id="CONTRAINDICATIONS" data-evt="smpcSectionOpen"

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Severe renal impairment (CrCL <3 0 mL/min) in adult patients • eGFR < 50 mL/min/1.73m 2 in paediatric patients • 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. These are switching anticoagulant therapy (see section 4.2), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.5) • Hepatic impairment or liver disease expected to have any impact on survival • Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see section 4.5) • Prosthetic heart valves requiring anticoagulant treatment ( see section 5.1). <summary id="CLINICAL_PRECAUTIONS" data-evt="smpcSectionOpen"

4.4. Special warnings and precautions for use

Haemorrhagic risk Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet concentrates are other possible options (see also section 4.9). Use of platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal anti-inflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux increase the risk of GI bleeding. Risk factors Table 3 summarises factors which may increase the haemorrhagic risk. Table 3: Factors which may increase the haemorrhagic risk. Risk factor Pharmacodynamic and kinetic factors Age ≥75 years Factors increasing dabigatran plasma levels Major : • Moderate renal impairment in adult patients (30-50 mL/min CrCL) • Strong P-gp inhibitors (see section 4.3 and 4.5) • Mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, verapamil, quinidine and ticagrelor; see section 4.5) Minor : • Low body weight (< 50 kg) in adult patients Pharmacodynamic interactions (see section 4.5) • ASA and other platelet aggregation inhibitors such as clopidogrel • NSAIDs • SSRIs or SNRIs • Other medicinal products which may impair haemostasis Diseases / procedures with special haemorrhagic risks • Congenital or acquired coagulation disorders • Thrombocytopenia or functional platelet defects • Recent biopsy, major trauma • Bacterial endocarditis • Esophagitis, gastritis or gastroesophageal reflux Limited data is available in adult patients < 50 kg (see section 5.2). The concomitant use of dabigatran etexilate with P-gp-inhibitors has not been studied in paediatric patients but may increase the risk of bleeding (see section 4.5). Precautions and management of the haemorrhagic risk For the management of bleeding complications, see also section 4.9. Benefit-risk assessment 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. Limited clinical data are available for paediatric patients with risk factors, including patients with active meningitis, encephalitis and intracranial abscess (see section 5.1). In these patients, dabigatran etexilate should only be given if the expected benefit outweighs bleeding risks. Close clinical surveillance Close observation for signs of bleeding or anaemia is recommended throughout the treatment period, especially if risk factors are combined (see table 3 above). Particular caution should be exercised when dabigatran etexilate is co-administered with verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors) and particularly in the occurrence of bleeding, notably in patients having a reduced renal function (see section 4.5). Close observation for signs of bleeding is recommended in patients concomitantly treated with NSAIDs (see section 4.5). Discontinuation of dabigatran etexilate Patients who develop acute renal failure must discontinue dabigatran etexilate (see also section 4.3). When severe bleedings occur, treatment must be discontinued, the source of bleeding investigated and use of the specific reversal agent (idarucizumab) may be considered in adult patients. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran. Use of proton-pump inhibitors The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding. In case of paediatric patients local labeling recommendations for proton pump inhibitors have to be followed. Laboratory coagulation parameters Although this medicinal product does not in general require routine anticoagulant monitoring, the measurement of dabigatran related anticoagulation may be helpful to detect excessive high exposure to dabigatran in the presence of additional risk factors. Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but results should be interpreted with caution due to inter-test variability (see section 5.1). The international normalised ratio (INR) test is unreliable in patients on dabigatran etexilate and false positive INR elevations have been reported. Therefore INR tests should not be performed. Table 4 shows coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding. Respective thresholds for paediatric patients are not known (see section 5.1). Table 4: Coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding. Test (trough value) Threshold dTT [ng/mL] > 67 ECT [x-fold upper limit of normal] No data aPTT [x-fold upper limit of normal] > 1.3 INR Should not be performed 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 upper limit of normal (ULN) according to the local reference range. 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 (idarucizumab) to dabigatran is available for adult patients. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Dabigatran etexilate treatment can be re-initiated 24 hours after administration of idarucizumab, if 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. Table 5 summarises discontinuation rules before invasive or surgical procedures for adult patients. Table 5: Discontinuation rules before invasive or surgical procedures for adult patients Renal function (CrCL in mL/min) Estimated half-life (hours) Dabigatran etexilate should be stopped before elective surgery High risk of bleeding or major surgery Standard risk ≥80 ~ 13 2 days before 24 hours before ≥50-< 80 ~ 15 2-3 days before 1-2 days before ≥30-< 50 ~ 18 4 days before 2-3 days before (> 48 hours) Discontinuation rules before invasive or surgical procedures for paediatric patients are summarised in table 6. Table 6: Discontinuation rules before invasive or surgical procedures for paediatric patients Renal function (eGFR in mL/min/1.73m 2 ) Stop dabigatran before elective surgery > 80 24 hours before 50 – 80 2 days before < 50 These patients have not been studied (see section 4.3). 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 reduced renal function (see also table 3), 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 etexilate 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. Hepatic impairment Patients with elevated liver enzymes > 2 ULN were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of dabigatran etexilate is not recommended in this population. Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see section 4.3). Interaction with P-gp inducers Concomitant administration of P-gp inducers is expected to result in decreased dabigatran plasma concentrations, and should be avoided (see sections 4.5 and 5.2). 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. Active cancer patients (paediatric VTE) There is limited data on efficacy and safety for paediatric patients with active cancer. Paediatric population For some very specific paediatric patients, e.g. patients with small bowel disease where absorption may be affected, use of an anticoagulant with parenteral route of administration should be considered. <summary id="INTERACTIONS" data-evt="smpcSectionOpen"

4.5. Interaction with other medicinal products and other forms of interaction

Transporter interactions Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see table 7) is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions may be required in combination with some P-gp inhibitors (see sections 4.2, 4.3, 4.4 and 5.1). Table 7: Transporter interactions P-gp inhibitors Concomitant use contraindicated (see section 4.3) Ketoconazole Ketoconazole increased total dabigatran AUC 0-∞ and C max values by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. Dronedarone When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC 0-∞ and C max values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg. Itraconazole, cyclosporine Based on in vitro results a similar effect as with ketoconazole may be expected. Glecaprevir / pibrentasvir The concomitant use of dabigatran etexilate with the fixed-dose combination of the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure of dabigatran and may increase the risk of bleeding. Concomitant use not recommended Tacrolimus Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has 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. Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4) Verapamil When dabigatran etexilate (150 mg) was co‑administered with oral verapamil, the C max and AUC of dabigatran were increased but the 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 the dabigatran etexilate intake (increase of C max by about 2.8-fold and AUC by about 2.5-fold). The effect was progressively decreased with administration of an extended release formulation (increase of C max by about 1.9-fold and AUC by about 1.7-fold) or administration of multiple doses of verapamil (increase of C max by about 1.6-fold and AUC by about 1.5-fold). There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increase of C max by about 1.1-fold and AUC by about 1.2-fold). This is explained by completed dabigatran absorption after 2 hours. Amiodarone When dabigatran etexilate was co-administered with a single oral dose of 600 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 1.6-fold and 1.5-fold, respectively. In view of the long half-life of amiodarone the potential for an interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4). 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 AUC 𝜏,ss and C max,ss were increased on average by 1.53-fold and 1.56-fold, respectively with concomitant quinidine (see sections 4.2 and 4.4). Clarithromycin When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 1.19-fold and C max by about 1.15-fold was observed. Ticagrelor When a single dose of 75 mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and C max were increased by 1.73-fold and 1.95-fold, respectively. After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is 1.56-fold and 1.46-fold for C max and AUC, respectively. Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUC 𝜏,ss and C max,ss by 1.49-fold and 1.65-fold, 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 𝜏,ss and C max,ss was reduced to 1.27-fold and 1.23-fold, 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 b.i.d. (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUC 𝜏,ss and C max,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate given alone. Posaconazole Posaconazole also inhibits P-gp to some extent but has not been clinically studied. Caution should be exercised when dabigatran etexilate is co-administered with posaconazole. P-gp inducers Concomitant use should be avoided. e.g. rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin Concomitant administration is expected to result in decreased dabigatran concentrations. 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. Protease inhibitors such as ritonavir Concomitant use not recommended e.g. ritonavir and its combinations with other protease inhibitors These 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 clinically relevant changes on dabigatran exposure have been observed. 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 antiplatelet 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 or during catheter ablation for atrial fibrillation (see section 4.3). Table 8: Interactions with anticoagulants and antiplatelet aggregation medicinal products NSAIDs NSAIDs given for short-term analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use in a phase III clinical trial comparing dabigatran to warfarin for stroke prevention in atrial fibrillation patients (RE-LY), NSAIDs increased the risk of bleeding by approximately 50% on both dabigatran etexilate and warfarin. Clopidogrel 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 𝜏,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 𝜏,ss and C max,ss were increased by about 30-40% (see section 4.4) . ASA Co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12% to 18% and 24% with 81 mg and 325 mg ASA, respectively (see section 4.4). LMWH The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has 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. Other interactions Table 9: Other interactions Selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine reuptake inhibitors (SNRIs) SSRIs, SNRIs SSRIs and SNRIs increased the risk of bleeding in all treatment groups of a phase III clinical trial comparing dabigatran to warfarin for stroke prevention in atrial fibrillation patients (RE-LY). Substances influencing gastric pH Pantoprazole When dabigatran was co-administered with pantoprazole, a decrease in the dabigatran AUC of approximately 30% was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with dabigatran in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of dabigatran. Ranitidine Ranitidine administration together with dabigatran etexilate had no clinically relevant effect on the extent of absorption of dabigatran. 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. Paediatric population Interaction studies have only been performed in adults. <summary id="PREGNANCY" data-evt="smpcSectionOpen"

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

There is limited amount of data from the use of dabigatran in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Dabigatran 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.

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).

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 Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; thereof approximately 35,000 patients were treated with dabigatran etexilate. In actively controlled VTE prevention trials 6,684 patients were treated with 150 mg or 220 mg dabigatran etexilate daily. The most commonly reported events are bleedings occurring 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 10 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 10: Adverse reactions SOC / Preferred term Frequency Blood and lymphatic system disorders Haemoglobin decreased Common Anaemia Uncommon Haematocrit decreased Uncommon Thrombocytopenia Rare Neutropenia Not known Agranulocytosis Not known Immune system disorder Drug hypersensitivity Uncommon Anaphylactic reaction Rare Angioedema Rare Urticaria Rare Rash Rare Pruritus Rare Bronchospasm Not known Nervous system disorders Intracranial haemorrhage Rare Vascular disorders Haematoma Uncommon Wound haemorrhage Uncommon Haemorrhage Rare Respiratory, thoracic and mediastinal disorders Epistaxis Uncommon Haemoptysis Rare Gastrointestinal disorders Gastrointestinal haemorrhage Uncommon Rectal haemorrhage Uncommon Haemorrhoidal haemorrhage Uncommon Diarrhoea Uncommon Nausea Uncommon Vomiting Uncommon Gastrointestinal ulcer, including oesophageal ulcer Rare Gastroesophagitis Rare Gastroesophageal reflux disease Rare Abdominal pain Rare Dyspepsia Rare Dysphagia Rare Hepatobiliary disorders Hepatic function abnormal/ Liver function Test abnormal Common Alanine aminotransferase increased Uncommon Aspartate aminotransferase increased Uncommon Hepatic enzyme increased Uncommon Hyperbilirubinaemia Uncommon Skin and subcutaneous tissue disorder Skin haemorrhage Uncommon Alopecia Not known Musculoskeletal and connective tissue disorders Haemarthrosis Uncommon Renal and urinary disorders Genitourological haemorrhage, including haematuria Uncommon General disorders and administration site conditions Injection site haemorrhage Rare Catheter site haemorrhage Rare Bloody discharge Rare Injury, poisoning and procedural complications Traumatic haemorrhage Uncommon Post procedural haematoma Uncommon Post procedural haemorrhage Uncommon Post procedural discharge Uncommon Wound secretion Uncommon Incision site haemorrhage Rare Anaemia postoperative Rare Surgical and medical procedures Wound drainage Rare Post procedural drainage Rare Description of selected adverse reactions Bleeding reactions Due to the pharmacological mode of action, the use of dabigatran etexilate may be associated with an increased risk of occult or overt bleeding from any tissue or organ. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. In the clinical studies mucosal bleedings (e.g. gastrointestinal, genitourinary) were seen more frequently during long term dabigatran etexilate treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit is of value to detect occult bleeding. The risk of bleedings may be increased in certain patient groups e.g. those patients with moderate renal impairment and/or on concomitant treatment affecting haemostasis or strong P-gp inhibitors (see section 4.4 Haemorrhagic risk). Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock. Known bleeding complications such as compartment syndrome and acute renal failure due to hypoperfusion and anticoagulant-related nephropathy in patients with predisposing risk factors have been reported for dabigatran etexilate. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient. For adult patients, a specific reversal agent for dabigatran, idarucizumab, is available in case of uncontrollable bleeding (see Section 4.9). The table 11 shows the number (%) of patients experiencing the adverse reaction bleeding during the treatment period in the indication primary VTE prevention after hip or knee replacement surgery in the two pivotal clinical trials, according to dose. Table 11: Number (%) of patients experiencing the adverse reaction bleeding Dabigatran etexilate 150 mg N (%) Dabigatran etexilate 220 mg N (%) Enoxaparin N (%) Treated 1,866(100.0) 1,825(100.0) 1,848(100.0) Major bleeding 24 (1.3) 33 (1.8) 27 (1.5) Any bleeding 258(13.8) 251(13.8) 247(13.4) Agranulocytosis and neutropenia Agranulocytosis and neutropenia have been reported very rarely during post approval use of dabigatran etexilate. Because adverse reactions are reported in the postmarketing surveillance setting from a population of uncertain size, it is not possible to reliably determine their frequency. The reporting rate was estimated as 7 events per 1 million patient years for agranulocytosis and as 5 events per 1 million patient years for neutropenia. Paediatric population The safety of dabigatran etexilate in the treatment of VTE and prevention of recurrent VTE in paediatric patients was studied in two phase III trials (DIVERSITY and 1160.108). In total, 328 paediatric patients had been treated with dabigatran etexilate. The patients received age and weight adjusted doses of an age-appropriate formulation of dabigatran etexilate. Overall, the safety profile in children is expected to be the same as in adults. In total, 26% of paediatric patients treated with dabigatran etexilate for VTE and for prevention of recurrent VTE experienced adverse reactions. Tabulated list of adverse reactions Table 12 shows the adverse reactions identified from the studies in the treatment of VTE and prevention of recurrent VTE in paediatric patients. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 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 12: Adverse reactions Frequency SOC / Preferred term treatment of VTE and prevention of recurrent VTE in paediatric patients Blood and lymphatic system disorders Anaemia Common Haemoglobin decreased Uncommon Thrombocytopenia Common Haematocrit decreased Uncommon Neutropenia Uncommon Agranulocytosis Not known Immune system disorder Drug hypersensitivity Uncommon Rash Common Pruritus Uncommon Anaphylactic reaction Not known Angioedema Not known Urticaria Common Bronchospasm Not known Nervous system disorders Intracranial haemorrhage Uncommon Vascular disorders Haematoma Common Haemorrhage Not known Respiratory, thoracic and mediastinal disorders Epistaxis Common Haemoptysis Uncommon Gastrointestinal disorders Gastrointestinal haemorrhage Uncommon Abdominal pain Uncommon Diarrhoea Common Dyspepsia Common Nausea Common Rectal haemorrhage Uncommon Haemorrhoidal haemorrhage Not known Gastrointestinal ulcer, including oesophageal ulcer Not known Gastroesophagitis Uncommon Gastroesophageal reflux disease Common Vomiting Common Dysphagia Uncommon Hepatobiliary disorders Hepatic function abnormal/ Liver function Test abnormal Not known Alanine aminotransferase increased Uncommon Aspartate aminotransferase increased Uncommon Hepatic enzyme increased Common Hyperbilirubinaemia Uncommon Skin and subcutaneous tissue disorder Skin haemorrhage Uncommon Alopecia Common Musculoskeletal and connective tissue disorders Haemarthrosis Not known Renal and urinary disorders Genitourological haemorrhage, including haematuria Uncommon General disorders and administration site conditions Injection site haemorrhage Not known Catheter site haemorrhage Not known Injury, poisoning and procedural complications Traumatic haemorrhage Uncommon Incision site haemorrhage Not known Bleeding reactions In the two phase III trials in the indication treatment of VTE and prevention of recurrent VTE in paediatric patients, a total of 7 patients (2.1%) had a major bleeding event, 5 patients (1.5%) a clinically relevant non-major bleeding event and 75 patients (22.9%) a minor bleeding event. The frequency of bleeding events was overall higher in the oldest age group (12 to < 18 years: 28.6%) than in the younger age groups (birth to < 2 years: 23.3%; 2 to < 12 years: 16.2%). Major or severe bleeding, regardless of location, may lead to disabling, life-threatening or even fatal outcomes. 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 or search for MHRA Yellow Card in the Google Play or Apple App Store. <summary id="OVERDOSE" data-evt="smpcSectionOpen"

4.9. Overdose

Dabigatran etexilate doses 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 dabigatran etexilate treatment. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. As protein binding is low, dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies (see section 5.2).

Management of bleeding complications

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

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

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

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