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.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischemic attack (TIA); age ≥ 75 years; heart failure (NYHA Class ≥ II); diabetes mellitus; hypertension.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Treatment of VTE and prevention of recurrent VTE in paediatric patients from birth 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 Etexilate Krka capsules can be used in adults and paediatric patients aged 8 years or older who are able to swallow the capsules whole. There are other age appropriate dose forms for the treatment of children below 8 years.

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.

Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF).

Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (DVT/PE)

The recommended doses of dabigatran etexilate in the indications SPAF, DVT and PE are shown in table 2.

Table 2: Dose recommendations for SPAF, DVT and PE

Dose recommendation

Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF)

300 mg dabigatran etexilate taken as one 150 mg capsule twice daily

Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (DVT/PE)

300 mg dabigatran etexilate taken as one 150 mg capsule twice daily following treatment with a parenteral anticoagulant for at least 5 days

Dose reduction recommended

Patients aged ≥ 80 years

daily dose of 220 mg dabigatran etexilate taken as one 110 mg capsule twice daily

Patients who receive concomitant verapamil

Dose reduction for consideration

Patients between 75-80 years

daily dose of dabigatran etexilate of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding

Patients with moderate renal impairment (CrCL 30-50 mL/min)

Patients with gastritis, esophagitis or gastroesophageal reflux

Other patients at increased risk of bleeding

For DVT/PE the recommendation for the use of 220 mg dabigatran etexilate taken as one 110 mg capsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in this clinical setting. See further down and sections 4.4, 4.5, 5.1 and 5.2.

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

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).

Additional requirements in patients with mild to moderate renal impairment and in patients aged over 75 years:

- Renal function should be assessed during treatment with dabigatran etexilate at least once a year or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (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.

Duration of use

The duration of use of dabigatran etexilate in the indications SPAF, DVT and PE are shown in table 3.

Table 3: Duration of use for SPAF and DVT/PE

Indication

Duration of use

SPAF

Therapy should be continued long term.

DVT/PE

The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4).

Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.

Missed dose

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

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

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 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):

The starting time of the VKA should be adjusted based on CrCL as follows:

- CrCL ≥ 50 mL/min, VKA should be started 3 days before discontinuing dabigatran etexilate

- CrCL ≥ 30-< 50 mL/min, VKA should be started 2 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.

Cardioversion (SPAF)

Patients can stay on dabigatran etexilate while being cardioverted.

Catheter ablation for atrial fibrillation (SPAF)

There are no data available for 110 mg twice daily dabigatran etexilate treatment.

Percutaneous coronary intervention (PCI) with stenting (SPAF)

Patients with non valvular atrial fibrillation who undergo a PCI with stenting can be treated with dabigatran etexilate in combination with antiplatelets after haemostasis is achieved (see section 5.1).

Special populations

Elderly

For dose modifications in this population see table 2 above.

Patients at risk of bleeding

Patients with an increased bleeding risk (see sections 4.4, 4.5, 5.1 and 5.2) should be closely monitored clinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient (see table 2 above). A coagulation test (see section 4.4) may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. When excessive dabigatran exposure is identified in patients at high risk of bleeding, a reduced dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted.

For subjects with gastritis, esophagitis, or gastroesophageal reflux, a dose reduction may be considered due to the elevated risk of major gastro-intestinal bleeding (see table 2 above and section 4.4).

Renal impairment

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

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

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

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

Dose reductions are recommended for patients who receive concomitantly verapamil (see table 2 above and sections 4.4 and 4.5). In this situation dabigatran etexilate and verapamil should be taken at the same time.

Weight

No dose adjustment is necessary (see section 5.2), but close clinical surveillance is recommended in patients with a body weight < 50 kg (see section 4.4).

Gender

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 prevention of stroke and systemic embolism in patients with NVAF.

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 4. 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 4: 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:

150 mg:

as two 110 mg capsules

as one 75 mg plus one 110 mg capsule

as 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/1.73m2 is contraindicated (see section 4.3).

Patients with an eGFR ≥50 mL/min/1.73m2 should be treated with the dose according to table 4.

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 section 5.2).

4.3. Contraindications

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

- Severe renal impairment (CrCL < 30 mL/min) in adult patients

- eGFR <50 mL/min/1.73m2 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).

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).

In clinical trials, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (≥ 75 years) for the 150 mg twice daily dose regimen. Further risk factors (see also table 5) comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux.

Risk factors

Table 5 summarises factors which may increase the haemorrhagic risk.

Table 5: 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 5 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 6 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 6: Coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding

Test (trough value)

Indication

Primary prevention of VTE in orthopaedic surgery

SPAF and DVT/PE

dTT [ng/mL]

> 67

> 200

ECT [x-fold upper limit of normal]

No data

> 3

aPTT [x-fold upper limit of normal]

> 1.3

> 2

INR

Should not be performed

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.

Patients can stay on dabigatran etexilate while being cardioverted. There are no data available for 110 mg twice daily dabigatran etexilate treatment in patients undergoing catheter ablation for atrial fibrillation (see section 4.2).

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 etexilate is available for adult patients. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran.

Reversing dabigatran etexilate 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 7 summarises discontinuation rules before invasive or surgical procedures for adult patients.

Table 7: 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 8.

Table 8: Discontinuation rules before invasive or surgical procedures for paediatric patients

Renal function

(eGFR in mL/min/1.73m2)

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 treatment should be resumed / started 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 5), 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.

Myocardial Infarction (MI)

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

In the three active controlled DVT/PE phase III studies, a higher rate of MI was reported in patients who received dabigatran etexilate than in those who received warfarin: 0.4% vs. 0.2% in the short- term RE-COVER and RE-COVER II studies; and 0.8% vs. 0.1% in the long-term RE-MEDY trial. The increase was statistically significant in this study (p=0.022).

In the RE-SONATE study, which compared dabigatran etexilate to placebo, the rate of MI was 0.1% for patients who received dabigatran etexilate and 0.2% for patients who received placebo.

Active cancer patients (DVT/PE, paediatric VTE)

The efficacy and safety have not been established for DVT/PE patients with active cancer. 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.

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 9) 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 9: Transporter interactions

P-gp inhibitors

Concomitant use contraindicated (see section 4.3)

Ketoconazole

Ketoconazole increased total dabigatran AUC0-∞ and Cmax 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 AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-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 Cmax 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 Cmax 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 Cmax by about 1.9-fold and AUC by about 1.7-fold) or administration of multiple doses of verapamil (increase of Cmax by about 1.6-fold and AUC by about 1.5-fold).

There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increase of Cmax 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 Cmax 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 AUCτ,ss and Cmax,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 Cmax 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 Cmax 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 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 AUCτ,ss and Cmax,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 AUCτ,ss and Cmax,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 AUCτ,ss and Cmax,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).

From the data collected in the phase III study RE-LY (see section 5.1) it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both dabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another (see section 4.3). Furthermore, concomitant use of antiplatelets, ASA or clopidogrel approximately doubled major bleeding rates with both dabigatran etexilate and warfarin (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 10: 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 the RE-LY study, 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 AUCτ,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 AUCτ,ss and Cmax,ss were increased by about 30-40% (see section 4.4) .

ASA

Co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase 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 11: Other interactions

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

SSRIs, SNRIs

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

Substances influencing gastric pH

Pantoprazole

When dabigatran etexilate 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 etexilate 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans 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 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 total, about 9% of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days), 22% of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14% of patients treated for DVT/PE and 15% of patients treated for DVT/PE prevention experienced adverse reactions.

The most commonly reported events are bleedings occurring in approximately 14% of patients treated short-term for elective hip or knee replacement surgery, 16.6% in patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism, and in 14.4% of adult patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4% of patients in the DVT/PE prevention trial RE- MEDY (adult patients) and in 10.5% of patients in the DVT/PE prevention trial RE‑SONATE (adult patients).

Since the patient populations treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and provided in tables 13-17 below.

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

Tabulated list of adverse reactions

Table 12 shows the adverse reactions identified from studies and post-marketing data in the indications primary VTE prevention after hip or knee replacement surgery, prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation, DVT/PE treatment and DVT/PE prevention. 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.

Primary VTE prevention after hip or knee replacement surgery

Stroke and systemic embolism prevention in patients with atrial fibrillation

DVT/PE treatment and DVT/PE prevention

Blood and lymphatic system disorders

Anaemia

Uncommon

Common

Uncommon

Haemoglobin decreased

Common

Uncommon

Not known

Thrombocytopenia

Rare

Uncommon

Rare

Haematocrit decreased

Uncommon

Rare

Not known

Neutropenia

Not known

Not known

Not known

Agranulocytosis

Not known

Not known

Not known

Immune system disorder

Drug hypersensitivity

Uncommon

Uncommon

Uncommon

Rash

Rare

Uncommon

Uncommon

Pruritus

Rare

Uncommon

Uncommon

Anaphylactic reaction

Rare

Rare

Rare

Angioedema

Rare

Rare

Rare

Urticaria

Rare

Rare

Rare

Bronchospasm

Not known

Not known

Not known

Nervous system disorders

Intracranial haemorrhage

Rare

Uncommon

Rare

Vascular disorders

Haematoma

Uncommon

Uncommon

Uncommon

Haemorrhage

Rare

Uncommon

Uncommon

Wound haemorrhage

Uncommon

-

Respiratory, thoracic and mediastinal disorders

Epistaxis

Uncommon

Common

Common

Haemoptysis

Rare

Uncommon

Uncommon

Gastrointestinal disorders

Gastrointestinal haemorrhage

Uncommon

Common

Common

Abdominal pain

Rare

Common

Uncommon

Diarrhoea

Uncommon

Common

Uncommon

Dyspepsia

Rare

Common

Common

Nausea

Uncommon

Common

Uncommon

Rectal haemorrhage

Uncommon

Uncommon

Common

Haemorrhoidal haemorrhage

Uncommon

Uncommon

Uncommon

Gastrointestinal ulcer, including oesophageal ulcer

Rare

Uncommon

Uncommon

Gastroesophagitis

Rare

Uncommon

Uncommon

Gastroesophageal reflux disease

Rare

Uncommon

Uncommon

Vomiting

Uncommon

Uncommon

Uncommon

Dysphagia

Rare

Uncommon

Rare

Hepatobiliary disorders

Hepatic function abnormal/ Liver function Test abnormal

Common

Uncommon

Uncommon

Alanine aminotransferase increased

Uncommon

Uncommon

Uncrommon

Aspartate aminotransferase increased

Uncommon

Uncommon

Uncommon

Hepatic enzyme increased

Uncommon

Rare

Uncommon

Hyperbilirubinaemia

Uncommon

Rare

Not known

Skin and subcutaneous tissue disorder

Skin haemorrhage

Uncommon

Common

Common

Alopecia

Not known

Not known

Not known

Musculoskeletal and connective tissue disorders

Haemarthrosis

Uncommon

Rare

Uncommon

Renal and urinary disorders

Genitourological haemorrhage, including haematuria

Uncommon

Common

Common

General disorders and administration site conditions

Injection site haemorrhage

Rare

Rare

Rare

Catheter site haemorrhage

Rare

Rare

Rare

Bloody discharge

Rare

-

Injury, poisoning and procedural complications

Traumatic haemorrhage

Uncommon

Rare

Uncommon

Incision site haemorrhage

Rare

Rare

Rare

Post procedural haematoma

Uncommon

-

-

Post procedural haemorrhage

Uncommon

-

Anaemia postoperative

Rare

-

-

Post procedural discharge

Uncommon

-

-

Wound secretion

Uncommon

-

-

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 (ARN) 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).

Primary prevention of VTE in orthopaedic surgery

The table 13 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 13: Number (%) of patients experiencing the adverse reaction bleeding

Dabigatran etexilate 150 mg once daily

N (%)

Dabigatran etexilate 220 mg once daily

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)

Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors

The table 14 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation.

Table 14: Bleeding events in a study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation

Dabigatran etexilate

110 mg twice daily

Dabigatran etexilate

150 mg twice daily

Warfarin

Subjects randomized

6,015

6,076

6,022

Major bleeding

347 (2.92%)

409 (3.40%)

426 (3.61%)

Intracranial bleeding

27 (0.23%)

39 (0.32%)

91 (0.77%)

GI bleeding

134 (1.13%)

192 (1.60%)

128 (1.09%)

Fatal bleeding

26 (0.22%)

30 (0.25%)

42 (0.36%)

Minor bleeding

1,566 (13.16%)

1,787 (14.85%)

1,931 (16.37%)

Any bleeding

1,759 (14.78%)

1,997 (16.60%)

2,169 (18.39%)

Subjects randomized to dabigatran etexilate 110 mg twice daily or 150 mg twice daily had a significantly lower risk for life-threatening bleeds and intracranial bleeding compared to warfarin [p < 0.05]. Both dose strengths of dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomized to 110 mg dabigatran etexilate twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81 [p=0.0027]). Subjects randomized to 150 mg dabigatran etexilate twice daily had a significantly higher risk for major GI bleeds compared with warfarin (hazard ratio 1.48 [p=0.0005]. This effect was seen primarily in patients ≥ 75 years.

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

Treatment of DVT and PE, and prevention of recurrent DVT and PE in adults (DVT/PE treatment)

Table 15 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II testing the treatment of DVT and PE. In the pooled studies the primary safety endpoints of major bleeding, major or clinically relevant bleeding and any bleeding were significantly lower than warfarin at a nominal alpha level of 5%.

Table 15: Bleeding events in the studies RE-COVER and RE-COVER II testing the treatment of DVT and PE

Dabigatran etexilate

150 mg

twice daily

Warfarin

Hazard ratio vs. warfarin (95% confidence interval)

Patients included in safety analysis

2,456

2,462

Major bleeding events

24 (1.0%)

40 (1.6%)

0.60 (0.36, 0.99)

Intracranial Bleeding

2 (0.1%)

4 (0.2%)

0.50 (0.09, 2.74)

Major GI bleeding

10 (0.4%)

12 (0.5%)

0.83 (0.36, 1.93)

Life-threatening bleed

4 (0.2%)

6 (0.2%)

0.66 (0.19, 2.36)

Major bleeding events/clinically relevant bleeds

109 (4.4%)

189 (7.7%)

0.56 (0.45, 0.71)

Any bleeding

354 (14.4%)

503 (20.4%)

0.67 (0.59, 0.77)

Any GI bleeding

70 (2.9%)

55 (2.2%)

1.27 (0.90, 1.82)

Bleeding events for both treatments are counted from the first intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events, which occurred during dabigatran etexilate therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.

Table 16 shows bleeding events in pivotal study RE-MEDY testing prevention of DVT and PE. Some bleeding events (MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of 5% in patients receiving dabigatran etexilate as compared with those receiving warfarin.

Table 16: Bleeding events in study RE-MEDY testing prevention of DVT and PE

Dabigatran etexilate

150 mg twice daily

Warfarin

Hazard ratio vs warfarin (95% Confidence Interval)

Treated patients

1,430

1,426

Majory bleeding events

13 (0.9%)

25 (1.8%)

0.54 (0.25, 1.16)

Intracranial bleeding

2 (0.1%)

4 (0.3%)

Not calculable*

Major GI bleeding

4 (0.3%)

8 (0.5%)

Not calculable*

Life-threatening bleed

1 (0.1%)

3 (0.2%))

Not calculable*

Major bleeding event /clinically relevant bleeds

80 (5.6%)

145 (10.2%)

0.55 ( 0.41, 0.72)

Any bleeding

278 (19.4%)

373 (26.2%)

0.71 (0.61, 0.83)

Any GI bleeds

45 (3.1%)

32 (2.2%)

1.39 (0.87, 2.20)

*HR not estimable as there is no event in either one cohort/treatment

Table 17 shows bleeding events in pivotal study RE-SONATE testing prevention of DVT and PE. The rate of the combination of MBEs/CRBEs and the rate of any bleeding was significantly lower at a nominal alpha level of 5% in patients receiving placebo as compared with those receiving dabigatran etexilate.

Table 17: Bleeding events in study RE-SONATE testing prevention of DVT and PE

Dabigatran etexilate

150 mg twice daily

Placebo

Hazard ratio vs placebo (95% confidence interval)

Treated patients

684

659

Major bleeding events

2 (0.3%)

0

Not calculable*

Intracranial bleeding

0

0

Not calculable*

Major GI bleeding

2 (0.3%)

0

Not calculable*

Life-threatening bleeds

0

0

Not calculable*

Major bleeding event/clinical relevant bleeds

36 (5.3%)

13 (2.0%)

2.69 (1.43, 5.07)

Any bleeding

72 (10.5%)

40 (6.1%)

1.77 (1.20, 2.61)

Any GI bleeds

5 (0.7%)

2 (0.3%)

2.38 (0.46, 12.27)

*HR not estimable as there is no event in either one treatment.

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 18 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 18: 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: yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 etexilate is required the specific reversal agent (idarucizumab) antagonizing the pharmacodynamic effect of dabigatran etexilate 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.