Pradaxa

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 75 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

Capsules with white, opaque cap and white, opaque body of size 2 (approx. 18 x 6 mm) filled with 
yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with 
“R75”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

Treatment of VTE and prevention of recurrent VTE in paediatric patients from birth to less than 
18 years of age.

For age appropriate dose forms, see section 4.2.

4.2 Posology and method of administration

Posology

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. Pradaxa powder and solvent for oral solution should 
only be used in children aged less than 1 year.

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 for the age and weight 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.



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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).



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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.



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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 age and weight as 
shown in table 2. The table provides the single doses which are to be administered twice daily. The 
dose should be adjusted according to age and weight as treatment progresses.

Table 2: Single dabigatran etexilate dose in milligrams (mg) by weight in kilograms (kg) and 
age in years of the patient to be administered twice daily

Age in years
8 to <9 9 to 

<10
10 to 
<11

11 to 
<12

12 to 
<13

13 to 
<14

14 to 
<15

15 to 
<16

16 to 
<17

17 to 
<18

W
ei

gh
t 

[k
g]

>81 300 mg
as two 150 mg capsules

or
four 75 mg capsules

71 to <81

61 to <71

51 to <61

260 mg
as one 110 mg plus one 150 mg capsule

or
one 110 mg plus two 75 mg capsules

41 to <51
220 mg

as two 110 mg capsules

31 to <41
185 mg

as one 75 mg plus one 110 mg capsule

26 to <31
150 mg

as one 150 mg capsule
or

two 75 mg capsules21 to <26

16 to <21
One 110 mg capsule

13 to <16

11 to <13
One 
75 mg
capsule

Means that no dosing recommendation can be provided.

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.

Treatment with dabigatran etexilate in paediatric patients with eGFR <50 mL/min/1.73m2 is 
contraindicated (see section 4.3).

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



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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).

4.3 Contraindications

? Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
? Severe renal impairment (CrCL <30 mL/min) in adult patients
? eGFR <50 mL/min/1.73m2 in paediatric patients
? Active clinically significant bleeding
? Lesion or condition, if considered a significant risk factor for major bleeding. This may include

current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of 
bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent 
intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous 
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

? Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), 
oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances. 
These are switching anticoagulant therapy (see section 4.2), when UFH is given at doses 



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necessary to maintain an open central venous or arterial catheter or when UFH is given during 
catheter ablation for atrial fibrillation (see section 4.5)

? Hepatic impairment or liver disease expected to have any impact on survival
? Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, 

cyclosporine, itraconazole, dronedarone and the fixed-dose combination 
glecaprevir/pibrentasvir (see section 4.5)

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

4.4 Special warnings and precautions for use

Haemorrhagic risk

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

For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the 
anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available. 
The efficacy and safety of idarucizumab have not been established in paediatric patients. 
Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, 
coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet 
concentrates are other possible options (see also section 4.9).

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 



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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.



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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. 



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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/1.73m2)

Stop dabigatran before elective surgery

>80 24 hours before
50 – 80 2 days before
<50 These patients have not been studied (see section 4.3).

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

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

Postoperative phase

Dabigatran etexilate 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.



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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.

4.5 Interaction with other medicinal products and other forms of interaction

Transporter interactions

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp 
inhibitors (see table 7) is expected to result in increased dabigatran plasma concentrations.

If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or 
anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions 
may be required in combination with some P-gp inhibitors (see sections 4.2, 4.3, 4.4 and 5.1).

Table 7: Transporter interactions

P-gp inhibitors

Concomitant use contraindicated (see section 4.3)

Ketoconazole Ketoconazole increased total dabigatran 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. 



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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 AUC?,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 



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dabigatran etexilate (in steady state) increased the dabigatran AUC?,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 AUC?,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 AUC?,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).



14

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

Table 8: Interactions with anticoagulants and antiplatelet aggregation medicinal products

NSAIDs NSAIDs given for short-term analgesia have been shown not to be associated with 
increased bleeding risk when given in conjunction with dabigatran etexilate. With 
chronic use in a phase III clinical trial comparing dabigatran to warfarin for stroke 
prevention in atrial fibrillation patients (RE-LY), NSAIDs increased the risk of bleeding 
by approximately 50 % on both dabigatran etexilate and warfarin. 

Clopidogrel In young healthy male volunteers, the concomitant administration of dabigatran 
etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times 
compared to clopidogrel monotherapy. In addition, dabigatran AUC?,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 AUC?,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.



15

Interactions linked to dabigatran etexilate and dabigatran metabolic profile

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

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; 
thereof approximately 35,000 patients were treated with dabigatran etexilate.

In actively controlled VTE prevention trials 6,684 patients were treated with 150 mg or 220 mg 
dabigatran etexilate daily.



16

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



17

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 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.



18

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



19

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.



20

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.

4.9 Overdose

Dabigatran etexilate doses beyond those recommended, expose the patient to increased risk of 
bleeding.

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

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

Management of bleeding complications

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

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

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

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


21

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

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

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

In patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg 
dabigatran etexilate once daily,
? the 90th percentile of dabigatran plasma concentrations was 67 ng/mL, measured at trough 

(20-28 hours after the previous dose) (see section 4.4 and 4.9),
? the 90th percentile of aPTT at trough (20-28 hours after the previous dose) was 51 seconds, 

which would be 1.3-fold upper limit of normal.



22

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

Clinical efficacy and safety

Ethnic origin

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

Clinical trials in VTE prophylaxis following major joint replacement surgery

In 2 large randomised, parallel group, double-blind, dose-confirmatory trials, patients undergoing 
elective major orthopaedic surgery (one for knee replacement surgery and one for hip replacement 
surgery) received 75 mg or 110 mg dabigatran etexilate within 1-4 hours of surgery followed by 
150 mg or 220 mg once daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on the 
day prior to surgery and daily thereafter. 
In the RE-MODEL trial (knee replacement) treatment was for 6-10 days and in the RE-NOVATE trial 
(hip replacement) for 28-35 days. Totals of 2,076 patients (knee) and 3,494 (hip) were treated 
respectively.

Composite of total VTE (including pulmonary embolism (PE), proximal and distal deep vein 
thrombosis (DVT), whatever symptomatic or asymptomatic detected by routine venography) and 
all-cause mortality constituted the primary end-point for both studies. Composite of major VTE 
(including PE and proximal DVT, whatever symptomatic or asymptomatic detected by routine 
venography) and VTE-related mortality constituted a secondary end-point and is considered of better 
clinical relevance.
Results of both studies showed that the antithrombotic effect of 220 mg and 150 mg dabigatran 
etexilate were statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The 
point estimate for incidence of major VTE and VTE related mortality for the 150 mg dose was slightly 
worse than enoxaparin (table 13). Better results were seen with the 220 mg dose where the point 
estimate of Major VTE was slightly better than enoxaparin (table 13).

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

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

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

Data for the major VTE and VTE-related mortality endpoint were homogeneous with regards to the 
primary efficacy endpoint and are shown in table 13.

Data for the total VTE and all cause mortality endpoint are shown in table 14.

Data for adjudicated major bleeding endpoints are shown in table 15 below.



23

Table 13: Analysis of major VTE and VTE-related mortality during the treatment period in the 
RE-MODEL and the RE-NOVATE orthopaedic surgery studies

Trial Dabigatran etexilate
220 mg

Dabigatran etexilate
150 mg

Enoxaparin
40 mg

RE-NOVATE (hip)
N 909 888 917
Incidences (%) 28 (3.1) 38 (4.3) 36 (3.9)
Risk ratio over 
enoxaparin

0.78 1.09

95 % CI 0.48, 1.27 0.70, 1.70
RE-MODEL (knee)
N 506 527 511
Incidences (%) 13 (2.6) 20 (3.8) 18 (3.5)
Risk ratio over 
enoxaparin

0.73 1.08

95 % CI 0.36, 1.47 0.58, 2.01

Table 14: Analysis of total VTE and all cause mortality during the treatment period in the 
RE-NOVATE and the RE-MODEL orthopaedic surgery studies

Trial Dabigatran etexilate
220 mg

Dabigatran etexilate
150 mg

Enoxaparin 
40 mg

RE-NOVATE (hip)
N 880 874 897
Incidences (%) 53 (6.0) 75 (8.6) 60 (6.7)
Risk ratio over 
enoxaparin

0.9 1.28

95 % CI (0.63, 1.29) (0.93, 1.78)
RE-MODEL (knee)
N 503 526 512
Incidences (%) 183 (36.4) 213 (40.5) 193 (37.7)
Risk ratio over 
enoxaparin

0.97 1.07

95 % CI (0.82, 1.13) (0.92, 1.25)

Table 15: Major bleeding events by treatment in the individual RE-MODEL and the 
RE-NOVATE studies

Trial Dabigatran etexilate
220 mg

Dabigatran etexilate
150 mg

Enoxaparin
40 mg

RE-NOVATE (hip)
Treated patients N 1,146 1,163 1,154
Number of MBE 
N(%)

23 (2.0) 15 (1.3) 18 (1.6)

RE-MODEL (knee)
Treated patients N 679 703 694
Number of MBE 
N(%)

10 (1.5) 9 (1.3) 9 (1.3)

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

A phase II study examined dabigatran etexilate and warfarin in a total of 252 patients with recent 
mechanical valve replacement surgery (i.e. within the current hospital stay) and in patients who 
received a mechanical heart valve replacement more than three months ago. More thromboembolic 
events (mainly strokes and symptomatic/asymptomatic prosthetic valve thrombosis) and more 



24

bleeding events were observed with dabigatran etexilate than with warfarin. In the early post-operative 
patients, major bleeding manifested predominantly as haemorrhagic pericardial effusions, specifically 
in patients who started dabigatran etexilate early (i.e. on Day 3) after heart valve replacement surgery 
(see section 4.3).

Paediatric population

Clinical trials in VTE prophylaxis following major joint replacement surgery

The European Medicines Agency has waived the obligation to submit the results of studies with 
Pradaxa in all subsets of the paediatric population in prevention of thromboembolic events for the 
indication of primary prevention of VTE in patients who have undergone elective total hip 
replacement surgery or total knee replacement surgery (see section 4.2 for information on paediatric 
use).

Treatment of VTE and prevention of recurrent VTE in paediatric patients

The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilate 
compared to standard of care (SOC) for the treatment of VTE in paediatric patients from birth to less 
than 18 years of age. The study was designed as an open-label, randomised, parallel-group, non-
inferiority study. Patients enrolled were randomised according to a 2:1 scheme to either an age-
appropriate formulation (capsules, coated granules or oral solution) of dabigatran etexilate (doses 
adjusted for age and weight) or SOC comprised of low molecular weight heparins (LMWH) or 
vitamin K antagonists (VKA) or fondaparinux (1 patient 12 years old). The primary endpoint was a 
composite endpoint of patients with complete thrombus resolution, freedom from recurrent VTE, and 
freedom from mortality related to VTE. Exclusion criteria included active meningitis, encephalitis and 
intracranial abscess.
In total, 267 patients had been randomised. Of those, 176 patients were treated with dabigatran 
etexilate and 90 patients according to SOC (1 randomised patient was not treated). 168 patients were 
12 to less than 18 years old, 64 patients 2 to less than 12 years, and 35 patients were younger than 
2 years.
Of the 267 randomised patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients 
(42.2%) in the SOC group met the criteria for the composite primary endpoint (complete thrombus 
resolution, freedom from recurrent VTE, and freedom from mortality-related VTE). The 
corresponding rate difference demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent 
results were also generally observed across subgroups: there were no significant differences in the 
treatment effect for the subgroups by age, sex, region, and presence of certain risk factors. For the 
3 different age strata, the proportions of patients that met the primary efficacy endpoint in the 
dabigatran etexilate and SOC groups, respectively, were 13/22 (59.1%) and 7/13 (53.8%) for patients 
from birth to <2 years, 21/43 (48.8%) and 12/21 (57.1%) for patients aged 2 to <12 years, and 47/112 
(42.0%) and 19/56 (33.9%) for patients aged 12 to <18 years.
Adjudicated major bleeds were reported for 4 patients (2.3%) in the dabigatran etexilate group and 
2 patients (2.2%) in the SOC group. There was no statistically significant difference in the time to first 
major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients 
(24.4%) in the SOC arm had any adjudicated bleeding event, most of them categorised as minor. The 
combined endpoint of adjudicated major bleeding event (MBE) or clinically relevant non-major 
(CRNM) bleeding (on treatment) was reported for 6 (3.4%) patients in the dabigatran etexilate group 
and 3 (3.3%) patients in the SOC group.

An open label, single arm safety prospective cohort, multi-centre, phase III study (1160.108) was 
conducted to assess the safety of dabigatran etexilate for the prevention of recurrent VTE in paediatric 
patients from birth to less than 18 years. Patients who required further anticoagulation due to the 
presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 
3 months) or after completing the DIVERSITY study were allowed to be included in the study. 
Eligible patients received age and weight adjusted doses of an age-appropriate formulation (capsules, 
coated granules or oral solution) of dabigatran etexilate until the clinical risk factor resolved, or up to a 
maximum of 12 months. The primary endpoints of the study included the recurrence of VTE, major 



25

and minor bleeding events and the mortality (overall and related to thrombotic or thromboembolic 
events) at 6 and 12 months. Outcome events were adjudicated by an independent blinded adjudication 
committee.
Overall, 214 patients entered the study; among them 162 patients in age stratum 1 (from 12 to less 
than 18 years of age), 43 patients in age stratum 2 (from 2 to less than 12 years of age) and 9 patients 
in age stratum 3 (from birth to less than 2 years of age). During the on-treatment period, 3 patients 
(1.4%) had an adjudication-confirmed recurrent VTE within the first 12 months after treatment start. 
Adjudication-confirmed bleeding events during the on-treatment period were reported for 48 patients 
(22.5%) within the first 12 months. The majority of the bleeding events were minor. In 3 patients 
(1.4%), an adjudication-confirmed major bleeding event occurred within the first 12 months. For 
3 patients (1.4%), adjudication-confirmed CRNM bleeding was reported within the first 12 months. 
No on-treatment deaths occurred. During the on-treatment period, 3 patients (1.4%) developed post-
thrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.

5.2 Pharmacokinetic properties

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

The oral bioavailability may be increased by 75 % after a single dose and 37 % at steady state 
compared to the reference capsule formulation when the pellets are taken without the 
Hydroxypropylmethylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsules 
should always be preserved in clinical use to avoid unintentionally increased bioavailability of 
dabigatran etexilate (see section 4.2).

Distribution

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

Biotransformation

Metabolism and excretion of dabigatran were studied following a single intravenous dose of 
radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived 



26

radioactivity was eliminated primarily in the urine (85 %). Faecal excretion accounted for 6 % of the 
administered dose. Recovery of the total radioactivity ranged from 88-94 % of the administered dose 
by 168 hours post dose. 
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four 
positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of total 
dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical 
methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of 
approximately 100 mL/min corresponding to the glomerular filtration rate.

Elimination

Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 
11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was 
observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as 
shown in table 16.

Special populations

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

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

Table 16: Half-life of total dabigatran in healthy subjects and subjects with impaired renal 
function.

glomerular filtration rate 
(CrCL,)

[mL/min]

gMean (gCV%; range) 
half-life 

[h] 
?80 13.4 (25.7 %; 11.0-21.6)

?50-<80 15.3 (42.7 %;11.7-34.1) 

?30-<50 18.4 (18.5 %;13.3-23.0) 
<30 27.2(15.3 %; 21.6-35.0)

Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open label 
randomised pharmacokinetic study in NVAF patients with severe renal impairment (defined as 
creatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate 75 mg twice daily.
This regimen resulted in a geometric mean trough concentration of 155 ng/ml (gCV of 76.9 %), 
measured immediately before administration of the next dose and in a geometric mean peak 
concentration of 202 ng/ml (gCV of 70.6 %) measured two hours after the administration of the last 
dose.

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



27

Elderly patients
Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60 % in the 
AUC and of more than 25 % in Cmax compared to young subjects.
The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31 % 
higher trough concentration for subjects ? 75 years and by about 22 % lower trough level for subjects 
<65 years compared to subjects between 65 and 75 years (see sections 4.2 and 4.4).

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

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

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

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

Paediatric population
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.

Pharmacokinetic interactions 

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

5.3 Preclinical safety data

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

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

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

In a juvenile toxicity study conducted in Han Wistar rats, mortality was associated with bleeding 
events at similar exposures, at which bleeding was seen in adult animals. In both adult and juvenile 



28

rats, mortality is considered to be related to the exaggerated pharmacological activity of dabigatran in 
association with the exertion of mechanical forces during dosing and handling. Data of the juvenile 
toxicity study did neither indicate an increased sensitivity in toxicity, nor any toxicity specific to 
juvenile animals.

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

Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in the environment.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Tartaric acid
Acacia
Hypromellose
Dimeticone 350
Talc
Hydroxypropylcellulose

Capsule shell
Carrageenan
Potassium chloride
Titanium dioxide
Hypromellose

Black printing ink
Shellac
Iron oxide black
Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister and bottle

3 years

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

6.4 Special precautions for storage

Blister

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

Bottle

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



29

6.5 Nature and contents of container

Perforated aluminium unit dose blisters of 10 x 1 hard capsules. Each carton contains 10, 30 or 60 hard 
capsules.

Perforated aluminium unit dose white blisters of 10 x 1 hard capsules. Each carton contains 60 hard 
capsules.

Polypropylene bottle with a screw cap containing 60 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

? One individual blister should be teared off from the blister card along the perforated line.
? The backing foil should be peeled off and the capsule can be removed.
? The hard capsules should not be pushed through the blister foil.
? The blister foil should only be peeled off, when a hard capsule is required.

When taking a hard capsule out of the bottle, the following instructions should be observed:

? The cap opens by pushing and turning.
? After taking the capsule out, the cap should be returned on the bottle right away and the bottle 

should be tightly closed.

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/001
EU/1/08/442/002
EU/1/08/442/003
EU/1/08/442/004
EU/1/08/442/017

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 March 2008
Date of latest renewal: 08 January 2018



30

10. DATE OF REVISION OF THE TEXT

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

http://www.emea.europa.eu/


31

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 110 mg of dabigatran etexilate (as mesilate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

Capsules with light blue, opaque cap and light blue, opaque body of size 1 (approx. 19 x 7 mm) filled 
with yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body 
with “R110”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

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

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

Treatment of VTE and prevention of recurrent VTE in paediatric patients from birth to less than 
18 years of age.

For age appropriate dose forms, see section 4.2.

4.2 Posology and method of administration

Posology

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. Pradaxa powder and solvent for oral solution should 
only be used in children aged less than 1 year.

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 for the age and weight 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.



32

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).



33

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.



34

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 



35

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:



36

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.



37

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 age and weight as 
shown in table 4. The table provides the single doses which are to be administered twice daily. The 
dose should be adjusted according to age and weight as treatment progresses.



38

Table 4: Single dabigatran etexilate dose in milligrams (mg) by weight in kilograms (kg) and 
age in years of the patient to be administered twice daily

Age in years
8 to <9 9 to 

<10
10 to 
<11

11 to 
<12

12 to 
<13

13 to 
<14

14 to 
<15

15 to 
<16

16 to 
<17

17 to 
<18

W
ei

g
h

t 
[k

g
]

>81 300 mg
as two 150 mg capsules

or
four 75 mg capsules

71 to <81

61 to <71

51 to <61

260 mg
as one 110 mg plus one 150 mg capsule

or
one 110 mg plus two 75 mg capsules

41 to <51
220 mg

as two 110 mg capsules

31 to <41
185 mg

as one 75 mg plus one 110 mg capsule

26 to <31
150 mg

as one 150 mg capsule
or

two 75 mg capsules21 to <26

16 to <21
One 110 mg capsule

13 to <16

11 to <13
One 
75 mg
capsule

Means that no dosing recommendation can be provided.

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.

Treatment with dabigatran etexilate in paediatric patients with eGFR <50 mL/min/1.73m2 is 
contraindicated (see section 4.3).

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

While on treatment, renal function should be assessed in certain clinical situations when it is suspected 
that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain 
co-medications, etc).

Duration of use

The duration of therapy should be individualised based on the benefit risk assessment.

Missed dose

A forgotten dabigatran etexilate dose may still be taken up to 6 hours prior to the next scheduled dose. 
From 6 hours prior to the next scheduled dose onwards, the missed dose should be omitted. 
A double dose to make up for missed individual doses must never be taken.



39

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).

4.3 Contraindications

? Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
? Severe renal impairment (CrCL <30 mL/min) in adult patients
? eGFR <50 mL/min/1.73m2 in paediatric patients
? Active clinically significant bleeding
? Lesion or condition, if considered a significant risk factor for major bleeding. This may include 

current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of 
bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent 
intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous 
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

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

? Hepatic impairment or liver disease expected to have any impact on survival
? Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, 

cyclosporine, itraconazole, dronedarone and the fixed-dose combination 
glecaprevir/pibrentasvir (see section 4.5)

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



40

4.4 Special warnings and precautions for use

Haemorrhagic risk

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

For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the 
anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available. 
The efficacy and safety of idarucizumab have not been established in paediatric patients. 
Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, 
coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet 
concentrates are other possible options (see also section 4.9).

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

Risk factors

Table 5 summarises factors which may increase the haemorrhagic risk.

Table 5: Factors which may increase the haemorrhagic risk.

Risk factor
Pharmacodynamic and kinetic factors Age ?75 years
Factors increasing dabigatran plasma levels Major:

? Moderate renal impairment in adult 
patients (30-50 mL/min CrCL)

? Strong P-gp inhibitors (see section 4.3 and 
4.5)

? Mild to moderate P-gp inhibitor 
co-medication (e.g. amiodarone, verapamil, 
quinidine and ticagrelor; see section 4.5)

Minor:
? Low body weight (<50 kg) in adult patients

Pharmacodynamic interactions (see section 4.5) ? ASA and other platelet aggregation 
inhibitors such as clopidogrel

? NSAIDs
? SSRIs or SNRIs
? Other medicinal products which may 

impair haemostasis
Diseases / procedures with special 
haemorrhagic risks

? Congenital or acquired coagulation 
disorders

? Thrombocytopenia or functional platelet 
defects

? Recent biopsy, major trauma
? Bacterial endocarditis
? Esophagitis, gastritis or gastroesophageal 

reflux



41

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.



42

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.



43

Elective surgery

If possible, dabigatran etexilate should be discontinued at least 24 hours before invasive or surgical 
procedures. In patients at higher risk of bleeding or in major surgery where complete haemostasis may 
be required consider stopping dabigatran etexilate 2-4 days before surgery. 

Table 7 summarises discontinuation rules before invasive or surgical procedures for adult patients.

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

Renal function
(CrCL in
mL/min)

Estimated half-life 
(hours)

Dabigatran etexilate should be stopped before elective 
surgery

High risk of bleeding or 
major surgery

Standard risk

?80 ~ 13 2 days before 24 hours before
?50-<80 ~ 15 2-3 days before 1-2 days before
?30-<50 ~ 18 4 days before 2-3 days before (>48 hours)

Discontinuation rules before invasive or surgical procedures for paediatric patients are summarised in 
table 8.

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

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

Stop dabigatran before elective surgery

>80 24 hours before
50 – 80 2 days before
<50 These patients have not been studied (see section 4.3).

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

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

Postoperative phase

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

Patients at risk for bleeding or patients at risk of overexposure, notably patients with reduced renal 
function (see also table 5), should be treated with caution (see sections 4.4 and 5.1). 

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

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

Hip fracture surgery

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



44

Hepatic impairment

Patients with elevated liver enzymes >2 ULN were excluded in the main trials. No treatment 
experience is available for this subpopulation of patients, and therefore the use of dabigatran etexilate 
is not recommended in this population. Hepatic impairment or liver disease expected to have any 
impact on survival is contraindicated (see section 4.3).

Interaction with P-gp inducers

Concomitant administration of P-gp inducers is expected to result in decreased dabigatran plasma 
concentrations, and should be avoided (see sections 4.5 and 5.2).

Patients with antiphospholipid syndrome

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

Myocardial Infarction (MI)

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

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

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

Active cancer patients (DVT/PE, paediatric VTE)

The efficacy and safety have not been established for DVT/PE patients with active cancer. There is 
limited data on efficacy and safety for paediatric patients with active cancer.

Paediatric population

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

4.5 Interaction with other medicinal products and other forms of interaction

Transporter interactions

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp 
inhibitors (see table 9) is expected to result in increased dabigatran plasma concentrations.



45

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 



46

discontinuation of amiodarone (see sections 4.2 and 4.4).
Quinidine Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1,000 mg. 

Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day 
either with or without quinidine. Dabigatran AUC?,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 AUC?,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 AUC?,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 AUC?,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.



47

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 AUC?,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 AUC?,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.



48

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.

4.6 Fertility, pregnancy and lactation

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 



49

increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an 
increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to 
a plasma exposure level 4-fold higher than observed in patients).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; 
thereof approximately 35,000 patients were treated with dabigatran etexilate.
In total, about 9% of patients treated for elective hip or knee surgery (short-term treatment for up to 
42 days), 22% of patients with atrial fibrillation treated for the prevention of stroke and systemic 
embolism (long-term treatment for up to 3 years), 14% of patients treated for DVT/PE and 15% of 
patients treated for DVT/PE prevention experienced adverse reactions.

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

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

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

Tabulated list of adverse reactions

Table 12 shows the adverse reactions identified from studies and post-marketing data in the 
indications primary VTE prevention after hip or knee replacement surgery, prevention of 
thromboembolic stroke and systemic embolism in patients with atrial fibrillation, DVT/PE treatment 
and DVT/PE prevention. They are ranked under headings of System Organ Class (SOC) and 
frequency using the following convention: very common (?1/10), common (?1/100 to <1/10), 
uncommon (?1/1,000 to <1/100), rare (?1/10,000 to <1/1,000), very rare (<1/10,000), not known 
(cannot be estimated from the available data).

Table 12: Adverse reactions

Frequency

SOC / Preferred term. Primary VTE 
prevention after hip or 
knee replacement 
surgery

Stroke and systemic 
embolism
prevention in 
patients with atrial 
fibrillation

DVT/PE 
treatment and 
DVT/PE 
prevention 

Blood and lymphatic system disorders
Anaemia Uncommon Common Uncommon
Haemoglobin decreased Common Uncommon Not known
Thrombocytopenia Rare Uncommon Rare
Haematocrit decreased Uncommon Rare Not known



50

Neutropenia Not known Not known Not known
Agranulocytosis Not known Not known Not known

Immune system disorder
Drug hypersensitivity Uncommon Uncommon Uncommon 
Rash Rare Uncommon Uncommon
Pruritus Rare Uncommon Uncommon 
Anaphylactic reaction Rare Rare Rare 
Angioedema Rare Rare Rare
Urticaria Rare Rare Rare 
Bronchospasm Not known Not known Not known 

Nervous system disorders
Intracranial haemorrhage Rare Uncommon Rare

Vascular disorders
Haematoma Uncommon Uncommon Uncommon 
Haemorrhage Rare Uncommon Uncommon 
Wound haemorrhage Uncommon -

Respiratory, thoracic and mediastinal disorders
Epistaxis Uncommon Common Common 
Haemoptysis Rare Uncommon Uncommon 

Gastrointestinal disorders
Gastrointestinal 
haemorrhage

Uncommon Common Common 

Abdominal pain Rare Common Uncommon 
Diarrhoea Uncommon Common Uncommon 
Dyspepsia Rare Common Common 
Nausea Uncommon Common Uncommon 
Rectal haemorrhage Uncommon Uncommon Common 
Haemorrhoidal haemorrhage Uncommon Uncommon Uncommon 
Gastrointestinal ulcer, 
including oesophageal ulcer

Rare Uncommon Uncommon 

Gastroesophagitis Rare Uncommon Uncommon 
Gastroesophageal reflux 
disease 

Rare Uncommon Uncommon 

Vomiting Uncommon Uncommon Uncommon 
Dysphagia Rare Uncommon Rare 

Hepatobiliary disorders
Hepatic function abnormal/ 
Liver function Test 
abnormal

Common Uncommon Uncommon 

Alanine aminotransferase 
increased

Uncommon Uncommon Uncrommon 

Aspartate aminotransferase 
increased

Uncommon Uncommon Uncommon 

Hepatic enzyme increased Uncommon Rare Uncommon 
Hyperbilirubinaemia Uncommon Rare Not known 

Skin and subcutaneous tissue disorder
Skin haemorrhage Uncommon Common Common 
Alopecia Not known Not known Not known

Musculoskeletal and connective tissue disorders
Haemarthrosis Uncommon Rare Uncommon 

Renal and urinary disorders
Genitourological 
haemorrhage, including 
haematuria

Uncommon Common Common 

General disorders and administration site conditions



51

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 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 



52

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%. 



53

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

Dabigatran etexilate
150 mg twice daily

Warfarin Hazard ratio vs. 
warfarin

(95% confidence 
interval)

Patients included in safety 
analysis 

2,456 2,462 

Major bleeding events 24 (1.0 %) 40 (1.6 %) 0.60 (0.36, 0.99)
           Intracranial
           Bleeding

2 (0.1 %) 4 (0.2 %) 0.50 (0.09, 2.74)

          Major GI bleeding 10 (0.4 %) 12 (0.5 %) 0.83 (0.36, 1.93)
           Life-threatening
           bleed

4 (0.2 %) 6 (0.2 %) 0.66 (0.19, 2.36)

Major bleeding 
events/clinically relevant 
bleeds 

109 (4.4 %) 189 (7.7 %) 0.56 (0.45, 0.71)

Any bleeding 354 (14.4 %) 503 (20.4 %) 0.67 (0.59, 0.77)
          Any GI bleeding 70 (2.9 %) 55 (2.2 %) 1.27 (0.90, 1.82)

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

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

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

Dabigatran etexilate
150 mg twice daily 

Warfarin Hazard ratio vs 
warfarin 

(95% Confidence 
Interval)

Treated patients 1,430 1,426 
Majory bleeding events 13 (0.9 %) 25 (1.8 %) 0.54 (0.25, 1.16)

Intracranial bleeding 2 (0.1 %) 4 (0.3 %) Not calculable*
Major GI bleeding 4 (0.3%) 8 (0.5%) Not calculable* 
Life-threatening 
bleed

1 (0.1 %) 3 (0.2 %)) Not calculable*

Major bleeding event 
/clinically relevant bleeds 

80 (5.6 %) 145 (10.2 %) 0.55 ( 0.41, 0.72)

Any bleeding 278 (19.4 %) 373 (26.2 %) 0.71 (0.61, 0.83)

Any GI bleeds 45 (3.1%) 32 (2.2%) 1.39 (0.87, 2.20)
*HR not estimable as there is no event in either one cohort/treatment 

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



54

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

Dabigatran etexilate
150 mg twice daily 

Placebo Hazard ratio vs 
placebo

(95% confidence 
interval)

Treated patients 684 659 
Major bleeding events 2 (0.3 %) 0 Not 

calculable*
Intracranial bleeding 0 0 Not 

calculable*
Major GI bleeding 2 (0.3%) 0 Not 

calculable*
Life-threatening 
bleeds

0 0 Not 
calculable*

Major bleeding 
event/clinical relevant bleeds

36 (5.3 %) 13 (2.0 %) 2.69 (1.43, 5.07)

Any bleeding 72 (10.5 %) 40 (6.1 %) 1.77 (1.20, 2.61)
Any GI bleeds 5 (0.7%) 2 (0.3%) 2.38 (0.46, 12.27)

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

Agranulocytosis and neutropenia

Agranulocytosis and neutropenia have been reported very rarely during post approval use of 
dabigatran etexilate. Because adverse reactions are reported in the postmarketing surveillance setting 
from a population of uncertain size, it is not possible to reliably determine their frequency. The 
reporting rate was estimated as 7 events per 1 million patient years for agranulocytosis and as 5 events 
per 1 million patient years for neutropenia.

Paediatric population

The safety of dabigatran etexilate in the treatment of VTE and prevention of recurrent VTE in 
paediatric patients was studied in two phase III trials (DIVERSITY and 1160.108). In total,
328 paediatric patients had been treated with dabigatran etexilate. The patients received age and 
weight adjusted doses of an age-appropriate formulation of dabigatran etexilate.

Overall, the safety profile in children is expected to be the same as in adults.

In total, 26% of paediatric patients treated with dabigatran etexilate for VTE and for prevention of 
recurrent VTE experienced adverse reactions.

Tabulated list of adverse reactions

Table 18 shows the adverse reactions identified from the studies in the treatment of VTE and 
prevention of recurrent VTE in paediatric patients. They are ranked under headings of System Organ 
Class (SOC) and frequency using the following convention: very common (?1/10), common (?1/100 
to <1/10), uncommon (?1/1,000 to <1/100), rare (?1/10,000 to <1/1,000), very rare (<1/10,000), not 
known (cannot be estimated from the available data).

Table 18: Adverse reactions

Frequency

SOC / Preferred term. treatment of VTE and prevention of recurrent VTE in 
paediatric patients

Blood and lymphatic system disorders



55

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



56

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. 

4.9 Overdose

Dabigatran etexilate doses beyond those recommended expose the patient to increased risk of 
bleeding.

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

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

Management of bleeding complications

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

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

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

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


57

major bleedings.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic 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 6) is considered to be associated with an increased risk of bleeding.

Primary prevention of VTE in orthopaedic surgery

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

In a dedicated study exclusively in patients with moderate renal impairment (creatinine clearance, 
CrCL 30-50 mL/min) treated with dabigatran etexilate 150 mg QD, the dabigatran geometric mean 



58

trough concentration, measured at the end of the dosing interval, was on average 47.5 ng/mL, with a 
range of 29.6 - 72.2 ng/mL (25th-75th percentile range).

In patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg 
dabigatran etexilate once daily,
? the 90th percentile of dabigatran plasma concentrations was 67 ng/mL, measured at trough 

(20-28 hours after the previous dose) (see section 4.4 and 4.9),
? the 90th percentile of aPTT at trough (20-28 hours after the previous dose) was 51 seconds, 

which would be 1.3-fold upper limit of normal.

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

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

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

For patients with NVAF treated for prevention of stroke and systemic embolism with 150 mg 
dabigatran etexilate twice daily,
? the 90th percentile of dabigatran plasma concentrations measured at trough (10-16 hours after 

the previous dose) was about 200 ng/mL,
? an ECT at trough (10-16 hours after the previous dose), elevated approximately 3-fold upper 

limit of normal refers to the observed 90th percentile of ECT prolongation of 103 seconds,
? an aPTT ratio greater than 2-fold upper limit of normal (aPTT prolongation of about 

80 seconds), at trough (10-16 hours after the previous dose) reflects the 90th percentile of 
observations.

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

In patients treated for DVT and PE with 150 mg dabigatran etexilate twice daily, the dabigatran 
geometric mean trough concentration, measured within 10?16 hours after dose, at the end of the 
dosing interval (i.e. 12 hours after the 150 mg dabigatran evening dose), was 59.7 ng/ml, with a range 
of 38.6 - 94.5 ng/ml (25th-75th percentile range). For treatment of DVT and PE, with dabigatran 
etexilate 150 mg twice daily,
? the 90th percentile of dabigatran plasma concentrations measured at trough (10-16 hours after 

the previous dose) was about 146 ng/ml,
? an ECT at trough (10-16 hours after the previous dose), elevated approximately 2.3-fold 

compared to baseline refers to the observed 90th percentile of ECT prolongation of 74 seconds,
? the 90th percentile of aPTT at trough (10-16 hours after the previous dose) was 62 seconds, 

which would be 1.8-fold compared to baseline.

In patients treated for prevention of recurrent of DVT and PE with 150 mg dabigatran etexilate twice 
daily no pharmacokinetic data are available. 

Clinical efficacy and safety 

Ethnic origin

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



59

Clinical trials in VTE prophylaxis following major joint replacement surgery

In 2 large randomised, parallel group, double-blind, dose-confirmatory trials, patients undergoing 
elective major orthopaedic surgery (one for knee replacement surgery and one for hip replacement 
surgery) received 75 mg or 110 mg dabigatran etexilate within 1-4 hours of surgery followed by 
150 mg or 220 mg once daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on the 
day prior to surgery and daily thereafter.
In the RE-MODEL trial (knee replacement) treatment was for 6-10 days and in the RE-NOVATE trial 
(hip replacement) for 28-35 days. Totals of 2,076 patients (knee) and 3,494 (hip) were treated 
respectively.

Composite of total VTE (including PE, proximal and distal DVT, whatever symptomatic or 
asymptomatic detected by routine venography) and all-cause mortality constituted the primary 
end-point for both studies. Composite of major VTE (including PE and proximal DVT, whatever 
symptomatic or asymptomatic detected by routine venography) and VTE-related mortality constituted 
a secondary end-point and is considered of better clinical relevance.
Results of both studies showed that the antithrombotic effect of 220 mg and 150 mg dabigatran 
etexilate were statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The 
point estimate for incidence of Major VTE and VTE related mortality for the 150 mg dose was slightly 
worse than enoxaparin (table 19). Better results were seen with the 220 mg dose where the point 
estimate of Major VTE was slightly better than enoxaparin (table 19).

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

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

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

Data for the major VTE and VTE-related mortality endpoint were homogeneous with regards to the 
primary efficacy endpoint and are shown in table 19.

Data for the total VTE and all cause mortality endpoint are shown in table 20.

Data for adjudicated major bleeding endpoints are shown in table 21 below.

Table 19: Analysis of major VTE and VTE-related mortality during the treatment period in the 
RE-MODEL and the RE-NOVATE orthopaedic surgery studies.

Trial Dabigatran etexilate
220 mg once daily

Dabigatran etexilate
150 mg once daily

Enoxaparin 
40 mg

RE-NOVATE (hip)
N 909 888 917
Incidences (%) 28 (3.1) 38 (4.3) 36 (3.9)
Risk ratio over enoxaparin 0.78 1.09
95 % CI 0.48, 1.27 0.70, 1.70
RE-MODEL (knee)
N 506 527 511
Incidences (%) 13 (2.6) 20 (3.8) 18 (3.5)
Risk ratio over enoxaparin 0.73 1.08
95 % CI 0.36, 1.47 0.58, 2.01



60

Table 20: Analysis of total VTE and all cause mortality during the treatment period in the 
RE-NOVATE and the RE-MODEL orthopaedic surgery studies.

Trial Dabigatran etexilate
220 mg once daily

Dabigatran etexilate
150 mg once daily

Enoxaparin 
40 mg

RE-NOVATE (hip)
N 880 874 897
Incidences (%) 53 (6.0) 75 (8.6) 60 (6.7)
Risk ratio over enoxaparin 0.9 1.28
95 % CI (0.63, 1.29) (0.93, 1.78)
RE-MODEL (knee)
N 503 526 512
Incidences (%) 183 (36.4) 213 (40.5) 193 (37.7)
Risk ratio over enoxaparin 0.97 1.07
95 % CI (0.82, 1.13) (0.92, 1.25)

Table 21: Major bleeding events by treatment in the individual RE-MODEL and the 
RE-NOVATE studies.

Trial Dabigatran etexilate
220 mg once daily

Dabigatran etexilate
150 mg once daily

Enoxaparin
40 mg

RE-NOVATE (hip)
Treated patients N 1,146 1,163 1,154
Number of MBE N(%) 23 (2.0) 15 (1.3) 18 (1.6)
RE-MODEL (knee)
Treated patients N 679 703 694
Number of MBE N(%) 10 (1.5) 9 (1.3) 9 (1.3)

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

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

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

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



61

Tables 22-24 display details of key results in the overall population:

Table 22: Analysis of first occurrence of stroke or systemic embolism (primary endpoint) 
during the study period in RE-LY.

Dabigatran etexilate
110 mg twice daily

Dabigatran etexilate
150 mg twice daily

Warfarin 

Subjects randomised 6,015 6,076 6,022

Stroke and/or systemic 
embolism

Incidences (%) 183 (1.54) 135 (1.12) 203 (1.72)
Hazard ratio over 
warfarin (95 % CI)

0.89 (0.73, 1.09) 0.65 (0.52, 0.81)

p value superiority p=0.2721 p=0.0001
% refers to yearly event rate

Table 23: Analysis of first occurrence of ischemic or haemorrhagic strokes during the study 
period in RE-LY.

Dabigatran etexilate
110 mg twice daily

Dabigatran etexilate
150 mg twice daily

Warfarin

Subjects randomised 6,015 6,076 6,022
Stroke

Incidences (%) 171 (1.44) 123 (1.02) 187 (1.59)
Hazard ratio vs. 
warfarin (95 % CI)

0.91 (0.74, 1.12) 0.64 (0.51, 0.81)

p-value 0.3553 0.0001
Systemic embolism

Incidences (%) 15 (0.13) 13 (0.11) 21 (0.18)
Hazard ratio vs. 
warfarin (95 % CI)

0.71 (0.37, 1.38) 0.61 (0.30, 1.21)

p-value 0.3099 0.1582
Ischemic stroke

Incidences (%) 152 (1.28) 104 (0.86) 134 (1.14)
Hazard ratio vs. 
warfarin (95 % CI) 

1.13 (0.89, 1.42) 0.76 (0.59, 0.98)

p-value 0.3138 0.0351
Haemorrhagic stroke

Incidences (%) 14 (0.12) 12 (0.10) 45 (0.38)
Hazard ratio vs. 
warfarin (95 % CI)

0.31 (0.17, 0.56) 0.26 (0.14, 0.49)

p-value 0.0001 <0.0001
% refers to yearly event rate 



62

Table 24: Analysis of all cause and cardiovascular survival during the study period in RE-LY.

Dabigatran etexilate
110 mg twice daily

Dabigatran etexilate
150 mg twice daily

Warfarin

Subjects randomised 6,015 6,076 6,022 
All-cause mortality

Incidences (%) 446 (3.75) 438 (3.64) 487 (4.13)
Hazard ratio vs. 
warfarin (95 % CI)

0.91 (0.80, 1.03) 0.88 (0.77, 1.00)

p-value 0.1308 0.0517
Vascular mortality

Incidences (%) 289 (2.43) 274 (2.28) 317 (2.69)
Hazard ratio vs. 
warfarin (95 % CI)

0.90 (0.77, 1.06) 0.85 (0.72, 0.99)

p-value 0.2081 0.0430
% refers to yearly event rate 

Tables 25-26 display results of the primary efficacy and safety endpoint in relevant sub-populations:

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

Table 25: Hazard Ratio and 95 % CI for stroke/systemic embolism by subgroups

Endpoint Dabigatran etexilate
110 mg twice daily vs. Warfarin

Dabigatran etexilate
150 mg twice daily vs. warfarin

Age (years)
<65 1.10 (0.64, 1.87) 0.51 (0.26, 0.98)

65? and <75 0.86 (0.62, 1.19) 0.67 (0.47, 0.95)
?75 0.88 (0.66, 1.17) 0.68 (0.50, 0.92)
?80 0.68 (0.44, 1.05) 0.67 (0.44, 1.02)

CrCL(mL/min)
30? and <50 0.89 (0.61, 1.31) 0.48 (0.31, 0.76)
50? and <80 0.91 (0.68, 1.20) 0.65 (0.47, 0.88)

?80 0.81 (0.51, 1.28) 0.69 (0.43, 1.12)

For the primary safety endpoint of major bleeding there was an interaction of treatment effect and age. 
The relative risk of bleeding with dabigatran compared to warfarin increased with age. Relative risk 
was highest in patients ?75 years. The concomitant use of antiplatelets ASA or clopidogrel 
approximately doubles MBE rates with both dabigatran etexilate and warfarin. There was no 
significant interaction of treatment effects with the subgroups of renal function and CHADS2 score.



63

Table 26: Hazard Ratio and 95 % CI for major bleeds by subgroups

Endpoint Dabigatran etexilate
110 mg twice daily vs. Warfarin

Dabigatran etexilate
150 mg twice daily vs. Warfarin

Age (years)
<65 0.32 (0.18, 0.57) 0.35 (0.20, 0.61)

65? and <75 0.71 (0.56, 0.89) 0.82 (0.66, 1.03)
?75 1.01 (0.84, 1.23) 1.19 (0.99, 1.43)
?80 1.14 (0.86, 1.51) 1.35 (1.03, 1.76)

CrCL(mL/min)
30? and <50 1.02 (0.79, 1.32) 0.94 (0.73, 1.22)
50? and <80 0.75 (0.61, 0.92) 0.90 (0.74, 1.09)

?80 0.59 (0.43, 0.82) 0.87 (0.65, 1.17)
ASA use 0.84 (0.69, 1.03) 0.97 (0.79, 1.18)

Clopidogrel use 0.89 (0.55, 1.45) 0.92 (0.57, 1.48)

RELY-ABLE (Long term multi-center extension of dabigatran treatment in patients with atrial 
fibrillation who completed the RE-LY trial)

The RE-LY extension study (RELY-ABLE) provided additional safety information for a cohort of 
patients which continued the same dose of dabigatran etexilate as assigned in the RE-LY trial. Patients 
were eligible for the RELY-ABLE trial if they had not permanently discontinued study medication at 
the time of their final RE-LY study visit. Enrolled patients continued to receive the same double-blind 
dabigatran etexilate dose randomly allocated in RE-LY, for up to 43 months of follow up after RE-LY 
(total mean follow-up RE-LY + RELY-ABLE, 4.5 years). There were 5897 patients enrolled, 
representing 49 % of patients originally randomly assigned to receive dabigatran etexilate in RE-LY 
and 86 % of RELY-ABLE–eligible patients. 
During the additional 2.5 years of treatment in RELY-ABLE, with a maximum exposure of over 
6 years (total exposure in RELY + RELY-ABLE), the long-term safety profile of dabigatran etexilate 
was confirmed for both test doses 110 mg b.i.d. and 150 mg b.i.d.. No new safety findings were 
observed.
The rates of outcome events including, major bleed and other bleeding events were consistent with 
those seen in RE-LY.

Data from non-interventional studies

A non-interventional study (GLORIA-AF) prospectively collected (in its second phase) safety and 
effectiveness data in newly diagnosed NVAF patients on dabigatran etexilate in a real-world setting. 
The study included 4,859 patients on dabigatran etexilate (55% treated with 150 mg bid, 43% treated 
with 110 mg bid, 2% treated with 75 mg bid). Patients were followed-up for 2 years. The mean 
CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. Mean on-therapy follow-up time was 
18.3 months. Major bleeding occurred in 0.97 per 100 patient-years. Life-threatening bleeding was 
reported in 0.46 per 100 patient-years, intracranial haemorrhage in 0.17 per 100 patient-years and 
gastrointestinal bleeding in 0.60 per 100 patient-years. Stroke occurred in 0.65 per 100 patient-years. 

In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157-164] in more 
than 134,000 elderly patients with NVAF in the United States (contributing more than 37,500 patient-
years of on-therapy follow-up time) dabigatran etexilate (84% patients treated with 150 mg bid, 16% 
patients treated with 75 mg bid) was associated with a reduced risk of ischemic stroke (hazard ratio 
0.80, 95% confidence interval [CI] 0.67 – 0.96), intracranial haemorrhage (hazard ratio 0.34, CI 0.26 –
0.46), and mortality (hazard ratio 0.86, CI 0.77 – 0.96) and increased risk of gastrointestinal bleeding 

(hazard ratio 1.28, CI 1.14 – 1.44) compared to warfarin. No difference was found for major bleeding 
(hazard ratio 0.97, CI 0.88 – 1.07).

These observations in real-world settings are consistent with the established safety and efficacy profile 
for dabigatran etexilate in the RE-LY study in this indication.



64

Patients who underwent percutaneous coronary intervention (PCI) with stenting

A prospective, randomised, open-label, blinded endpoint (PROBE) study (Phase IIIb) to evaluate dual-
therapy with dabigatran etexilate (110 mg or 150 mg bid) plus clopidogrel or ticagrelor (P2Y12 
antagonist) vs. triple-therapy with warfarin (adjusted to a INR 2.0 – 3.0) plus clopidogrel or ticagrelor 
and ASA was conducted in 2725 patients with non valvular atrial fibrillation who underwent a PCI 
with stenting (RE-DUAL PCI). Patients were randomised to dabigatran etexilate 110 mg bid dual-
therapy, dabigatran etexilate 150 mg bid dual-therapy or warfarin triple-therapy. Elderly patients 
outside of the United States (?80 years of age for all countries, ?70 years of age for Japan) were 
randomly assigned to the dabigatran etexilate 110 mg dual-therapy group or the warfarin triple-therapy 
group. The primary endpoint was a combined endpoint of major bleeds based on ISTH definition or 
clinically relevant non-major bleeding event.

The incidence of the primary endpoint was 15.4% (151 patients) in the dabigatran etexilate 110 mg 
dual-therapy group as compared with 26.9% (264 patients) in the warfarin triple-therapy group (HR 
0.52; 95% CI 0.42, 0.63; P<0.0001 for non-inferiority and P<0.0001 for superiority) and 20.2% 
(154 patients) in the dabigatran etexilate 150 mg dual-therapy group as compared with 25.7 % 
(196 patients) in the corresponding warfarin triple-therapy group (HR 0.72; 95% CI 0.58, 0.88; 
P<0.0001 for non-inferiority and P=0.002 for superiority). As part of the descriptive analysis, TIMI 
(Thrombolysis In Myocardial Infarction) major bleeding events was lower in both dabigatran etexilate 
dual-therapy groups than in the warfarin triple-therapy group: 14 events (1.4%) in the dabigatran 
etexilate 110 mg dual-therapy group as compared with 37 events (3.8%) in the warfarin triple-therapy 
group (HR 0.37; 95% CI 0.20, 0.68; P=0.002) and 16 events (2.1%) in the dabigatran etexilate 150 mg 
dual-therapy group as compared with 30 events (3.9%) in the corresponding warfarin triple-therapy 
group (HR 0.51; 95% CI 0.28, 0.93; P=0.03). Both dabigatran etexilate dual-therapy groups had lower 
rates of intracranial hemorrhage than the corresponding warfarin triple-therapy group: 3 events (0.3%) 
in the 110 mg dabigatran etexilate dual-therapy group as compared with 10 events (1.0%) in the 
warfarin triple-therapy group (HR 0.30; 95% CI 0.08, 1.07; P=0.06) and 1 event (0.1%) in the 150 mg 
dabigatran etexilate dual-therapy group as compared with 8 events (1.0%) in the corresponding 
warfarin triple-therapy group (HR 0.12; 95% CI 0.02, 0.98; P=0.047). The incidence of the composite 
efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, or systemic 
embolism) or unplanned revascularization in the two dabigatran etexilate dual-therapy groups 
combined was non-inferior to the warfarin triple-therapy group (13.7% vs. 13.4% respectively; HR 
1.04; 95% CI: 0.84, 1.29; P=0.0047 for non-inferiority).There were no statistical differences in the 
individual components of the efficacy endpoints between either dabigatran etexilate dual-therapy 
groups and warfarin triple-therapy.

This study demonstrated that dual-therapy with dabigatran etexilate and a P2Y12 antagonist 
significantly reduced the risk of bleeding vs. warfarin triple-therapy with non-inferiority for composite 
of thromboembolic events in patients with atrial fibrillation who underwent a PCI with stenting.

Treatment of DVT and PE in adults (DVT/PE treatment)

The efficacy and safety was investigated in two multi-center, randomised, double blind, parallel-
group, replicate studies RE-COVER and RE-COVER II. These studies compared dabigatran etexilate 
(150 mg bid) with warfarin (target INR 2.0-3.0) in patients with acute DVT and/or PE. The primary 
objective of these studies was to determine if dabigatran etexilate was non-inferior to warfarin in 
reducing the occurrence of the primary endpoint which was the composite of recurrent symptomatic 
DVT and/or PE and related deaths within the 6 month treatment period. 

In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were randomised and 
5,107 were treated.

The duration of treatment with fixed dose of dabigatran was 174.0 days without coagulation 
monitoring. For patients randomised to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) 
was 60.6%. 



65

The trials, demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior
to the treatment with warfarin (non-inferiority margin for RE-COVER, and RE-COVER II: 3.6 for risk 
difference and 2.75 for hazard ratio). 

Table 27: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of 
DVT and/or PE) until the end of post-treatment period for the pooled studies RE-
COVER and RE-COVER II

Dabigatran etexilate
150 mg twice daily 

Warfarin

Treated patients 2,553 2,554 
Recurrent symptomatic 
VTE and VTE-related 
death

68 ( 2.7 %) 62 ( 2.4 %)

Hazard ratio vs warfarin
(95% confidence 
interval)

1.09
(0.77, 1.54)

Secondary efficacy 
endpoints
Recurrent symptomatic 
VTE and all-cause 
deaths

109 (4.3 %) 104 (4.1 %)

95 % confidence 
interval 

3.52, 5.13 3.34, 4.91

Symptomatic DVT 45 (1.8 %) 39 (1.5 %)
95 % confidence 
interval

1.29, 2.35 1.09, 2.08

Symptomatic PE 27 (1.1 %) 26 (1.0 %)
95 % confidence 
interval

0.70, 1.54 0.67, 1.49

VTE-related deaths 4 (0.2 %) 3 (0.1 %)
95 % confidence 
interval

0.04, 0.40 0.02, 0.34

All-cause deaths 51 (2.0 %) 52 (2.0 %)
95 % confidence 
interval

1.49, 2.62 1.52, 2.66

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

Two randomised, parallel group, double-blind studies were performed in patients previously treated 
with anticoagulation therapy. RE-MEDY, warfarin controlled study, enrolled patients already treated 
for 3 to 12 months with the need for further anticoagulant treatment and RE-SONATE, the placebo 
controlled study, enrolled patients already treated for 6 to 18 months with Vitamin K inhibitors.

The objective of the RE-MEDY study was to compare the safety and efficacy of oral dabigatran 
etexilate (150 mg bid) to warfarin (target INR 2.0-3.0) for the long-term treatment and prevention of 
recurrent, symptomatic DVT and/or PE. A total of 2,866 patients were randomised and 2,856 patients 
were treated. Duration of dabigatran etexilate treatment ranged from 6 to 36 months (median 
534.0 days). For patients randomised to warfarin, the median time in therapeutic range (INR 2.0-3.0) 
was 64.9 %.

RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior 
to warfarin (non-inferiority margin: 2.85 for hazard ratio and 2.8 for risk difference). 



66

Table 28: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of 
DVT and/or PE) until the end of post-treatment period for the RE-MEDY study

Dabigatran etexilate
150 mg twice daily

Warfarin

Treated patients 1430 1426 
Recurrent symptomatic VTE and VTE-
related death

26 (1.8 %) 18 (1.3 %)

Hazard ratio vs warfarin
(95% confidence interval)

1.44
(0.78, 2.64)

non-inferiority margin 2.85 
Patients with event  at 18 months 22 17
Cumulative risk at 
18 months (%)

1.7 1.4

Risk difference vs. warfarin (%) 0.4

95% confidence interval
non-inferiority margin 2.8
Secondary efficacy endpoints
Recurrent symptomatic VTE and all-
cause deaths

42 (2.9 %) 36 (2.5 %)

95 % confidence interval 2.12, 3.95 1.77, 3.48
Symptomatic DVT 17 (1.2 %) 13 (0.9 %)
95 % confidence interval 0.69, 1.90 0.49, 1.55
Symptomatic PE 10 (0.7 %) 5 (0.4 %)
95 % confidence interval 0.34, 1.28 0.11, 0.82
VTE-related deaths 1 (0.1 %) 1 (0.1 %)
95 % confidence interval 0.00, 0.39 0.00, 0.39
All-cause deaths 17 (1.2 %) 19 (1.3 %)
95 % confidence interval 0.69, 1.90 0.80, 2.07

The objective of the RE-SONATE study was to evaluate superiority of dabigatran etexilate versus 
placebo for the prevention of recurrent symptomatic DVT and/or PE in patients who had already 
completed 6 to 18 months of treatment with VKA. The intended therapy was 6 months dabigatran 
etexilate 150 mg twice daily without need for monitoring. 

RE-SONATE demonstrated dabigatran etexilate was superior to placebo for the prevention of 
recurrent symptomatic DVT/PE events including unexplained deaths, with a risk reduction from 5.6% 
to 0.4% (relative risk reduction 92% based on hazard ratio ) during the treatment period (p<0.0001). 
All secondary and sensitivity analyses of the primary endpoint and all secondary endpoints showed 
superiority of dabigatran etexilate over placebo.

The study included observational follow-up for 12 months after the conclusion of treatment. After 
discontinuation of study medication the effect was maintained until the end of the follow-up, 
indicating that the initial treatment effect of dabigatran etexilate was sustained. No rebound effect was 
observed. At the end of the follow-up VTE events in patients treated with dabigatran etexilate was 
6.9% vs. 10.7% among the placebo group (hazard ratio 0.61 (95% CI 0.42, 0.88), p=0.0082).



67

Table 29: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of 
DVT and/or PE) until the end of post-treatment period for the RE-SONATE study.

Dabigatran etexilate
150 mg twice daily

Placebo

Treated patients 681 662 
Recurrent symptomatic 
VTE and related deaths

3 (0.4 %) 37 (5.6 %)

Hazard Ratio vs 
placebo
(95% confidence 
interval)

0.08
(0.02, 0.25)

p-value for superiority <0.0001
Secondary efficacy  
endpoints
Recurrent symptomatic 
VTE and all-cause 
deaths

3 (0.4 %) 37 (5.6 %)

95% confidence interval 0.09, 1.28 3.97, 7.62
Symptomatic DVT 2 (0.3 %) 23 (3.5 %)
95% confidence interval 0.04, 1.06 2.21, 5.17
Symptomatic PE 1 (0.1 %) 14 (2.1 %)
95% confidence interval 0.00, 0.82 1.16, 3.52
VTE-related deaths 0 (0) 0 (0)
95% confidence interval 0.00, 0.54 0.00, 0.56
Unexplained deaths 0 (0) 2 (0.3 %)
95% confidence interval 0.00, 0.54 0.04, 1.09
All-cause deaths 0 (0) 2 (0.3 %)
95% confidence interval 0.00, 0.54 0.04, 1.09

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

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

Paediatric population

Clinical trials in VTE prophylaxis following major joint replacement surgery
Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors

The European Medicines Agency has waived the obligation to submit the results of studies with 
Pradaxa in all subsets of 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
and the indication of prevention of stroke and systemic embolism in patients with NVAF (see section 
4.2 for information on paediatric use).



68

Treatment of VTE and prevention of recurrent VTE in paediatric patients

The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilate 
compared to standard of care (SOC) for the treatment of VTE in paediatric patients from birth to less 
than 18 years of age. The study was designed as an open-label, randomised, parallel-group, non-
inferiority study. Patients enrolled were randomised according to a 2:1 scheme to either an age-
appropriate formulation (capsules, coated granules or oral solution) of dabigatran etexilate (doses 
adjusted for age and weight) or SOC comprised of low molecular weight heparins (LMWH) or 
vitamin K antagonists (VKA) or fondaparinux (1 patient 12 years old). The primary endpoint was a 
composite endpoint of patients with complete thrombus resolution, freedom from recurrent VTE, and 
freedom from mortality related to VTE. Exclusion criteria included active meningitis, encephalitis and 
intracranial abscess.
In total, 267 patients had been randomised. Of those, 176 patients were treated with dabigatran 
etexilate and 90 patients according to SOC (1 randomised patient was not treated). 168 patients were 
12 to less than 18 years old, 64 patients 2 to less than 12 years, and 35 patients were younger than 
2 years.
Of the 267 randomised patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients 
(42.2%) in the SOC group met the criteria for the composite primary endpoint (complete thrombus 
resolution, freedom from recurrent VTE, and freedom from mortality-related VTE). The 
corresponding rate difference demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent 
results were also generally observed across subgroups: there were no significant differences in the 
treatment effect for the subgroups by age, sex, region, and presence of certain risk factors. For the 
3 different age strata, the proportions of patients that met the primary efficacy endpoint in the 
dabigatran etexilate and SOC groups, respectively, were 13/22 (59.1%) and 7/13 (53.8%) for patients 
from birth to <2 years, 21/43 (48.8%) and 12/21 (57.1%) for patients aged 2 to <12 years, and 47/112 
(42.0%) and 19/56 (33.9%) for patients aged 12 to <18 years.
Adjudicated major bleeds were reported for 4 patients (2.3%) in the dabigatran etexilate group and 
2 patients (2.2%) in the SOC group. There was no statistically significant difference in the time to first 
major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients 
(24.4%) in the SOC arm had any adjudicated bleeding event, most of them categorised as minor. The 
combined endpoint of adjudicated major bleeding event (MBE) or clinically relevant non-major 
(CRNM) bleeding (on treatment) was reported for 6 (3.4%) patients in the dabigatran etexilate group 
and 3 (3.3%) patients in the SOC group.

An open label, single arm safety prospective cohort, multi-centre, phase III study (1160.108) was
conducted to assess the safety of dabigatran etexilate for the prevention of recurrent VTE in paediatric 
patients from birth to less than 18 years. Patients who required further anticoagulation due to the 
presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 
3 months) or after completing the DIVERSITY study were allowed to be included in the study. 
Eligible patients received age and weight adjusted doses of an age-appropriate formulation (capsules, 
coated granules or oral solution) of dabigatran etexilate until the clinical risk factor resolved, or up to a 
maximum of 12 months. The primary endpoints of the study included the recurrence of VTE, major 
and minor bleeding events and the mortality (overall and related to thrombotic or thromboembolic 
events) at 6 and 12 months. Outcome events were adjudicated by an independent blinded adjudication 
committee.
Overall, 214 patients entered the study; among them 162 patients in age stratum 1 (from 12 to less 
than 18 years of age), 43 patients in age stratum 2 (from 2 to less than 12 years of age) and 9 patients 
in age stratum 3 (from birth to less than 2 years of age). During the on-treatment period, 3 patients 
(1.4%) had an adjudication-confirmed recurrent VTE within the first 12 months after treatment start. 
Adjudication-confirmed bleeding events during the on-treatment period were reported for 48 patients 
(22.5%) within the first 12 months. The majority of the bleeding events were minor. In 3 patients 
(1.4%), an adjudication-confirmed major bleeding event occurred within the first 12 months. For 
3 patients (1.4%), adjudication-confirmed CRNM bleeding was reported within the first 12 months. 
No on-treatment deaths occurred. During the on-treatment period, 3 patients (1.4%) developed post-
thrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.



69

5.2 Pharmacokinetic properties

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

The oral bioavailability may be increased by 75% after a single dose and 37% at steady state 
compared to the reference capsule formulation when the pellets are taken without the 
Hydroxypropylmethylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsules 
should always be preserved in clinical use to avoid unintentionally increased bioavailability of 
dabigatran etexilate (see section 4.2).

Distribution

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

Biotransformation

Metabolism and excretion of dabigatran were studied following a single intravenous dose of 
radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived 
radioactivity was eliminated primarily in the urine (85%). Faecal excretion accounted for 6% of the 
administered dose. Recovery of the total radioactivity ranged from 88-94% of the administered dose 
by 168 hours post dose.
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four 
positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10% of total 
dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical 
methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of 
approximately 100 mL/min corresponding to the glomerular filtration rate.

Elimination

Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 
11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was 



70

observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as 
shown in table 30.

Special populations

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

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

Table 30: Half-life of total dabigatran in healthy subjects and subjects with impaired renal 
function.

glomerular filtration rate 
(CrCL,)

[mL/min]

gMean (gCV %; range) 
half-life 

[h] 
?80 13.4 (25.7 %; 11.0-21.6)

?50-<80 15.3 (42.7 %;11.7-34.1) 

?30-<50 18.4 (18.5 %;13.3-23.0) 
<30 27.2(15.3 %; 21.6-35.0)

Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open label 
randomised pharmacokinetic study in NVAF patients with severe renal impairment (defined as 
creatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate 75 mg twice daily.
This regimen resulted in a geometric mean trough concentration of 155 ng/ml (gCV of 76.9 %), 
measured immediately before administration of the next dose and in a geometric mean peak 
concentration of 202 ng/ml (gCV of 70.6 %) measured two hours after the administration of the last 
dose.

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

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

The median CrCL in the RE-COVER study was 100.4 mL/min. 21.7% of patients had mild renal 
impairment (CrCL >50 - <80 mL/min) and 4.5% of patients had a moderate renal impairment (CrCL 
between 30 and 50 mL/min). Patients with mild and moderate renal impairment had at steady state an 
average 1.8-fold and 3.6-fold higher pre-dose dabigatran plasma concentrations compared with 
patients with CrCL >80 mL/min, respectively. Similar values for CrCL were found in RE-COVER II.

The median CrCL in the RE-MEDY and RE-SONATE studies were 99.0 mL/min and 99.7 mL/min, 
respectively. 22.9% and 22.5% of the patients had a CrCL >50-<80 mL/min, and 4.1% and 4.8% had 
a CrCL between 30 and 50 mL/min in the RE-MEDY and RE-SONATE studies.



71

Elderly patients
Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60% in the 
AUC and of more than 25% in Cmax compared to young subjects.
The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31% 
higher trough concentration for subjects ?75 years and by about 22% lower trough level for subjects 
<65 years compared to subjects between 65 and 75 years (see sections 4.2 and 4.4).

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

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

Gender
Active substance exposure in the primary VTE prevention studies was about 40% to 50% higher in 
female patients and no dose adjustment is recommended. In atrial fibrillation patients females had on 
average 30% higher trough and post-dose concentrations. No dose adjustment is required (see section 
4.2).

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

Paediatric population
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.

Pharmacokinetic interactions

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

5.3 Preclinical safety data

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

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

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



72

In a juvenile toxicity study conducted in Han Wistar rats, mortality was associated with bleeding 
events at similar exposures, at which bleeding was seen in adult animals. In both adult and juvenile 
rats, mortality is considered to be related to the exaggerated pharmacological activity of dabigatran in 
association with the exertion of mechanical forces during dosing and handling. Data of the juvenile 
toxicity study did neither indicate an increased sensitivity in toxicity, nor any toxicity specific to 
juvenile animals.

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

Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in the environment.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Tartaric acid
Acacia
Hypromellose
Dimeticone 350
Talc
Hydroxypropylcellulose

Capsule shell
Carrageenan
Potassium chloride
Titanium dioxide
Indigo carmine
Hypromellose

Black printing ink
Shellac
Iron oxide black
Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister and bottle

3 years

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

6.4 Special precautions for storage

Blister

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



73

Bottle

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

6.5 Nature and contents of container

Perforated aluminium unit dose blisters of 10 x 1 hard capsules. Each carton contains 10, 30 or 60 hard 
capsules.
Multipack containing 3 packs of 60 x 1 hard capsules (180 hard capsules). Each individual pack of the 
multipack contains 6 perforated aluminium unit dose blisters of 10 x 1 hard capsules.
Multipack containing 2 packs of 50 x 1 hard capsules (100 hard capsules). Each individual pack of the 
multipack contains 5 perforated aluminium unit dose blisters of 10 x 1 hard capsules.
Perforated aluminium unit dose white blisters of 10 x 1 hard capsules. Each carton contains 60 hard 
capsules.

Polypropylene bottle with a screw cap containing 60 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

? One individual blister should be teared off from the blister card along the perforated line.
? The backing foil should be peeled off and the capsule can be removed.
? The hard capsules should not be pushed through the blister foil.
? The blister foil should only be peeled off, when a hard capsule is required.

When taking a hard capsule out of the bottle, the following instructions should be observed:

? The cap opens by pushing and turning.
? After taking the capsule out, the cap should be returned on the bottle right away and the bottle 

should be tightly closed.

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/005
EU/1/08/442/006
EU/1/08/442/007
EU/1/08/442/008
EU/1/08/442/014
EU/1/08/442/015
EU/1/08/442/018



74

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 March 2008
Date of latest renewal: 08 January 2018

10. DATE OF REVISION OF THE TEXT

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

http://www.ema.europa.eu/


75

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

Capsules with light blue, opaque cap and white, opaque body of size 0 (approx. 22 x 8 mm) filled with 
yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with 
“R150”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 birth to less than 18 years of age.

For age appropriate dose forms, see section 4.2.

4.2 Posology and method of administration

Posology

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. Pradaxa powder and solvent for oral solution should 
only be used in children aged less than 1 year.

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 for the age and weight 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.



76

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. 



77

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.



78

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).



79

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 age and weight as 
shown in table 3. The table provides the single doses which are to be administered twice daily. The 
dose should be adjusted according to age and weight as treatment progresses.

Table 3: Single dabigatran etexilate dose in milligrams (mg) by weight in kilograms (kg) and 
age in years of the patient to be administered twice daily

Age in years
8 to <9 9 to 

<10
10 to 
<11

11 to 
<12

12 to 
<13

13 to 
<14

14 to 
<15

15 to 
<16

16 to 
<17

17 to 
<18

W
ei

gh
t 

[k
g]

>81 300 mg
as two 150 mg capsules

or
four 75 mg capsules

71 to <81

61 to <71

51 to <61

260 mg
as one 110 mg plus one 150 mg capsule

or
one 110 mg plus two 75 mg capsules

41 to <51
220 mg

as two 110 mg capsules

31 to <41
185 mg

as one 75 mg plus one 110 mg capsule

26 to <31
150 mg

as one 150 mg capsule
or

two 75 mg capsules21 to <26

16 to <21
One 110 mg capsule

13 to <16

11 to <13
One 
75 mg
capsule

Means that no dosing recommendation can be provided.



80

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.

Treatment with dabigatran etexilate in paediatric patients with eGFR <50 mL/min/1.73m2 is 
contraindicated (see section 4.3).

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



81

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

4.3 Contraindications

? Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
? Severe renal impairment (CrCL <30 mL/min) in adult patients
? eGFR <50 mL/min/1.73m2 in paediatric patients
? Active clinically significant bleeding
? Lesion or condition, if considered a significant risk factor for major bleeding. This may include 

current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of 
bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent 
intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous 
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

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

? Hepatic impairment or liver disease expected to have any impact on survival
? Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, 

cyclosporine, itraconazole, dronedarone and the fixed-dose combination 
glecaprevir/pibrentasvir (see section 4.5)

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

4.4 Special warnings and precautions for use

Haemorrhagic risk

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

For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the 
anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available. 
The efficacy and safety of idarucizumab have not been established in paediatric patients. 
Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, 
coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet 
concentrates are other possible options (see also section 4.9).

In clinical trials, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) 
bleeding. An increased risk was seen in the elderly (?75 years) for the 150 mg twice daily dose 
regimen. Further risk factors (see also table 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.



82

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.



83

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.



84

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)



85

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/1.73m2)

Stop dabigatran before elective surgery

>80 24 hours before
50 – 80 2 days before
<50 These patients have not been studied (see section 4.3).

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

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

Postoperative phase

Dabigatran etexilate treatment should be resumed / 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.



86

Myocardial Infarction (MI) 

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

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

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

Active cancer patients (DVT/PE, paediatric VTE)

The efficacy and safety have not been established for DVT/PE patients with active cancer. There is 
limited data on efficacy and safety for paediatric patients with active cancer.

Paediatric population

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

4.5 Interaction with other medicinal products and other forms of interaction

Transporter interactions

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp 
inhibitors (see table 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, Based on in vitro results a similar effect as with ketoconazole may be expected. 



87

cyclosporine
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 AUC?,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 AUC?,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 AUC?,ss and Cmax,ss
was reduced to 1.27-fold and 1.23-fold, respectively, compared with dabigatran 



88

etexilate given alone. This staggered intake is the recommended administration for 
start of ticagrelor with a loading dose.

Concomitant administration of 90 mg ticagrelor b.i.d. (maintenance dose) with 
110 mg dabigatran etexilate increased the adjusted dabigatran AUC?,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 



89

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 AUC?,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 AUC?,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.



90

Interactions linked to dabigatran etexilate and dabigatran metabolic profile

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

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; 
thereof approximately 35,000 patients were treated with dabigatran etexilate.
In total, 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.



91

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



92

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 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 



93

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%. 



94

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 %) 0.60 (0.36, 0.99)
           Intracranial
           Bleeding

2 (0.1 %) 4 (0.2 %) 0.50 (0.09, 2.74)

           Major GI bleeding 10 (0.4 %) 12 (0.5 %) 0.83 (0.36, 1.93)
           Life-threatening
           bleed

4 (0.2 %) 6 (0.2 %) 0.66 (0.19, 2.36)

Major bleeding 
events/clinically relevant 
bleeds 

109 (4.4 %) 189 (7.7 %) 0.56 (0.45, 0.71)

Any bleeding 354 (14.4 %) 503 (20.4 %) 0.67 (0.59, 0.77)
          Any GI bleeding 70 (2.9 %) 55 (2.2 %) 1.27 (0.90, 1.82)

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

Table 14 shows bleeding events in pivotal study RE-MEDY testing prevention of DVT and PE. Some 
bleeding events (MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of 5% 
in patients receiving dabigatran etexilate as compared with those receiving warfarin.

Table 14: Bleeding events in study RE-MEDY testing prevention of DVT and PE

Dabigatran etexilate
150 mg twice daily 

Warfarin Hazard ratio vs 
warfarin 

(95% Confidence 
Interval)

Treated patients 1,430 1,426 
Majory bleeding events 13 (0.9 %) 25 (1.8 %) 0.54 (0.25, 1.16)

Intracranial bleeding 2 (0.1 %) 4 (0.3 %) Not calculable*
Major GI bleeding 4 (0.3%) 8 (0.5%) Not calculable* 
Life-threatening 
bleed

1 (0.1 %) 3 (0.2 %)) Not calculable*

Major bleeding event 
/clinically relevant bleeds 

80 (5.6 %) 145 (10.2 %) 0.55 ( 0.41, 0.72)

Any bleeding 278 (19.4 %) 373 (26.2 %) 0.71 (0.61, 0.83)

Any GI bleeds 45 (3.1%) 32 (2.2%) 1.39 (0.87, 2.20)
*HR not estimable as there is no event in either one cohort/treatment 

Table 15 shows bleeding events in pivotal study RE-SONATE testing prevention of DVT and PE. The 
rate of the combination of MBEs/CRBEs and the rate of any bleeding was significantly lower at a 
nominal alpha level of 5% in patients receiving placebo as compared with those receiving dabigatran 
etexilate.



95

Table 15: Bleeding events in study RE-SONATE testing prevention of DVT and PE

Dabigatran etexilate
150 mg twice daily 

Placebo Hazard ratio vs 
placebo

(95% confidence 
interval)

Treated patients 684 659 
Major bleeding events 2 (0.3 %) 0 Not 

calculable*
Intracranial bleeding 0 0 Not 

calculable*
Major GI bleeding 2 (0.3%) 0 Not 

calculable*
Life-threatening 
bleeds

0 0 Not 
calculable*

Major bleeding event/clinical 
relevant bleeds

36 (5.3 %) 13 (2.0 %) 2.69 (1.43, 5.07)

Any bleeding 72 (10.5 %) 40 (6.1 %) 1.77 (1.20, 2.61)
Any GI bleeds 5 (0.7%) 2 (0.3%) 2.38 (0.46, 12.27)

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

Agranulocytosis and neutropenia

Agranulocytosis and neutropenia have been reported very rarely during post approval use of 
dabigatran etexilate. Because adverse reactions are reported in the postmarketing surveillance setting 
from a population of uncertain size, it is not possible to reliably determine their frequency. The 
reporting rate was estimated as 7 events per 1 million patient years for agranulocytosis and as 5 events 
per 1 million patient years for neutropenia.

Paediatric population

The safety of dabigatran etexilate in the treatment of VTE and prevention of recurrent VTE in 
paediatric patients was studied in two phase III trials (DIVERSITY and 1160.108). In total,
328 paediatric patients had been treated with dabigatran etexilate. The patients received age and 
weight adjusted doses of an age-appropriate formulation of dabigatran etexilate.

Overall, the safety profile in children is expected to be the same as in adults.

In total, 26% of paediatric patients treated with dabigatran etexilate for VTE and for prevention of 
recurrent VTE experienced adverse reactions.

Tabulated list of adverse reactions

Table 16 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 16: Adverse reactions

Frequency

SOC / Preferred term. treatment of VTE and prevention of recurrent VTE in 
paediatric patients

Blood and lymphatic system disorders



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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



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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. 

4.9 Overdose

Dabigatran etexilate doses beyond those recommended, expose the patient to increased risk of 
bleeding.

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

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

Management of bleeding complications

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

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

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

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


98

major bleedings.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic 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 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)

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



99

For patients with NVAF treated for prevention of stroke and systemic embolism with 150 mg 
dabigatran etexilate twice daily,
? the 90th percentile of dabigatran plasma concentrations measured at trough (10-16 hours after 

the previous dose) was about 200 ng/mL,
? an ECT at trough (10-16 hours after the previous dose), elevated approximately 3-fold upper 

limit of normal refers to the observed 90th percentile of ECT prolongation of 103 seconds,
? an aPTT ratio greater than 2-fold upper limit of normal (aPTT prolongation of about 

80 seconds), at trough (10-16 hours after the previous dose) reflects the 90th percentile of 
observations.

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

In patients treated for DVT and PE with 150 mg dabigatran etexilate twice daily, the dabigatran 
geometric mean trough concentration, measured within 10?16 hours after dose, at the end of the 
dosing interval (i.e. 12 hours after the 150 mg dabigatran evening dose), was 59.7 ng/ml, with a range 
of 38.6 - 94.5 ng/ml (25th-75th percentile range). For treatment of DVT and PE, with dabigatran 
etexilate 150 mg twice daily,
? the 90th percentile of dabigatran plasma concentrations measured at trough (10-16 hours after 

the previous dose) was about 146 ng/ml,
? an ECT at trough (10-16 hours after the previous dose), elevated approximately 2.3-fold 

compared to baseline refers to the observed 90th percentile of ECT prolongation of 74 seconds,
? the 90th percentile of aPTT at trough (10-16 hours after the previous dose) was 62 seconds, 

which would be 1.8-fold compared to baseline.

In patients treated for prevention of recurrent of DVT and PE with 150 mg dabigatran etexilate twice 
daily no pharmacokinetic data are available. 

Clinical efficacy and safety

Ethnic origin

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

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

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

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

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



100

p=0.1240, respectively). With improving monitoring of INR the observed benefits of dabigatran 
etexilate compared to warfarin diminish.

Tables 17-19 display details of key results in the overall population:

Table 17: Analysis of first occurrence of stroke or systemic embolism (primary endpoint) 
during the study period in RE-LY.

Dabigatran etexilate
110 mg twice daily

Dabigatran etexilate
150 mg twice daily

Warfarin 

Subjects randomised 6,015 6,076 6,022
Stroke and/or systemic 

embolism
Incidences (%) 183 (1.54) 135 (1.12) 203 (1.72)
Hazard ratio over 
warfarin (95 % CI)

0.89 (0.73, 1.09) 0.65 (0.52, 0.81)

p value superiority p=0.2721 p=0.0001
% refers to yearly event rate

Table 18: Analysis of first occurrence of ischemic or haemorrhagic strokes during the study 
period in RE-LY.

Dabigatran etexilate
110 mg twice daily

Dabigatran etexilate
150 mg twice daily

Warfarin 

Subjects randomised 6,015 6,076 6,022
Stroke

Incidences (%) 171 (1.44) 123 (1.02) 187 (1.59)
Hazard ratio vs. 
warfarin (95 % CI)

0.91 (0.74, 1.12) 0.64 (0.51, 0.81)

          p-value 0.3553 0.0001
Systemic embolism

Incidences (%) 15 (0.13) 13 (0.11) 21 (0.18)
Hazard ratio vs. 
warfarin (95 % CI)

0.71 (0.37, 1.38) 0.61 (0.30, 1.21)

          p-value 0.3099 0.1582
Ischemic stroke

Incidences (%) 152 (1.28) 104 (0.86) 134 (1.14)
Hazard ratio vs. 
warfarin (95 % CI) 

1.13 (0.89, 1.42) 0.76 (0.59, 0.98)

          p-value 0.3138 0.0351
Haemorrhagic stroke

Incidences (%) 14 (0.12) 12 (0.10) 45 (0.38)
Hazard ratio vs. 
warfarin (95 % CI)

0.31 (0.17, 0.56) 0.26 (0.14, 0.49)

          p-value 0.0001 <0.0001
% refers to yearly event rate



101

Table 19: Analysis of all cause and cardiovascular survival during the study period in RE-LY.

Dabigatran etexilate
110 mg twice daily

Dabigatran etexilate
150 mg twice daily

Warfarin 

Subjects randomised 6,015 6,076 6,022 
All-cause mortality

Incidences (%) 446 (3.75) 438 (3.64) 487 (4.13)
Hazard ratio vs. 
warfarin (95 % CI)

0.91 (0.80, 1.03) 0.88 (0.77, 1.00)

p-value 0.1308 0.0517
Vascular mortality

Incidences (%) 289 (2.43) 274 (2.28) 317 (2.69)
Hazard ratio vs. 
warfarin (95 % CI)

0.90 (0.77, 1.06) 0.85 (0.72, 0.99)

          p-value 0.2081 0.0430
% refers to yearly event rate

Tables 20-21 display results of the primary efficacy and safety endpoint in relevant sub-populations:

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

Table 20: Hazard Ratio and 95 % CI for stroke/systemic embolism by subgroups

Endpoint Dabigatran etexilate
110 mg twice daily vs. warfarin

Dabigatran etexilate
150 mg twice daily vs. warfarin

Age (years)
<65 1.10 (0.64, 1.87) 0.51 (0.26, 0.98)

65? and <75 0.86 (0.62, 1.19) 0.67 (0.47, 0.95)
?75 0.88 (0.66, 1.17) 0.68 (0.50, 0.92)
?80 0.68 (0.44, 1.05) 0.67 (0.44, 1.02)

CrCL(mL/min)
30? and <50 0.89 (0.61, 1.31) 0.48 (0.31, 0.76)
50? and <80 0.91 (0.68, 1.20) 0.65 (0.47, 0.88)

?80 0.81 (0.51, 1.28) 0.69 (0.43, 1.12)

For the primary safety endpoint of major bleeding there was an interaction of treatment effect and age. 
The relative risk of bleeding with dabigatran compared to warfarin increased with age. Relative risk 
was highest in patients ?75 years. The concomitant use of antiplatelets ASA or clopidogrel 
approximately doubles MBE rates with both dabigatran etexilate and warfarin. There was no 
significant interaction of treatment effects with the subgroups of renal function and CHADS2 score.



102

Table 21: Hazard Ratio and 95 % CI for major bleeds by subgroups

Endpoint Dabigatran etexilate
110 mg twice daily vs. warfarin

Dabigatran etexilate
150 mg twice daily vs. warfarin

Age (years)
<65 0.32 (0.18, 0.57) 0.35 (0.20, 0.61)

65? and <75 0.71 (0.56, 0.89) 0.82 (0.66, 1.03)
?75 1.01 (0.84, 1.23) 1.19 (0.99, 1.43)
?80 1.14 (0.86, 1.51) 1.35 (1.03, 1.76)

CrCL(mL/min)
30? and <50 1.02 (0.79, 1.32) 0.94 (0.73, 1.22)
50? and <80 0.75 (0.61, 0.92) 0.90 (0.74, 1.09)

?80 0.59 (0.43, 0.82) 0.87 (0.65, 1.17)
ASA use 0.84 (0.69, 1.03) 0.97 (0.79, 1.18)

Clopidogrel use 0.89 (0.55, 1.45) 0.92 (0.57, 1.48)

RELY-ABLE (Long term multi-center extension of dabigatran treatment in patients with atrial 
fibrillation who completed the RE-LY trial)

The RE-LY extension study (RELY-ABLE) provided additional safety information for a cohort of 
patients which continued the same dose of dabigatran etexilate as assigned in the RE-LY trial. Patients 
were eligible for the RELY-ABLE trial if they had not permanently discontinued study medication at 
the time of their final RE-LY study visit. Enrolled patients continued to receive the same double-blind 
dabigatran etexilate dose randomly allocated in RE-LY, for up to 43 months of follow up after RE-LY 
(total mean follow-up RE-LY + RELY-ABLE, 4.5 years). There were 5897 patients enrolled, 
representing 49% of patients originally randomly assigned to receive dabigatran etexilate in RE-LY 
and 86% of RELY-ABLE–eligible patients. 
During the additional 2.5 years of treatment in RELY-ABLE, with a maximum exposure of over 
6 years (total exposure in RELY + RELY-ABLE), the long-term safety profile of dabigatran etexilate 
was confirmed for both test doses 110 mg b.i.d. and 150 mg b.i.d.. No new safety findings were 
observed.
The rates of outcome events including, major bleed and other bleeding events were consistent with 
those seen in RE-LY.

Data from non-interventional studies

A non-interventional study (GLORIA-AF) prospectively collected (in its second phase) safety and 
effectiveness data in newly diagnosed NVAF patients on dabigatran etexilate in a real-world setting. 
The study included 4,859 patients on dabigatran etexilate (55% treated with 150 mg bid, 43% treated 
with 110 mg bid, 2% treated with 75 mg bid). Patients were followed-up for 2 years. The mean 
CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. Mean on-therapy follow-up time was 
18.3 months. Major bleeding occurred in 0.97 per 100 patient-years. Life-threatening bleeding was 
reported in 0.46 per 100 patient-years, intracranial haemorrhage in 0.17 per 100 patient-years and 
gastrointestinal bleeding in 0.60 per 100 patient-years. Stroke occurred in 0.65 per 100 patient-years. 

In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157-164] in more 
than 134,000 elderly patients with NVAF in the United States (contributing more than 37,500 patient-
years of on-therapy follow-up time) dabigatran etexilate (84% patients treated with 150 mg bid, 16% 
patients treated with 75 mg bid) was associated with a reduced risk of ischemic stroke (hazard ratio 
0.80, 95% confidence interval [CI] 0.67 – 0.96), intracranial haemorrhage (hazard ratio 0.34, CI 0.26 –
0.46), and mortality (hazard ratio 0.86, CI 0.77 – 0.96) and increased risk of gastrointestinal bleeding 

(hazard ratio 1.28, CI 1.14 – 1.44) compared to warfarin. No difference was found for major bleeding 
(hazard ratio 0.97, CI 0.88 – 1.07).

These observations in real-world settings are consistent with the established safety and efficacy profile 
for dabigatran etexilate in the RE-LY study in this indication.



103

Patients undergoing catheter ablation for atrial fibrillation

A prospective, randomised, open-label, multicenter, exploratory study with blinded, centrally 
adjudicated endpoint evaluation (RE-CIRCUIT) was conducted in 704 patients who were under stable 
anticoagulant treatment. The study compared 150 mg twice daily uninterrupted dabigatran etexilate 
with uninterrupted INR-adjusted warfarin in catheter ablation of paroxysmal or persistent atrial 
fibrillation. Of the 704 enrolled patients, 317 underwent atrial fibrillation ablation on uninterrupted 
dabigatran and 318 underwent atrial fibrillation ablation on uninterrupted warfarin. All patients 
underwent a Trans-oesophageal Echocardiography (TEE) prior to catheter ablation. The primary 
outcome (adjudicated major bleeding according to ISTH criteria) occurred in 5 (1.6%) patients in the 
dabigatran etexilate group and 22 (6.9%) patients in the warfarin group (risk difference ?5.3%; 95% 
CI ?8.4, ?2.2; P=0.0009). There was no stroke/systemic embolism/TIA (composite) event in the 
dabigatran etexilate arm, and one event (TIA) in the warfarin arm from the time of ablation and until
8 weeks post-ablation. This exploratory study showed that dabigatran etexilate was associated with a 
significant reduction in MBE rate compared with INR-adjusted warfarin in the setting of ablation.

Patients who underwent percutaneous coronary intervention (PCI) with stenting

A prospective, randomised, open-label, blinded endpoint (PROBE) study (Phase IIIb) to evaluate dual-
therapy with dabigatran etexilate (110 mg or 150 mg bid) plus clopidogrel or ticagrelor (P2Y12 
antagonist) vs. triple-therapy with warfarin (adjusted to a INR 2.0 – 3.0) plus clopidogrel or ticagrelor 
and ASA was conducted in 2725 patients with non valvular atrial fibrillation who underwent a PCI 
with stenting (RE-DUAL PCI). Patients were randomised to dabigatran etexilate 110 mg bid dual-
therapy, dabigatran etexilate 150 mg bid dual-therapy or warfarin triple-therapy. Elderly patients 
outside of the United States (?80 years of age for all countries, ?70 years of age for Japan) were 
randomly assigned to the dabigatran etexilate 110 mg dual-therapy group or the warfarin triple-therapy 
group. The primary endpoint was a combined endpoint of major bleeds based on ISTH definition or 
clinically relevant non-major bleeding event.

The incidence of the primary endpoint was 15.4% (151 patients) in the dabigatran etexilate 110 mg 
dual-therapy group as compared with 26.9% (264 patients) in the warfarin triple-therapy group (HR 
0.52; 95% CI 0.42, 0.63; P<0.0001 for non-inferiority and P<0.0001 for superiority) and 20.2% 
(154 patients) in the dabigatran etexilate 150 mg dual-therapy group as compared with 25.7% 
(196 patients) in the corresponding warfarin triple-therapy group (HR 0.72; 95% CI 0.58, 0.88; 
P<0.0001 for non-inferiority and P=0.002 for superiority). As part of the descriptive analysis, TIMI 
(Thrombolysis In Myocardial Infarction) major bleeding events was lower in both dabigatran etexilate 
dual-therapy groups than in the warfarin triple-therapy group: 14 events (1.4%) in the dabigatran 
etexilate 110 mg dual-therapy group as compared with 37 events (3.8%) in the warfarin triple-therapy 
group (HR 0.37; 95% CI 0.20, 0.68; P=0.002) and 16 events (2.1%) in the dabigatran etexilate 150 mg 
dual-therapy group as compared with 30 events (3.9%) in the corresponding warfarin triple-therapy 
group (HR 0.51; 95% CI 0.28, 0.93; P=0.03). Both dabigatran etexilate dual-therapy groups had lower 
rates of intracranial hemorrhage than the corresponding warfarin triple-therapy group: 3 events (0.3%) 
in the 110 mg dabigatran etexilate dual-therapy group as compared with 10 events (1.0%) in the 
warfarin triple-therapy group (HR 0.30; 95% CI 0.08, 1.07; P=0.06) and 1 event (0.1%) in the 150 mg 
dabigatran etexilate dual-therapy group as compared with 8 events (1.0%) in the corresponding 
warfarin triple-therapy group (HR 0.12; 95% CI 0.02, 0.98; P=0.047). The incidence of the composite 
efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, or systemic 
embolism) or unplanned revascularization in the two dabigatran etexilate dual-therapy groups 
combined was non-inferior to the warfarin triple-therapy group (13.7% vs. 13.4% respectively; HR 
1.04; 95% CI: 0.84, 1.29; P=0.0047 for non-inferiority).There were no statistical differences in the 
individual components of the efficacy endpoints between either dabigatran etexilate dual-therapy 
groups and warfarin triple-therapy.

This study demonstrated that dual-therapy with dabigatran etexilate and a P2Y12 antagonist 
significantly reduced the risk of bleeding vs. warfarin triple-therapy with non-inferiority for composite 
of thromboembolic events in patients with atrial fibrillation who underwent a PCI with stenting.



104

Treatment of DVT and PE in adults (DVT/PE treatment)

The efficacy and safety was investigated in two multi-center, randomised, double blind, parallel-
group, replicate studies RE-COVER and RE-COVER II. These studies compared dabigatran etexilate 
(150 mg bid) with warfarin (target INR 2.0-3.0) in patients with acute DVT and/or PE. The primary 
objective of these studies was to determine if dabigatran etexilate was non-inferior to warfarin in 
reducing the occurrence of the primary endpoint which was the composite of recurrent symptomatic 
DVT and/or PE and related deaths within the 6 month treatment period. 

In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were randomised and 
5,107 were treated.

The duration of treatment with fixed dose of dabigatran was 174.0 days without coagulation 
monitoring. For patients randomised to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) 
was 60.6%. 

The trials, demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior 
to the treatment with warfarin (non-inferiority margin for RE-COVER and RE-COVER II: 3.6 for risk 
difference and 2.75 for hazard ratio).

Table 22: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of 
DVT and/or PE) until the end of post-treatment period for the pooled studies RE-
COVER and RE-COVER II

Dabigatran etexilate
150 mg twice daily 

Warfarin

Treated patients 2,553 2,554 

Recurrent symptomatic 
VTE and VTE-related 
death

68 ( 2.7 %) 62 ( 2.4 %)

Hazard ratio vs warfarin
(95% confidence 
interval)

1.09
(0.77, 1.54)

Secondary efficacy 
endpoints
Recurrent symptomatic 
VTE and all-cause 
deaths

109 (4.3 %) 104 (4.1 %)

95 % confidence 
interval 

3.52, 5.13 3.34, 4.91

Symptomatic DVT 45 (1.8 %) 39 (1.5 %)
95 % confidence 
interval

1.29, 2.35 1.09, 2.08

Symptomatic PE 27 (1.1 %) 26 (1.0 %)
95 % confidence 
interval

0.70, 1.54 0.67, 1.49

VTE-related deaths 4 (0.2 %) 3 (0.1 %)
95 % confidence 
interval

0.04, 0.40 0.02, 0.34

All-cause deaths 51 (2.0 %) 52 (2.0 %)
95 % confidence 
interval

1.49, 2.62 1.52, 2.66



105

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

Two randomised, parallel group, double-blind studies were performed in patients previously treated 
with anticoagulation therapy. RE-MEDY, warfarin controlled study, enrolled patients already treated 
for 3 to 12 months with the need for further anticoagulant treatment and RE-SONATE, the placebo 
controlled study, enrolled patients already treated for 6 to 18 months with Vitamin K inhibitors.

The objective of the RE-MEDY study was to compare the safety and efficacy of oral dabigatran 
etexilate (150 mg bid) to warfarin (target INR 2.0-3.0) for the long-term treatment and prevention of 
recurrent, symptomatic DVT and/or PE. A total of 2,866 patients were randomised and 2,856 patients 
were treated. Duration of dabigatran etexilate treatment ranged from 6 to 36 months (median 
534.0 days). For patients randomised to warfarin, the median time in therapeutic range (INR 2.0-3.0) 
was 64.9%. 

RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior 
to warfarin (non-inferiority margin: 2.85 for hazard ratio and 2.8 for risk difference).

Table 23: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of 
DVT and/or PE) until the end of post-treatment period for the RE-MEDY study

Dabigatran etexilate
150 mg twice daily

Warfarin

Treated patients 1430 1426 
Recurrent symptomatic VTE and VTE-
related death

26 (1.8 %) 18 (1.3 %)

Hazard ratio vs warfarin 
(95% confidence interval)

1.44
(0.78, 2.64)

non-inferiority margin 2.85
Patients with event  at 18 months 22 17
Cumulative risk at 
18 months (%)

1.7 1.4

Risk difference vs. warfarin (%) 0.4

95% confidence interval
non-inferiority margin 2.8
Secondary efficacy endpoints
Recurrent symptomatic VTE and all-
cause deaths

42 (2.9 %) 36 (2.5 %)

95 % confidence interval 2.12, 3.95 1.77, 3.48
Symptomatic DVT 17 (1.2 %) 13 (0.9 %)
95 % confidence interval 0.69, 1.90 0.49, 1.55
Symptomatic PE 10 (0.7 %) 5 (0.4 %)
95 % confidence interval 0.34, 1.28 0.11, 0.82
VTE-related deaths 1 (0.1 %) 1 (0.1 %)
95 % confidence interval 0.00, 0.39 0.00, 0.39
All-cause deaths 17 (1.2 %) 19 (1.3 %)
95 % confidence interval 0.69, 1.90 0.80, 2.07

The objective of the RE-SONATE study was to evaluate superiority of dabigatran etexilate versus 
placebo for the prevention of recurrent symptomatic DVT and/or PE in patients who had already 
completed 6 to 18 months of treatment with VKA. The intended therapy was 6 months dabigatran 
etexilate 150 mg twice daily without need for monitoring. 

RE-SONATE demonstrated dabigatran etexilate was superior to placebo for the prevention of 
recurrent symptomatic DVT/PE events including unexplained deaths, with a risk reduction from 5.6% 
to 0.4% (relative risk reduction 92% based on hazard ratio) during the treatment period (p<0.0001). 



106

All secondary and sensitivity analyses of the primary endpoint and all secondary endpoints showed 
superiority of dabigatran etexilate over placebo.

The study included observational follow-up for 12 months after the conclusion of treatment. After 
discontinuation of study medication the effect was maintained until the end of the follow-up, 
indicating that the initial treatment effect of dabigatran etexilate was sustained. No rebound effect was 
observed. At the end of the follow-up VTE events in patients treated with dabigatran etexilate was 
6.9% vs. 10.7% among the placebo group (hazard ratio 0.61 (95% CI 0.42, 0.88), p=0.0082).

Table 24: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of 
DVT and/or PE) until the end of post-treatment period for the RE-SONATE study.

Dabigatran etexilate
150 mg twice daily

Placebo

Treated patients 681 662 
Recurrent symptomatic 
VTE and related deaths

3 (0.4 %) 37 (5.6 %)

Hazard Ratio vs placebo 
(95% confidence 
interval)

0.08
(0.02, 0.25)

p-value for superiority <0.0001
Secondary efficacy  
endpoints
Recurrent symptomatic 
VTE and all-cause 
deaths

3 (0.4 %) 37 (5.6 %)

95% confidence interval 0.09, 1.28 3.97, 7.62
Symptomatic DVT 2 (0.3 %) 23 (3.5 %)
95% confidence interval 0.04, 1.06 2.21, 5.17
Symptomatic PE 1 (0.1 %) 14 (2.1 %)
95% confidence interval 0.00, 0.82 1.16, 3.52
VTE-related deaths 0 (0) 0 (0)
95% confidence interval 0.00, 0.54 0.00, 0.56
Unexplained deaths 0 (0) 2 (0.3 %)
95% confidence interval 0.00, 0.54 0.04, 1.09
All-cause deaths 0 (0) 2 (0.3 %)
95% confidence interval 0.00, 0.54 0.04, 1.09

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

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



107

Paediatric population

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

The European Medicines Agency has waived the obligation to submit the results of studies with 
Pradaxa in all subsets of the paediatric population for the indication of prevention of stroke and 
systemic embolism in patients with NVAF (see section 4.2 for information on paediatric use).

Treatment of VTE and prevention of recurrent VTE in paediatric patients

The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilate 
compared to standard of care (SOC) for the treatment of VTE in paediatric patients from birth to less 
than 18 years of age. The study was designed as an open-label, randomised, parallel-group, non-
inferiority study. Patients enrolled were randomised according to a 2:1 scheme to either an age-
appropriate formulation (capsules, coated granules or oral solution) of dabigatran etexilate (doses 
adjusted for age and weight) or SOC comprised of low molecular weight heparins (LMWH) or 
vitamin K antagonists (VKA) or fondaparinux (1 patient 12 years old). The primary endpoint was a 
composite endpoint of patients with complete thrombus resolution, freedom from recurrent VTE, and 
freedom from mortality related to VTE. Exclusion criteria included active meningitis, encephalitis and 
intracranial abscess.
In total, 267 patients had been randomised. Of those, 176 patients were treated with dabigatran 
etexilate and 90 patients according to SOC (1 randomised patient was not treated). 168 patients were 
12 to less than 18 years old, 64 patients 2 to less than 12 years, and 35 patients were younger than 
2 years. 
Of the 267 randomised patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients 
(42.2%) in the SOC group met the criteria for the composite primary endpoint (complete thrombus 
resolution, freedom from recurrent VTE, and freedom from mortality-related VTE). The 
corresponding rate difference demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent 
results were also generally observed across subgroups: there were no significant differences in the 
treatment effect for the subgroups by age, sex, region, and presence of certain risk factors. For the 
3 different age strata, the proportions of patients that met the primary efficacy endpoint in the 
dabigatran etexilate and SOC groups, respectively, were 13/22 (59.1%) and 7/13 (53.8%) for patients 
from birth to <2 years, 21/43 (48.8%) and 12/21 (57.1%) for patients aged 2 to <12 years, and 47/112 
(42.0%) and 19/56 (33.9%) for patients aged 12 to <18 years.
Adjudicated major bleeds were reported for 4 patients (2.3%) in the dabigatran etexilate group and 
2 patients (2.2%) in the SOC group. There was no statistically significant difference in the time to first 
major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients 
(24.4%) in the SOC arm had any adjudicated bleeding event, most of them categorised as minor. The 
combined endpoint of adjudicated major bleeding event (MBE) or clinically relevant non-major 
(CRNM) bleeding (on treatment) was reported for 6 (3.4%) patients in the dabigatran etexilate group 
and 3 (3.3%) patients in the SOC group.

An open label, single arm safety prospective cohort, multi-centre, phase III study (1160.108) was 
conducted to assess the safety of dabigatran etexilate for the prevention of recurrent VTE in paediatric 
patients from birth to less than 18 years. Patients who required further anticoagulation due to the 
presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 
3 months) or after completing the DIVERSITY study were allowed to be included in the study. 
Eligible patients received age and weight adjusted doses of an age-appropriate formulation (capsules, 
coated granules or oral solution) of dabigatran etexilate until the clinical risk factor resolved, or up to a 
maximum of 12 months. The primary endpoints of the study included the recurrence of VTE, major 
and minor bleeding events and the mortality (overall and related to thrombotic or thromboembolic 
events) at 6 and 12 months. Outcome events were adjudicated by an independent blinded adjudication 
committee.
Overall, 214 patients entered the study; among them 162 patients in age stratum 1 (from 12 to less 
than 18 years of age), 43 patients in age stratum 2 (from 2 to less than 12 years of age) and 9 patients 
in age stratum 3 (from birth to less than 2 years of age). During the on-treatment period, 3 patients 
(1.4%) had an adjudication-confirmed recurrent VTE within the first 12 months after treatment start. 



108

Adjudication-confirmed bleeding events during the on-treatment period were reported for 48 patients 
(22.5%) within the first 12 months. The majority of the bleeding events were minor. In 3 patients 
(1.4%), an adjudication-confirmed major bleeding event occurred within the first 12 months. For 
3 patients (1.4%), adjudication-confirmed CRNM bleeding was reported within the first 12 months. 
No on-treatment deaths occurred. During the on-treatment period, 3 patients (1.4%) developed post-
thrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.

5.2 Pharmacokinetic properties

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

The oral bioavailability may be increased by 75% after a single dose and 37% at steady state 
compared to the reference capsule formulation when the pellets are taken without the 
Hydroxypropylmethylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsules 
should always be preserved in clinical use to avoid unintentionally increased bioavailability of 
dabigatran etexilate (see section 4.2).

Distribution

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

Biotransformation

Metabolism and excretion of dabigatran were studied following a single intravenous dose of 
radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived 
radioactivity was eliminated primarily in the urine (85%). Faecal excretion accounted for 6% of the
administered dose. Recovery of the total radioactivity ranged from 88-94% of the administered dose 
by 168 hours post dose.
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four 
positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10% of total 
dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical 



109

methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of 
approximately 100 mL/min corresponding to the glomerular filtration rate.

Elimination

Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 
11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was 
observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as 
shown in table 25.

Special populations

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

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

Table 25: Half-life of total dabigatran in healthy subjects and subjects with impaired renal 
function.

glomerular filtration rate 
(CrCL,)

[mL/min]

gMean (gCV %; range) 
half-life 

[h] 
?80 13.4 (25.7 %; 11.0-21.6)

?50-<80 15.3 (42.7 %;11.7-34.1) 

?30-<50 18.4 (18.5 %;13.3-23.0) 
<30 27.2(15.3 %; 21.6-35.0)

Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open label 
randomised pharmacokinetic study in NVAF patients with severe renal impairment (defined as 
creatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate 75 mg twice daily.
This regimen resulted in a geometric mean trough concentration of 155 ng/ml (gCV of 76.9%), 
measured immediately before administration of the next dose and in a geometric mean peak 
concentration of 202 ng/ml (gCV of 70.6%) measured two hours after the administration of the last 
dose.

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

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

The median CrCL in the RE-COVER study was 100.4 mL/min. 21.7% of patients had mild renal 
impairment (CrCL >50 - <80 mL/min) and 4.5% of patients had a moderate renal impairment (CrCL 



110

between 30 and 50 mL/min). Patients with mild and moderate renal impairment had at steady state an 
average 1.8-fold and 3.6-fold higher pre-dose dabigatran plasma concentrations compared with 
patients with CrCL >80 mL/min, respectively. Similar values for CrCL were found in RE-COVER II.

The median CrCL in the RE-MEDY and RE-SONATE studies were 99.0 mL/min and 99.7 mL/min, 
respectively. 22.9% and 22.5% of the patients had a CrCL >50-<80 mL/min, and 4.1% and 4.8% had 
a CrCL between 30 and 50 mL/min in the RE-MEDY and RE-SONATE studies.

Elderly patients
Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60% in the 
AUC and of more than 25% in Cmax compared to young subjects.
The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31% 
higher trough concentration for subjects ?75 years and by about 22% lower trough level for subjects 
<65 years compared to subjects between 65 and 75 years (see sections 4.2 and 4.4).

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

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

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

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

Paediatric population
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.

Pharmacokinetic interactions

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

5.3 Preclinical safety data

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

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



111

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

In a juvenile toxicity study conducted in Han Wistar rats, mortality was associated with bleeding 
events at similar exposures, at which bleeding was seen in adult animals. In both adult and juvenile 
rats, mortality is considered to be related to the exaggerated pharmacological activity of dabigatran in 
association with the exertion of mechanical forces during dosing and handling. Data of the juvenile 
toxicity study did neither indicate an increased sensitivity in toxicity, nor any toxicity specific to 
juvenile animals.

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

Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in the environment.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Tartaric acid
Acacia
Hypromellose
Dimeticone 350
Talc
Hydroxypropylcellulose

Capsule shell
Carrageenan
Potassium chloride
Titanium dioxide
Indigo carmine
Hypromellose

Black printing ink
Shellac
Iron oxide black
Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister and bottle
3 years

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



112

6.4 Special precautions for storage

Blister

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

Bottle

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

6.5 Nature and contents of container

Perforated aluminium unit dose blisters of 10 x 1 hard capsules. Each carton contains 10, 30 or 60 hard 
capsules.
Multipack containing 3 packs of 60 x 1 hard capsules (180 hard capsules). Each individual pack of the 
multipack contains 6 perforated aluminium unit dose blisters of 10 x 1 hard capsules.
Multipack containing 2 packs of 50 x 1 hard capsules (100 hard capsules). Each individual pack of the 
multipack contains 5 perforated aluminium unit dose blisters of 10 x 1 hard capsules.
Perforated aluminium unit dose white blisters of 10 x 1 hard capsules. Each carton contains 60 hard 
capsules.

Polypropylene bottle with a screw cap containing 60 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

? One individual blister should be teared off from the blister card along the perforated line.
? The backing foil should be peeled off and the capsule can be removed.
? The hard capsules should not be pushed through the blister foil.
? The blister foil should only be peeled off, when a hard capsule is required.

When taking a hard capsule out of the bottle, the following instructions should be observed:

? The cap opens by pushing and turning.
? After taking the capsule out, the cap should be returned on the bottle right away and the bottle 

should be tightly closed.

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/009
EU/1/08/442/010



113

EU/1/08/442/011
EU/1/08/442/012
EU/1/08/442/013
EU/1/08/442/016
EU/1/08/442/019

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 March 2008
Date of latest renewal: 08 January 2018

10. DATE OF REVISION OF THE TEXT

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

http://www.ema.europa.eu/


114

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 20 mg coated granules
Pradaxa 30 mg coated granules
Pradaxa 40 mg coated granules
Pradaxa 50 mg coated granules
Pradaxa 110 mg coated granules
Pradaxa 150 mg coated granules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet contains coated granules with 20 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 30 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 40 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 50 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 110 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 150 mg dabigatran etexilate (as mesilate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Coated granules.

Yellowish coated granules.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of venous thromboembolic events (VTE) and prevention of recurrent VTE in paediatric 
patients from birth to less than 18 years of age.

For age appropriate dose forms, see section 4.2.

4.2 Posology and method of administration

Posology

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. Pradaxa powder and solvent for oral solution should only 
be used in children aged less than 1 year.

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 for the age and weight 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.



115

The recommended dose of dabigatran etexilate coated granules is based on the patient’s age and 
weight as shown in tables 1 and 2. The tables provide the single doses which are to be administered 
twice daily. The dose should be adjusted according to age and weight as treatment progresses.

Table 1: Single dabigatran etexilate dose in milligrams (mg) for patients aged less than 
2.5 years. The dose depends on weight in kilograms (kg) and age in months or years of 
the patient and has to be administered twice daily.

Age in months Age in years

0 to 
<1

1 to 
<3

3 to 
<4

4 to 
<5

5 to 
<6

6 to 
<8

8 to 
<9

9 to 
<10

10 to 
<11

11 to 
<12

1 to 
<1.5

1.5 
to <2

2 to 
<2.5

W
ei

gh
t 

[k
g

]

21 to <26 140 180

16 to <21 110 110 140

13 to <16 80 100 100 110 140

11 to <13 70 70 80 80 80 100 100

9 to <11 50 60 60 60 60 70 70 80 80

7 to <9 40 50 50 50 50 60 60 60 60 60 70

5 to <7 20 20 40 40 40 40 50 50 50 50 50 50

4 to <5 20 20 20 20 40 40 40

3 to <4 20 20 20

2.5 to <3 20

Convenient sachet combinations to achieve the single doses recommended in the dosing 
table are provided below. Other combinations are possible.
20: One 20 mg sachet 80: Two 40 mg sachets

40: One 40 mg sachet 100: Two 50 mg sachets

50: One 50 mg sachet 110: One 110 mg sachet

60: Two 30 mg sachets 140: One 30 mg plus one 110 mg sachet

70: One 30 mg plus one 40 mg sachet 180: One 30 mg plus one 150 mg sachet

Means that no dosing recommendation can be provided.



116

Table 2: Single dabigatran etexilate dose in milligrams (mg) for patients aged 2.5 years to 
<12 years. The dose depends on weight in kilograms (kg) and age in years of the 
patient and has to be administered twice daily.

Age in years
2.5 to <4 4 to <5 5 to <6 6 to <7 7 to <9 9 to <10 10 to <12

W
ei

g
h

t 
[k

g
]

>81 330

71 to <81 330 330 330

61 to <71 330 330 330 330

51 to <61 300 300 300 300 300

41 to <51 260 260 260 260 260 260

31 to <41 190 190 190 190 190 190 190

26 to <31 180 180 180 180 180 180 180

21 to <26 180 180 180 180 180 180 180

16 to <21 140 140 140 140 140 140 140

13 to <16 140 140 140 140 140 140 140

11 to <13 110 110 110 110 110

9 to <11 80 80 80 80

7 to <9 70

Convenient sachet combinations to achieve the single doses recommended in the dosing 

table are provided below. Other combinations are possible.

70: One 30 mg plus one 40 mg sachet 190: One 40 mg plus one 150 mg sachet

80: Two 40 mg sachets 260: One 110 mg plus one 150 mg sachet

110: One 110 mg sachet 300: Two 150 mg sachets

140: One 30 mg plus one 110 mg sachet 330: Three 110 mg sachets

180: One 30 mg plus one 150 mg sachet

Means that no dosing recommendation can be provided.

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.

Treatment with dabigatran etexilate in paediatric patients with eGFR <50 mL/min/1.73m2 is 
contraindicated (see section 4.3).

Patients with an eGFR ? 50 mL/min/1.73m2 should be treated with the dose according to tables 1 and 
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).



117

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. If a dose has only been 
taken partially, there should be no attempt to administer a second dose at that time-point, and the next 
dose should be taken as scheduled approximately 12 hours later.

Discontinuation of dabigatran etexilate

Dabigatran etexilate treatment should not be discontinued without medical advice. Caregivers should 
be instructed to contact the treating physician if their treated child 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 coated granules should be mixed with food prior to intake and only be used with apple juice or the 
soft foods mentioned in the instructions for use. After mixing with food or apple juice, the medicinal 
product has to be administered within 30 minutes. The coated granules are not compatible with milk or 
milk products.

This medicinal product is not compatible with feeding tubes.

Detailed instructions for the use of this medicinal product are provided in ‘Instructions for use’ in the 
package leaflet.

4.3 Contraindications

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



118

? eGFR <50 mL/min/1.73m2 in paediatric patients
? Active clinically significant bleeding
? Lesion or condition, if considered a significant risk factor for major bleeding. This may include 

current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of 
bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent 
intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous 
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

? Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), 
oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances. 
These are switching anticoagulant therapy (see section 4.2) 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).

4.4 Special warnings and precautions for use

Haemorrhagic risk

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

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.



119

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).



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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.



121

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/1.73m2)

Stop dabigatran before elective surgery

>80 24 hours before
50 – 80 2 days before
<50 These patients have not been studied (see section 4.3).

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

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

Postoperative phase

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

Patients at risk for bleeding or patients at risk of overexposure (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-



122

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.

4.5 Interaction with other medicinal products and other forms of interaction

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)



123

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 AUC?,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 AUC?,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 AUC?,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 AUC?,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



124

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).



125

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 AUC?,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 AUC?,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.



126

4.6 Fertility, pregnancy and lactation

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).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; 
thereof approximately 35,000 patients were treated with dabigatran etexilate. 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).



127

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



128

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 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.

4.9 Overdose

Dabigatran etexilate doses beyond those recommended, expose the patient to increased risk of 
bleeding.

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

Excessive anticoagulation may require interruption of dabigatran etexilate treatment. Since dabigatran 
is excreted predominantly by the renal route adequate diuresis must be maintained. As protein binding 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


129

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

5.1 Pharmacodynamic 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.



130

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

The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilate 
compared to standard of care (SOC) for the treatment of VTE in paediatric patients from birth to less 
than 18 years of age. The study was designed as an open-label, randomised, parallel-group, non-
inferiority study. Patients enrolled were randomised according to a 2:1 scheme to either an age-
appropriate formulation (capsules, coated granules or oral solution) of dabigatran etexilate (doses 
adjusted for age and weight) or SOC comprised of low molecular weight heparins (LMWH) or 
vitamin K antagonists (VKA) or fondaparinux (1 patient 12 years old). The primary endpoint was a 
composite endpoint of patients with complete thrombus resolution, freedom from recurrent VTE, and 
freedom from mortality related to VTE. Exclusion criteria included active meningitis, encephalitis and 
intracranial abscess.
In total, 267 patients had been randomised. Of those, 176 patients were treated with dabigatran 
etexilate and 90 patients according to SOC (1 randomised patient was not treated). 168 patients were 
12 to less than 18 years old, 64 patients 2 to less than 12 years, and 35 patients were younger than 
2 years. 
Of the 267 randomised patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients 
(42.2%) in the SOC group met the criteria for the composite primary endpoint (complete thrombus 
resolution, freedom from recurrent VTE, and freedom from mortality-related VTE). The 
corresponding rate difference demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent 
results were also generally observed across subgroups: there were no significant differences in the 
treatment effect for the subgroups by age, sex, region, and presence of certain risk factors. For the 3 
different age strata, the proportions of patients that met the primary efficacy endpoint in the dabigatran 
etexilate and SOC groups, respectively, were 13/22 (59.1%) and 7/13 (53.8%) for patients from birth 
to <2 years, 21/43 (48.8%) and 12/21 (57.1%) for patients aged 2 to <12 years, and 47/112 (42.0%) 
and 19/56 (33.9%) for patients aged 12 to <18 years.
Adjudicated major bleeds were reported for 4 patients (2.3%) in the dabigatran etexilate group and 
2 patients (2.2%) in the SOC group. There was no statistically significant difference in the time to first 
major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients 
(24.4%) in the SOC arm had any adjudicated bleeding event, most of them categorised as minor. The 
combined endpoint of adjudicated major bleeding event (MBE) or clinically relevant non-major 
(CRNM) bleeding (on treatment) was reported for 6 (3.4%) patients in the dabigatran etexilate group 
and 3 (3.3%) patients in the SOC group.

An open label, single arm safety prospective cohort, multi-centre, phase III study (1160.108) was 
conducted to assess the safety of dabigatran etexilate for the prevention of recurrent VTE in paediatric 
patients from birth to less than 18 years. Patients who required further anticoagulation due to the 
presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 
3 months) or after completing the DIVERSITY study were allowed to be included in the study. 
Eligible patients received age and weight adjusted doses of an age-appropriate formulation (capsules, 
coated granules or oral solution) of dabigatran etexilate until the clinical risk factor resolved, or up to a 
maximum of 12 months. The primary endpoints of the study included the recurrence of VTE, major 
and minor bleeding events and the mortality (overall and related to thrombotic or thromboembolic 
events) at 6 and 12 months. Outcome events were adjudicated by an independent blinded adjudication 
committee.



131

Overall, 214 patients entered the study; among them 162 patients in age stratum 1 (from 12 to less 
than 18 years of age), 43 patients in age stratum 2 (from 2 to less than 12 years of age) and 9 patients 
in age stratum 3 (from birth to less than 2 years of age). During the on-treatment period, 3 patients 
(1.4%) had an adjudication-confirmed recurrent VTE within the first 12 months after treatment start. 
Adjudication-confirmed bleeding events during the on-treatment period were reported for 48 patients 
(22.5%) within the first 12 months. The majority of the bleeding events were minor. In 3 patients 
(1.4%), an adjudication-confirmed major bleeding event occurred within the first 12 months. For 
3 patients (1.4%), adjudication-confirmed CRNM bleeding was reported within the first 12 months. 
No on-treatment deaths occurred. During the on-treatment period, 3 patients (1.4%) developed post-
thrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.

5.2 Pharmacokinetic properties

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

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



132

Biotransformation

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.

Metabolism and excretion of dabigatran were studied following a single intravenous dose of 
radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived 
radioactivity was eliminated primarily in the urine (85%). Faecal excretion accounted for 6% of the 
administered dose. Recovery of the total radioactivity ranged from 88-94% of the administered dose 
by 168 hours post dose.
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four 
positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10% of total 
dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical 
methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of 
approximately 100 mL/min corresponding to the glomerular filtration rate.

Elimination

Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 
11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was 
observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as 
shown in table 9.

Special populations

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

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

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

glomerular filtration rate 
(CrCL,)

[mL/min]

gMean (gCV %; range) 
half-life 

[h] 
?80 13.4 (25.7 %; 11.0-21.6)

?50-<80 15.3 (42.7 %;11.7-34.1) 

?30-<50 18.4 (18.5 %;13.3-23.0) 
<30 27.2(15.3 %; 21.6-35.0)

Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open label 
randomised pharmacokinetic study in non-valvular atrial fibrillation (NVAF) patients with severe 
renal impairment (defined as creatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate 
75 mg twice daily.
This regimen resulted in a geometric mean trough concentration of 155 ng/ml (gCV of 76.9%), 
measured immediately before administration of the next dose and in a geometric mean peak 
concentration of 202 ng/ml (gCV of 70.6%) measured two hours after the administration of the last 
dose.

Clearance of dabigatran by haemodialysis was investigated in 7 patients with end-stage renal disease 
(ESRD) without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flow rate, 



133

four hour duration and a blood flow rate of either 200 mL/min or 350-390 mL/min. This resulted in a 
removal of 50% to 60% of dabigatran concentrations, respectively. The amount of substance cleared 
by dialysis is proportional to the blood flow rate up to a blood flow rate of 300 mL/min. The 
anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PD 
relationship was not affected by the procedure.

Hepatic impairment
No change in dabigatran exposure was seen in 12 adult subjects with moderate hepatic insufficiency 
(Child Pugh B) compared to 12 controls (see section 4.4).

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

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

Pharmacokinetic interactions

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

5.3 Preclinical safety data

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

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

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

In a juvenile toxicity study conducted in Han Wistar rats, mortality was associated with bleeding 
events at similar exposures, at which bleeding was seen in adult animals. In both adult and juvenile 
rats, mortality is considered to be related to the exaggerated pharmacological activity of dabigatran in 
association with the exertion of mechanical forces during dosing and handling. Data of the juvenile 
toxicity study did neither indicate an increased sensitivity in toxicity, nor any toxicity specific to 
juvenile animals.

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

Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in the environment.



134

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tartaric acid
Acacia
Hypromellose
Dimeticone 350
Talc
Hydroxypropylcellulose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

After first opening of the aluminium bag

Once the aluminium bag containing the sachets with the coated granules and the desiccant is opened, 
the medicinal product must be used within 6 months.

After first opening of the sachet

The opened sachet cannot be stored and must be used immediately after opening.

After preparation

After mixing with soft food or apple juice, the medicinal product has to be administered within 
30 minutes.

6.4 Special precautions for storage

The aluminium bag containing the sachets with the coated granules should only be opened 
immediately prior to use of the first sachet in order to protect from moisture.

After opening of the aluminium bag, the individual sachets should be kept unopened until immediately 
prior to use in order to protect from moisture.

6.5 Nature and contents of container

Aluminium bag containing 60 silver-coloured PET/Alu/LDPE sachets with the coated granules and 
one desiccant (labelled “DO NOT EAT” including pictogram and “SILICA GEL”).

6.6 Special precautions for disposal and other handling

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



135

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/025
EU/1/08/442/026
EU/1/08/442/027
EU/1/08/442/028
EU/1/08/442/029
EU/1/08/442/030

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 March 2008
Date of latest renewal: 08 January 2018

10. DATE OF REVISION OF THE TEXT

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

http://www.ema.europa.eu/


136

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 6.25 mg/mL powder and solvent for oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of reconstituted oral solution contains 6.25 mg of dabigatran etexilate (as mesilate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for oral solution

Components for reconstitution of the oral solution:
The powder for oral solution is yellowish-white.
The solvent is a clear, colourless solution.
The sucralose powder is white to almost white.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of venous thromboembolic events (VTE) and prevention of recurrent VTE in paediatric 
patients from birth to less than 18 years of age.

For age appropriate dose forms, see section 4.2.

Pradaxa powder and solvent for oral solution should not be used in patients aged 1 year or older.

4.2 Posology and method of administration

Posology

Pradaxa powder and solvent for oral solution should only be used in children aged less than 1 year.
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 for the age and weight 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 oral solution 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 oral solution is based on the patient’s age and weight 
as shown in table 1. The table provides the single doses which are to be administered twice daily. The 
dose should be adjusted according to age and weight as treatment progresses.



137

Table 1: Single dabigatran etexilate dose in millilitres (mL) by weight in kilograms (kg) and 
age in months of the patient to be administered twice daily

Age in months

<1
1 to
<2

2 to
<3

3 to
<4

4 to
<5

5 to
<6

6 to
<7

7 to
<8

8 to
<9

9 to 
<10

10 to 
<11

11 to 
<12

W
ei

gh
t 

[k
g]

13 to <16 12 mL 12 mL

11 to <13 10 mL 10 mL 10 mL 11 mL

9 to <11 7 mL 7 mL 8 mL 8 mL 9 mL 9 mL 9 mL

7 to <9 5 mL 6 mL 6 mL 7 mL 7 mL 7 mL 7 mL 8 mL 8 mL

5 to <7 3 mL 3 mL 4 mL 4 mL 5 mL 5 mL 5 mL 5 mL 6 mL 6 mL 6 mL 7 mL

4 to <5 2 mL 3 mL 3 mL 4 mL 4 mL 4 mL 4 mL 4 mL 5 mL 5 mL

3 to <4 2 mL 2 mL 3 mL 3 mL 3 mL 3 mL

2.5 to <3 2 mL 2 mL 2 mL 2 mL 3 mL

Means that no dosing recommendation can be provided.

oral solution 
[mL]

2 3 4 5 6 7 8 9 10 11 12

contains 
dabigatran 

etexilate [mg]
12.50 18.75 25.00 31.25 37.50 43.75 50.00 56.25 62.50 68.75 75.00

The maximum dose stated in the dosing table for Pradaxa oral solution must not be exceeded (see also 
section 5.3).

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.

Treatment with dabigatran etexilate in paediatric patients with eGFR <50 mL/min/1.73m2 is 
contraindicated (see section 4.3).

Patients with an eGFR ? 50 mL/min/1.73m2 should be treated with the dose according to table 1.

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.



138

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. If a dose has only been 
taken partially, there should be no attempt to administer a second dose at that time-point, and the next 
dose should be taken as scheduled approximately 12 hours later.

Discontinuation of dabigatran etexilate

Dabigatran etexilate treatment should not be discontinued without medical advice. Caregivers should 
be instructed to contact the treating physician if their treated child 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.

Instructions For Use must be carefully followed. Detailed instructions for the preparation of the oral 
solution and the administration with the dosing pipette are provided in ‘Instructions for use’ in the 
package leaflet.

Pradaxa oral solution should be reconstituted by a healthcare professional. Caregivers may reconstitute 
the oral solution themselves if the treating physician determines that it is appropriate.

In case the anticoagulant treatment has been initiated in the hospital and has to be continued after 
discharge the following options are possible:
? the treatment is continued with Pradaxa powder and solvent for oral solution if reconstitution of 

the oral solution on a daily basis, either by a healthcare professional or a caregiver, is assured. 
The instructions for use and particularly the storage conditions for the reconstituted oral solution 
have to always be carefully followed.

? the treatment is continued with Pradaxa coated granules
? the treatment is continued with standard of care

After reconstitution, Pradaxa oral solution is a clear colourless to clear yellowish solution. The pH of 
the reconstituted oral solution is approximately 2.1.



139

The oral solution should not be mixed with milk, other beverages or food.

The dosing pipettes provided are not compatible with feeding tubes. The oral solution should not be 
administered via feeding tubes.

4.3 Contraindications

? Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
? eGFR <50 mL/min/1.73m2 in paediatric patients
? Active clinically significant bleeding
? Lesion or condition, if considered a significant risk factor for major bleeding. This may include 

current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of 
bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent 
intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous 
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

? Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), 
oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances. 
These are switching anticoagulant therapy (see section 4.2) 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).

4.4 Special warnings and precautions for use

Haemorrhagic risk

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

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.



140

Risk factors

Table 2 summarises factors which may increase the haemorrhagic risk. 

Table 2: 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 2 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).



141

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.



142

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 3.

Table 3: Discontinuation rules before invasive or surgical procedures for paediatric patients

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

Stop dabigatran before elective surgery

>80 24 hours before
50 – 80 2 days before
<50 These patients have not been studied (see section 4.3).

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

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

Postoperative phase

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

Patients at risk for bleeding or patients at risk of overexposure (see table 2) 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-



143

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.

4.5 Interaction with other medicinal products and other forms of interaction

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 4) 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 4: 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)



144

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 AUC?,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 AUC?,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 AUC?,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 AUC?,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



145

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).



146

Table 5: Interactions with anticoagulants and antiplatelet aggregation medicinal products

NSAIDs NSAIDs given for short-term analgesia have been shown not to be associated with 
increased bleeding risk when given in conjunction with dabigatran etexilate. With 
chronic use in a phase III clinical trial comparing dabigatran to warfarin for stroke 
prevention in atrial fibrillation patients (RE-LY), NSAIDs increased the risk of bleeding 
by approximately 50% on both dabigatran etexilate and warfarin. 

Clopidogrel In young healthy male volunteers, the concomitant administration of dabigatran 
etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times 
compared to clopidogrel monotherapy. In addition, dabigatran AUC?,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 AUC?,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 6: 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.



147

4.6 Fertility, pregnancy and lactation

Pradaxa powder and solvent for oral solution is intended to be used in children below the age of 
12 months. Information regarding pregnancy and breast-feeding will not be relevant in the context of 
this patient group.

4.7 Effects on ability to drive and use machines

Dabigatran etexilate powder and solvent for oral solution is intended to be used in children below the 
age of 12 months. Information in this section will not be relevant in the context of this patient group.

4.8 Undesirable effects

Summary of the safety profile

Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; 
thereof approximately 35,000 patients were treated with dabigatran etexilate. 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 7 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 7: 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



148

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



149

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 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.

4.9 Overdose

Dabigatran etexilate doses beyond those recommended, expose the patient to increased risk of 
bleeding.

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

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

Management of bleeding complications

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

Coagulation factor concentrates (activated or non-activated) or recombinant Factor VIIa may be taken 

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150

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

5.1 Pharmacodynamic 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.



151

Clinical efficacy and safety

The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilate 
compared to standard of care (SOC) for the treatment of VTE in paediatric patients from birth to less 
than 18 years of age. The study was designed as an open-label, randomised, parallel-group, non-
inferiority study. Patients enrolled were randomised according to a 2:1 scheme to either an age-
appropriate formulation (capsules, coated granules or oral solution) of dabigatran etexilate (doses 
adjusted for age and weight) or SOC comprised of low molecular weight heparins (LMWH) or 
vitamin K antagonists (VKA) or fondaparinux (1 patient 12 years old). The primary endpoint was a 
composite endpoint of patients with complete thrombus resolution, freedom from recurrent VTE, and 
freedom from mortality related to VTE. Exclusion criteria included active meningitis, encephalitis and 
intracranial abscess.
In total, 267 patients had been randomised. Of those, 176 patients were treated with dabigatran 
etexilate and 90 patients according to SOC (1 randomised patient was not treated). 168 patients were 
12 to less than 18 years old, 64 patients 2 to less than 12 years, and 35 patients were younger than 
2 years. 
Of the 267 randomised patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients 
(42.2%) in the SOC group met the criteria for the composite primary endpoint (complete thrombus 
resolution, freedom from recurrent VTE, and freedom from mortality-related VTE). The 
corresponding rate difference demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent 
results were also generally observed across subgroups: there were no significant differences in the 
treatment effect for the subgroups by age, sex, region, and presence of certain risk factors. For the 3 
different age strata, the proportions of patients that met the primary efficacy endpoint in the dabigatran 
etexilate and SOC groups, respectively, were 13/22 (59.1%) and 7/13 (53.8%) for patients from birth 
to <2 years, 21/43 (48.8%) and 12/21 (57.1%) for patients aged 2 to <12 years, and 47/112 (42.0%) 
and 19/56 (33.9%) for patients aged 12 to <18 years.
Adjudicated major bleeds were reported for 4 patients (2.3%) in the dabigatran etexilate group and 
2 patients (2.2%) in the SOC group. There was no statistically significant difference in the time to first 
major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients 
(24.4%) in the SOC arm had any adjudicated bleeding event, most of them categorised as minor. The 
combined endpoint of adjudicated major bleeding event (MBE) or clinically relevant non-major 
(CRNM) bleeding (on treatment) was reported for 6 (3.4%) patients in the dabigatran etexilate group 
and 3 (3.3%) patients in the SOC group.

An open label, single arm safety prospective cohort, multi-centre, phase III study (1160.108) was 
conducted to assess the safety of dabigatran etexilate for the prevention of recurrent VTE in paediatric 
patients from birth to less than 18 years. Patients who required further anticoagulation due to the 
presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 
3 months) or after completing the DIVERSITY study were allowed to be included in the study. 
Eligible patients received age and weight adjusted doses of an age-appropriate formulation (capsules, 
coated granules or oral solution) of dabigatran etexilate until the clinical risk factor resolved, or up to a 
maximum of 12 months. The primary endpoints of the study included the recurrence of VTE, major 
and minor bleeding events and the mortality (overall and related to thrombotic or thromboembolic 
events) at 6 and 12 months. Outcome events were adjudicated by an independent blinded adjudication 
committee.
Overall, 214 patients entered the study; among them 162 patients in age stratum 1 (from 12 to less 
than 18 years of age), 43 patients in age stratum 2 (from 2 to less than 12 years of age) and 9 patients 
in age stratum 3 (from birth to less than 2 years of age). During the on-treatment period, 3 patients 
(1.4%) had an adjudication-confirmed recurrent VTE within the first 12 months after treatment start. 
Adjudication-confirmed bleeding events during the on-treatment period were reported for 48 patients 
(22.5%) within the first 12 months. The majority of the bleeding events were minor. In 3 patients 
(1.4%), an adjudication-confirmed major bleeding event occurred within the first 12 months. For 
3 patients (1.4%), adjudication-confirmed CRNM bleeding was reported within the first 12 months. 
No on-treatment deaths occurred. During the on-treatment period, 3 patients (1.4%) developed post-
thrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.



152

5.2 Pharmacokinetic properties

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 oral solution should not be mixed with milk, other beverages or 
food (see section 4.5).

Cmax and AUC were dose proportional.

Distribution

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

Biotransformation

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.

Metabolism and excretion of dabigatran were studied following a single intravenous dose of 
radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived 
radioactivity was eliminated primarily in the urine (85%). Faecal excretion accounted for 6% of the 
administered dose. Recovery of the total radioactivity ranged from 88-94% of the administered dose 
by 168 hours post dose.
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four 
positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10% of total 
dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical 
methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of 
approximately 100 mL/min corresponding to the glomerular filtration rate.



153

Elimination

Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 
11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was 
observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as 
shown in table 8.

Special populations

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

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

Table 8: Half-life of total dabigatran in healthy subjects and subjects with impaired renal 
function (adults).

glomerular filtration rate 
(CrCL,)

[mL/min]

gMean (gCV %; range) 
half-life 

[h] 
?80 13.4 (25.7 %; 11.0-21.6)

?50-<80 15.3 (42.7 %;11.7-34.1) 

?30-<50 18.4 (18.5 %;13.3-23.0) 
<30 27.2(15.3 %; 21.6-35.0)

Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open label 
randomised pharmacokinetic study in non-valvular atrial fibrillation (NVAF) patients with severe 
renal impairment (defined as creatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate 
75 mg twice daily.
This regimen resulted in a geometric mean trough concentration of 155 ng/ml (gCV of 76.9%), 
measured immediately before administration of the next dose and in a geometric mean peak 
concentration of 202 ng/ml (gCV of 70.6%) measured two hours after the administration of the last 
dose.

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

Hepatic impairment
No change in dabigatran exposure was seen in 12 adult subjects with moderate hepatic insufficiency 
(Child Pugh B) compared to 12 controls (see section 4.4).

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



154

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

Pharmacokinetic interactions

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

5.3 Preclinical safety data

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

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

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

In a juvenile toxicity study conducted in Han Wistar rats, mortality was associated with bleeding
events at similar exposures, at which bleeding was seen in adult animals. In both adult and juvenile 
rats, mortality is considered to be related to the exaggerated pharmacological activity of dabigatran in 
association with the exertion of mechanical forces during dosing and handling. Data of the juvenile 
toxicity study did neither indicate an increased sensitivity in toxicity, nor any toxicity specific to 
juvenile animals.

In lifetime toxicology studies in rats and mice, there was no evidence for a tumorigenic potential of 
dabigatran up to maximum doses of 200 mg/kg. At doses exceeding the maximum recommended 
human dose for patients aged less than 1 year, a mesilate ester assumed to be mutagenic due to its 
structure may be present above acceptable levels.

Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in the environment.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pradaxa powder for oral solution
Mannitol
Hydroxypropylcellulose

Solvent for Pradaxa oral solution
Tartaric acid
Hydrochloric acid (for pH-adjustment)
Water, purified



155

Sucralose powder
Sucralose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

After first opening of the aluminium bag

Once the aluminium bag containing the sachets with the powder for oral solution and the desiccant is 
opened, the medicinal product must be used within 4 months. 

After first opening of the sachet with the powder for oral solution

The opened sachet cannot be stored and must be used immediately after opening.

After reconstitution 

Once reconstituted, the oral solution in the bottle can be stored for 2 hours below 25°C, or for 18 hours 
at 2-8°C (refrigerator). The bottles must be stored in an upright position.

6.4 Special precautions for storage

The aluminium bag containing the sachets with the powder for oral solution should only be opened 
immediately prior to use of the first sachet in order to protect from moisture.

After opening of the aluminium bag, the individual sachets should be kept unopened until immediately 
prior to use in order to protect from moisture.

For storage conditions after reconstitution and first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Pradaxa powder and solvent for oral solution is supplied as several components for reconstitution in a 
kit that contains:

? 1 carton box containing the Pradaxa powder for oral solution.
30 PET/Alu/LDPE sachets are packaged in one aluminium bag that also contains a desiccant 
(labelled with “DO NOT EAT” including pictogram and “SILICA GEL”). Each sachet 
contains 180.4 mg powder for oral solution.

? 30 carton boxes which are referred to as individual preparation packs.
Each pack contains one white PET/Alu/LDPE sachet with 70 mg sucralose powder, one amber 
glass bottle with a PP/HDPE screw-cap containing 28 mL solvent to prepare the oral solution, 
two dosing pipettes (12 mL) and one adapter for the bottle.

The co-packaged dosing pipettes (CE 0124) and the adapter (CE) are medical devices.
On the 12 mL dosing pipette, a scale from 0 to 12 mL with 0.25 mL graduation is printed.

6.6 Special precautions for disposal and other handling

Detailed instructions for the preparation of the oral solution and the administration with the dosing 
pipette are provided in ‘Instructions for use’ in the package leaflet.

After reconstitution, the oral solution is a clear colourless to clear yellowish solution.



156

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/031

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 March 2008
Date of latest renewal: 08 January 2018

10. DATE OF REVISION OF THE TEXT

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

http://www.ema.europa.eu/


157

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



158

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release of Pradaxa capsules:

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
88397 Biberach an der Riss
Germany

Name and address of the manufacturer(s) responsible for batch release of Pradaxa coated granules:

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Name and address of the manufacturer(s) responsible for batch release of Pradaxa powder and solvent 
for oral solution:

Catalent Germany Schorndorf GmbH
Steinbeisstr. 1 und 2
73614 Schorndorf
Germany

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

? Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
references dates (EURD list) provided for under Artical 107c(7) of Directive 1002/83/EC and any 
subsequent updates published on the European medicines web-portal. 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

? Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 



159

An updated RMP should be submitted
? At the request of the European Medicines Agency;
? Whenever the risk management system is modified, especially as th result of new information 

being received that may lead to significant change to the benefit/risk profile or as the result. of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

? Additional risk minimisation measures 

The MAH shall provide an educational pack for each therapeutic indication, targeting all physicians 
who are expected to prescribe/use Pradaxa. This educational pack is aimed at increasing awareness 
about the potential risk of bleeding during treatment with Pradaxa and providing guidance on how to 
manage that risk.

The MAH must agree the content and format of the educational material, together with a 
communication plan, with the national competent authority prior to distribution of the educational 
pack. The educational pack must be available for distribution for all therapeutic indications prior to 
launch) in the Member State.

The physician educational pack should contain:
? The Summary of Product Characteristics
? Prescriber Guides
? Patient Alert Cards
? A mandatory training video for Pradaxa powder and solvent for oral solution
? Ad hoc technical support via phone for Pradaxa powder and solvent for oral solution

The Prescriber Guide should contain the following key safety messages:
? Details of populations potentially at higher risk of bleeding
? Information on medicinal products that are contraindicated or which should be used with 

caution due to an increased risk of bleeding and/or increased dabigatran exposure
? Contraindication for patients with prosthetic heart valves requiring anticoagulant treatment
? Dosing tables for the different dosage forms (only for paediatric VTE)
? Recommendation for kidney function measurement
? Recommendations for dose reduction in at risk populations (only for adult indications)
? Management of overdose situations
? The use of coagulation tests and their interpretation
? That all patients/carers should be provided with a Patient alert card and be counselled about:
? Signs or symptoms of bleeding and when to seek attention from a health care provider.
? Importance of treatment compliance
? Necessity to carry the Patient alert card with them at all times
?   The need to inform Health Care Professionals about all medicines the patient is currently 

taking
?   The need to inform Health Care Professionals that they are taking Pradaxa if they need to 

have any surgery or invasive procedure.
? An instruction how to take Pradaxa
? Recommendation that all parents/caregivers of paediatric patients administered Pradaxa powder 

and solvent for oral solution should be counselled about the reconstitution and dosing of the oral 
solution

The MAH shall also provide a patient alert card in each pack of the medicinal product, the text of 
which is included in Annex III.



160

A digital training video for reconstitution and dosing of the oral solution should contain the following 
key messages:

? Reconstitution of the oral solution
? Administration of the prepared oral solution and correct use of the devices
? Storage and disposal of the prepared oral solution



161

ANNEX III

LABELLING AND PACKAGE LEAFLET



162

A. LABELLING



163

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

FOLDING BOX FOR BLISTER for 75 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 75 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
10 x 1 hard capsule
30 x 1 hard capsule
60 x 1 hard capsule

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

Tear-off

Peel-off

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



164

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/001 10 x 1 hard capsules
EU/1/08/442/002 30 x 1 hard capsules
EU/1/08/442/003 60 x 1 hard capsules
EU/1/08/442/017 60 x 1 hard capsules

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 75 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



165

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



166

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER FOR 75 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 75 mg hard capsules
dabigatran etexilate

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Peel back



167

MINIMUM PARTICULARS TO APPEAR ON WHITE BLISTERS OR STRIPS

BLISTER FOR 75 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 75 mg hard capsules
dabigatran etexilate

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Peel back



168

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

FOLDING BOX AND LABEL FOR BOTTLE for 75 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 75 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
60 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Once opened, the product must be used within 4 months.

9. SPECIAL STORAGE CONDITIONS

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



169

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 75 mg (only applicable for folding box, not applicable for bottle label)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included. (only applicable for folding box, not applicable for 
bottle label)

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
(only applicable for folding box, not applicable for bottle label)

PC:
SN:
NN:



170

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

FOLDING BOX FOR BLISTER for 110 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 110 mg dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
10 x 1 hard capsule
30 x 1 hard capsule
60 x 1 hard capsule

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

Tear-off

Peel-off

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



171

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/005 10 x 1 hard capsules
EU/1/08/442/006 30 x 1 hard capsules
EU/1/08/442/007 60 x 1 hard capsules
EU/1/08/442/018 60 x 1 hard capsules

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 110 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



172

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



173

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

MULTIPACK OF 180 (3 PACKS OF 60 HARD-CAPSULES) – WITHOUT BLUE BOX –
110 mg HARD CAPSULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 110 mg dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
60x1 hard capsules. Component of a multipack, can´t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

Tear-off

Peel-off

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



174

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/014

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 110 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



175

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER WRAPPER LABEL ON MULTIPACK OF 180 (3 PACKS OF 60 HARD CAPSULES) 
WRAPPED IN TRANSPARENT FOIL – INCLUDING THE BLUE BOX – 110 mg HARD 
CAPSULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 110 mg dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
Multipack: 180 (3 packs of 60x1) hard capsules.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



176

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/014

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 110 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



177

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

MULTIPACK OF 100 (2 PACKS OF 50 HARD-CAPSULES) – WITHOUT BLUE BOX –
110 mg HARD CAPSULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 110 mg dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
50x1 hard capsules. Component of a multipack, can´t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

Tear-off

Peel-off

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



178

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/015

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 110 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



179

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER WRAPPER LABEL ON MULTIPACK OF 100 (2 PACKS OF 50 HARD CAPSULES) 
WRAPPED IN TRANSPARENT FOIL – INCLUDING THE BLUE BOX – 110 mg HARD 
CAPSULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 110 mg dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
Multipack:100 (2 packs of 50x1) hard capsules.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



180

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/015

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 110 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



181

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER FOR 110 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules
dabigatran etexilate

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Peel back



182

MINIMUM PARTICULARS TO APPEAR ON WHITE BLISTERS OR STRIPS

BLISTER FOR 110 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules
dabigatran etexilate

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Peel back



183

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING.

FOLDING BOX AND LABEL FOR BOTTLE for 110 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 110 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 110 mg dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
60 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Once opened, the product must be used within 4 months.

9. SPECIAL STORAGE CONDITIONS

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



184

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/008

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 110 mg (only applicable for folding box, not applicable for bottle label)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included. (only applicable for folding box, not applicable for 
bottle label)

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
(only applicable for folding box, not applicable for bottle label)

PC:
SN:
NN:



185

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

FOLDING BOX FOR BLISTER for 150 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
10 x 1 hard capsule
30 x 1 hard capsule
60 x 1 hard capsule

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

Tear-off

Peel-off

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



186

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/009 10 x 1 hard capsules
EU/1/08/442/010 30 x 1 hard capsules
EU/1/08/442/011 60 x 1 hard capsules
EU/1/08/442/019 60 x 1 hard capsules

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 150 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



187

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



188

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

MULTIPACK OF 180 (3 PACKS OF 60 HARD-CAPSULES) – WITHOUT BLUE BOX –
150 mg HARD CAPSULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
60x1 hard capsules. Component of a multipack, can´t be sold seperately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

Tear-off

Peel-off

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



189

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/012

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 150 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



190

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER WRAPPER LABEL ON MULTIPACK OF 180 (3 PACKS OF 60 HARD CAPSULES) 
WRAPPED IN TRANSPARENT FOIL – INCLUDING THE BLUE BOX – 150 mg HARD 
CAPSULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
Multipack: 180 (3 packs of 60x1) hard capsules.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



191

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/012

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 150 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



192

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

MULTIPACK OF 100 (2 PACKS OF 50 HARD-CAPSULES) – WITHOUT BLUE BOX –
150 mg HARD CAPSULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
50x1 hard capsules. Component of a multipack, can´t be sold seperately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

Tear-off

Peel-off

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



193

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/016

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 150 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



194

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER WRAPPER LABEL ON MULTIPACK OF 100 (2 PACKS OF 50 HARD CAPSULES) 
WRAPPED IN TRANSPARENT FOIL – INCLUDING THE BLUE BOX – 150 mg HARD 
CAPSULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
Multipack: 100 (2 packs of 50x1) hard capsules.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



195

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/016

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 150 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



196

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER FOR 150 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules
dabigatran etexilate

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Peel back



197

MINIMUM PARTICULARS TO APPEAR ON WHITE BLISTERS OR STRIPS

BLISTER FOR 150 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules
dabigatran etexilate

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Peel back



198

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING.

FOLDING BOX AND LABEL FOR BOTTLE for 150 mg

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 150 mg hard capsules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

hard capsule
60 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Swallow whole, do not chew or break the capsule.
Read the package leaflet before use.
Oral use.
Patient alert card inside.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Once opened, the product must be used within 4 months.

9. SPECIAL STORAGE CONDITIONS

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



199

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/013

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa 150 mg (only applicable for folding box, not applicable for bottle label)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included. (only applicable for folding box, not applicable for 
bottle label)

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
(only applicable for folding box, not applicable for bottle label)

PC:
SN:
NN:



200

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE INTERMEDIATE
PACKAGING

FOLDING BOX AND ALUMINIUM BAG FOR COATED GRANULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 20 mg coated granules
Pradaxa 30 mg coated granules
Pradaxa 40 mg coated granules
Pradaxa 50 mg coated granules
Pradaxa 110 mg coated granules
Pradaxa 150 mg coated granules
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each sachet contains coated granules with 20 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 30 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 40 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 50 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 110 mg dabigatran etexilate (as mesilate).
Each sachet contains coated granules with 150 mg dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

coated granules
60 sachets with coated granules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Patient alert card and package leaflet in local language inside.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



201

8. EXPIRY DATE

EXP
Once opened, the medicine must be used within 6 months.
Keep the sachets closed until use.
After mixing with soft food or apple juice, use within 30 minutes.

9. SPECIAL STORAGE CONDITIONS

The aluminium bag containing the sachets with the Pradaxa coated granules should only be opened 
immediately prior to use of the first sachet in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/442/025 60 x Pradaxa 20 mg coated granules
EU/1/08/442/026 60 x Pradaxa 30 mg coated granules
EU/1/08/442/027 60 x Pradaxa 40 mg coated granules
EU/1/08/442/028 60 x Pradaxa 50 mg coated granules
EU/1/08/442/029 60 x Pradaxa 110 mg coated granules
EU/1/08/442/030 60 x Pradaxa 150 mg coated granules

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE



202

16. INFORMATION IN BRAILLE

Pradaxa 20 mg coated granules
Pradaxa 30 mg coated granules
Pradaxa 40 mg coated granules
Pradaxa 50 mg coated granules
Pradaxa 110 mg coated granules
Pradaxa 150 mg coated granules

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



203

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

SACHET FOR COATED GRANULES

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 20 mg coated granules
Pradaxa 30 mg coated granules
Pradaxa 40 mg coated granules
Pradaxa 50 mg coated granules
Pradaxa 110 mg coated granules
Pradaxa 150 mg coated granules
dabigatran etexilate

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



204

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX – 30 PREPARATIONS – INCLUDING THE BLUE BOX – POWDER AND 
SOLVENT FOR ORAL SOLUTION

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 6.25 mg/mL powder and solvent for oral solution
Medicine kit
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL of reconstituted oral solution contains 6.25 mg of dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for oral solution

Pradaxa powder and solvent for oral solution is supplied as several components for reconstitution in a 
kit that contains:

? 1 carton box containing the Pradaxa powder for oral solution:
30 aluminium sachets are packaged in one aluminium bag that also contains a desiccant 
(labelled with “DO NOT EAT” including pictogram and “SILICA GEL”).

? 30 carton boxes which are referred to as individual preparation packs containing:
One sucralose sachet (70 mg).
One bottle with solvent (28 mL).
One pipette adapter (CE) for the bottle.
Two 12 mL dosing pipettes (CE 0124).

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use
Patient alert card and package leaflet in local language inside.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



205

8. EXPIRY DATE

EXP

Once the aluminium bag containing the sachets with the Pradaxa powder for oral solution and the 
desiccant is opened, the medicine must be used within 4 months. Keep the sachets closed until use.

Once prepared, the oral solution in the bottle can be stored for 2 hours below 25°C, or for 18 hours at 
2-8°C (refrigerator). The bottles must be stored in an upright position.

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/031

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Pradaxa powder and solvent for oral solution

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



206

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



207

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

INNER BOX – INDIVIDUAL PREPARATION PACK FOR ORAL SOLUTION – WITHOUT 
BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa 6.25 mg/mL powder and solvent for oral solution
Individual preparation pack

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL of reconstituted oral solution contains 6.25 mg of dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for oral solution

Each individual preparation pack contains: 
? One sucralose sachet (70 mg).
? One bottle with solvent (28 mL).
? One pipette adapter (CE) for the bottle.
? Two 12 mL dosing pipettes (CE 0124).

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

Once prepared, the oral solution in the bottle can be stored for 2 hours below 25°C, or for 18 hours at 
2-8°C (refrigerator). The bottles must be stored in an upright position.



208

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/031

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



209

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

INNER BOX – PRADAXA POWDER FOR ORAL SOLUTION – WITHOUT BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa powder for oral solution
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL of reconstituted oral solution contains 6.25 mg of dabigatran etexilate (as mesilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

powder for oral solution

Contains 30 sachets with Pradaxa powder for oral solution and one desiccant (labelled “DO NOT 
EAT” including pictogram and “SILICA GEL”) packaged in an aluminium bag.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

Once the aluminium bag containing the sachets with the Pradaxa powder for oral solution and the 
desiccant is opened, the medicine must be used within 4 months. Keep the sachets closed until use.

9. SPECIAL STORAGE CONDITIONS

This medicine does not require any special storage conditions.



210

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/031

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



211

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

ALUMINIUM BAG – PRADAXA POWDER FOR ORAL SOLUTION

1. NAME OF THE MEDICINAL PRODUCT

Pradaxa powder for oral solution
dabigatran etexilate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

powder for oral solution

30 sachets with 180.4 mg Pradaxa powder for oral solution
1 desiccant (labelled with “DO NOT EAT” including pictogram and “SILICA GEL”)

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

Once the aluminium bag containing the sachets with the Pradaxa powder for oral solution and the 
desiccant is opened, the medicine must be used within 4 months. Keep the sachets closed until use.

9. SPECIAL STORAGE CONDITIONS

This medicine does not require any special storage conditions.



212

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



213

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

SOLVENT BOTTLE LABEL FOR ORAL SOLUTION

1. NAME OF THE MEDICINAL PRODUCT

Solvent for Pradaxa 6.25 mg/mL oral solution

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each bottle contains 28 mL of solvent.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

solvent for oral solution

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

Once prepared, the oral solution in the bottle can be stored for 2 hours below 25°C, or for 18 hours at 
2-8°C (refrigerator). The bottles must be stored in an upright position.

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



214

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/08/442/031

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

Date and Time of preparation:

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



215

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

SACHET --- PRADAXA POWDER FOR ORAL SOLUTION

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Pradaxa 180.4 mg powder for oral solution

2. METHOD OF ADMINISTRATION

Read the package leaflet before use.

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



216

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

SACHET --- SUCRALOSE FOR ORAL SOLUTION

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

70 mg Sucralose for Pradaxa oral solution

2. METHOD OF ADMINISTRATION

Read the package leaflet before use.

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



217

B. PACKAGE LEAFLET



218

Package leaflet: Information for the patient

Pradaxa 75 mg hard capsules
dabigatran etexilate

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Pradaxa is and what it is used for
2. What you need to know before you take Pradaxa
3. How to take Pradaxa
4. Possible side effects
5. How to store Pradaxa
6. Contents of the pack and other information

1. What Pradaxa is and what it is used for

Pradaxa contains the active substance dabigatran etexilate and belongs to a group of medicines called 
anticoagulants. It works by blocking a substance in the body which is involved in blood clot 
formation.

Pradaxa is used in adults to:

- prevent the formation of blood clots in the veins after knee or hip replacement surgery.

Pradaxa is used in children to:

- treat blood clots and to prevent blood clots from reoccurring.

2. What you need to know before you take Pradaxa

Do not take Pradaxa

- if you are allergic to dabigatran etexilate or any of the other ingredients of this medicine (listed 
in section 6).

- if you have severely reduced kidney function.
- if you are currently bleeding.
- if you have a disease in an organ of the body that increases the risk of serious bleeding (e.g., 

stomach ulcer, injury or bleeding in the brain, recent surgery of the brain or eyes).
- if you have an increased tendency to bleed. This may be inborn, of unknown cause or due to 

other medicines.
- if you are taking medicines to prevent blood clotting (e.g. warfarin, rivaroxaban, apixaban or 

heparin), except when changing anticoagulant treatment, while having a venous or arterial line 
and you get heparin through this line to keep it open or while your heart beat is being restored to 
normal by a procedure called catheter ablation for atrial fibrillation.

- if you have a severely reduced liver function or liver disease which could possibly cause death.



219

- if you are taking oral ketoconazole or itraconazole, medicines to treat fungal infections.
- if you are taking oral cyclosporine, a medicine to prevent organ rejection after transplantation.
- if you are taking dronedarone, a medicine used to treat abnormal heart beat.
- if you are taking a combination product of glecaprevir and pibrentasvir, an antiviral medicine 

used to treat hepatitis C
- if you have received an artificial heart valve which requires permanent blood thinning.

Warnings and precautions

Talk to your doctor before taking Pradaxa. You may also need to talk to your doctor during treatment 
with this medicine if you experience symptoms or if you have to undergo surgery.

Tell your doctor if you have or have had any medical conditions or illnesses, in particular any of 
those included in the following list:

- if you have an increased bleeding risk, such as:
? if you have been recently bleeding.
? if you have had a surgical tissue removal (biopsy) in the past month.
? if you have had a serious injury (e.g. a bone fracture, head injury or any injury requiring 

surgical treatment).
? if you are suffering from an inflammation of the gullet or stomach.
? if you have problems with reflux of gastric juice into the gullet.
? if you are receiving medicines which could increase the risk of bleeding. See 'Other medicines 

and Pradaxa' below.
? if you are taking anti-inflammatory medicines such as diclofenac, ibuprofen, piroxicam.
? if you are suffering from an infection of the heart (bacterial endocarditis).
? if you know you have decreased kidney function, or you are suffering from dehydration 

(symptoms include feeling thirsty and passing reduced amounts of dark-coloured 
(concentrated) / foaming urine).

? if you are older than 75 years.
? if you are an adult patient and weigh 50 kg or less.
? only if used for children: if the child has an infection around or within the brain.

- if you have had a heart attack or if you have been diagnosed with conditions that increase the 
risk to develop a heart attack.

- if you have a liver disease that is associated with changes in the blood tests. The use of this 
medicine is not recommended in this case.

Take special care with Pradaxa

- if you need to have an operation:
In this case Pradaxa will need to be stopped temporarily due to an increased bleeding risk 
during and shortly after an operation. It is very important to take Pradaxa before and after the 
operation exactly at the times you have been told by your doctor.

- if an operation involves a catheter or injection into your spinal column (e.g. for epidural or 
spinal anaesthesia or pain reduction):

? it is very important to take Pradaxa before and after the operation exactly at the times 
you have been told by your doctor.

? tell your doctor immediately if you get numbness or weakness of your legs or problems 
with your bowel or bladder after the end of anaesthesia, because urgent care is 
necessary.

- if you fall or injure yourself during treatment, especially if you hit your head. Please seek urgent 
medical attention. You may need to be checked by a doctor, as you may be at increased risk of 
bleeding.



220

- if you know that you have a disease called antiphospholipid syndrome (a disorder of the 
immune system that causes an increased risk of blood clots), tell your doctor who will decide if 
the treatment may need to be changed.

Other medicines and Pradaxa

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. In particular you should tell your doctor before taking Pradaxa, if you are taking one 
of the medicines listed below:

- Medicines to reduce blood clotting (e.g. warfarin, phenprocoumon, acenocoumarol, heparin, 
clopidogrel, prasugrel, ticagrelor, rivaroxaban, acetylsalicylic acid)

- Medicines to treat fungal infections (e.g. ketoconazole, itraconazole), unless they are only 
applied to the skin

- Medicines to treat abnormal heart beats (e.g. amiodarone, dronedarone, quinidine, verapamil).
If you are taking amiodarone, quinidine or verapamil containing medicines, your doctor may tell 
you to use a reduced dose of Pradaxa depending on the condition for which it is prescribed to 
you. See also section 3.

- Medicines to prevent organ rejection after transplantation (e.g. tacrolimus, cyclosporine)
- A combination product of glecaprevir and pibrentasvir (an antiviral medicine used to treat 

hepatitis C)
- Anti-inflammatory and pain reliever medicines (e.g. acetylsalicylic acid, ibuprofen, diclofenac)
- St. John´s wort, a herbal medicine for depression
- Antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin-

norepinephrine re-uptake inhibitors
- Rifampicin or clarithromycin (two antibiotics)
- Anti-viral medicines for AIDS (e.g. ritonavir)
- Certain medicines for treatment of epilepsy (e.g. carbamazepine, phenytoin)

Pregnancy and breast-feeding

The effects of Pradaxa on pregnancy and the unborn child are not known. You should not take this 
medicine if you are pregnant unless your doctor advises you that it is safe to do so. If you are a woman 
of child-bearing age, you should avoid becoming pregnant while you are taking Pradaxa.

You should not breast-feed while you are taking Pradaxa.

Driving and using machines

Pradaxa has no known effects on the ability to drive or use machines.

3. How to take Pradaxa

Pradaxa capsules can be used in adults and children aged 8 years or older who are able to swallow the 
capsules whole. There are other age appropriate dose forms for the treatment of children below 
8 years.

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure.

Take Pradaxa as recommended for the following conditions:

Prevention of blood clot formation after knee or hip replacement surgery 

The recommended dose is 220 mg once a day (taken as 2 capsules of 110 mg).



221

If your kidney function is decreased by more than half or if you are 75 years of age or older, the 
recommended dose is 150 mg once a day (taken as 2 capsules of 75 mg).

If you are taking amiodarone, quinidine or verapamil containing medicines the recommended dose 
is 150 mg once a day (taken as 2 capsules of 75 mg).

If you are taking verapamil containing medicines and your kidney function is decreased by more 
than half, you should be treated with a reduced dose of 75 mg Pradaxa because your bleeding risk may 
be increased.

For both surgery types, treatment should not be started if there is bleeding from the site of operation. If 
the treatment cannot be started until the day after surgery, dosing should be started with 2 capsules 
once a day.

After knee replacement surgery

You should start treatment with Pradaxa within 1-4 hours after surgery finishes, taking a single 
capsule. Thereafter two capsules once a day should be taken for a total of 10 days.

After hip replacement surgery
You should start treatment with Pradaxa within 1-4 hours after surgery finishes, taking a single 
capsule. Thereafter two capsules once a day should be taken for a total of 28-35 days.

Treatment of blood clots and prevention of blood clots from reoccurring in children

Pradaxa 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 depends on age and weight. Your doctor will determine the correct dose. Your 
doctor may adjust the dose as treatment progresses. Keep using all other medicines, unless your doctor 
tells you to stop using any.

Single Pradaxa dose to be given twice daily in milligrams (mg) by weight in kilograms (kg) and age in 
years of the patient:



222

Age in years
8 to <9 9 to 

<10
10 to 
<11

11 to 
<12

12 to 
<13

13 to 
<14

14 to 
<15

15 to 
<16

16 to 
<17

17 to 
<18

W
ei

g
h

t 
[k

g
]

>81 300 mg
as two 150 mg capsules

or
four 75 mg capsules

71 to <81

61 to <71

51 to <61

260 mg
as one 110 mg plus one 150 mg capsule

or
one 110 mg plus two 75 mg capsules

41 to <51
220 mg

as two 110 mg capsules

31 to <41
185 mg

as one 75 mg plus one 110 mg capsule

26 to <31
150 mg

as one 150 mg capsule
or

two 75 mg capsules21 to <26

16 to <21
One 110 mg capsule

13 to <16

11 to <13
One 
75 mg
capsule

Means that no dosing recommendation can be provided.

How to take Pradaxa

Pradaxa can be taken with or without food. The capsule should be swallowed whole with a glass of 
water, to ensure delivery to the stomach. Do not break, chew, or empty the pellets from the capsule 
since this may increase the risk of bleeding.

Instructions for opening the blisters

The following pictogram illustrates how to take Pradaxa capsules out of the blister

Tear off one individual blister from the blister card along the perforated line

Peel off the backing foil and remove the capsule.

? Do not push the capsules through the blister foil.
? Do not peel off the blister foil until a capsule is required.



223

Instructions for the bottle

? Push and turn for opening.
? After removing the capsule, place the cap back on the bottle and tightly close the bottle right 

away after you take your dose.

Change of anticoagulant treatment

Without specific guidance from your doctor do not change your anticoagulant treatment.

If you take more Pradaxa than you should

Taking too much of this medicine increases the risk of bleeding. Contact your doctor immediately if 
you have taken too many capsules. Specific treatment options are available.

If you forget to take Pradaxa

Prevention of blood clot formation after knee or hip replacement surgery
Continue with your remaining daily doses of Pradaxa at the same time of the next day.
Do not take a double dose to make up for a forgotten dose.

Treatment of blood clots and prevention of blood clots from reoccurring in children
A forgotten dose can still be taken up to 6 hours prior to the next due dose.
A missed dose should be omitted if the remaining time is below 6 hours prior to the next due dose.
Do not double a dose to make up for a forgotten dose.

If you stop taking Pradaxa

Take Pradaxa exactly as prescribed. Do not stop taking this medicine without talking to your doctor 
first, because the risk of developing a blood clot could be higher if you stop treatment too early.
Contact your doctor if you experience indigestion after taking Pradaxa.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Pradaxa affects blood clotting, so most side effects are related to signs such as bruising or bleeding. 
Major or severe bleeding may occur, these constitute the most serious side effects and, regardless of 
location, may become disabling, life-threatening or even lead to death. In some cases these bleedings 
may not be obvious.

If you experience any bleeding event that does not stop by itself or if you experience signs of 
excessive bleeding (exceptional weakness, tiredness, paleness, dizziness, headache or unexplained 
swelling) consult your doctor immediately. Your doctor may decide to keep you under closer 
observation or change your medicine.

Tell your doctor immediately, if you experience a serious allergic reaction which causes difficulty in 
breathing or dizziness.

Possible side effects are listed below, grouped by how likely they are to happen.

Prevention of blood clot formation after knee or hip replacement surgery

Common (may affect up to 1 in 10 people):



224

- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- Unusual laboratory test results on liver function

Uncommon (may affect up to 1 in 100 people):
- Bleeding may happen from the nose, into the stomach or bowel, from penis/vagina or urinary 

tract (incl. blood in the urine that stains the urine pink or red), from piles, from the rectum, 
under the skin, into a joint, from or after an injury or after an operation

- Haematoma formation or bruising occurring after an operation
- Blood detected in the stools by a laboratory test
- A fall in the number of red cells in the blood
- A decrease in the proportion of blood cells
- Allergic reaction
- Vomiting
- Frequent loose or liquid bowel movements
- Feeling sick
- Wound secretion (liquid exuding from the surgical wound)
- Liver enzymes increased
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Rare (may affect up to 1 in 1,000 people):
- Bleeding
- Bleeding may happen in the brain, from a surgical incision, from the site of entry of an injection 

or from the site of entry of a catheter into a vein
- Blood-stained discharge from the site of entry of a catheter into a vein
- Coughing of blood or blood stained sputum
- A fall in the number of platelets in the blood
- A fall in the number of red cells in the blood after an operation
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Itching
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Inflammation of the gullet and stomach
- Reflux of gastric juice into the gullet
- Belly ache or stomach ache
- Indigestion
- Difficulty in swallowing
- Fluid exiting a wound
- Fluid exiting a wound after an operation

Not known (frequency cannot be estimated from the available data):
- Difficulty in breathing or wheezing
- Decreases in the number or even lack of white blood cells (which help to fight infections)
- Hair loss

Treatment of blood clots and prevention of blood clots from reoccurring in children

Common (may affect up to 1 in 10 people):
- A fall in the number of red cells in the blood
- A fall in the number of platelets in the blood
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Haematoma formation
- Nosebleed
- Reflux of gastric juice into the gullet
- Vomiting



225

- Feeling sick
- Frequent loose or liquid bowel movements
- Indigestion
- Hair loss
- Liver enzymes increased

Uncommon (may affect up to 1 in 100 people):
- Decrease in the number of white blood cells (which help to fight infections)
- Bleeding may happen into the stomach or bowel, from the brain, from the rectum, from 

penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under
the skin

- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- A decrease in the proportion of blood cells
- Itching
- Coughing of blood or blood stained sputum
- Belly ache or stomach ache
- Inflammation of the gullet and stomach
- Allergic reaction
- Difficulty in swallowing
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Not known (frequency cannot be estimated from the available data):
- Lack of white blood cells (which help to fight infections)
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Difficulty in breathing or wheezing
- Bleeding
- Bleeding may happen into a joint or from an injury, from a surgical incision, or from the site of 

entry of an injection or from the site of entry of a catheter into a vein
- Bleeding may happen from piles 
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Unusual laboratory test results on liver function

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Pradaxa

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, blister or bottle after 
“EXP”. The expiry date refers to the last day of that month.

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

Bottle: Once opened, the medicine must be used within 4 months. Keep the bottle tightly closed. 
Store in the original package in order to protect from moisture.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


226

6. Contents of the pack and other information

What Pradaxa contains

- The active substance is dabigatran. Each hard capsule contains 75 mg dabigatran etexilate (as 
mesilate).

- The other ingredients are tartaric acid, acacia, hypromellose, dimeticone 350, talc, and 
hydroxypropylcellulose.

- The capsule shell contains carrageenan, potassium chloride, titanium dioxide, and
hypromellose.

- The black printing ink contains shellac, iron oxide black and potassium hydroxide.

What Pradaxa looks like and contents of the pack

Pradaxa 75 mg are hard capsules (approx. 18 x 6 mm) with an opaque, white cap and an opaque, white
body. The Boehringer Ingelheim logo is printed on the cap and “R75” on the body of the hard capsule.

This medicine is available in packs containing 10 x 1, 30 x 1 or 60 x 1 hard capsules in aluminium 
perforated unit dose blisters. Furthermore, Pradaxa is available in packs containing 60 x 1 hard 
capsules in aluminium perforated unit dose white blisters.

This medicine is also available in polypropylene (plastic) bottles with 60 hard capsules.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

and

Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
88397 Biberach an der Riss
Germany



227

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 5 2595942

????????
????????? ????????? ??? ???? ? ??. ?? –
???? ????????
???: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

?eská republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe 
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena-Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG 
Podru?nica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG 
organiza?ná zlo?ka
Tel: +421 2 5810 1211



228

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas fili?le
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/

http://www.ema.europa.eu


229

Package leaflet: Information for the patient

Pradaxa 110 mg hard capsules
dabigatran etexilate

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.

- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Pradaxa is and what it is used for
2. What you need to know before you take Pradaxa
3. How to take Pradaxa
4. Possible side effects
5. How to store Pradaxa
6. Contents of the pack and other information

1. What Pradaxa is and what it is used for

Pradaxa contains the active substance dabigatran etexilate and belongs to a group of medicines called 
anticoagulants. It works by blocking a substance in the body which is involved in blood clot 
formation.

Pradaxa is used in adults to:

- prevent the formation of blood clots in the veins after knee or hip replacement surgery.

- prevent blood clots in the brain (stroke) and other blood vessels in the body if you have a form 
of irregular heart rhythm called nonvalvular atrial fibrillation and at least one additional risk 
factor.

- treat blood clots in the veins of your legs and lungs and to prevent blood clots from re-occurring 
in the vein of your legs and lungs.

Pradaxa is used in children to:

- treat blood clots and to prevent blood clots from reoccurring.

2. What you need to know before you take Pradaxa

Do not take Pradaxa

- if you are allergic to dabigatran etexilate or any of the other ingredients of this medicine (listed 
in section 6).

- if you have severely reduced kidney function.
- if you are currently bleeding.
- if you have a disease in an organ of the body that increases the risk of serious bleeding (e.g., 

stomach ulcer, injury or bleeding in the brain, recent surgery of the brain or eyes).



230

- if you have an increased tendency to bleed. This may be inborn, of unknown cause or due to 
other medicines.

- if you are taking medicines to prevent blood clotting (e.g.warfarin, rivaroxaban, apixaban or 
heparin), except when changing anticoagulant treatment, while having a venous or arterial line 
and you get heparin through this line to keep it open or while your heart beat is being restored to 
normal by a procedure called catheter ablation for atrial fibrillation.

- if you have a severely reduced liver function or liver disease which could possibly cause death.
- if you are taking oral ketoconazole or itraconazole, medicines to treat fungal infections.
- if you are taking oral cyclosporine, a medicine to prevent organ rejection after transplantation.
- if you are taking dronedarone, a medicine used to treat abnormal heart beat.
- if you are taking a combination product of glecaprevir and pibrentasvir, an antiviral medicine 

used to treat hepatitis C
- if you have received an artificial heart valve which requires permanent blood thinning.

Warnings and precautions

Talk to your doctor before taking Pradaxa. You may also need to talk to your doctor during treatment 
with this medicine if you experience symptoms or if you have to undergo surgery.

Tell your doctor if you have or have had any medical conditions or illnesses, in particular any of 
those included in the following list:

- if you have an increased bleeding risk, such as:
? if you have been recently bleeding.
? if you have had a surgical tissue removal (biopsy) in the past month.
? if you have had a serious injury (e.g. a bone fracture, head injury or any injury requiring 

surgical treatment).
? if you are suffering from an inflammation of the gullet or stomach.
? if you have problems with reflux of gastric juice into the gullet.
? if you are receiving medicines which could increase the risk of bleeding. See 'Other medicines 

and Pradaxa' below.
? if you are taking anti-inflammatory medicines such as diclofenac, ibuprofen, piroxicam.
? if you are suffering from an infection of the heart (bacterial endocarditis).
? if you know you have decreased kidney function, or you are suffering from dehydration 

(symptoms include feeling thirsty and passing reduced amounts of dark-coloured 
(concentrated) /foaming urine).

? if you are older than 75 years.
? if you are an adult patient and weigh 50 kg or less.
? only if used for children: if the child has an infection around or within the brain.

- if you have had a heart attack or if you have been diagnosed with conditions that increase the 
risk to develop a heart attack.

- if you have a liver disease that is associated with changes in the blood tests. The use of this 
medicine is not recommended in this case.

Take special care with Pradaxa

- if you need to have an operation:
In this case Pradaxa will need to be stopped temporarily due to an increased bleeding risk 
during and shortly after an operation. It is very important to take Pradaxa before and after the 
operation exactly at the times you have been told by your doctor.

- if an operation involves a catheter or injection into your spinal column (e.g. for epidural or 
spinal anaesthesia or pain reduction):

? it is very important to take Pradaxa before and after the operation exactly at the times 
you have been told by your doctor.



231

? tell your doctor immediately if you get numbness or weakness of your legs or problems 
with your bowel or bladder after the end of anaesthesia, because urgent care is 
necessary.

- if you fall or injure yourself during treatment, especially if you hit your head. Please seek urgent 
medical attention. You may need to be checked by a doctor, as you may be at increased risk of 
bleeding.

- if you know that you have a disease called antiphospholipid syndrome (a disorder of the 
immune system that causes an increased risk of blood clots), tell your doctor who will decide if 
the treatment may need to be changed.

Other medicines and Pradaxa

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. In particular you should tell your doctor before taking Pradaxa, if you are taking one 
of the medicines listed below:

- Medicines to reduce blood clotting (e.g. warfarin, phenprocoumon, acenocoumarol, heparin, 
clopidogrel, prasugrel, ticagrelor, rivaroxaban, acetylsalicylic acid)

- Medicines to treat fungal infections (e.g. ketoconazole, itraconazole), unless they are only 
applied to the skin

- Medicines to treat abnormal heart beats (e.g. amiodarone, dronedarone, quinidine, verapamil).
If you are taking amiodarone, quinidine or verapamil containing medicines, your doctor may tell 
you to use a reduced dose of Pradaxa depending on the condition for which it is prescribed to
you. See section 3.

- Medicines to prevent organ rejection after transplantation (e.g. tacrolimus, cyclosporine)
- A combination product of glecaprevir and pibrentasvir (an antiviral medicine used to treat 

hepatitis C)
- Anti-inflammatory and pain reliever medicines (e.g. acetylsalicylic acid, ibuprofen, diclofenac)
- St. John´s wort, a herbal medicine for depression
- Antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin-

norepinephrine re-uptake inhibitors
- Rifampicin or clarithromycin (two antibiotics)
- Anti-viral medicines for AIDS (e.g. ritonavir)
- Certain medicines for treatment of epilepsy (e.g. carbamazepine, phenytoin)

Pregnancy and breast-feeding 

The effects of Pradaxa on pregnancy and the unborn child are not known. You should not take this 
medicine if you are pregnant unless your doctor advises you that it is safe to do so. If you are a woman 
of child-bearing age, you should avoid becoming pregnant while you are taking Pradaxa.

You should not breast-feed while you are taking Pradaxa.

Driving and using machines

Pradaxa has no known effects on the ability to drive or use machines.

3. How to take Pradaxa

Pradaxa capsules can be used in adults and children aged 8 years or older who are able to swallow the 
capsules whole. There are other age appropriate dose forms for the treatment of children below 
8 years.



232

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure.

Take Pradaxa as recommended for the following conditions:

Prevention of blood clot formation after knee or hip replacement surgery

The recommended dose is 220 mg once a day (taken as 2 capsules of 110 mg).

If your kidney function is decreased by more than half or if you are 75 years of age or older, the 
recommended dose is 150 mg once a day (taken as 2 capsules of 75 mg).

If you are taking amiodarone, quinidine or verapamil containing medicines the recommended dose 
is 150 mg once a day (taken as 2 capsules of 75 mg).

If you are taking verapamil containing medicines and your kidney function is decreased by more 
than half, you should be treated with a reduced dose of 75 mg Pradaxa because your bleeding risk may 
be increased.

For both surgery types, treatment should not be started if there is bleeding from the site of operation. If 
the treatment cannot be started until the day after surgery, dosing should be started with 2 capsules 
once a day.

After knee replacement surgery

You should start treatment with Pradaxa within 1-4 hours after surgery finishes, taking a single 
capsule. Thereafter two capsules once a day should be taken for a total of 10 days.

After hip replacement surgery 
You should start treatment with Pradaxa within 1-4 hours after surgery finishes, taking a single 
capsule. Thereafter two capsules once a day should be taken for a total of 28-35 days.

Prevention of brain or body vessel obstruction by blood clot formation developing after abnormal 
heart beats and Treatment of blood clots in the veins of your legs and lungs including prevention of 
blood clots from re-occurring in the vein of your legs and lungs

The recommended dose is 300 mg taken as one 150 mg capsule twice a day.

If you are 80 years or older, the recommended dose is 220 mg taken as one 110 mg capsule twice a 
day.

If you are taking verapamil containing medicines, you should be treated with a reduced Pradaxa dose 
of 220 mg taken as one 110 mg capsule twice a day, because your bleeding risk may be increased.

If you have a potentially higher risk for bleeding, your doctor may decide to prescribe a dose of 
220 mg taken as one 110 mg capsule twice a day.

You can continue to take this medicine if your heart beat needs to be restored to normal by a procedure 
called cardioversion. Take Pradaxa as your physician has told you.

If a medical device (stent) has been deployed in a blood vessel to keep it open in a procedure called 
percutaneous coronary intervention with stenting, you can be treated with Pradaxa after your physician 
has decided that normal control of blood coagulation is achieved. Take Pradaxa as your physician has 
told you.



233

Treatment of blood clots and prevention of blood clots from reoccurring in children

Pradaxa 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 depends on age and weight. Your doctor will determine the correct dose. Your 
doctor may adjust the dose as treatment progresses. Keep using all other medicines, unless your doctor 
tells you to stop using any.

Single Pradaxa dose to be given twice daily in milligrams (mg) by weight in kilograms (kg) and age in 
years of the patient:

Age in years
8 to <9 9 to 

<10
10 to 
<11

11 to 
<12

12 to 
<13

13 to 
<14

14 to 
<15

15 to 
<16

16 to 
<17

17 to 
<18

W
ei

gh
t 

[k
g]

>81 300 mg
as two 150 mg capsules

or
four 75 mg capsules

71 to <81

61 to <71

51 to <61

260 mg
as one 110 mg plus one 150 mg capsule

or
one 110 mg plus two 75 mg capsules

41 to <51
220 mg

as two 110 mg capsules

31 to <41
185 mg

as one 75 mg plus one 110 mg capsule

26 to <31
150 mg

as one 150 mg capsule
or

two 75 mg capsules21 to <26

16 to <21
One 110 mg capsule

13 to <16

11 to <13
One 
75 mg
capsule

Means that no dosing recommendation can be provided.

How to take Pradaxa

Pradaxa can be taken with or without food. The capsule should be swallowed whole with a glass of 
water, to ensure delivery to the stomach. Do not break, chew, or empty the pellets from the capsule 
since this may increase the risk of bleeding.

Instructions for opening the blisters

The following pictogram illustrates how to take Pradaxa capsules out of the blister

Tear off one individual blister from the blister card along the perforated line



234

Peel off the backing foil and remove the capsule.

? Do not push the capsules through the blister foil.
? Do not peel off the blister foil until a capsule is required.

Instructions for the bottle

? Push and turn for opening.
? After removing the capsule, place the cap back on the bottle and tightly close the bottle right 

away after you take your dose.

Change of anticoagulant treatment

Without specific guidance from your doctor do not change your anticoagulant treatment.

If you take more Pradaxa than you should

Taking too much of this medicine increases the risk of bleeding. Contact your doctor immediately if 
you have taken too many capsules. Specific treatment options are available.

If you forget to take Pradaxa

Prevention of blood clot formation after knee or hip replacement surgery
Continue with your remaining daily doses of Pradaxa at the same time of the next day.
Do not take a double dose to make up for a forgotten dose.

Use in adults: Prevention of brain or body vessel obstruction by blood clot formation developing after 
abnormal heart beats and treatment of blood clots in the veins of your legs and lungs including 
prevention of blood clots from re-occurring in the vein of your legs and lungs
Use in children: Treatment of blood clots and prevention of blood clots from reoccurring
A forgotten dose can still be taken up to 6 hours prior to the next due dose.
A missed dose should be omitted if the remaining time is below 6 hours prior to the next due dose.
Do not double a dose to make up for a forgotten dose.

If you stop taking Pradaxa

Take Pradaxa exactly as prescribed. Do not stop taking this medicine without talking to your doctor 
first, because the risk of developing a blood clot could be higher if you stop treatment too early.
Contact your doctor if you experience indigestion after taking Pradaxa.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Pradaxa affects blood clotting, so most side effects are related to signs such as bruising or bleeding.
Major or severe bleeding may occur, these constitute the most serious side effects and, regardless of 
location, may become disabling, life-threatening or even lead to death. In some cases these bleedings 
may not be obvious.



235

If you experience any bleeding event that does not stop by itself or if you experience signs of 
excessive bleeding (exceptional weakness, tiredness, paleness, dizziness, headache or unexplained 
swelling) consult your doctor immediately. Your doctor may decide to keep you under closer 
observation or change your medicine.

Tell your doctor immediately, if you experience a serious allergic reaction which causes difficulty in 
breathing or dizziness.

Possible side effects are listed below, grouped by how likely they are to happen.

Prevention of blood clot formation after knee or hip replacement surgery

Common (may affect up to 1 in 10 people):
- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- Unusual laboratory test results on liver function

Uncommon (may affect up to 1 in 100 people):
- Bleeding may happen from the nose, into the stomach or bowel, from penis/vagina or urinary 

tract (incl. blood in the urine that stains the urine pink or red), from piles, from the rectum, 
under the skin, into a joint, from or after an injury or after an operation

- Haematoma formation or bruising occurring after an operation
- Blood detected in the stools by a laboratory test
- A fall in the number of red cells in the blood
- A decrease in the proportion of blood cells
- Allergic reaction
- Vomiting
- Frequent loose or liquid bowel movements
- Feeling sick
- Wound secretion (liquid exuding from the surgical wound)
- Liver enzymes increased
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Rare (may affect up to 1 in 1,000 people):
- Bleeding
- Bleeding may happen in the brain, from a surgical incision, from the site of entry of an injection 

or from the site of entry of a catheter into a vein
- Blood-stained discharge from the site of entry of a catheter into a vein
- Coughing  of blood or blood stained sputum
- A fall in the number of platelets in the blood
- A fall in the number of red cells in the blood after an operation
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Itching
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Inflammation of the gullet and stomach
- Reflux of gastric juice into the gullet
- Belly ache or stomach ache
- Indigestion
- Difficulty in swallowing
- Fluid exiting a wound
- Fluid exiting a wound after an operation

Not known (frequency cannot be estimated from the available data):
- Difficulty in breathing or wheezing
- Decreases in the number or even lack of white blood cells (which help to fight infections)



236

- Hair loss

Prevention of brain or body vessel obstruction by blood clot formation developing after abnormal 
heart beats

Common (may affect up to 1 in 10 people):
- Bleeding may happen from the nose, into the stomach or bowel, from penis/vagina or urinary 

tract (incl. blood in the urine that stains the urine pink or red), or under the skin
- A fall in the number of red cells in the blood
- Belly ache or stomach ache
- Indigestion
- Frequent loose or liquid bowel movements
- Feeling sick

Uncommon (may affect up to 1 in 100 people):
- Bleeding
- Bleeding may happen from piles, from the rectum, or in the brain.
- Haematoma formation
- Coughing of blood or blood stained sputum
- A fall in the number of platelets in the blood
- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- Allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Itching
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Inflammation of the gullet and stomach
- Reflux of gastric juice into the gullet
- Vomiting
- Difficulty in swallowing
- Unusual laboratory test results on liver function

Rare (may affect up to 1 in 1,000 people):
- Bleeding may happen into a joint, from a surgical incision, from an injury, from the site of entry 

of an injection or from the site of entry of a catheter into a vein
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- A decrease in the proportion of blood cells
- Liver enzymes increased
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Not known (frequency cannot be estimated from the available data):
- Difficulty in breathing or wheezing
- Decreases in the number or even lack of white blood cells (which help to fight infections)
- Hair loss

In a clinical trial the rate of heart attacks with Pradaxa was numerically higher than with warfarin. The 
overall occurence was low.

Treatment of blood clots in the veins of your legs and lungs including prevention of blood clots from 
re-occurring in the veins of your legs and/or lungs

Common (may affect up to 1 in 10 people):
- Bleeding may happen from the nose, into the stomach or bowel, from the rectum, from 

penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under 
the skin

- Indigestion



237

Uncommon (may affect up to 1 in 100 people):
- Bleeding
- Bleeding may happen into a joint or from an injury 
- Bleeding may happen from piles
- A fall in the number of red cells in the blood
- Haematoma formation
- Coughing of blood or blood stained sputum
- Allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Itching
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Inflammation of the gullet and stomach
- Reflux of gastric juice into the gullet
- Feeling sick
- Vomiting
- Belly ache or stomach ache
- Frequent loose or liquid bowel movements
- Unusual laboratory test results on liver function
- Liver enzymes increased

Rare (may affect up to 1 in 1,000 people):
- Bleeding may happen, from a surgical incision, or from the site of entry of an injection or from 

the site of entry of a catheter into a vein or from the brain  
- A fall in the number of platelets in the blood
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Difficulty in swallowing

Not known (frequency cannot be estimated from the available data):
- Difficulty in breathing or wheezing
- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- A decrease in the proportion of blood cells
- Decreases in the number or even lack of white blood cells (which help to fight infections)
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems
- Hair loss

In the trial program the rate of heart attacks with Pradaxa was higher than with warfarin. The overall 
occurence was low. No imbalance in the rate of heart attacks was observed in patients treated with 
dabigatran versus patients treated with placebo.

Treatment of blood clots and prevention of blood clots from reoccurring in children

Common (may affect up to 1 in 10 people):
- A fall in the number of red cells in the blood
- A fall in the number of platelets in the blood
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Haematoma formation
- Nosebleed
- Reflux of gastric juice into the gullet
- Vomiting
- Feeling sick
- Frequent loose or liquid bowel movements
- Indigestion
- Hair loss



238

- Liver enzymes increased

Uncommon (may affect up to 1 in 100 people):
- Decrease in the number of white blood cells (which help to fight infections)
- Bleeding may happen into the stomach or bowel, from the brain, from the rectum, from 

penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under 
the skin

- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- A decrease in the proportion of blood cells
- Itching
- Coughing of blood or blood stained sputum
- Belly ache or stomach ache
- Inflammation of the gullet and stomach
- Allergic reaction
- Difficulty in swallowing
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Not known (frequency cannot be estimated from the available data):
- Lack of white blood cells (which help to fight infections)
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Difficulty in breathing or wheezing
- Bleeding
- Bleeding may happen into a joint or from an injury, from a surgical incision, or from the site of 

entry of an injection or from the site of entry of a catheter into a vein
- Bleeding may happen from piles 
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Unusual laboratory test results on liver function

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Pradaxa

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, blister or bottle after 
“EXP”. The expiry date refers to the last day of that month.

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

Bottle: Once opened, the medicine must be used within 4 months. Keep the bottle tightly closed. 
Store in the original package in order to protect from moisture.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


239

6. Contents of the pack and other information

What Pradaxa contains

- The active substance is dabigatran. Each hard capsule contains 110 mg dabigatran etexilate (as 
mesilate).

- The other ingredients are tartaric acid, acacia, hypromellose, dimeticone 350, talc, and 
hydroxypropylcellulose.

- The capsule shell contains carrageenan, potassium chloride, titanium dioxide, indigo carmine, 
and hypromellose.

- The black printing ink contains shellac, iron oxide black and potassium hydroxide.

What Pradaxa looks like and contents of the pack

Pradaxa 110 mg are hard capsules (approx. 19 x 7 mm) with an opaque, light blue-coloured cap and an 
opaque, light blue -coloured body. The Boehringer Ingelheim logo is printed on the cap and “R110” 
on the body of the hard capsule.

This medicine is available in packs containing 10 x 1, 30 x 1 or 60 x 1 hard capsules, a multipack 
containing 3 packs of 60 x 1 hard capsules (180 hard capsules) or a multipack containing 2 packs of 
50 x 1 hard capsules (100 hard capsules) in aluminium perforated unit dose blisters. Furthermore, 
Pradaxa is available in packs containing 60 x 1 hard capsules in aluminium perforated unit dose white 
blisters.

This medicine is also available in polypropylene (plastic) bottles with 60 hard capsules.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

and 

Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
88397 Biberach an der Riss
Germany



240

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 5 2595942

????????
????????? ????????? ??? ???? ? ??. ?? –
???? ????????
???: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

?eská republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe 
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena-Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG 
Podru?nica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG 
organiza?ná zlo?ka
Tel: +421 2 5810 1211



241

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas fili?le
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/

http://www.ema.europa.eu


242

Package leaflet: Information for the patient

Pradaxa 150 mg hard capsules
dabigatran etexilate

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.

- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Pradaxa is and what it is used for
2. What you need to know before you take Pradaxa
3. How to take Pradaxa
4. Possible side effects
5. How to store Pradaxa
6. Contents of the pack and other information

1. What Pradaxa is and what it is used for

Pradaxa contains the active substance dabigatran etexilate and belongs to a group of medicines called 
anticoagulants. It works by blocking a substance in the body which is involved in blood clot 
formation.

Pradaxa is used in adults to:

- prevent blood clots in the brain (stroke) and other blood vessels in the body if you have a form 
of irregular heart rhythm called nonvalvular atrial fibrillation and at least one additional risk 
factor.

- treat blood clots in the veins of your legs and lungs and to prevent blood clots from re-occurring 
in the vein of your legs and lungs.

Pradaxa is used in children to:

- treat blood clots and to prevent blood clots from reoccurring.

2. What you need to know before you take Pradaxa

Do not take Pradaxa

- if you are allergic to dabigatran etexilate or any of the other ingredients of this medicine (listed 
in section 6).

- if you have severely reduced kidney function.
- if you are currently bleeding.
- if you have a disease in an organ of the body that increases the risk of serious bleeding (e.g., 

stomach ulcer, injury or bleeding in the brain, recent surgery of the brain or eyes).
- if you have an increased tendency to bleed. This may be inborn, of unknown cause or due to 

other medicines.



243

- if you are taking medicines to prevent blood clotting (e.g.warfarin, rivaroxaban, apixaban or 
heparin), except when changing anticoagulant treatment, while having a venous or arterial line 
and you get heparin through this line to keep it open or while your heart beat is being restored to 
normal by a procedure called catheter ablation for atrial fibrillation.

- if you have a severely reduced liver function or liver disease which could possibly cause death.
- if you are taking oral ketoconazole or itraconazole, medicines to treat fungal infections.
- if you are taking oral cyclosporine, a medicine to prevent organ rejection after transplantation.
- if you are taking dronedarone, a medicine used to treat abnormal heart beat.
- if you are taking a combination product of glecaprevir and pibrentasvir, an antiviral medicine 

used to treat hepatitis C
- if you have received an artificial heart valve which requires permanent blood thinning.

Warnings and precautions

Talk to your doctor before taking Pradaxa. You may also need to talk to your doctor during treatment 
with this medicine if you experience symptoms or if you have to undergo surgery.

Tell your doctor if you have or have had any medical conditions or illnesses, in particular any of 
those included in the following list:

- if you have an increased bleeding risk, such as:
? if you have been recently bleeding.
? if you have had a surgical tissue removal (biopsy) in the past month.
? if you have had a serious injury (e.g. a bone fracture, head injury or any injury requiring 

surgical treatment).
? if you are suffering from an inflammation of the gullet or stomach.
? if you have problems with reflux of gastric juice into the gullet.
? if you are receiving medicines which could increase the risk of bleeding. See 'Other medicines 

and Pradaxa' below.
? if you are taking anti-inflammatory medicines such as diclofenac, ibuprofen, piroxicam.
? if you are suffering from an infection of the heart (bacterial endocarditis).
? if you know you have decreased kidney function, or you are suffering from dehydration 

(symptoms include feeling thirsty and passing reduced amounts of dark-coloured 
(concentrated) / foaming urine).

? if you are older than 75 years.
? if you are an adult patient and weigh 50 kg or less.
? only if used for children: if the child has an infection around or within the brain.

- if you have had a heart attack or if you have been diagnosed with conditions that increase the 
risk to develop a heart attack.

- if you have a liver disease that is associated with changes in the blood tests. The use of this 
medicine is not recommended in this case.

Take special care with Pradaxa

- if you need to have an operation:
In this case Pradaxa will need to be stopped temporarily due to an increased bleeding risk 
during and shortly after an operation. It is very important to take Pradaxa before and after the 
operation exactly at the times you have been told by your doctor.

- if an operation involves a catheter or injection into your spinal column (e.g. for epidural or 
spinal anaesthesia or pain reduction):

? it is very important to take Pradaxa before and after the operation exactly at the times 
you have been told by your doctor.



244

? tell your doctor immediately if you get numbness or weakness of your legs or problems 
with your bowel or bladder after the end of anaesthesia, because urgent care is 
necessary.

- if you fall or injure yourself during treatment, especially if you hit your head. Please seek urgent 
medical attention. You may need to be checked by a doctor, as you may be at increased risk of 
bleeding.

- if you know that you have a disease called antiphospholipid syndrome (a disorder of the 
immune system that causes an increased risk of blood clots), tell your doctor who will decide if 
the treatment may need to be changed.

Other medicines and Pradaxa

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. In particular you should tell your doctor before taking Pradaxa, if you are taking one 
of the medicines listed below:

- Medicines to reduce blood clotting (e.g. warfarin, phenprocoumon, acenocoumarol, heparin, 
clopidogrel, prasugrel, ticagrelor, rivaroxaban, acetylsalicylic acid)

- Medicines to treat fungal infections (e.g. ketoconazole, itraconazole), unless they are only 
applied to the skin

- Medicines to treat abnormal heart beats (e.g. amiodarone, dronedarone, quinidine, verapamil).
If you are taking verapamil containing medicines, your doctor may tell you to use a reduced 
dose of Pradaxa depending on the condition for which it is prescribed to you. See section 3.

- Medicines to prevent organ rejection after transplantation (e.g. tacrolimus, cyclosporine)
- A combination product of glecaprevir and pibrentasvir (an antiviral medicine used to treat 

hepatitis C)
- Anti-inflammatory and pain reliever medicines (e.g. acetylsalicylic acid, ibuprofen, diclofenac)
- St. John´s wort, a herbal medicine for depression
- Antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin-

norepinephrine re-uptake inhibitors
- Rifampicin or clarithromycin (two antibiotics)
- Anti-viral medicines for AIDS (e.g. ritonavir)
- Certain medicines for treatment of epilepsy (e.g. carbamazepine, phenytoin)

Pregnancy and breast-feeding 

The effects of Pradaxa on pregnancy and the unborn child are not known. You should not take this 
medicine if you are pregnant unless your doctor advises you that it is safe to do so. If you are a woman 
of child-bearing age, you should avoid becoming pregnant while you are taking Pradaxa.

You should not breast-feed while you are taking Pradaxa.

Driving and using machines

Pradaxa has no known effects on the ability to drive or use machines.

3. How to take Pradaxa

Pradaxa capsules can be used in adults and children aged 8 years or older who are able to swallow the 
capsules whole. There are other age appropriate dose forms for the treatment of children below 
8 years.

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure.



245

Take Pradaxa as recommended for the following conditions:

Prevention of brain or body vessel obstruction by blood clot formation developing after abnormal 
heart beats and Treatment of blood clots in the veins of your legs and lungs including prevention of 
blood clots from re-occurring in the vein of your legs and lungs

The recommended dose is 300 mg taken as one 150 mg capsule twice a day.

If you are 80 years or older, the recommended dose is 220 mg taken as one 110 mg capsule twice 
daily.

If you are taking verapamil containing medicines, you should be treated with a reduced Pradaxa dose 
of 220 mg taken as one 110 mg capsule twice a day, because your bleeding risk may be increased.

If you have a potentially higher risk for bleeding, your doctor may decide to prescribe a dose of 
220 mg taken as one 110 mg capsule twice a day.

You can continue to take this medicine if your heart beat needs to be restored to normal by a procedure 
called cardioversion or by a procedure called catheter ablation for atrial fibrillation. Take Pradaxa as 
your physician has told you.

If a medical device (stent) has been deployed in a blood vessel to keep it open in a procedure called 
percutaneous coronary intervention with stenting, you can be treated with Pradaxa after your physician 
has decided that normal control of blood coagulation is achieved. Take Pradaxa as your physician has 
told you.

Treatment of blood clots and prevention of blood clots from reoccurring in children

Pradaxa 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 depends on age and weight. Your doctor will determine the correct dose. Your 
doctor may adjust the dose as treatment progresses. Keep using all other medicines, unless your doctor 
tells you to stop using any.

Single Pradaxa dose to be given twice daily in milligrams (mg) by weight in kilograms (kg) and age in 
years of the patient:



246

Age in years
8 to <9 9 to 

<10
10 to 
<11

11 to 
<12

12 to 
<13

13 to 
<14

14 to 
<15

15 to 
<16

16 to 
<17

17 to 
<18

W
ei

g
h

t 
[k

g
]

>81 300 mg
as two 150 mg capsules

or
four 75 mg capsules

71 to <81

61 to <71

51 to <61

260 mg
as one 110 mg plus one 150 mg capsule

or
one 110 mg plus two 75 mg capsules

41 to <51
220 mg

as two 110 mg capsules

31 to <41
185 mg

as one 75 mg plus one 110 mg capsule

26 to <31
150 mg

as one 150 mg capsule
or

two 75 mg capsules21 to <26

16 to <21
One 110 mg capsule

13 to <16

11 to <13
One 
75 mg
capsule

Means that no dosing recommendation can be provided.

How to take Pradaxa

Pradaxa can be taken with or without food. The capsule should be swallowed whole with a glass of 
water, to ensure delivery to the stomach. Do not break, chew, or empty the pellets from the capsule 
since this may increase the risk of bleeding. 

Instructions for opening the blisters

The following pictogram illustrates how to take Pradaxa capsules out of the blister

Tear off one individual blister from the blister card along the perforated line

Peel off the backing foil and remove the capsule.

? Do not push the capsules through the blister foil.
? Do not peel off the blister foil until a capsule is required.



247

Instructions for the bottle

? Push and turn for opening.
? After removing the capsule, place the cap back on the bottle and tightly close the bottle right 

away after you take your dose.

Change of anticoagulant treatment

Without specific guidance from your doctor do not change your anticoagulant treatment.

If you take more Pradaxa than you should

Taking too much of this medicine increases the risk of bleeding. Contact your doctor immediately if 
you have taken too many capsules. Specific treatment options are available.

If you forget to take Pradaxa

A forgotten dose can still be taken up to 6 hours prior to the next due dose.
A missed dose should be omitted if the remaining time is below 6 hours prior to the next due dose.
Do not double a dose to make up for a forgotten dose.

If you stop taking Pradaxa

Take Pradaxa exactly as prescribed. Do not stop taking this medicine without talking to your doctor 
first, because the risk of developing a blood clot could be higher if you stop treatment too early.
Contact your doctor if you experience indigestion after taking Pradaxa.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Pradaxa affects blood clotting, so most side effects are related to signs such as bruising or bleeding. 
Major or severe bleeding may occur, these constitute the most serious side effects and, regardless of 
location, may become disabling, life-threatening or even lead to death. In some cases these bleedings 
may not be obvious.

If you experience any bleeding event that does not stop by itself or if you experience signs of 
excessive bleeding (exceptional weakness, tiredness, paleness, dizziness, headache or unexplained 
swelling) consult your doctor immediately. Your doctor may decide to keep you under closer 
observation or change your medicine.

Tell your doctor immediately, if you experience a serious allergic reaction which causes difficulty in 
breathing or dizziness.

Possible side effects are listed below, grouped by how likely they are to happen.

Prevention of brain or body vessel obstruction by blood clot formation developing after abnormal 
heart beats

Common (may affect up to 1 in 10 people):
- Bleeding may happen from the nose, into the stomach or bowel, from penis/vagina or urinary 

tract (incl. blood in the urine that stains the urine pink or red), or under the skin
- A fall in the number of red cells in the blood
- Belly ache or stomach ache



248

- Indigestion
- Frequent loose or liquid bowel movements
- Feeling sick

Uncommon (may affect up to 1 in 100 people):
- Bleeding
- Bleeding may happen from piles, from the rectum, or in the brain.
- Haematoma formation
- Coughing of blood or blood stained sputum
- A fall in the number of platelets in the blood
- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- Allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Itching
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Inflammation of the gullet and stomach
- Reflux of gastric juice into the gullet
- Vomiting
- Difficulty in swallowing
- Unusual laboratory test results on liver function

Rare (may affect up to 1 in 1,000 people):
- Bleeding may happen into a joint, from a surgical incision, from an injury, from the site of entry 

of an injection or from the site of entry of a catheter into a vein
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- A decrease in the proportion of blood cells
- Liver enzymes increased
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Not known (frequency cannot be estimated from the available data): 
- Difficulty in breathing or wheezing
- Decreases in the number or even lack of white blood cells (which help to fight infections)
- Hair loss

In a clinical trial the rate of heart attacks with Pradaxa was numerically higher than with warfarin. The 
overall occurence was low.

Treatment of blood clots in the veins of your legs and lungs including prevention of blood clots from 
re-occurring in the veins of your legs and/or lungs

Common (may affect up to 1 in 10 people):
- Bleeding may happen from the nose, into the stomach or bowel, from the rectum, from 

penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under 
the skin

- Indigestion

Uncommon (may affect up to 1 in 100 people):
- Bleeding
- Bleeding may happen into a joint or from an injury 
- Bleeding may happen from piles
- A fall in the number of red cells in the blood
- Haematoma formation
- Coughing of blood or blood stained sputum
- Allergic reaction
- Sudden change of the skin which affects its colour and appearance



249

- Itching
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Inflammation of the gullet and stomach
- Reflux of gastric juice into the gullet
- Feeling sick
- Vomiting
- Belly ache or stomach ache
- Frequent loose or liquid bowel movements
- Unusual laboratory test results on liver function
- Liver enzymes increased

Rare (may affect up to 1 in 1,000 people):
- Bleeding may happen, from a surgical incision,or from the site of entry of an injection or from 

the site of entry of a catheter into a vein or from the brain  
- A fall in the number of platelets in the blood
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Difficulty in swallowing

Not known (frequency cannot be estimated from the available data):
- Difficulty in breathing or wheezing
- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- A decrease in the proportion of blood cells
- Decreases in the number or even lack of white blood cells (which help to fight infections)
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems
- Hair loss

In the trial program the rate of heart attacks with Pradaxa was higher than with warfarin. The overall 
occurence was low. No imbalance in the rate of heart attacks was observed in patients treated with 
dabigatran versus patients treated with placebo.

Treatment of blood clots and prevention of blood clots from reoccurring in children

Common (may affect up to 1 in 10 people):
- A fall in the number of red cells in the blood
- A fall in the number of platelets in the blood
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Haematoma formation
- Nosebleed
- Reflux of gastric juice into the gullet
- Vomiting
- Feeling sick
- Frequent loose or liquid bowel movements
- Indigestion
- Hair loss
- Liver enzymes increased

Uncommon (may affect up to 1 in 100 people):
- Decrease in the number of white blood cells (which help to fight infections)
- Bleeding may happen into the stomach or bowel, from the brain, from the rectum, from 

penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under 
the skin

- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
- A decrease in the proportion of blood cells
- Itching



250

- Coughing of blood or blood stained sputum
- Belly ache or stomach ache
- Inflammation of the gullet and stomach
- Allergic reaction
- Difficulty in swallowing
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Not known (frequency cannot be estimated from the available data):
- Lack of white blood cells (which help to fight infections)
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Difficulty in breathing or wheezing
- Bleeding
- Bleeding may happen into a joint or from an injury, from a surgical incision, or from the site of 

entry of an injection or from the site of entry of a catheter into a vein
- Bleeding may happen from piles 
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Unusual laboratory test results on liver function

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Pradaxa

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, blister or bottle after 
“EXP”. The expiry date refers to the last day of that month.

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

Bottle: Once opened, the medicine must be used within 4 months. Keep the bottle tightly closed. 
Store in the original package in order to protect from moisture.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Pradaxa contains

- The active substance is dabigatran. Each hard capsule contains 150 mg dabigatran etexilate (as 
mesilate).

- The other ingredients are tartaric acid, acacia, hypromellose, dimeticone 350, talc, and 
hydroxypropylcellulose.

- The capsule shell contains carrageenan, potassium chloride, titanium dioxide, indigo carmine, 
and hypromellose.

- The black printing ink contains shellac, iron oxide black and potassium hydroxide.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


251

What Pradaxa looks like and contents of the pack

Pradaxa 150 mg are hard capsules (approx. 22 x 8 mm) with an opaque, light blue-coloured cap and an 
opaque, white body. The Boehringer Ingelheim logo is printed on the cap and “R150” on the body of 
the hard capsule.

This medicine is available in packs containing 10 x 1, 30 x 1 or 60 x 1 hard capsules, a multipack 
containing 3 packs of 60 x 1 hard capsules (180 hard capsules) or a multipack containing 2 packs of 
50 x 1 hard capsules (100 hard capsules) in aluminium perforated unit dose blisters. Furthermore, 
Pradaxa is available in packs containing 60 x 1 hard capsules in aluminium perforated unit dose white 
blisters.

This medicine is also available in polypropylene (plastic) bottles with 60 hard capsules.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

and 

Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
88397 Biberach an der Riss
Germany



252

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 5 2595942

????????
????????? ????????? ??? ???? ? ??. ?? –
???? ????????
???: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

?eská republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe 
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena-Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG 
Podru?nica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG 
organiza?ná zlo?ka
Tel: +421 2 5810 1211



253

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas fili?le
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/

http://www.emea.europa.eu


254

Package leaflet: Information for the patient

Pradaxa 20 mg coated granules
Pradaxa 30 mg coated granules
Pradaxa 40 mg coated granules
Pradaxa 50 mg coated granules
Pradaxa 110 mg coated granules
Pradaxa 150 mg coated granules

dabigatran etexilate

Read all of this leaflet carefully before your child starts taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your child’s doctor or pharmacist.
- This medicine has been prescribed for your child only. Do not pass it on to others. It may harm 

them, even if their signs of illness are the same as your child’s.
- If your child gets any side effects, talk to your child’s doctor or pharmacist. This includes any 

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Pradaxa is and what it is used for
2. What you need to know before your child takes Pradaxa
3. How to take Pradaxa 
4. Possible side effects
5. How to store Pradaxa
6. Contents of the pack and other information

1. What Pradaxa is and what it is used for

Pradaxa contains the active substance dabigatran etexilate and belongs to a group of medicines called 
anticoagulants. It works by blocking a substance in the body which is involved in blood clot 
formation.

Pradaxa is used in children to treat blood clots and to prevent blood clots from reoccurring.

2. What you need to know before your child takes Pradaxa

Do not use Pradaxa

- if your child is allergic to dabigatran etexilate or any of the other ingredients of this medicine 
(listed in section 6).

- if your child has severely reduced kidney function.
- if your child is currently bleeding.
- if your child has a disease in an organ of the body that increases the risk of serious bleeding 

(e.g., stomach ulcer, injury or bleeding in the brain, recent surgery of the brain or eyes).
- if your child has an increased tendency to bleed. This may be inborn, of unknown cause or due 

to other medicines.
- if your child is given medicines to prevent blood clotting (e.g.warfarin, rivaroxaban, apixaban or 

heparin), except when changing anticoagulant treatment or while having a venous or arterial 
line and your child gets heparin through this line to keep it open.

- if your child has a severely reduced liver function or liver disease which could possibly cause 
death.

- if your child is given oral ketoconazole or itraconazole, medicines to treat fungal infections.



255

- if your child is given oral cyclosporine, a medicine to prevent organ rejection after 
transplantation.

- if your child is given dronedarone, a medicine used to treat abnormal heart beat.
- if your child is given a combination product of glecaprevir and pibrentasvir, an antiviral 

medicine used to treat hepatitis C
- if your child has received an artificial heart valve which requires permanent blood thinning.

Warnings and precautions

Talk to your child’s doctor before you give your child Pradaxa. You may also need to talk to your 
child’s doctor during treatment with this medicine if your child experiences symptoms or if your child 
has to undergo surgery.

Tell your child’s doctor if your child has or has had any medical conditions or illnesses, in particular 
any of those included in the following list:

- if your child has an increased bleeding risk, such as:
? if your child has been recently bleeding.
? if your child has had a surgical tissue removal (biopsy) in the past month.
? if your child has had a serious injury (e.g. a bone fracture, head injury or any injury requiring 

surgical treatment).
? if your child is suffering from an inflammation of the gullet or stomach.
? if your child has problems with reflux of gastric juice into the gullet.
? if your child is receiving medicines which could increase the risk of bleeding. See 'Other 

medicines and Pradaxa' below.
? if your child is given anti-inflammatory medicines such as diclofenac, ibuprofen, piroxicam.
? if your child is suffering from an infection of the heart (bacterial endocarditis).
? if you know your child has decreased kidney function, or your child is suffering from 

dehydration (symptoms include feeling thirsty and passing reduced amounts of dark-coloured 
(concentrated) / foaming urine).

? if your child has an infection around or within the brain.

- if your child has had a heart attack or if your child has been diagnosed with conditions that 
increase the risk to develop a heart attack.

- if your child has a liver disease that is associated with changes in the blood tests. The use of this 
medicine is not recommended in this case.

Take special care with Pradaxa

- if your child needs to have an operation:
In this case Pradaxa will need to be stopped temporarily due to an increased bleeding risk 
during and shortly after an operation. It is very important to give Pradaxa before and after the 
operation exactly at the times you have been told by your child’s doctor.

- if an operation involves a catheter or injection into your child’s spinal column (e.g. for epidural 
or spinal anaesthesia or pain reduction):

? it is very important to give Pradaxa before and after the operation exactly at the times 
you have been told by your child’s doctor.

? tell your child’s doctor immediately if your child gets numbness or weakness of the legs 
or problems with his/her bowel or bladder after the end of anaesthesia, because urgent 
care is necessary.

- if your child falls or injures himself/herself during treatment, especially if your child hits his/her 
head. Please seek urgent medical attention. Your child may need to be checked by a doctor, as 
your child may be at increased risk of bleeding.



256

- if you know that your child has a disease called antiphospholipid syndrome (a disorder of the 
immune system that causes an increased risk of blood clots), tell your child’s doctor who will 
decide if the treatment may need to be changed.

Other medicines and Pradaxa

Tell your child’s doctor or pharmacist if your child is given or has recently been given other 
medicines. In particular you should tell your child’s doctor before taking Pradaxa, if your child 
is given one of the medicines listed below:

- Medicines to reduce blood clotting (e.g. warfarin, phenprocoumon, acenocoumarol, heparin, 
clopidogrel, prasugrel, ticagrelor, rivaroxaban, acetylsalicylic acid)

- Medicines to treat fungal infections (e.g. ketoconazole, itraconazole), unless they are only 
applied to the skin

- Medicines to treat abnormal heart beats (e.g. amiodarone, dronedarone, quinidine, verapamil).
- Medicines to prevent organ rejection after transplantation (e.g. tacrolimus, cyclosporine)
- A combination product of glecaprevir and pibrentasvir (an antiviral medicine used to treat 

hepatitis C)
- Anti-inflammatory and pain reliever medicines (e.g. acetylsalicylic acid, ibuprofen, diclofenac)
- St. John´s wort, a herbal medicine for depression
- Antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin-

norepinephrine re-uptake inhibitors
- Rifampicin or clarithromycin (two antibiotics)
- Anti-viral medicines for AIDS (e.g. ritonavir)
- Certain medicines for treatment of epilepsy (e.g. carbamazepine, phenytoin)

Pradaxa with food and drink

Do not mix Pradaxa coated granules with milk or soft food containing milk products. Only use this 
medicine with apple juice or one of the soft foods mentioned in the instructions for use at the end of 
the package leaflet.

Pregnancy and breast-feeding 

This medicine is intended to be used in children below the age of 12 years. Information regarding 
pregnancy and breast-feeding may not be relevant in the context of your child’s treatment.

The effects of Pradaxa on pregnancy and the unborn child are not known. A pregnant woman should 
not take this medicine unless her doctor advises her that it is safe to do so. A woman of child-bearing 
age should avoid becoming pregnant while she is taking Pradaxa.

Breast-feeding should be stopped during treatment with Pradaxa.

Driving and using machines

Pradaxa has no known effects on the ability to drive or use machines.

3. How to take Pradaxa

Pradaxa coated granules can be used for children below 12 years as soon as they are able to swallow 
soft food. There are other age appropriate dose forms for the treatment of babies below 12 months and 
children aged 8 years or older.

Always give this medicine exactly as your child’s doctor has told you. Check with your child’s doctor 
if you are not sure.



257

Pradaxa 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 depends on age and weight. Your child’s doctor will determine the correct 
dose for your child based on your child’s age and weight. Your child’s doctor may adjust the dose as 
treatment progresses. Your child must keep using all other medicines, unless your child’s doctor tells 
you to stop using any.

Single Pradaxa dose to be given twice daily in milligrams (mg) for patients aged less than 2.5 years. 
The dose depends on weight in kilograms (kg) and age in months or years of the patient:

Age in months Age in years

0 to 
<1

1 to 
<3

3 to 
<4

4 to 
<5

5 to 
<6

6 to 
<8

8 to 
<9

9 to 
<10

10 to 
<11

11 to 
<12

1 to 
<1.5

1.5 
to <2

2 to 
<2.5

W
ei

gh
t 

[k
g]

21 to <26 140 180

16 to <21 110 110 140

13 to <16 80 100 100 110 140

11 to <13 70 70 80 80 80 100 100

9 to <11 50 60 60 60 60 70 70 80 80

7 to <9 40 50 50 50 50 60 60 60 60 60 70

5 to <7 20 20 40 40 40 40 50 50 50 50 50 50

4 to <5 20 20 20 20 40 40 40

3 to <4 20 20 20

2.5 to <3 20

Convenient sachet combinations to achieve the single doses recommended in the dosing 

table are provided below. Other combinations are possible.

20: One 20 mg sachet 80: Two 40 mg sachets

40: One 40 mg sachet 100: Two 50 mg sachets

50: One 50 mg sachet 110: One 110 mg sachet

60: Two 30 mg sachets 140: One 30 mg plus one 110 mg sachet

70: One 30 mg plus one 40 mg sachet 180: One 30 mg plus one 150 mg sachet

Means that no dosing recommendation can be provided.

Single Pradaxa dose to be given twice daily in milligrams (mg) for patients aged 2.5 years to 
<12 years. The dose depends on weight in kilograms (kg) and age in years of the patient:



258

Age in years
2.5 to <4 4 to <5 5 to <6 6 to <7 7 to <9 9 to <10 10 to <12

W
ei

g
h

t 
[k

g
]

>81 330

71 to <81 330 330 330

61 to <71 330 330 330 330

51 to <61 300 300 300 300 300

41 to <51 260 260 260 260 260 260

31 to <41 190 190 190 190 190 190 190

26 to <31 180 180 180 180 180 180 180

21 to <26 180 180 180 180 180 180 180

16 to <21 140 140 140 140 140 140 140

13 to <16 140 140 140 140 140 140 140

11 to <13 110 110 110 110 110

9 to <11 80 80 80 80

7 to <9 70

Convenient sachet combinations to achieve the single doses recommended in the dosing 

table are provided below. Other combinations are possible.

70: One 30 mg plus one 40 mg sachet 190: One 40 mg plus one 150 mg sachet

80: Two 40 mg sachets 260: One 110 mg plus one 150 mg sachet

110: One 110 mg sachet 300: Two 150 mg sachets

140: One 30 mg plus one 110 mg sachet 330: Three 110 mg sachets

180: One 30 mg plus one 150 mg sachet

Means that no dosing recommendation can be provided.

Method and route of administration

This medicine is given together with apple juice or one of the soft food options mentioned in the 
instructions for use. Do not mix this medicine with milk or soft food containing milk products.

Detailed instructions for the use of this medicine are provided in ‘Instructions for use’ at the end 
of the package leaflet.

Change of anticoagulant treatment

Without specific guidance from your child’s doctor do not change your child’s anticoagulant 
treatment.

If you give more Pradaxa than you should

Taking too much of this medicine increases the risk of bleeding. Contact your child’s doctor 
immediately if you have given too much of it. Specific treatment options are available.



259

If you forget to give your child Pradaxa

A forgotten dose can still be given up to 6 hours prior to the next due dose.
A missed dose should be omitted if the remaining time is below 6 hours prior to the next due dose.
Do not give a double dose to make up for a forgotten dose.
If a dose has only been taken partially, do not attempt to administer a second dose at that time-point.
Give the next dose as scheduled approximately 12 hours later.

If you stop giving Pradaxa

Give Pradaxa exactly as prescribed. Do not stop giving this medicine without talking to your child’s 
doctor first, because the risk of developing a blood clot could be higher if you stop treatment too early. 
Contact your child’s doctor if your child experiences indigestion after giving Pradaxa.

If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Pradaxa affects blood clotting, so most side effects are related to signs such as bruising or bleeding. 
Major or severe bleeding may occur, these constitute the most serious side effects and, regardless of 
location, may become disabling, life-threatening or even lead to death. In some cases these bleedings 
may not be obvious.

If your child experiences any bleeding event that does not stop by itself or if your child experiences 
signs of excessive bleeding (exceptional weakness, tiredness, paleness, dizziness, headache or 
unexplained swelling) consult your child’s doctor immediately. Your child’s doctor may decide to 
keep your child under closer observation or change the medicine.

Tell your child’s doctor immediately, if your child experiences a serious allergic reaction which causes 
difficulty in breathing or dizziness.

Possible side effects are listed below, grouped by how likely they are to happen.

Common (may affect up to 1 in 10 people):
- A fall in the number of red cells in the blood
- A fall in the number of platelets in the blood
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Haematoma formation
- Nosebleed
- Reflux of gastric juice into the gullet
- Vomiting
- Feeling sick
- Frequent loose or liquid bowel movements
- Indigestion
- Hair loss
- Liver enzymes increased

Uncommon (may affect up to 1 in 100 people):
- Decrease in the number of white blood cells (which help to fight infections)
- Bleeding may happen into the stomach or bowel, from the brain, from the rectum, from 

penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under 
the skin

- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)



260

- A decrease in the proportion of blood cells
- Itching
- Coughing of blood or blood stained sputum
- Belly ache or stomach ache
- Inflammation of the gullet and stomach
- Allergic reaction
- Difficulty in swallowing
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Not known (frequency cannot be estimated from the available data):
- Lack of white blood cells (which help to fight infections)
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Difficulty in breathing or wheezing
- Bleeding
- Bleeding may happen into a joint or from an injury, from a surgical incision, or from the site of 

entry of an injection or from the site of entry of a catheter into a vein
- Bleeding may happen from piles 
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Unusual laboratory test results on liver function

Reporting of side effects
If your child gets any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Pradaxa

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiry 
date refers to the last day of that month.

Before first use, do not open the aluminium bag containing the sachets with the Pradaxa coated 
granules in order to protect from moisture.

Once the aluminium bag containing the sachets with the coated granules and the desiccant is opened, 
the medicine must be used within 6 months. The opened sachet cannot be stored and must be used 
immediately after opening.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Pradaxa contains

- The active substance is dabigatran. Each sachet of Pradaxa 20 mg coated granules contains 
coated granules with 20 mg dabigatran etexilate (as mesilate).

- The active substance is dabigatran. Each sachet of Pradaxa 30 mg coated granules contains 
coated granules with 30 mg dabigatran etexilate (as mesilate).

- The active substance is dabigatran. Each sachet of Pradaxa 40 mg coated granules contains 
coated granules with 40 mg dabigatran etexilate (as mesilate).

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


261

- The active substance is dabigatran. Each sachet of Pradaxa 50 mg coated granules contains 
coated granules with 50 mg dabigatran etexilate (as mesilate).

- The active substance is dabigatran. Each sachet of Pradaxa 110 mg coated granules contains 
coated granules with 110 mg dabigatran etexilate (as mesilate).

- The active substance is dabigatran. Each sachet of Pradaxa 150 mg coated granules contains 
coated granules with 150 mg dabigatran etexilate (as mesilate).

- The other ingredients are tartaric acid, acacia, hypromellose, dimeticone 350, talc and 
hydroxypropylcellulose.

What Pradaxa looks like and contents of the pack

The sachets of Pradaxa coated granules contain yellowish coated granules.

Each pack of this medicine contains an aluminium bag which in turn contains 60 silver-coloured 
aluminium sachets with Pradaxa coated granules and a desiccant (labelled “DO NOT EAT” including 
pictogram and “SILICA GEL”).

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany



262

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 5 2595942

????????
????????? ????????? ??? ???? ? ??. ?? –
???? ????????
???: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

?eská republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe 
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena-Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG 
Podru?nica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG 
organiza?ná zlo?ka
Tel: +421 2 5810 1211



263

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas fili?le
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/

http://www.emea.europa.eu


264

Instructions for use

Do not administer Pradaxa coated granules 
? via syringes or feeding tubes
? with other than the soft foods or apple juice as indicated below

Administer Pradaxa coated granules either with soft foods or apple juice. The instructions are provided 
below under A) for soft foods and B) for apple juice.

The prepared medicine should be given before meals in order to ensure that the patient takes the full 
dose.

Administer the prepared medicine to the patient immediately or within 30 minutes after mixing. Do 
not give this medicine if it has been in contact with the food or apple juice for more than 30 minutes.

In case of an incomplete intake of the prepared medicine, do not apply a second dose, wait until the 
next dosing time-point.

A) Administration of Pradaxa coated granules with soft foods

The food should be at room temperature before mixing with the coated granules. The medicine can be 
administered with one of the following soft foods: 

? Baby rice cereal, prepared with water
? Mashed carrots
? Apple sauce (for administration with apple juice see B))
? Mashed banana

Do not use soft food containing milk products.

Step 1 – Prepare cup or bowl

? Transfer two teaspoons of the soft food 
into a small cup or bowl.

Step 2 – Collect sachet(s)

? Upon first opening, open the silver 
aluminium bag by cutting at the top 
using scissors. The aluminium bag 
includes 60 silver-coloured sachets 
(medicine) and one desiccant with the 
imprint “DO NOT EAT” including 
pictogram and “SILICA GEL”.



265

? Do not open or consume the desiccant.

? Collect the required number of sachets 
with Pradaxa coated granules according 
to the prescribed dose.

? Put the unused sachets back into the 
aluminium bag.

Step 3 – Open sachet(s)

? Take the sachet containing the Pradaxa
coated granules.

? Tap the sachet on the table to ensure 
that the contents settle to the bottom.

? Keep the sachet in an upright position.
? Open the sachet by cutting at the top 

using scissors.

Step 4 – Pour sachet(s) content

? Empty the entire content of the sachet 
into the small cup or bowl containing 
the soft food.

? Repeat Steps 3 and 4 if more than one 
sachet is needed.



266

Step 5 – Stir soft food to mix coated granules

? Stir soft food with the feeding spoon to 
thoroughly mix the coated granules 
with the soft food.

Step 6 – Administer soft food

? Administer the soft food with the coated 
granules to the patient immediately 
using the feeding spoon.

? Assure that all soft food is eaten.

B) Administration of Pradaxa coated granules with apple juice

Step 1 – Have a cup of apple juice ready before the next step

Step 2 – Collect sachet(s)
? Upon first opening, open the silver 

aluminium bag by cutting at the top 
using scissors. The aluminium bag 
includes 60 silver-coloured sachets 
(medicine) and one desiccant with the 
imprint “DO NOT EAT” including 
pictogram and “SILICA GEL”.

? Do not open or consume the desiccant.



267

? Collect the required number of sachets 
with Pradaxa coated granules according 
to the prescribed dose.

? Put the unused sachets back into the 
aluminium bag.

Step 3 – Open sachet(s)

? Take the sachet containing the Pradaxa
coated granules.

? Tap the sachet on the table to ensure 
that the contents settle to the bottom.

? Keep the sachet in an upright position.
? Open the sachet by cutting at the top 

using scissors.

Step 4 – Administer Pradaxa coated granules with apple juice
? Administer all of the coated granules directly from the sachet or using a feeding spoon into the 

child’s mouth and offer the child as much apple juice as needed to swallow the coated 
granules.

? Inspect child’s mouth to ensure that all coated granules are swallowed.
? Optional: If the Pradaxa coated granules are mixed in the apple juice cup, start with a small 

amount of apple juice (that your child is likely to drink completely) and ensure that all coated 
granules are taken. If coated granules are sticking to the cup, add another small amount of 
apple juice and again apply to your child. Repeat until no remaining coated granules are 
sticking to the cup.



268

Package leaflet: Information for the patient

Pradaxa 6.25 mg/mL powder and solvent for oral solution
dabigatran etexilate

Read all of this leaflet carefully before your child starts taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your child’s doctor or pharmacist.
- This medicine has been prescribed for your child only. Do not pass it on to others. It may harm 

them, even if their signs of illness are the same as your child’s.
- If your child gets any side effects, talk to your child’s doctor or pharmacist. This includes any 

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Pradaxa is and what it is used for
2. What you need to know before your child takes Pradaxa
3. How to take Pradaxa
4. Possible side effects
5. How to store Pradaxa
6. Contents of the pack and other information

1. What Pradaxa is and what it is used for

Pradaxa contains the active substance dabigatran etexilate and belongs to a group of medicines called 
anticoagulants. It works by blocking a substance in the body which is involved in blood clot 
formation.

Pradaxa is used in children to treat blood clots and to prevent blood clots from reoccurring.

Pradaxa powder and solvent for oral solution should not be used in children aged 1 year or older.

2. What you need to know before your child takes Pradaxa

Do not use Pradaxa

- if your child is allergic to dabigatran etexilate or any of the other ingredients of this medicine 
(listed in section 6).

- if your child has severely reduced kidney function.
- if your child is currently bleeding.
- if your child has a disease in an organ of the body that increases the risk of serious bleeding

(e.g., stomach ulcer, injury or bleeding in the brain, recent surgery of the brain or eyes).
- if your child has an increased tendency to bleed. This may be inborn, of unknown cause or due 

to other medicines.
- if your child is given medicines to prevent blood clotting (e.g.warfarin, rivaroxaban, apixaban or 

heparin), except when changing anticoagulant treatment or while having a venous or arterial 
line and your child gets heparin through this line to keep it open.

- if your child has a severely reduced liver function or liver disease which could possibly cause 
death.

- if your child is given oral ketoconazole or itraconazole, medicines to treat fungal infections.
- if your child is given oral cyclosporine, a medicine to prevent organ rejection after 

transplantation.
- if your child is given dronedarone, a medicine used to treat abnormal heart beat.



269

- if your child is given a combination product of glecaprevir and pibrentasvir, an antiviral 
medicine used to treat hepatitis C

- if your child has received an artificial heart valve which requires permanent blood thinning.

Warnings and precautions

Talk to your child’s doctor before you give your child Pradaxa. You may also need to talk to your 
child’s doctor during treatment with this medicine if your child experiences symptoms or if your child 
has to undergo surgery. 

Tell your child’s doctor if your child has or has had any medical conditions or illnesses, in particular 
any of those included in the following list:

- if your child has an increased bleeding risk, such as:
? if your child has been recently bleeding.
? if your child has had a surgical tissue removal (biopsy) in the past month.
? if your child has had a serious injury (e.g. a bone fracture, head injury or any injury requiring 

surgical treatment).
? if your child is suffering from an inflammation of the gullet or stomach.
? if your child has problems with reflux of gastric juice into the gullet.
? if your child is receiving medicines which could increase the risk of bleeding. See 'Other 

medicines and Pradaxa' below.
? if your child is given anti-inflammatory medicines such as diclofenac, ibuprofen, piroxicam.
? if your child is suffering from an infection of the heart (bacterial endocarditis).
? if you know your child has decreased kidney function, or your child is suffering from 

dehydration (symptoms include feeling thirsty and passing reduced amounts of dark-coloured 
(concentrated) / foaming urine).

? if your child has an infection around or within the brain.

- if your child has had a heart attack or if your child has been diagnosed with conditions that 
increase the risk to develop a heart attack.

- if your child has a liver disease that is associated with changes in the blood tests. The use of this 
medicine is not recommended in this case.

Take special care with Pradaxa

- if your child needs to have an operation:
In this case Pradaxa will need to be stopped temporarily due to an increased bleeding risk 
during and shortly after an operation. It is very important to give Pradaxa before and after the 
operation exactly at the times you have been told by your child’s doctor.

- if an operation involves a catheter or injection into your child’s spinal column (e.g. for epidural 
or spinal anaesthesia or pain reduction):

? it is very important to give Pradaxa before and after the operation exactly at the times 
you have been told by your child’s doctor.

? tell your child’s doctor immediately if your child gets numbness or weakness of the legs 
or problems with his/her bowel or bladder after the end of anaesthesia, because urgent 
care is necessary.

- if your child falls or injures himself/herself during treatment, especially if your child hits his/her 
head. Please seek urgent medical attention. Your child may need to be checked by a doctor, as 
your child may be at increased risk of bleeding.

- if you know that your child has a disease called antiphospholipid syndrome (a disorder of the 
immune system that causes an increased risk of blood clots), tell your child’s doctor who will 
decide if the treatment may need to be changed.



270

Other medicines and Pradaxa

Tell your child’s doctor or pharmacist if your child is given or has recently been given other 
medicines. In particular you should tell your child’s doctor before taking Pradaxa, if your child 
is given one of the medicines listed below:

- Medicines to reduce blood clotting (e.g. warfarin, phenprocoumon, acenocoumarol, heparin, 
clopidogrel, prasugrel, ticagrelor, rivaroxaban, acetylsalicylic acid)

- Medicines to treat fungal infections (e.g. ketoconazole, itraconazole), unless they are only 
applied to the skin

- Medicines to treat abnormal heart beats (e.g. amiodarone, dronedarone, quinidine, verapamil).
- Medicines to prevent organ rejection after transplantation (e.g. tacrolimus, cyclosporine)
- A combination product of glecaprevir and pibrentasvir (an antiviral medicine used to treat 

hepatitis C)
- Anti-inflammatory and pain reliever medicines (e.g. acetylsalicylic acid, ibuprofen, diclofenac)
- St. John´s wort, a herbal medicine for depression
- Antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin-

norepinephrine re-uptake inhibitors
- Rifampicin or clarithromycin (two antibiotics)
- Anti-viral medicines for AIDS (e.g. ritonavir)
- Certain medicines for treatment of epilepsy (e.g. carbamazepine, phenytoin)

Pregnancy and breast-feeding 

This medicine is intended to be used in children below the age of 12 months. Information regarding 
pregnancy and breast-feeding will not be relevant in the context of your child’s treatment.

Driving and using machines

This medicine is intended to be used in children below the age of 12 months. Information regarding 
driving and using machines will not be relevant in the context of your child’s treatment.

3. How to take Pradaxa

Pradaxa powder and solvent for oral solution should only be used in children below 1 year. There are 
other age appropriate dose forms for the treatment of children and adolescents aged 1 year or older.

Always give this medicine exactly as your child’s doctor has told you. Check with your child’s doctor 
if you are not sure.

Pradaxa 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 depends on age and weight. Your child’s doctor will determine the correct 
dose for your child based on your child’s age and weight. Your child’s doctor may adjust the dose as 
treatment progresses. Your child must keep using all other medicines, unless your child’s doctor tells 
you to stop using any.

Single Pradaxa dose to be given twice daily in millilitres (mL) by weight in kilograms (kg) and age in 
months of the patient:



271

Age in months

<1
1 to
<2

2 to
<3

3 to
<4

4 to
<5

5 to
<6

6 to
<7

7 to
<8

8 to
<9

9 to 
<10

10 to 
<11

11 to 
<12

W
ei

gh
t 

[k
g]

13 to <16 12 mL 12 mL

11 to <13 10 mL 10 mL 10 mL 11 mL

9 to <11 7 mL 7 mL 8 mL 8 mL 9 mL 9 mL 9 mL

7 to <9 5 mL 6 mL 6 mL 7 mL 7 mL 7 mL 7 mL 8 mL 8 mL

5 to <7 3 mL 3 mL 4 mL 4 mL 5 mL 5 mL 5 mL 5 mL 6 mL 6 mL 6 mL 7 mL

4 to <5 2 mL 3 mL 3 mL 4 mL 4 mL 4 mL 4 mL 4 mL 5 mL 5 mL

3 to <4 2 mL 2 mL 3 mL 3 mL 3 mL 3 mL

2.5 to <3 2 mL 2 mL 2 mL 2 mL 3 mL

Means that no dosing recommendation can be provided.

oral solution 
[mL]

2 3 4 5 6 7 8 9 10 11 12

contains 
dabigatran 

etexilate [mg]
12.50 18.75 25.00 31.25 37.50 43.75 50.00 56.25 62.50 68.75 75.00

Instructions for preparing and giving Pradaxa oral solution

Pradaxa oral solution is prepared from Pradaxa powder, a sweetener (sucralose) and a solvent. It is 
administered with a dosing pipette into your child’s mouth. Pradaxa oral solution should not be mixed 
with milk, other beverages or food.

Detailed instructions for the preparation of the oral solution and the administration with the 
dosing pipette are provided in’Instructions for use’ at the end of the package leaflet.

The instructions for use contain all steps necessary for the correct preparation of this medicine and its 
administration to the patient. This medicine should be prepared by a doctor, nurse or pharmacist. Lay 
caregivers can prepare the oral solution if the healthcare professional determines that it is appropriate. 
In this case all steps of the instructions for use should be followed.
In case your doctor, nurse or pharmacist has provided you the prepared oral solution, please follow 
steps 11-22 of the instructions for use.

Change of anticoagulant treatment

Without specific guidance from your child’s doctor do not change your child’s anticoagulant 
treatment.

If you give more Pradaxa than you should

Taking too much of this medicine increases the risk of bleeding. Contact your child’s doctor 
immediately if you have given too much of it. Specific treatment options are available.



272

If you forget to give your child Pradaxa

A forgotten dose can still be given up to 6 hours prior to the next due dose.
A missed dose should be omitted if the remaining time is below 6 hours prior to the next due dose.
Do not give a double dose to make up for a forgotten dose.
If a dose has only been taken partially, do not attempt to administer a second dose at that time-point.
Give the next dose as scheduled approximately 12 hours later.

If you stop giving Pradaxa

Give Pradaxa exactly as prescribed. Do not stop giving this medicine without talking to your child’s 
doctor first, because the risk of developing a blood clot could be higher if you stop treatment too early.
Contact your child’s doctor if your child experiences indigestion after giving Pradaxa.

If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Pradaxa affects blood clotting, so most side effects are related to signs such as bruising or bleeding. 
Major or severe bleeding may occur, these constitute the most serious side effects and, regardless of 
location, may become disabling, life-threatening or even lead to death. In some cases these bleedings 
may not be obvious.

If your child experiences any bleeding event that does not stop by itself or if your child experiences 
signs of excessive bleeding (exceptional weakness, tiredness, paleness, dizziness, headache or 
unexplained swelling) consult your child’s doctor immediately. Your child’s doctor may decide to 
keep your child under closer observation or change the medicine.

Tell your child’s doctor immediately, if your child experiences a serious allergic reaction which causes 
difficulty in breathing or dizziness.

Possible side effects are listed below, grouped by how likely they are to happen.

Common (may affect up to 1 in 10 people):
- A fall in the number of red cells in the blood
- A fall in the number of platelets in the blood
- Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
- Sudden change of the skin which affects its colour and appearance
- Haematoma formation
- Nosebleed
- Reflux of gastric juice into the gullet
- Vomiting
- Feeling sick
- Frequent loose or liquid bowel movements
- Indigestion
- Hair loss
- Liver enzymes increased

Uncommon (may affect up to 1 in 100 people):
- Decrease in the number of white blood cells (which help to fight infections)
- Bleeding may happen into the stomach or bowel, from the brain, from the rectum, from 

penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under 
the skin

- A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)



273

- A decrease in the proportion of blood cells
- Itching
- Coughing of blood or blood stained sputum
- Belly ache or stomach ache
- Inflammation of the gullet and stomach
- Allergic reaction
- Difficulty in swallowing
- Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Not known (frequency cannot be estimated from the available data):
- Lack of white blood cells (which help to fight infections)
- Serious allergic reaction which causes difficulty in breathing or dizziness
- Serious allergic reaction which causes swelling of the face or throat
- Difficulty in breathing or wheezing
- Bleeding
- Bleeding may happen into a joint or from an injury, from a surgical incision, or from the site of 

entry of an injection or from the site of entry of a catheter into a vein
- Bleeding may happen from piles 
- Ulcer in the stomach or bowel (incl. ulcer in the gullet)
- Unusual laboratory test results on liver function

Reporting of side effects
If your child gets any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Pradaxa

Keep this medicine out of the sight and reach of children.

This medicine is prepared from three components which may have different expiry dates. Do not 
prepare and use this medicine after the shortest expiry date which is stated on the outer carton after 
“EXP”. Note that individual components may have later expiry dates. The expiry date refers to the last 
day of that month.

Once the aluminium bag containing the sachets with the Pradaxa powder for oral solution and the 
desiccant is opened, the medicine must be used within 4 months. The opened sachet cannot be stored 
and must be used immediately after opening.

Once prepared, the oral solution in the bottle can be stored for up to 18 hours at 2-8°C (refrigerator)
or, if needed, for up to 2 hours at room temperature (20-25°C). The bottles must be stored in an 
upright position.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Pradaxa contains

- The active substance is dabigatran. Each mL of reconstituted oral solution contains 6.25 mg of 
dabigatran etexilate (as mesilate).

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


274

- The other ingredients of the Pradaxa powder for oral solution are mannitol and 
hydroxypropylcellulose.

- The solvent for Pradaxa oral solution contains tartaric acid, hydrochloric acid (for pH-
adjustment) and purified water.

- The sucralose sachets contain sucralose.

What Pradaxa looks like and contents of the pack

Pradaxa powder and solvent for oral solution is supplied as several components for reconstitution in a 
kit that contains:

? 1 carton box containing the Pradaxa powder for oral solution.
30 aluminium sachets are packaged in one aluminium bag that also contains a desiccant 
(labelled with “DO NOT EAT” including pictogram and “SILICA GEL”). Each sachet 
contains 180.4 mg powder for oral solution. Pradaxa powder for oral solution is a yellowish-
white powder.

? 30 carton boxes which are referred to as individual preparation packs.
Each pack contains one white aluminium sachet with 70 mg sucralose powder (white to 
almost white powder), one amber glass bottle with a screw-cap containing 28 mL solvent 
(clear, colourless solution) to prepare the oral solution, two dosing pipettes (12 mL) and one 
adapter for the bottle.

The co-packaged dosing pipettes (CE 0124) and the adapter (CE) are medical devices.
On the 12 mL dosing pipette, a scale from 0 to 12 mL with 0.25 mL graduation is printed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Manufacturer

Catalent Germany Schorndorf GmbH
Steinbeisstr. 1 und 2
73614 Schorndorf
Germany



275

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 5 2595942

????????
????????? ????????? ??? ???? ? ??. ?? –
???? ????????
???: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

?eská republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe 
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena-Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG 
Podru?nica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG 
organiza?ná zlo?ka
Tel: +421 2 5810 1211



276

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

??????
Boehringer Ingelheim Ellas A.E.
T??: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas fili?le
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/

http://www.emea.europa.eu


277

Instructions for use

Pradaxa 6.25 mg/mL powder and solvent for 
oral solution

Read instructions before use

You have received an oral solution kit containing 30 preparation packs and one aluminum bag 
containing 30 silver coloured sachets. One silver coloured sachet contains yellowish-white powder 
(medicine) for preparing an oral solution. The aluminum bag also contains a desiccant (labelled with 
“DO NOT EAT” including pictogram and “SILICA GEL”) to keep the medicine dry.

The instructions for use contain all steps necessary for the correct preparation of the oral solution and 
administration to the patient. The oral solution should be prepared by a doctor, nurse or pharmacist. 
Lay caregivers can prepare the oral solution if the treating physician determines that it is appropriate. 
All steps of the instructions for use should be followed. In case your doctor, nurse or pharmacist has 
provided you the prepared oral solution, please follow steps 11-22.

You can preserve the prepared oral solution for 2 hours at room temperature or 18 hours in a 
refrigerator. Give two doses per day with an interval as close to 12 hours as possible.

Supplies for preparing medicine

You will need the following supplies to prepare the medicine, included in each individual preparation 
pack:

A. Bottle containing 28 mL solvent.
B. Pipette adapter.
C. White (sucralose) sachet containing sweetener.
D. 2 Dosing pipettes (12 mL).

Discard dosing pipette after use (single use only).



278

You will need the following other supplies, not included in each individual preparation pack:

E. Silver (dabigatran etexilate) sachet containing powder (medicine), included in the aluminum 
bag.

F. Pair of scissors (not supplied).
G. Pen (not supplied).

Warnings and Cautions

Read all warnings and cautions before preparing the medicine.

Warnings
? Store prepared oral solution in the bottle for up to 18 hours in a refrigerator at 2°C to 8°C. 

The oral solution may be stored for a maximum of 2 hours at room tempature (20°C to 
25°C).

? Safely throw away any unused oral solution left in the bottle after 18 hours.
? Do not prepare oral solution with liquid other than the solvent that comes in the kit.
? Do not mix prepared oral solution with milk, other beverages, baby formula or any other kind 

of food.
? Do not use a measuring device other than the dosing pipettes that come in your kit to measure 

and give a dose of this medicine.
? Do not heat oral solution.

Cautions
? To avoid a reduced dose of medicine, make sure to pour all contents of silver sachet 

(medicine) into solvent bottle.
? Take care to adjust dosing pipette carefully to the prescribed dose. Check dose before 

administration.
? The interval between dosing of this medicine should be as close to 12 hours as possible.
? If a dose is missed for any reason, the forgotten dose may still be taken up to 6 hours prior to 

the next scheduled dose.
? If a missed dose cannot be taken up to 6 hours prior to the next scheduled dose, omit the 

missed dose and administer the next dose as scheduled.
? Do not administer a double dose to make up for a missed individual dose or for an incomplete 

dose intake.
? Do not use feeding tubes.



279

A Prepare Oral Solution

1 Place one silver sachet (dabigatran 
etexilate) in an individual preparation 
pack

A. Place 1 silver sachet from the aluminum 
bag in each individual preparation pack.

B. The bag contains a desiccant (labelled 
with “DO NOT EAT” including 
pictogram and “SILICA GEL”) with 
silica gel to keep contents dry. 

Do not use desiccant to prepare the oral 
solution.

C. Before each use, make sure each 
individual preparation pack contains: 
1 bottle, 1 silver (dabigatran etexilate) 
sachet, 1 white (sucralose) sachet, 
1 adapter and 2 dosing pipettes (12 mL).

If you are going to travel make sure you have 
completed Step 1 before travelling for all 
doses to be given during travel.

To avoid preparing the oral solution without 
medicine, it is recommended that you 
complete all individual preparation packs 
with the silver sachet at the point in time when 
you are preparing the first dose of a new oral 
solution kit.

2 Prepare bottle

D. Take the bottle with solvent out of the 
individual preparation pack.

E. Open bottle in an upright position by 
pressing down on the child resistant cap 
and simultaneously turning the cap 
counter-clockwise.

F. Leave the open bottle on the table.

3 Open silver (dabigatran etexilate) 
sachet

A. Take the silver (dabigatran etexilate) 
sachet containing powder (medicine).

B. Tap the silver sachet on the table to 
ensure the silver sachet contents settle to 
the bottom.

C. Keep the silver sachet in upright 



280

position.
D. Open the silver sachet by cutting at the 

top using scissors.

4 Pour silver sachet contents

A. Hold and squeeze the silver sachet to 
ensure a circular opening.

B. Carefully pour all the content of the 
silver sachet (medicine) into the bottle, 
tapping the sachet until it is empty.

To avoid a reduced dose of medicine, 
make sure to pour all contents of sachet 
into solvent bottle.

5 Open white (sucralose) sachet

A. Take the white (sucralose) sachet 
containing sweetener.

B. Tap the white sachet on the table to 
ensure the white sachet contents settle to 
the bottom.

C. Keep the white sachet in upright 
position.

D. Open the white sachet by cutting at the 
top using scissors.

6 Pour white sachet contents

A. Hold and squeeze the white sachet to 
ensure a circular opening.

B. Carefully pour all the content of the 
white sachet (sweetener) into the bottle, 
tapping the sachet until it is empty.



281

7 Insert adapter

A. With the open bottle on the table, hold 
the bottle with one hand and press the 
pipette adapter into the bottle opening 
with the other hand.

Make sure the adapter is completely 
inserted in bottle neck until the adapter 
cannot be pushed any further.

8 Close bottle and write date and time on 
label

A. Tightly close the bottle with the cap (turn 
the cap clockwise).

B. Assure that the cap is securely attached 
to avoid medicine from spilling.

C. Write the date and time on the bottle 
label next to “Date and Time of 
preparation:”.

9 Shake bottle to dissolve medicine

A. Shake the bottle vigorously for at least 
2 minutes to dissolve the medicine
powder in the solution. Use a stopwatch 
or clock to measure 2 minutes.

Shaking the bottle for less than 2 minutes 
could lead to undissolved powder in the 
bottle leading to a reduced dose of the 
medicine.

10 Wait for 1 minute

A. Wait for at least 1 minute after shaking 
bottle to let most of the bubbles 
disappear. Use a stopwatch or clock to 
measure 1 minute. 

B. Check if all powder in the bottle is 
dissolved. If not, shake bottle until 
powder (medicine) in the solution is 
dissolved.

If you do not allow the bottle to sit for at 
least 1 minute, there may be air bubbles 
in the oral solution. You may not be able 
to measure and give the correct dose of 
the medicine.



282

B Fill Dosing Pipette

11 Check prescribed dose

Your doctor should tell you the amount (dose) of Pradaxa oral solution to give to your child in 
millilitres (mL).

The dose of this medicine will change based on your child’s age and weight over time as your child 
grows. Ask your doctor or pharmacist if you are not sure.

12 Fill dosing pipette with air

Take the empty 12 mL dosing pipette and pull 
back on the plunger half way to fill the dosing 
pipette with 7 mL of air.

13 Attach dosing pipette and push air into 
the bottle

A. Attach the empty dosing pipette onto the 
adapter until it feels secure and cannot be 
pushed further.

B. Press in the plunger carefully and slowly, 
pushing the air into the bottle.

Push air into the bottle to avoid low-
pressure problems especially with large 
(? 6 mL) volumes.

14 Fill dosing pipette

A. Turn the dosing pipette together with the 
bottle upside down.

B. While holding the bottle together with 
the dosing pipette barrel with one hand, 
pull the plunger to the correct dosing 
volume with the other hand.

C. Stop when the upper edge of the plunger 
is at the mark corresponding to the 
correct dosing volume.

15 Check dosing pipette for air



283

A. If there are air bubbles in the dosing 
pipette, tap on the barrel of the dosing 
pipette to move any air bubbles to the 
top.

B. Slowly press up on the plunger until all 
air bubbles have been removed.

C. Check that the dose is correct. If not, pull 
back on the plunger until you get the 
prescribed dose.

Leaving air bubbles in the solution in the 
dosing pipette leads to a reduced dose of 
the medicine.

16 Remove dosing pipette

A. Holding the dosing pipette by the barrel 
to avoid readjusting the dose by mistake, 
put the bottle back on the table.

B. Holding the dosing pipette by the barrel, 
pull the dosing pipette off of the adapter 
and bottle.

C. Make sure the dosing pipette is still filled 
with the correct dose.

Note: The plunger’s position might be 
different from the image on the right.

C Administer Oral Solution

17 Position child

Position the child upright to give the oral 
solution.

18 Administer oral solution

You should administer the required dose to the 
child within 10 minutes of filling the dosing 
pipette.



284

Give two doses per day with an interval as 
close to 12 hours as possible.

A. Place the dosing pipette in the child’s 
mouth, so the tip is near the inner side of 
the cheek.

B. Press the plunger carefully and slowly to 
give the child sufficient time to swallow 
the solution.

Do not give the oral solution if it has been
stored for more than 2 hours at room 
temperature.

Discard the oral solution if it has been 
stored for more than 2 hours at room 
temperature.

Do not store the oral solution in dosing
pipette.

19 Close bottle and discard used dosing 
pipette

A. Leave the pipette adapter in the bottle.
B. Close the bottle tightly with the cap.

Note: Make sure that the pipette adapter is 
inserted completely so that you are able to 
close the bottle properly.

C. Discard the used dosing pipette.
D. If you will not be administering another 

dose from the same bottle, continue 
directly to Step 22 to discard the bottle.

D Store Or Discard Oral Solution

20 Store bottle in refrigerator until second 
dose

Place the closed bottle containing the medicine
immediately in the refrigerator in an upright 
position.

Give two doses per day with an interval as close 
to 12 hours as possible. Use the oral solution 
within 18 hours and discard the bottle after 
18 hours or after giving the second dose.

The interval between dosing of this 



285

medicine should be as close to 12 hours 
as possible.

The bottle with the medicine can be 
stored for up to 18 hours in the 
refrigerator. Discard bottle after
18 hours or after giving the second dose, 
even if there is oral solution still left in it.

21 Administer second dose

Follow these steps if the prepared medicine is 
used a second time about 12 hours later:

A. Remove medicine bottle from the 
refrigerator.

B. If the child does not like the cold 
medicine you can let the bottle of oral 
solution sit at room temperature to warm 
up. Once removed from the refridgerator, 
you must give the oral solution within 2 
hours.

Do not use microwave, hot water or other 
heating devices.

C. Open the bottle.
D. Collect the second dosing pipette.

Each dosing pipette is a single use device.

E. Repeat Steps 11 through 19 to 
administer a second dose to the child.

22 Discard used items and bottle

A. Discard all empty used dosing pipettes 
and empty sachets.

Discard dosing pipette after use (single 
use only).

B. Once dosing is complete, or after the 
medicine is beyond use (2 hours at room 
temperature, or 18 hours in a 
refrigerator), discard the closed bottle.



286

PATIENT ALERT CARD  [for Pradaxa 75 mg / 110 mg / 150 mg capsules]

Table of Content 

Pradaxa® capsules
dabigatran etexilate

? This card should be with you / the caregiver at all times
? Make sure to use the latest version

[xxxx 20xx]
[Boehringer Ingelheim logo]

Dear Patient / Caregiver of a paediatric patient, 

Your / your child’s doctor has initiated treatment with Pradaxa®. In order to use Pradaxa® safely, 
please consider the important information in the package leaflet.
As this patient alert card contains important information about your / your child’s treatment, this card 
should be with you / your child at all times to inform healthcare professionals about your / your child’s 
intake of Pradaxa®.

[Pradaxa logo]

Pradaxa® Information for Patients / Caregivers of paediatric patients

About your / your child’s treatment
• Pradaxa® thins the blood. It is used to treat existing blood clots or to prevent the formation of 

dangerous blood clots.
• Follow your / your child’s doctor’s instructions when taking Pradaxa®. Never skip a dose or 

stop the intake of Pradaxa® without talking to your / your child’s doctor.
• Inform your / your child’s doctor about all medicines you / your child are / is currently taking.
• Inform your / your child’s doctor about the intake of Pradaxa® before any surgery / invasive 

procedure.
• Pradaxa® capsules can be taken with or without food. The capsule should be swallowed whole 

with a glass of water. The capsule must not be broken or chewed and the pellets must not be
emptied from the capsule.

When to seek medical advice
• Taking Pradaxa® may increase the risk of bleeding. Speak to your / your child’s doctor 

immediately if you / your child experience(s) signs and symptoms of bleeding such as: 
swelling, discomfort, unusual pain or headache, dizziness, paleness, weakness, unusual 
bruising, nosebleeds, bleeding of gums, unusual long bleeding cuts, abnormal menstrual flow 
or vaginal bleeding, blood in the urine which may be pink or brown, red/black stools, 
coughing up blood, vomiting blood or coffee ground like material.

• In case of fall or injury, especially if the head is hit, urgently seek medical advice. 
• Do not stop intake of Pradaxa® without talking to your / your child’s doctor, if you / your child

experience(s) heartburn, nausea, vomiting, stomach discomfort, bloating or upper abdominal 
pain.

Pradaxa® Information for Healthcare Professionals 

• Pradaxa® is an oral anticoagulant (direct thrombin inhibitor).
• Pradaxa® may need to be stopped in advance of surgical or other invasive procedures.
• In case of major bleeding events, Pradaxa® must be stopped immediately.
• A specific reversal agent (idarucizumab) is available for adult patients. The efficacy and safety 

of the specific reversal agent idarucizumab have not been established in paediatric patients.



287

For details and more advice to antagonise the anticoagulant effect of Pradaxa® please refer to 
the Summary of Product Characteristics of Pradaxa® and idarucizumab.

• Pradaxa® is mainly eliminated by the kidneys; adequate diuresis must be maintained. Pradaxa®

is dialyzable.

Please complete this section or ask your / your child’s doctor to do it. 

Patient Information 

________________________________
Name of the patient

_________________________________
Date of birth

_________________________________
Indication for anticoagulation

_________________________________
Dose of Pradaxa®



288

PATIENT ALERT CARD

Table of Content 

Pradaxa® coated granules
dabigatran etexilate

? This card should be with the caregiver or the patient at all times
? Make sure to use the latest version

[xxxx 20xx]
[Boehringer Ingelheim logo]

Dear Caregiver, 

Your child’s doctor has initiated treatment with Pradaxa®. In order to use Pradaxa® safely, please 
consider the important information in the package leaflet.
As this patient alert card contains important information about your child’s treatment, this card should 
be with you or your child at all times to inform healthcare professionals about your child’s intake of 
Pradaxa®.

[Pradaxa logo]

Pradaxa® Information for Caregivers

About your child’s treatment
• Pradaxa® thins the blood. It is used to treat existing blood clots or to prevent the formation of 

dangerous blood clots.
• Follow your child’s doctor’s instructions for Pradaxa® use. Always administer the prescribed 

dose, never skip a dose or stop the use of Pradaxa® without talking to your child’s doctor.
• Inform your child’s doctor about all medicines your child is currently taking.
• Inform your child’s doctor about your child’s intake of Pradaxa® before any surgery/invasive 

procedure.
• Pradaxa® coated granules should be administered with soft food or apple juice according to the

instructions for use in the package leaflet. Do not use soft food containing milk products. Do 
not administer Pradaxa® coated granules via syringes or feeding tubes.

When to seek medical advice
• Taking Pradaxa® may increase the risk of bleeding. Speak to your child’s doctor immediately 

if your child experiences any signs and symptoms of bleeding such as: swelling, discomfort, 
unusual pain or headache, dizziness, paleness, weakness, unusual bruising, nosebleeds, 
bleeding of gums, unusually long bleeding cuts, abnormal menstrual flow or vaginal bleeding, 
blood in the urine which may be pink or brown, red/black stools, coughing up blood, vomiting 
blood or coffee ground like material.

• If your child falls or injures herself/himself, especially if she/he hits her/his head, urgently 
seek medical advice. 

• Do not stop giving Pradaxa® without talking to your child’s doctor, if your child experiences
heartburn, nausea, vomiting, stomach discomfort, bloating or upper abdominal pain.

Pradaxa® Information for Healthcare Professionals

• Pradaxa® is an oral anticoagulant (direct thrombin inhibitor).
• Pradaxa® may need to be stopped in advance of surgical or other invasive procedures.
• In case of major bleeding events, Pradaxa® must be stopped immediately.
• Pradaxa® is mainly eliminated by the kidneys; adequate diuresis must be maintained. Pradaxa®

is dialyzable. See Summary of Product Characteristics.



289

Please complete this section or ask your child’s doctor to do it. 

Patient Information 

________________________________
Name of the patient

_________________________________
Date of birth

_________________________________
Indication for anticoagulation

_________________________________
Dose of Pradaxa®



290

PATIENT ALERT CARD

Table of Content 

Pradaxa® powder and solvent for oral solution
dabigatran etexilate

? This card should be with the caregiver at all times
? Make sure to use the latest version

[xxxx 20xx]
[Boehringer Ingelheim logo]

Dear Caregiver, 

Your child’s doctor has initiated treatment with Pradaxa®. In order to use Pradaxa® safely, please 
consider the important information in the package leaflet and the instructions for use.
As this patient alert card contains important information about your child’s treatment, please carry this 
card with you at all times to inform healthcare professionals about your child’s intake of Pradaxa®.

[Pradaxa logo]

Pradaxa® Information for Caregivers

About your child’s treatment
• Pradaxa® thins the blood. It is used to treat existing blood clots or to prevent the formation of 

dangerous blood clots.
• Follow your child’s doctor’s instructions for Pradaxa® use. Always administer the prescribed 

dose, never skip a dose or stop the use of Pradaxa® without talking to your child’s doctor.
• Inform your child’s doctor about all medicines your child is currently taking.
• Inform your child’s doctor about your child’s intake of Pradaxa® before any surgery/invasive 

procedure.
• Pradaxa® oral solution should be prepared by your child’s doctor, nurse or pharmacist. You 

may prepare Pradaxa® oral solution if your child’s doctor thinks that this is appropriate. For 
administration carefully follow the instructions for use. Do not administer Pradaxa® oral 
solution via feeding tubes.

When to seek medical advice
• Taking Pradaxa® may increase the risk of bleeding. Speak to your child’s doctor immediately 

if your child experiences any signs and symptoms of bleeding such as: swelling, discomfort, 
unusual pain or headache, dizziness, paleness, weakness, unusual bruising, nosebleeds, 
bleeding of gums, unusually long bleeding cuts, vaginal bleeding, blood in the urine which 
may be pink or brown, red/black stools, coughing up blood, vomiting blood or coffee ground 
like material.

• If your child falls or injures herself/himself, especially if she/he hits her/his head, urgently 
seek medical advice. 

• Do not stop giving Pradaxa® without talking to your child’s doctor, if your child experiences
heartburn, nausea, vomiting, stomach discomfort, bloating or upper abdominal pain.

Pradaxa® Information for Healthcare Professionals

• Pradaxa® is an oral anticoagulant (direct thrombin inhibitor).
• Pradaxa® may need to be stopped in advance of surgical or other invasive procedures.
• In case of major bleeding events, Pradaxa® must be stopped immediately.
• Pradaxa® is mainly eliminated by the kidneys; adequate diuresis must be maintained. Pradaxa®

is dialyzable. See Summary of Product Characteristics.



291

Please complete this section or ask your child’s doctor to do it. 

Patient Information 

________________________________
Name of the patient

_________________________________
Date of birth

_________________________________
Indication for anticoagulation

_________________________________
Dose of Pradaxa®


	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET