dabigatran etexilate: prescribing information – dosing, contraindications, interactions, side effects

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.

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 fromthe 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.

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 venous thromboembolic events (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.

Treatment of venous thromboembolic events (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.

Posology

Pradaxa capsules can be used in adults and paediatric patients aged 8 years or older who are able to swallow the capsules whole. Pradaxa 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
13 to < 16
8 to < 11
16 to < 21
8 to < 14
21 to < 26
8 to < 16
26 to < 31
8 to < 18
31 to < 41
8 to < 18
41 to < 51
8 to < 18
51 to < 61
8 to < 18
61 to < 71
8 to < 18
71 to < 81
8 to < 18
> 81
10 to < 18
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:
two 110 mg capsules
185 mg:
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/1.73 m2 is contraindicated (see section 4.3).

Patients with an eGFR ≥ 50 mL/min/1.73 m2 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).

Posology

Pradaxa capsules can be used in adults and paediatric patients aged 8 years or older who are able to swallow the capsules whole. Pradaxa 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.

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
13 to < 16
8 to < 11
16 to < 21
8 to < 14
21 to < 26
8 to < 16
26 to < 31
8 to < 18
31 to < 41
8 to < 18
41 to < 51
8 to < 18
51 to < 61
8 to < 18
61 to < 71
8 to < 18
71 to < 81
8 to < 18
> 81
10 to < 18
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:
two 110 mg capsules
185 mg:
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/1.73 m2 is contraindicated (see section 4.3).

Patients with an eGFR ≥ 50 mL/min/1.73 m2 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 sections 5.2 and 6.6).

Posology

Pradaxa capsules can be used in adults and paediatric patients aged 8 years or older who are able to swallow the capsules whole. Pradaxa 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.

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 1.

Table 1:
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 2.

Table 2:
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)

Catheter ablation can be conducted in patients on 150 mg twice daily dabigatran etexilate treatment.
Dabigatran etexilate treatment does not need to be interrupted (see section 5.1).

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 1 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 1 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 1 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 1 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 3. 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 3:
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
13 to < 16
8 to < 11
16 to < 21
8 to < 14
21 to < 26
8 to < 16
26 to < 31
8 to < 18
31 to < 41
8 to < 18
41 to < 51
8 to < 18
51 to < 61
8 to < 18
61 to < 71
8 to < 18
71 to < 81
8 to < 18
> 81
10 to < 18
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:
two 110 mg capsules
185 mg:
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/1.73 m2 is contraindicated (see section 4.3).

Patients with an eGFR ≥ 50 mL/min/1.73 m2 should be treated with the dose according to table 3.

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).

Posology

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

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.

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 coated granules 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 coated granules is based on the patient’s weight and age as shown in tables 1 and 2. The dose should be adjusted according to weight and age as treatment progresses.

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

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

Weight / age combinations
Single dose in mg
Total daily dose in mg
Weight in kg
Age in MONTHS

- 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/1.73 m2 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).

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• eGFR < 50 mL/min/1.73 m2 in paediatric patients
• Active clinically significant bleeding
• Lesion or condition, if considered a significant risk factor for major bleeding. This may 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) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).
- Hepatic impairment or liver disease expected to have any impact on survival
- Concomitant treatment with 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 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 the national reporting system listed in Appendix V.

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,
Rare
Uncommon
Uncommon

including oesophageal ulcer
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 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 randomised
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 randomised 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 randomised 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 randomised 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 %)

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, 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 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 are provided in tables 12-15 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 11 shows the adverse reactions identified studies and post-marketing data in the indications 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 11: Adverse reactions

Frequency
SOC / Preferred term.
Stroke and systemic embolism prevention in patients with atrial fibrillation
DVT/PE treatment and DVT/PE prevention
Blood and lymphatic system disorders

Anaemia
Common
Uncommon
Haemoglobin decreased
Uncommon
Not known
Thrombocytopenia
Uncommon
Rare
Haematocrit decreased
Rare
Not known
Neutropenia
Not known
Not known
Agranulocytosis
Not known
Not known
Immune system disorder
Drug hypersensitivity
Uncommon
Uncommon
Rash
Uncommon
Uncommon
Pruritus
Uncommon
Uncommon
Anaphylactic reaction
Rare
Rare
Angioedema
Rare
Rare
Urticaria
Rare
Rare
Bronchospasm
Not known
Not known
Nervous system disorders
Intracranial haemorrhage
Uncommon
Rare
Vascular disorders
Haematoma
Uncommon
Uncommon
Haemorrhage
Uncommon
Uncommon
Respiratory, thoracic and mediastinal disorders
Epistaxis
Common
Common
Haemoptysis
Uncommon
Uncommon
Gastrointestinal disorders
Gastrointestinal haemorrhage
Common
Common
Abdominal pain
Common
Uncommon
Diarrhoea
Common
Uncommon
Dyspepsia
Common
Common
Nausea
Common
Uncommon
Rectal haemorrhage
Uncommon
Common
Haemorrhoidal haemorrhage
Uncommon
Uncommon
Gastrointestinal ulcer, including oesophageal ulcer
Uncommon
Uncommon
Gastroesophagitis
Uncommon
Uncommon
Gastroesophageal reflux disease
Uncommon
Uncommon
Vomiting
Uncommon
Uncommon
Dysphagia
Uncommon
Rare

Hepatobiliary disorders
Hepatic function abnormal / Liver function Test abnormal
Uncommon
Uncommon
Alanine aminotransferase increased
Uncommon
Uncommon
Aspartate aminotransferase increased
Uncommon
Uncommon
Hepatic enzyme increased
Rare
Uncommon
Hyperbilirubinaemia
Rare
Not known
Skin and subcutaneous tissue disorder
Skin haemorrhage
Common
Common
Alopecia
Not known
Not known
Musculoskeletal and connective tissue disorders
Haemarthrosis
Rare
Uncommon
Renal and urinary disorders
Genitourological haemorrhage, including haematuria
Common
Common
General disorders and administration site conditions
Injection site haemorrhage
Rare
Rare
Catheter site haemorrhage
Rare
Rare
Injury, poisoning and procedural complications
Traumatic haemorrhage
Rare
Uncommon
Incision site haemorrhage
Rare
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).

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

The table 12 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 12:
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 randomised
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 randomised 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 randomised 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 randomised 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 13 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 13:
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 %)

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. 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 8 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 8:
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

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.

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 the national reporting system listed in Appendix V.

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 antiinflammatory 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/1.73 m2)
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.

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 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 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/1.73 m2)
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.

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 4) 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 4 summarises factors which may increase the haemorrhagic risk.

Table 4:
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 4 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 5 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 5:
Coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding.

Test (trough value)
Indication

SPAF and DVT/PE dTT [ng/mL]
> 200
ECT [x-fold upper limit of normal]
> 3 aPTT [x-fold upper limit of normal]
> 2
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.

Patients can stay on dabigatran etexilate while being cardioverted. Dabigatran etexilate treatment (150 mg twice daily) does not need to be interrupted 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 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 6 summarises discontinuation rules before invasive or surgical procedures for adult patients.

Table 6:
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 7.

Table 7:
Discontinuation rules before invasive or surgical procedures for paediatric patients

Renal function
(eGFR in mL/min/1.73 m2)
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 / startedafter 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 4), 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.

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.

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.

The efficacy and safety of the specific reversal agent idarucizumab used for adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, 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 antiinflammatory 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:
Risk factors which may increase the haemorrhagic risk.

Risk factor
Factors increasing dabigatran plasma levels
Major:
- 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)
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

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.

When severe bleedings occur, treatment must be discontinued and the source of bleeding investigated.
The efficacy and safety of the specific reversal agent (idarucizumab) to dabigatran have not been established in paediatric patients. Haemodialysis can remove dabigatran.

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.

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

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.

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

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.

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

Table 4:
Discontinuation rules before invasive or surgical procedures for paediatric patients

Renal function
(eGFR in mL/min/1.73 m2)
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 (see 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.

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

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

Very specific paediatric population

For some very specific paediatric patients, e.g. patients with small bowel disease where absorption may be affected, use of an anticoagulant with parenteral route of administration should be considered.

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 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).

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 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 9:
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 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 Pradaxa 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 Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.
Ranitidine
Ranitidine administration together with dabigatran etexilate had no 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.

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 Pradaxa 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 Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.
Ranitidine
Ranitidine administration together with dabigatran etexilate had no 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.

Transporter interactions

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see table 8) 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 8:
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
Concomitant administration is expected to result in decreased dabigatran concentrations.

perforatum), carbamazepine, or phenytoin
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 9: 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 10: 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 Pradaxa 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 Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.
Ranitidine
Ranitidine administration together with dabigatran etexilate had no 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.

Interaction studies have only been performed in adults.

Transporter interactions

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see table 5) is expected to result in increased dabigatran plasma concentrations.

If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. See also sections 4.3, 4.4 and 5.1).

Table 5:
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 section 4.4)

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

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

Table 6:
Interactions with anticoagulants and antiplatelet aggregation medicinal products

NSAIDs
NSAIDs given for short-term analgesia have been shown not to be associated 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 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 7:
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 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 Pradaxa 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 Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.
Ranitidine
Ranitidine administration together with dabigatran etexilate had no 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.

Women of childbearing potential

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

Pregnancy

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

Pradaxa should not be used during pregnancy unless clearly necessary.

Breast-feeding

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

Fertility

No human data available.

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

Women of childbearing potential

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

Pregnancy

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

Pradaxa should not be used during pregnancy unless clearly necessary.

Breast-feeding

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

Fertility

No human data available.

In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility (see section 5.3).

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

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.

5.
PHARMACOLOGICAL PROPERTIES

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.

5.
PHARMACOLOGICAL PROPERTIES

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.

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 adminstration 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.

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

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

After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

Pharmacodynamic effects

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

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

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

The ECT can provide a direct measure of the activity of direct thrombin inhibitors.

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

In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see section 4.4, table 4) is considered to be associated with an increased risk of bleeding.

Primary prevention of VTE in orthopaedic surgery

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

Mechanism of action

Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity.
After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

Pharmacodynamic effects

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

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

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

The ECT can provide a direct measure of the activity of direct thrombin inhibitors.

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

In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see section 4.4, table 6) is considered to be associated with an increased risk of bleeding.

Primary prevention of VTE in orthopaedic surgery

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

Mechanism of action

Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity.
After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

Pharmacodynamic effects

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

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

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

The ECT can provide a direct measure of the activity of direct thrombin inhibitors.

The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable

for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted with caution, a high aPTT value indicates that the patient is anticoagulated.

In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see section 4.4, table 5) is considered to be associated with an increased risk of bleeding.

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

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

Mechanism of action

Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity.
After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

Pharmacodynamic effects

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

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

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

The ECT can provide a direct measure of the activity of direct thrombin inhibitors.

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

In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk.

Clinical efficacy and safety

After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. The cleavage of the prodrug dabigatran etexilate by esterase-catalysed hydrolysis to the active principle dabigatran is the predominant metabolic reaction.
The absolute bioavailability of dabigatran following oral administration of Pradaxa was approximately 6.5 %.
After oral administration of Pradaxa in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterised by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0 hours post administration.

Absorption

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

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

Cmax and AUC were dose proportional.

After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. The cleavage of the prodrug dabigatran etexilate by esterase-catalysed hydrolysis to the active principle dabigatran is the predominant metabolic reaction.
The absolute bioavailability of dabigatran following oral administration of Pradaxa was approximately 6.5 %.
After oral administration of Pradaxa in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterised by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0 hours post administration.

Absorption

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

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

Cmax and AUC were dose proportional.

Oral administration of dabigatran etexilate according to the protocol defined dosing algorithm resulted in exposure within the range observed in adults with DVT / PE. Based on the pooled analysis of pharmacokinetic data of studies DIVERSITY and 1160.108, the observed geometric mean trough exposures were 53.9 ng/mL, 63.0 ng/mL and 99.1 ng/mL in 0 to < 2-year-old, 2 to < 12-year-old and 12 to < 18-year-old paediatric VTE patients, respectively.

Experience from adults

Absorption

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

After oral administration of Pradaxa in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterised by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0 hours post administration.
A study evaluating post-operative absorption of dabigatran etexilate, 1-3 hours following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached at 6 hours following administration in a postoperative period due to contributing factors such as anaesthesia, GI paresis, and surgical effects independent of the oral

medicinal product formulation. It was demonstrated in a further study that slow and delayed absorption is usually only present on the day of surgery. On subsequent days absorption of dabigatran is rapid with peak plasma concentrations attained 2 hours after medicinal product administration.

Food does not affect the bioavailability of dabigatran etexilate but delays the time to peak plasma concentrations by 2 hours. Pradaxa coated granules are not compatible with milk or milk products (see section 4.5).

Cmax and AUC were dose proportional.

Distribution