ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Pradaxa 75 mg hard capsules
2.
Each hard capsule contains 75 mg of dabigatran etexilate (as mesilate)
Excipients: Each hard capsule contains 2 micrograms sunset yellow (E110)
For a full list of excipients, see section 6.1.
3.
Hard capsule
Imprinted capsules with light blue, opaque cap and cream-coloured, opaque body of size 2 filled with
yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with
“R75”.
4.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip
replacement surgery or total knee replacement surgery.
Prevention of Venous Thromboembolism (VTE) in patients following elective knee replacement surgery:
The recommended dose of
Pradaxa
is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be
initiated orally within 1 – 4 hours of completed surgery with a single capsule and continuing with 2 capsules
once daily thereafter for a total of 10 days.
Prevention of Venous Thromboembolism (VTE) in patients following elective hip replacement surgery:
The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be
initiated orally within 1 – 4 hours of completed surgery with a single capsule and continuing with 2 capsules
once daily thereafter for a total of 28-35 days.
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.
Special patient populations:
Renal impairment:
Treatment with Pradaxa in patients with severe renal impairment (creatinine clearance < 30 ml/min) is
contraindicated (see section 4.3).
2
In patients with moderate renal impairment (creatinine clearance 30-50 ml/min), there is limited clinical
experience. These patients should be treated with caution. The recommended dose is 150 mg taken once
daily as 2 capsules of 75 mg (see section 4.4 and 5.1).
After knee replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery
with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.
After hip replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery
with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days.
Elderly:
In elderly patients ( > 75 years) there is limited clinical experience. These patients should be treated with
caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see section 4.4 and 5.1).
After knee replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery
with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.
After hip replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery
with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days.
Hepatic impairment:
Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in clinical trials.
Therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2). ALT should
be measured as part of the standard pre-operative evaluation (see section 4.4).
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).
Post-surgical patients with an increased risk for bleeding:
Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal
impairment (creatinine clearance 30 – 50 ml/min), should be treated with caution (see sections 4.4 and 5.1).
Children and adolescents:
There is no experience in children and adolescents.
Pradaxa is not recommended for use in patients below 18 years due to lack of data on safety and efficacy.
Concomitant use of Pradaxa with amiodarone or verapamil:
Dosing should be reduced to 150 mg Pradaxa daily in patients who received concomitantly dabigatran
etexilate and amiodarone or verapamil (see sections 4.4 and 4.5).
In patient with moderate renal impairment and concomitantly treated with dabigatran etexilate and
verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.4 and 4.5).
3
Switching from Pradaxa treatment to parenteral anticoagulant:
It is recommended to wait 24 hours after the last dose before switching from Pradaxa to a parenteral
anticoagulant (see section 4.5).
Switching from parenteral anticoagulants treatment to Pradaxa:
No data are available, therefore it is not recommended to start the administration of Pradaxa before the next
scheduled dose of the parenteral anticoagulant would have been due (see section 4.5).
Pradaxa should be swallowed as a whole with water, with or without food.
•
Hypersensitivity to the active substance or to any of the excipients
•
Patients with severe renal impairment (CrCl < 30 ml/min)
•
Active clinically significant bleeding
•
Organic lesion at risk of bleeding
•
Spontaneous or pharmacological impairment of haemostasis
•
Hepatic impairment or liver disease expected to have any impact on survival
•
Concomitant treatment with quinidine (see section 4.5)
Hepatic impairment:
Patients with elevated liver enzymes > 2 ULN were excluded in controlled clinical trials. Therefore the use
of Pradaxa is not recommended in this population. ALT should be measured as part of the standard pre-
operative evaluation.
Haemorrhagic risk:
Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the
treatment period, especially in the following situations that may increase the hemorrhagic risk: diseases
associated with an increased risk of bleeding, such as congenital or acquired coagulation disorders,
thrombocytopenia or functional platelet defects, active ulcerative gastrointestinal disease, recent biopsy or
major trauma, recent intracranial haemorrhage or brain, spinal or ophthalmic surgery, bacterial endocarditis.
Plasma concentrations of dabigatran might be elevated when co-administered with strong P-gp inhibitors
(e.g. verapamil, amiodarone). This may increase the risk of bleeding and these patients should be closely
clinically monitored (looking for signs of bleeding and anaemia) (see sections 4.2 and 4.5).
Patients with moderate renal impairment have an increased exposure to dabigatran. Limited data is available
in patients < 50 kg and the elderly (see sections 4.2 and 5.2). In these situations, Pradaxa should be used with
caution and a close clinical surveillance (looking for signs of bleeding or anemia) is required throughout the
treatment period (see section 4.2).
When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see
section 4.9).
Agents that may enhance the risk of haemorrhage should not be administered concomitantly or should be
administered with caution with Pradaxa (see section 4.5).
4
Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events:
There are limited efficacy and safety data for dabigatran available in
these
patients and therefore they should
be treated with caution.
Spinal anaesthesia/epidural anaesthesia/lumbar puncture:
In patients undergoing major orthopaedic surgery, epidural or spinal haematomas that may result in long-
term or permanent paralysis cannot be excluded with the concurrent use of dabigatran and spinal/epidural
anaesthesia or spinal puncture. The risk of these rare events may be higher with postoperative use of
indwelling epidural catheters or the concomitant use of other medicinal products affecting haemostasis.
Therefore the use of Pradaxa is not recommended in patients undergoing anaesthesia with post-operative
indwelling epidural catheters.
Administration of the first dose of Pradaxa should occur a minimum of two hours after the catheter is
removed. These patients require frequent observation for neurological signs and symptoms.
Hip fracture surgery:
There is no data on the use of Pradaxa in patients undergoing hip fracture surgery. Therefore treatment is not
recommended.
Colorants:
Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions.
Interaction studies have only been performed in adults.
Anticoagulants and platelet aggregation agents:
The following treatments are not recommended concomitantly with Pradaxa: unfractionated heparins and
heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents,
GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists.
It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent
central venous or arterial catheter (see sections 4.2 and 4.4).
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.
NSAIDs: When Pradaxa was coadministered with diclofenac, the plasma exposure of both medicinal
products remained unchanged indicating a lack of a pharmacokinetic interaction between dabigatran etexilate
and diclofenac. However, due to the risk of haemorrhage, notably with NSAIDs with elimination half-lives >
12 hours, close observation for signs of bleeding is recommended (see section 4.4).
5
Transporter interactions:
Amiodarone, verapamil and clarithromycin are inhibitors of the efflux transporter P-glycoprotein and
dabigatran etexilate a substrate of this transporter.
Amiodarone: When Pradaxa was coadministered with a single oral dose of 600 mg amiodarone, the extent
and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The
dabigatran AUC and C
max
were increased by about 60 % and 50 %, respectively. The mechanism of the
interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for
drug interaction may exist for weeks after discontinuation of amiodarone.
Dosing should be reduced to 150 mg Pradaxa daily in patients who received concomitantly dabigatran
etexilate and amiodarone (see section 4.2).
Verapamil: When dabigatran etexilate (150 mg) was coadministered with oral verapamil, the Cmax and
AUC of dabigatran were increased but magnitude of this change differs depending on timing of
administration and formulation of verapamil.
The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release
formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of C
max
by
about 180 % and AUC by about 150 %). The effect was progressively decreased with administration of an
extended release formulation (increased of C
max
by about 90 % and AUC by about 70 %) or administration of
multiple doses of verapamil (increased of C
max
by about 60 % and AUC by about 50 %).
Therefore, close clinical surveillance (looking for signs of bleeding or anemia) is required when dabigatran is
co-administrered with verapamil. In patient with normal renal function after the surgery, receiving dabigatran
etexilate and verapamil concomitantly, the dose of Pradaxa should be reduced to 150 mg daily. In patient
with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose
reduction of Pradaxa to 75 mg daily should be considered (see sections 4.2 and 4.4).
There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate
(increased of C
max
by about 10 % and AUC by about 20 %). This is explained by completed dabigatran
absorption after 2 hours (see section 4.4)
Clarithromycin: When clarithromycin (500 mg bid) was administered together with dabigatran etexilate in
healthy volunteers, increase of AUC by about 19 % and Cmax by about 15 % was observed without any
clinical safety concern. However, in patients receiving dabigatran, a clinically relevant interaction cannot be
excluded when combined with clarithromycin. Therefore, a close monitoring should be exercised when
dabigatran etexilate is combined with clarithromycine and particularly in the occurrence of bleeding, notably
in patient having a mild to moderate renal function.
P- glycoprotein inhibitors:
Caution should be exercised with strong P- glycoprotein inhibitors. The P- glycoprotein inhibitor quinidine is
contraindicated (see section 4.3).
P- glycoprotein inducers:
Potent P- glycoprotein inducers such as rifampicin or St John’s wort (Hypericum perforatum), may reduce
the systemic exposure of dabigatran. Caution is advised when co-administering these medicinal products.
Digoxin: In a study performed with 24 healthy subjects, when Pradaxa was coadministered with digoxin, no
changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.
Gastric pH:
6
Pantoprazole: When Pradaxa was coadministered with pantoprazole, a decrease in the dabigatran area under
the plasma concentration - time curve of approximately 30 % was observed. Pantoprazole and other proton-
pump inhibitors were co-administered with Pradaxa in clinical trials and no effects on bleeding or efficacy
were observed.
Ranitidine: Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of
absorption of dabigatran.
Pregnancy:
There are no adequate 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.
Women of child-bearing potential should avoid pregnancy during treatment with dabigatran etexilate.
Pradaxa should not be used during pregnancy unless clearly necessary.
Lactation:
There are no clinical data of the effect of dabigatran on infants during breast feeding.
Lactation should be discontinued during treatment with Pradaxa.
No studies on the effects on the ability to drive and use machines have been performed.
A total of 10.084 patients were treated in 4 actively controlled VTE prevention trials with at least one dose of
the medicinal product. Of these 5419 were treated with 150 mg or 220 mg daily of Pradaxa, while 389
received doses less than 150 mg daily and 1168 received doses in excess of 220 mg daily.
The most commonly reported adverse reactions are bleedings occurring in total in approximately 14 % of
patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %.
Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location,
may lead to disabling, life-threatening or even fatal outcomes.
The table 1 shows the number (%) of patients experiencing bleeding events during the treatment period in the
VTE prevention in the two pivotal clinical trials, according to dose.
Table 1 Bleeding events broken down to major and any bleeding in the pivotal hip and knee study
Dabigatran etexilate
150 mg
N (%)
Dabigatran etexilate
220 mg
N (%)
Enoxaparin
N (%)
Treated
1866(100.0)
1825(100.0)
1848(100.0)
Major Bleeding
24 (1.3)
33 (1.8)
27 (1.5)
Any bleeding
258(13.8)
251(13.8)
247(13.4)
7
Table 2 shows the adverse reactions ranked under headings of SOC and frequency using the following
convention: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1,000, <1/100); rare (≥
1/10,000, <1/1,000); very rare (< 1/10,000).
SOC / Preferred Term.
Dabigatran etexilate
150 mg
N (%)
Dabigatran etexilate
220 mg
N (%)
Enoxaparin
N (%)
Number of patients treated
2737(100)
2682(100)
3108(100)
Blood and lymphatic system disorders
Common
Anaemia
110 (4.0)
117 (4.4)
141 (4.5)
Uncommon
Thrombocytopenia
5 (0.2)
2 (0.1)
5 (0.2)
Vascular disorders
Common
Haematoma
38 (1.4)
37 (1.4)
55 (1.8)
Traumatichaematoma
37 (1.4)
41 (1.5)
51 (1.6)
Woundhaemorhhage
35 (1.3)
28 (1.0)
31 (1.0)
Uncommon
Haemorrhage
5 (0.2)
18 (0.7)
21 (0.7)
Respiratory and thoracic system disorders
Uncommon
Epistaxis
19 (0.7)
15 (0.6)
13 (0.4)
Gastrointestinal disorders
Common
Gastrointestinal
haemorrhage
33 (1.2)
17 (0.6)
20 (0.6)
Uncommon
Rectal haemorrhage
12 (0.4)
15 (0.6)
5 (0.2)
Haemorrhoidal
haemorrhage
4 (0.2)
8 (0.3)
2 (0.1)
Hepatobiliary disorders
Uncommon
Alaninine aminotransferase
increased
18 (0.7)
7 (0.3)
28 (0.9)
Aspartate aminotransferase
increased
9 (0.3)
5 (0.2)
15 (0.5)
Hepatic function abnormal/
Liver function Test
abnormal
6 (0.2)
10 (0.4)
7 (0.2)
Hepatic enzyme increased
4 (0.2)
5 (0.2)
11 (0.4)
Hyperbilirubinaemia
4 (0.1)
3 (0.1)
4 (0.1)
Transaminasesincreased
0 (0.0)
2 (0.1)
1 (0.0)
Skin and subcutaneous tissue disorder
Common
Skin haemorrhage
45 (1.6)
57 (2.1)
61 (2.0)
Musculoskeletal and connective tissue and bone disorders
Uncommon
Haemarthrosis
9 (0.3)
7 (0.3)
17 (0.6)
Renal and urinary disorders
8
SOC / Preferred Term.
Dabigatran etexilate
150 mg
N (%)
Dabigatran etexilate
220 mg
N (%)
Enoxaparin
N (%)
Common
Haematuria
38 (1.4)
33 (1.4)
25 (0.8)
General disorders and administration site conditions
Uncommon
Injection site haemorrhage
21 (0.8)
19 (0.7)
27 (0.9)
Bloodydischarge
2 (0.1)
6 (0.2)
6 (0.2)
Cathetersitehaemorrhage
2 (0.1)
1 (0.0)
7 (0.2)
Investigations
Common
Haemoglobindecreased
45 (1.6)
35 (1.3)
74 (2.4)
Uncommon
Haematocritdecreased
0 (0.0)
6 (0.2)
4 (0.1)
Injury, poisoning and procedural complications
Common
Wound secretion
130 (4.8)
130 (4.9)
93 (3.0)
Anaemia postoperative
99 (3.6)
87 (3.2)
120 (3.7)
Post procedural haematoma
66 (2.4)
45 (1.7)
78 (2.5)
Post procedural
haemorrhage
37 (1.4)
54 (2.0)
56 (1.8)
Post procedural discharge
31 (1.1)
34 (1.3)
31 (1.0)
Surgical and medial procedures
Uncommon
Post procedural drainage
11 (0.4)
13 (0.5)
16 (0.5)
Wounddrainage
1 (0.0)
4 (0.2)
2 (0.1)
Beyond the reported ALT findings the following laboratory chemistry data had been measured in phase 3
studies as presented in table 3.
Table 3: ALT findings the following laboratory chemistry
Dabigatran etexilate
150 mg
N (%)
Dabigatran etexilate
220 mg
N (%)
Enoxaparin
N (%)
Total rates of Alaninine
aminotransferase increased 3 x
ULN
68 (2.5)
58 (2.2)
95 (3.5)
There is no antidote to dabigatran. Doses of dabigatran etexilate beyond those recommended, expose the
patient to increased risk of bleeding. In the event of haemorrhagic complications, treatment must be
discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the
renal route adequate diuresis must be maintained. The initiation of appropriate treatment, e.g. surgical
haemostasis or the transfusion of fresh frozen plasma should be considered.
Dabigatran can be dialysed; there is no clinical experience to demonstrate the utility of this approach in
clinical studies.
9
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: direct thrombine inhibitors, ATC code: B01AE07
Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After
oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-
catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct
thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation
cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits free thrombin, fibrin-
bound thrombin and thrombin-induced platelet aggregation.
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.
Steady state (after day 3) dabigatran peak plasma concentration, measured 2 - 4 hours after 220 mg
dabigatran etexilate administration, is expected to be around 270 ng/ml, with an expected range of 80 - 460
ng/ml. The dabigatran trough concentration, measured at the end of the dosing interval (24 hours after the
last 220 mg dabigatran dose), is expected to be around 40 ng/ml, with expected range of 10-90 ng/ml.
Ethnic origin:
More than 99% of efficacy and safety data were generated in Caucasians.
Clinical trials in Venous Thromboembolism (VTE) prophylaxis following major joint replacement surgery:
In 2 large randomized, parallel group, double-blind, dose–confirmatory trials, patients undergoing elective
major orthopaedic surgery (one for knee replacement surgery and one for hip replacement surgery) received
Pradaxa 75 mg or 110 mg within 1-4 hours of surgery followed by 150 mg or 220 mg daily thereafter,
haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery and daily thereafter.
In the RE-MODEL trial (knee replacement) treatment was for 6 – 10 days and in the RE-NOVATE trial (hip
replacement) for 28 – 35 days. Totals of 2076 patients (knee) and 3494 (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 Pradaxa 220 mg and 150 mg were
statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The point estimate for
incidence of Major VTE and VTE related mortality for the 150 mg dose was slightly worse than enoxaparin
(table 4). Better results were seen with the 220mg dose where the point estimate of Major VTE was slightly
better than enoxaparin (table 4)."
The clinical studies have been conducted in a patient population with a mean age > 65 years.
10
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 (5539 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 4.
Data for the total VTE and all cause mortality endpoint are shown in table 5.
Data for adjudicated major bleeding endpoints are shown in tables 6 below.
Table 4: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL
and the RE-NOVATE orthopeadic 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
11
Table 5: 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 6: 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
1146
1163
1154
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)
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 characterized by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0
hours post administration.
Absorption:
A study evaluating post-operative absorption of dabigatran etexilate, 1-3 hours following surgery,
demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma
concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached
at 6 hours following administration in a postoperative period due to contributing factors such as anesthesia,
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.
12
Distribution:
Low (34-35 %) concentration independent binding of dabigatran to human plasma proteins was observed.
The volume of distribution of dabigtran of 60 – 70 L exceeded the volume of total body water indicating
moderate tissue distribution of dabigatran.
Cmax and the area under the plasma concentration-time curve were dose proportional. Plasma concentrations
of dabigatran showed a biexponential decline with a mean terminal half-life of 12 - 14 hours in healthy
volunteers and 14 – 17 hours in patients undergoing major orthopaedic surgery. The half-life was
independent of dose.
Metabolism and elimination:
Metabolism and excretion of dabigatran were studied following a single intravenous dose of radiolabeled
dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived radioactivity was
eliminated primarily in the urine (85 %). Faecal excretion accounted for 6 % of the administered dose.
Recovery of the total radioactivity ranged from 88 - 94 % of the administered dose by 168 hours post dose.
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four positional
isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of total dabigatran in
plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods.
Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 ml/min
corresponding to the glomerular filtration rate.
Special populations:
Renal insufficiency:
The exposure (AUC) of dabigatran after the oral administration of Pradaxa is approximately 2.7 fold higher
in volunteers with moderate renal insufficiency (CrCL between 30 – 50 ml/min) than in those without renal
insufficiency.
In a small number of volunteers with severe renal insufficiency (CrCL 10 - 30 ml/min), the exposure (AUC)
to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer than that
observed in a population without renal insufficiency (see sections 4.2, 4.3 and 4.4).
Elderly patients:
Specific pharmacokinetic studies with elderly subjects showed an increase of 40 to 60 % in the AUC and of
more than 25 % in C
max
compared to young subjects. Population-based pharmacokinetic studies have
evaluated the pharmacokinetics of dabigatran after repeated doses in patients (up to 88 years). The observed
increase of dabigatran exposure correlated with the age-related reduction in creatinine clearance (see sections
4.2 and 4.4).
Hepatic insufficiency:
No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh
B) compared to 12 controls (see sections 4.2 and 4.4).
Body weight:
Population pharmacokinetic studies have evaluated the pharmacokinetics of dabigatran in patients of 48 to
120 kg body weight. Body weight had a minor effect on the plasma clearance of dabigatran resulting in
higher exposure in patients with low body weight (see section 4.2 and 4.4).
Gender:
Active substance exposure in female patients is about 40 % to 50 % higher than in male patients and no dose
adjustment is recommended.
13
Ethnic origin:
The pharmacokinetics of dabigatran was investigated in Caucasian and Japanese volunteers after single and
multiple doses. Ethnic origin does not affect the pharmacokinetics of dabigatran in a clinically relevant
manner. No pharmacokinetic data in black patients are available.
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-
glycoprotein transporter interaction) and diclofenac (CYP2C9).
Dabigatran exposure in healthy subjects was increased by 60 % in the presence of amiodarone.
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 repeat-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).
Carcinogenicity studies have not yet been completed with dabigatran.
6.
6.1 List of excipients
Capsule fill
•
Tartaric acid
•
Acacia
•
Hypromellose
•
Dimeticone 350
•
Talc
•
Hydroxypropylcellulose
Capsule shell
•
Carrageenan
•
Potassium Chloride
•
Titanium Dioxide
•
Indigo Carmine (E132)
•
Sunset Yellow (E110)
•
Hypromellose
•
Water purified
14
Black printing ink
•
Shellac
•
N-Butyl alcohol
•
Isopropyl alcohol
•
Industrial methylated spirit
•
Iron oxide black (E172)
•
Purified water
•
Propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Blister and bottle:
3 years
Once the bottle is opened, the product must be used within 30 days
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
Cartons containing 1, 3, or 6 blister strips (10 x 1, 30 x 1, 60 x 1) in perforated aluminium unit dose blisters.
The blister consists of an aluminium lidding foil coated with polyvinylchloride-polyvinylacetate copolymer-
acrylate (PVCAC acrylate) in contact with the product and an aluminium bottom foil with polyvinylchloride
(PVC) in contact with the product.
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:
•
The hard capsules should be taken out of the blister card by peeling off the backing foil.
•
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, please observe the following instructions:
•
The cap opens by pushing and turning.
15
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/08/442/001
EU/1/08/442/002
EU/1/08/442/003
EU/1/08/442/004
9.
18 March 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
16
1.
Pradaxa 110 mg hard capsules
2.
Each hard capsule contains 110 mg of dabigatran etexilate (as mesilate)
Excipients: Each hard capsule contains 3 micrograms sunset yellow (E110)
For a full list of excipients, see section 6.1.
3.
Hard capsule
Imprinted capsules with light blue, opaque cap and cream-coloured, opaque body of size 1 filled with
yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with
“R110”.
4.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip
replacement surgery or total knee replacement surgery.
Prevention of Venous Thromboembolism (VTE) in patients following elective knee replacement surgery:
The recommended dose of
Pradaxa
is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be
initiated orally within 1 – 4 hours of completed surgery with a single capsule and continuing with 2 capsules
once daily thereafter for a total of 10 days.
Prevention of Venous Thromboembolism (VTE) in patients following elective hip replacement surgery:
The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be
initiated orally within 1 – 4 hours of completed surgery with a single capsule and continuing with 2 capsules
once daily thereafter for a total of 28-35 days.
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.
Special patient populations:
Renal impairment:
Treatment with Pradaxa in patients with severe renal impairment (creatinine clearance < 30 ml/min) is
contraindicated (see section 4.3).
17
In patients with moderate renal impairment (creatinine clearance 30-50 ml/min), there is limited clinical
experience. These patients should be treated with caution. The recommended dose is 150 mg taken once
daily as 2 capsules of 75 mg (see section 4.4 and 5.1).
After knee replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery
with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.
After hip replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery
with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days.
Elderly:
In elderly patients ( > 75 years) there is limited clinical experience. These patients should be treated with
caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see section 4.4 and 5.1).
After knee replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery
with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.
After hip replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery
with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days.
Hepatic impairment:
Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in clinical trials.
Therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2). ALT should
be measured as part of the standard pre-operative evaluation (see section 4.4).
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).
Post-surgical patients with an increased risk for bleeding:
Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal
impairment (creatinine clearance 30 – 50 ml/min), should be treated with caution (see sections 4.4 and 5.1).
Children and adolescents:
There is no experience in children and adolescents.
Pradaxa is not recommended for use in patients below 18 years due to lack of data on safety and efficacy.
Concomitant use of Pradaxa with amiodarone or verapamil:
Dosing should be reduced to 150 mg Pradaxa daily in patients who received concomitantly dabigatran
etexilate and amiodarone or verapamil (see sections 4.4 and 4.5).
In patient with moderate renal impairment and concomitantly treated with dabigatran etexilate and
verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.4 and 4.5).
18
Switching from Pradaxa treatment to parenteral anticoagulant:
It is recommended to wait 24 hours after the last dose before switching from Pradaxa to a parenteral
anticoagulant (see section 4.5).
Switching from parenteral anticoagulants treatment to Pradaxa:
No data are available, therefore it is not recommended to start the administration of Pradaxa before the next
scheduled dose of the parenteral anticoagulant would have been due (see section 4.5).
Pradaxa should be swallowed as a whole with water, with or without food.
•
Hypersensitivity to the active substance or to any of the excipients
•
Patients with severe renal impairment (CrCl < 30 ml/min)
•
Active clinically significant bleeding
•
Organic lesion at risk of bleeding
•
Spontaneous or pharmacological impairment of haemostasis
•
Hepatic impairment or liver disease expected to have any impact on survival
•
Concomitant treatment with quinidine (see section 4.5)
Hepatic impairment:
Patients with elevated liver enzymes > 2 ULN were excluded in controlled clinical trials. Therefore the use
of Pradaxa is not recommended in this population. ALT should be measured as part of the standard pre-
operative evaluation.
Haemorrhagic risk:
Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the
treatment period, especially in the following situations that may increase the hemorrhagic risk: diseases
associated with an increased risk of bleeding, such as congenital or acquired coagulation disorders,
thrombocytopenia or functional platelet defects, active ulcerative gastrointestinal disease, recent biopsy or
major trauma, recent intracranial haemorrhage or brain, spinal or ophthalmic surgery, bacterial endocarditis.
Plasma concentrations of dabigatran might be elevated when co-administered with strong P-gp inhibitors
(e.g. verapamil, amiodarone). This may increase the risk of bleeding and these patients should be closely
clinically monitored (looking for signs of bleeding and anaemia) (see sections 4.2 and 4.5).
Patients with moderate renal impairment have an increased exposure to dabigatran. Limited data is available
in patients < 50 kg and the elderly (see sections 4.2 and 5.2). In these situations, Pradaxa should be used with
caution and a close clinical surveillance (looking for signs of bleeding or anemia) is required throughout the
treatment period (see section 4.2).
When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see
section 4.9).
Agents that may enhance the risk of haemorrhage should not be administered concomitantly or should be
administered with caution with Pradaxa (see section 4.5).
19
Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events:
There are limited efficacy and safety data for dabigatran available in
these
patients and therefore they should
be treated with caution.
Spinal anaesthesia/epidural anaesthesia/lumbar puncture:
In patients undergoing major orthopaedic surgery, epidural or spinal haematomas that may result in long-
term or permanent paralysis cannot be excluded with the concurrent use of dabigatran and spinal/epidural
anaesthesia or spinal puncture. The risk of these rare events may be higher with postoperative use of
indwelling epidural catheters or the concomitant use of other medicinal products affecting haemostasis.
Therefore the use of Pradaxa is not recommended in patients undergoing anaesthesia with post-operative
indwelling epidural catheters.
Administration of the first dose of Pradaxa should occur a minimum of two hours after the catheter is
removed. These patients require frequent observation for neurological signs and symptoms.
Hip fracture surgery:
There is no data on the use of Pradaxa in patients undergoing hip fracture surgery. Therefore treatment is not
recommended.
Colorants:
Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions.
Interaction studies have only been performed in adults.
Anticoagulants and platelet aggregation agents:
The following treatments are not recommended concomitantly with Pradaxa: unfractionated heparins and
heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents,
GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists.
It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent
central venous or arterial catheter (see sections 4.2 and 4.4).
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.
NSAIDs: When Pradaxa was coadministered with diclofenac, the plasma exposure of both medicinal
products remained unchanged indicating a lack of a pharmacokinetic interaction between dabigatran etexilate
and diclofenac. However, due to the risk of haemorrhage, notably with NSAIDs with elimination half-lives >
12 hours, close observation for signs of bleeding is recommended (see section 4.4).
20
Transporter interactions:
Amiodarone, verapamil and clarithromycin are inhibitors of the efflux transporter P-glycoprotein and
dabigatran etexilate a substrate of this transporter.
Amiodarone: When Pradaxa was coadministered with a single oral dose of 600 mg amiodarone, the extent
and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The
dabigatran AUC and C
max
were increased by about 60 % and 50 %, respectively. The mechanism of the
interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for
drug interaction may exist for weeks after discontinuation of amiodarone.
Dosing should be reduced to 150 mg Pradaxa daily in patients who received concomitantly dabigatran
etexilate and amiodarone (see section 4.2).
Verapamil: When dabigatran etexilate (150 mg) was coadministered with oral verapamil, the Cmax and
AUC of dabigatran were increased but magnitude of this change differs depending on timing of
administration and formulation of verapamil.
The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release
formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of C
max
by
about 180 % and AUC by about 150 %). The effect was progressively decreased with administration of an
extended release formulation (increased of C
max
by about 90 % and AUC by about 70 %) or administration of
multiple doses of verapamil (increased of C
max
by about 60 % and AUC by about 50 %).
Therefore, close clinical surveillance (looking for signs of bleeding or anemia) is required when dabigatran is
co-administrered with verapamil. In patient with normal renal function after the surgery, receiving dabigatran
etexilate and verapamil concomitantly, the dose of Pradaxa should be reduced to 150 mg daily. In patient
with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose
reduction of Pradaxa to 75 mg daily should be considered (see sections 4.2 and 4.4).
There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate
(increased of C
max
by about 10 % and AUC by about 20 %). This is explained by completed dabigatran
absorption after 2 hours (see section 4.4)
Clarithromycin: When clarithromycin (500 mg bid) was administered together with dabigatran etexilate in
healthy volunteers, increase of AUC by about 19 % and Cmax by about 15 % was observed without any
clinical safety concern. However, in patients receiving dabigatran, a clinically relevant interaction cannot be
excluded when combined with clarithromycin. Therefore, a close monitoring should be exercised when
dabigatran etexilate is combined with clarithromycine and particularly in the occurrence of bleeding, notably
in patient having a mild to moderate renal function.
P- glycoprotein inhibitors:
Caution should be exercised with strong P- glycoprotein inhibitors. The P- glycoprotein inhibitor quinidine is
contraindicated (see section 4.3).
P- glycoprotein inducers:
Potent P- glycoprotein inducers such as rifampicin or St John’s wort (Hypericum perforatum), may reduce
the systemic exposure of dabigatran. Caution is advised when co-administering these medicinal products.
Digoxin: In a study performed with 24 healthy subjects, when Pradaxa was coadministered with digoxin, no
changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.
Gastric pH:
21
Pantoprazole: When Pradaxa was coadministered with pantoprazole, a decrease in the dabigatran area under
the plasma concentration - time curve of approximately 30 % was observed. Pantoprazole and other proton-
pump inhibitors were co-administered with Pradaxa in clinical trials and no effects on bleeding or efficacy
were observed.
Ranitidine: Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of
absorption of dabigatran.
Pregnancy:
There are no adequate 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.
Women of child-bearing potential should avoid pregnancy during treatment with dabigatran etexilate.
Pradaxa should not be used during pregnancy unless clearly necessary.
Lactation:
There are no clinical data of the effect of dabigatran on infants during breast feeding.
Lactation should be discontinued during treatment with Pradaxa.
No studies on the effects on the ability to drive and use machines have been performed.
A total of 10.084 patients were treated in 4 actively controlled VTE prevention trials with at least one dose of
the medicinal product. Of these 5419 were treated with 150 mg or 220 mg daily of Pradaxa, while 389
received doses less than 150 mg daily and 1168 received doses in excess of 220 mg daily.
The most commonly reported adverse reactions are bleedings occurring in total in approximately 14 % of
patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %.
Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location,
may lead to disabling, life-threatening or even fatal outcomes.
The table 1 shows the number (%) of patients experiencing bleeding events during the treatment period in the
VTE prevention in the two pivotal clinical trials, according to dose.
Table 1 Bleeding events broken down to major and any bleeding in the pivotal hip and knee study
Dabigatran etexilate
150 mg
N (%)
Dabigatran etexilate
220 mg
N (%)
Enoxaparin
N (%)
Treated
1866(100.0)
1825(100.0)
1848(100.0)
Major Bleeding
24 (1.3)
33 (1.8)
27 (1.5)
Any bleeding
258(13.8)
251(13.8)
247(13.4)
22
Table 2 shows the adverse reactions ranked under headings of SOC and frequency using the following
convention: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1,000, <1/100); rare (≥
1/10,000, <1/1,000); very rare (< 1/10,000).
SOC / Preferred Term.
Dabigatran etexilate
150 mg
N (%)
Dabigatran etexilate
220 mg
N (%)
Enoxaparin
N (%)
Number of patients treated
2737(100)
2682(100)
3108(100)
Blood and lymphatic system disorders
Common
Anaemia
110 (4.0)
117 (4.4)
141 (4.5)
Uncommon
Thrombocytopenia
5 (0.2)
2 (0.1)
5 (0.2)
Vascular disorders
Common
Haematoma
38 (1.4)
37 (1.4)
55 (1.8)
Traumatichaematoma
37 (1.4)
41 (1.5)
51 (1.6)
Woundhaemorhhage
35 (1.3)
28 (1.0)
31 (1.0)
Uncommon
Haemorrhage
5 (0.2)
18 (0.7)
21 (0.7)
Respiratory and thoracic system disorders
Uncommon
Epistaxis
19 (0.7)
15 (0.6)
13 (0.4)
Gastrointestinal disorders
Common
Gastrointestinal
haemorrhage
33 (1.2)
17 (0.6)
20 (0.6)
Uncommon
Rectal haemorrhage
12 (0.4)
15 (0.6)
5 (0.2)
Haemorrhoidal
haemorrhage
4 (0.2)
8 (0.3)
2 (0.1)
Hepatobiliary disorders
Uncommon
Alaninine aminotransferase
increased
18 (0.7)
7 (0.3)
28 (0.9)
Aspartate aminotransferase
increased
9 (0.3)
5 (0.2)
15 (0.5)
Hepatic function abnormal/
Liver function Test
abnormal
6 (0.2)
10 (0.4)
7 (0.2)
Hepatic enzyme increased
4 (0.2)
5 (0.2)
11 (0.4)
Hyperbilirubinaemia
4 (0.1)
3 (0.1)
4 (0.1)
Transaminasesincreased
0 (0.0)
2 (0.1)
1 (0.0)
Skin and subcutaneous tissue disorder
Common
Skin haemorrhage
45 (1.6)
57 (2.1)
61 (2.0)
Musculoskeletal and connective tissue and bone disorders
Uncommon
Haemarthrosis
9 (0.3)
7 (0.3)
17 (0.6)
Renal and urinary disorders
23
SOC / Preferred Term.
Dabigatran etexilate
150 mg
N (%)
Dabigatran etexilate
220 mg
N (%)
Enoxaparin
N (%)
Common
Haematuria
38 (1.4)
33 (1.4)
25 (0.8)
General disorders and administration site conditions
Uncommon
Injection site haemorrhage
21 (0.8)
19 (0.7)
27 (0.9)
Bloodydischarge
2 (0.1)
6 (0.2)
6 (0.2)
Cathetersitehaemorrhage
2 (0.1)
1 (0.0)
7 (0.2)
Investigations
Common
Haemoglobindecreased
45 (1.6)
35 (1.3)
74 (2.4)
Uncommon
Haematocritdecreased
0 (0.0)
6 (0.2)
4 (0.1)
Injury, poisoning and procedural complications
Common
Wound secretion
130 (4.8)
130 (4.9)
93 (3.0)
Anaemia postoperative
99 (3.6)
87 (3.2)
120 (3.7)
Post procedural haematoma
66 (2.4)
45 (1.7)
78 (2.5)
Post procedural
haemorrhage
37 (1.4)
54 (2.0)
56 (1.8)
Post procedural discharge
31 (1.1)
34 (1.3)
31 (1.0)
Surgical and medial procedures
Uncommon
Post procedural drainage
11 (0.4)
13 (0.5)
16 (0.5)
Wounddrainage
1 (0.0)
4 (0.2)
2 (0.1)
Beyond the reported ALT findings the following laboratory chemistry data had been measured in phase 3
studies as presented in table 3.
Table 3: ALT findings the following laboratory chemistry
Dabigatran etexilate
150 mg
N (%)
Dabigatran etexilate
220 mg
N (%)
Enoxaparin
N (%)
Total rates of Alaninine
aminotransferase increased 3 x
ULN
68 (2.5)
58 (2.2)
95 (3.5)
There is no antidote to dabigatran. Doses of dabigatran etexilate beyond those recommended, expose the
patient to increased risk of bleeding. In the event of haemorrhagic complications, treatment must be
discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the
renal route adequate diuresis must be maintained. The initiation of appropriate treatment, e.g. surgical
haemostasis or the transfusion of fresh frozen plasma should be considered.
Dabigatran can be dialysed; there is no clinical experience to demonstrate the utility of this approach in
clinical studies.
24
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: direct thrombine inhibitors, ATC code: B01AE07
Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After
oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-
catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct
thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation
cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits free thrombin, fibrin-
bound thrombin and thrombin-induced platelet aggregation.
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.
Steady state (after day 3) dabigatran peak plasma concentration, measured 2 - 4 hours after 220 mg
dabigatran etexilate administration, is expected to be around 270 ng/ml, with an expected range of 80 - 460
ng/ml. The dabigatran trough concentration, measured at the end of the dosing interval (24 hours after the
last 220 mg dabigatran dose), is expected to be around 40 ng/ml, with expected range of 10-90 ng/ml.
Ethnic origin:
More than 99% of efficacy and safety data were generated in Caucasians.
Clinical trials in Venous Thromboembolism (VTE) prophylaxis following major joint replacement surgery:
In 2 large randomized, parallel group, double-blind, dose–confirmatory trials, patients undergoing elective
major orthopaedic surgery (one for knee replacement surgery and one for hip replacement surgery) received
Pradaxa 75 mg or 110 mg within 1-4 hours of surgery followed by 150 mg or 220 mg daily thereafter,
haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery and daily thereafter.
In the RE-MODEL trial (knee replacement) treatment was for 6 – 10 days and in the RE-NOVATE trial (hip
replacement) for 28 – 35 days. Totals of 2076 patients (knee) and 3494 (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 Pradaxa 220 mg and 150 mg were
statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The point estimate for
incidence of Major VTE and VTE related mortality for the 150 mg dose was slightly worse than enoxaparin
(table 4). Better results were seen with the 220mg dose where the point estimate of Major VTE was slightly
better than enoxaparin (table 4)."
The clinical studies have been conducted in a patient population with a mean age > 65 years.
25
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 (5539 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 4.
Data for the total VTE and all cause mortality endpoint are shown in table 5.
Data for adjudicated major bleeding endpoints are shown in tables 6 below.
Table 4: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL
and the RE-NOVATE orthopeadic 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
26
Table 5: 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 6: 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
1146
1163
1154
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)
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 characterized by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0
hours post administration.
Absorption:
A study evaluating post-operative absorption of dabigatran etexilate, 1-3 hours following surgery,
demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma
concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached
at 6 hours following administration in a postoperative period due to contributing factors such as anesthesia,
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.
27
Distribution:
Low (34-35 %) concentration independent binding of dabigatran to human plasma proteins was observed.
The volume of distribution of dabigtran of 60 – 70 L exceeded the volume of total body water indicating
moderate tissue distribution of dabigatran.
Cmax and the area under the plasma concentration-time curve were dose proportional. Plasma concentrations
of dabigatran showed a biexponential decline with a mean terminal half-life of 12 - 14 hours in healthy
volunteers and 14 – 17 hours in patients undergoing major orthopaedic surgery. The half-life was
independent of dose.
Metabolism and elimination:
Metabolism and excretion of dabigatran were studied following a single intravenous dose of radiolabeled
dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived radioactivity was
eliminated primarily in the urine (85 %). Faecal excretion accounted for 6 % of the administered dose.
Recovery of the total radioactivity ranged from 88 - 94 % of the administered dose by 168 hours post dose.
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four positional
isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of total dabigatran in
plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods.
Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 ml/min
corresponding to the glomerular filtration rate.
Special populations:
Renal insufficiency:
The exposure (AUC) of dabigatran after the oral administration of Pradaxa is approximately 2.7 fold higher
in volunteers with moderate renal insufficiency (CrCL between 30 – 50 ml/min) than in those without renal
insufficiency.
In a small number of volunteers with severe renal insufficiency (CrCL 10 - 30 ml/min), the exposure (AUC)
to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer than that
observed in a population without renal insufficiency (see sections 4.2, 4.3 and 4.4).
Elderly patients:
Specific pharmacokinetic studies with elderly subjects showed an increase of 40 to 60 % in the AUC and of
more than 25 % in C
max
compared to young subjects. Population-based pharmacokinetic studies have
evaluated the pharmacokinetics of dabigatran after repeated doses in patients (up to 88 years). The observed
increase of dabigatran exposure correlated with the age-related reduction in creatinine clearance (see sections
4.2 and 4.4).
Hepatic insufficiency:
No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh
B) compared to 12 controls (see sections 4.2 and 4.4).
Body weight:
Population pharmacokinetic studies have evaluated the pharmacokinetics of dabigatran in patients of 48 to
120 kg body weight. Body weight had a minor effect on the plasma clearance of dabigatran resulting in
higher exposure in patients with low body weight (see section 4.2 and 4.4).
Gender:
Active substance exposure in female patients is about 40 % to 50 % higher than in male patients and no dose
adjustment is recommended.
28
Ethnic origin:
The pharmacokinetics of dabigatran was investigated in Caucasian and Japanese volunteers after single and
multiple doses. Ethnic origin does not affect the pharmacokinetics of dabigatran in a clinically relevant
manner. No pharmacokinetic data in black patients are available.
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-
glycoprotein transporter interaction) and diclofenac (CYP2C9).
Dabigatran exposure in healthy subjects was increased by 60 % in the presence of amiodarone.
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 repeat-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).
Carcinogenicity studies have not yet been completed with dabigatran.
6.
6.1 List of excipients
Capsule fill
•
Tartaric acid
•
Acacia
•
Hypromellose
•
Dimeticone 350
•
Talc
•
Hydroxypropylcellulose
Capsule shell
•
Carrageenan
•
Potassium Chloride
•
Titanium Dioxide
•
Indigo Carmine (E132)
•
Sunset Yellow (E110)
•
Hypromellose
•
Water purified
29
Black printing ink
•
Shellac
•
N-Butyl alcohol
•
Isopropyl alcohol
•
Industrial methylated spirit
•
Iron oxide black (E172)
•
Purified water
•
Propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Blister and bottle:
3 years
Once the bottle is opened, the product must be used within 30 days
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
Cartons containing 1, 3, or 6 blister strips (10 x 1, 30 x 1, 60 x 1) in perforated aluminium unit dose blisters.
The blister consists of an aluminium lidding foil coated with polyvinylchloride-polyvinylacetate copolymer-
acrylate (PVCAC acrylate) in contact with the product and an aluminium bottom foil with polyvinylchloride
(PVC) in contact with the product.
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:
•
The hard capsules should be taken out of the blister card by peeling off the backing foil.
•
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, please observe the following instructions:
•
The cap opens by pushing and turning.
30
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/08/442/005
EU/1/08/442/006
EU/1/08/442/007
EU/1/08/442/008
9.
18 March 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
31
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
32
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer responsible for batch release
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 5.2 dated 09 April 2009
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before
and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan, as agreed in version 01 dated 11 January 2007 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates
of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
•
At the request of the EMEA
33
ANNEX III
LABELLING AND PACKAGE LEAFLET
34
A. LABELLING
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX FOR BLISTER for 75 mg
1.
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
Contains sunset yellow (E 110) (see leaflet for further information)
4.
10 x 1 hard capsules
30 x 1 hard capsules
60 x 1 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Do not chew
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP MM YYYY
36
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
Any unused product or waste material should be disposed of in accordance with local requirements
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
EU/1/08/442/001
EU/1/08/442/002
EU/1/08/442/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Pradaxa 75 mg
37
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX FOR BLISTER for 110 mg
1.
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
Contains sunset yellow (E 110) (see leaflet for further information)
4.
10 x 1 hard capsules
30 x 1 hard capsules
60 x 1 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Do not chew
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP MM YYYY
38
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
Any unused product or waste material should be disposed of in accordance with local requirements
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
EU/1/08/442/005
EU/1/08/442/006
EU/1/08/442/007
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Pradaxa 110 mg
39
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER FOR 75 mg
1.
Pradaxa 75 mg hard capsules
Dabigatran etexilate
2.
Boehringer Ingelheim (logo)
3.
EXPIRY DATE
EXP MM YYYY
4.
BATCH NUMBER
Lot
5.
OTHER
Peel back
40
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER FOR 110 mg
1.
Pradaxa 110 mg hard capsules
Dabigatran etexilate
2.
Boehringer Ingelheim (logo)
3.
EXPIRY DATE
EXP MM YYYY
4.
BATCH NUMBER
Lot
5.
OTHER
Peel back
41
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
FOLDING BOX AND LABEL FOR BOTTLE for 75 mg
1.
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
Contains sunset yellow (E110) (see leaflet for further information)
4.
60 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Do not chew
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP MM YYYY
Once opened, the product must be used within 30 days
42
9.
SPECIAL STORAGE CONDITIONS
Keep the bottle tightly closed. 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
Any unused product or waste material should be disposed of in accordance with local requirements
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
EU/1/08/442/004
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Pradaxa 75 mg (only applicable for folding box, not applicable for bottle label)
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING.
FOLDING BOX AND LABEL FOR BOTTLE for 110 mg
1.
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
Contains sunset yellow (E110) (see leaflet for further information)
4.
60 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Do not chew
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP MM YYYY
Once opened, the product must be used within 30 days
44
9.
SPECIAL STORAGE CONDITIONS
Keep the bottle tightly closed. 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
Any unused product or waste material should be disposed of in accordance with local requirements
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
EU/1/08/442/008
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Pradaxa 110 mg (only applicable for folding box, not applicable for bottle label)
45
B. PACKAGE LEAFLET
46
PACKAGE LEAFLET: INFORMATION FOR THE USER
Pradaxa 75 mg hard capsules
Pradaxa 110 mg hard capsules
dabigatran etexilate
Read all of this leaflet carefully before you start taking this medicine.
-
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. Do not pass it on to others. It may harm them, even if their
symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
In this leaflet
:
1. What Pradaxa is and what it is used for
2. Before you take Pradaxa
3. How to take Pradaxa
4. Possible side effects
5.
How to store Pradaxa
6.
Further information
1.
WHAT PRADAXA IS AND WHAT IT IS USED FOR
What is Pradaxa:
Pradaxa is a medicine which is used to prevent the formation of blood clots. It works by blocking a substance
in the body which is involved in blood clot formation.
What Pradaxa is used for:
Pradaxa is used to prevent the formation of blood clots in the veins after knee or hip replacement surgery.
2.
BEFORE YOU TAKE PRADAXA
Do NOT take Pradaxa
-
if you are allergic to dabigatran etexilate, dabigatran or any of the other ingredients of Pradaxa.
-
if you have severely reduced kidney function.
-
if you have a disease in an organ of the body that increases the risk of serious bleeding.
-
if you have an increased tendency to bleed. This may be inborn, of unknown cause or due to other
medicines.
-
if you have a severely reduced liver function or liver disease which could possibly cause death.
-
if you are taking quinidine, a medicine to treat abnormal heart beats.
Take special care with Pradaxa
Tell your doctor if you have or have had any medical conditions or illnesses, in particular any of those
included in the following list:
47
-
if you are currently bleeding
- if you have a liver disease that is associated with changes in the blood tests, the use of Pradaxa is not
recommended.
- if you have an increased bleeding risk, as could be the case in the following situations:
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 receiving treatments which could increase the risk of bleeding.
if you are taking anti-inflammatory medicines.
if you are suffering from an infection of the heart (bacterial endocarditis).
if you have a moderately impaired kidney function.
Pradaxa should not be used in children.
- if you have a tube (catheters) inserted into the back:
A tube can be inserted into your back e.g. for anesthesia or pain relief during or after surgery. If you are
administered Pradaxa after removal of a catheter your doctor will examine you regularly.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription. For instance:
- Blood thinners (e.g. warfarin, heparin)
- Non-steroidal anti-inflammatory medicines
- St. John´s wort, rifampicin, verapamil, clarithromycin
- Amiodarone, verapamil
If you are taking amiodarone- or verapamil-containing medicines you should be treated with a reduced
dose of 150 mg Pradaxa because your bleeding risk may be increased.
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.
Taking Pradaxa with food and drink
Pradaxa can be taken with or without food.
Pregnancy and breast-feeding
The effects of Pradaxa on pregnancy and the unborn child are not known. You should not take Pradaxa 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
The effect of Pradaxa on the ability to drive and use machines is not known. Your doctor will tell you when
you can start to drive.
Important information about some of the ingredients of Pradaxa
Pradaxa hard capsules contain a colorant with the name sunset yellow, which may cause allergic reactions.
48
3.
HOW TO TAKE PRADAXA
When taking Pradaxa capsules out of the blister pack, please observe the following instructions
•
take the capsules by peeling off the backing foil of the blister card.
•
do not push the capsules through the blister foil.
•
do not peel off the blister foil until a capsule is required.
When taking Pradaxa capsules out of the bottle, please observe the following instructions
•
push and turn for opening
The generally recommended dose of Pradaxa 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- 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.
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
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.
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 daily.
Always take Pradaxa exactly as your doctor has told you. You should check with your doctor if you are not
sure. The capsule should be swallowed with some water. Do not chew the capsule.
Changing from treatment with Pradaxa to anticoagulant treatment given by injection
Do not start treatment with injectable anticoagulant medicines (for example, heparin) until 24 hours after the
final dose of Pradaxa.
Changing from anticoagulant treatment given by injection to treatment with Pradaxa
Stop the treatment by injection and then start taking Pradaxa at the time you would have had the next
injection.
If you take more Pradaxa than you should
If you take more Pradaxa than recommended, you may have an increased risk of bleeding. Your doctor can
perform a blood test to assess the risk of bleeding.
49
Inform your doctor as soon as possible if you take more than the prescribed dose of Pradaxa. If bleeding
occurs, surgical treatment or treatment with blood transfusions may be required.
If you forget to take Pradaxa
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 missed individual doses.
50
If you stop taking Pradaxa
Do not stop taking Pradaxa without first consulting your doctor, since the risk of developing a blood clot in a
vein could be higher if you stop treatment early.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Pradaxa can cause side effects, although not in all patients.
As this medicine affects blood clotting, most side effects are related to signs such as bruising or bleeding.
Although rarely reported in clinical trials, major or severe bleeding may occur and, regardless of location,
may become disabling, life-threatening or even lead to death.
The side effects are listed below, grouped by how likely they are to happen:
With Pradaxa the following common and uncommon side effects are known:
Common side effects (affects 1 to 10 users in 100):
-
A fall in the number of red cells in the blood
-
Haematoma formation
-
Bleeding from an injury
-
A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
-
Wound secretion (liquid exuding from the surgical wound)
-
Bruising occurring after an operation
-
Bleeding occurring after an operation
-
A fall in the number of red cells in the blood after an operation
-
Bruising due to an injury
-
Exudation of a small amount of liquid from the incision made for a surgical procedure
-
Blood found in the urine on laboratory testing.
Uncommon side effects (affects 1 to 10 users in 1,000):
-
Bleeding
-
Bleeding into a joint
-
A fall in the number of platelets in the blood
-
Nose bleed
-
Bleeding into the stomach or bowel
-
Bleeding from piles
-
Bleeding into the rectum
-
Blood in the urine that stains the urine pink or red
-
Bleeding under the skin
-
Blood-stained discharge from the site of entry of a catheter into a vein
-
Bleeding from the site of entry of a catheter into a vein
-
Blood detected in the stools by a laboratory test
-
A decrease in the proportion of red cells in the blood
-
Bleeding from a surgical incision
-
Unusual laboratory test results on liver function
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your
doctor or pharmacist.
51
5.
HOW TO STORE PRADAXA
Keep out of the reach and sight of children.
Do not use Pradaxa after the expiry date which is stated on the carton, blister or bottle. 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 product must be used within 30 days. Keep the bottle tightly closed. Store in the
original package in order to protect from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Pradaxa contains
The active substance is dabigatran, which is administered in the form of 75 mg or 110 mg dabigatran
etexilate given 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, sunset yellow,
hypromellose and purified water
The black printing ink contains shellac, N-butyl alcohol, isopropyl alcohol, industrial methylated spirit, iron
oxide black, purified water and propylene glycol
What Pradaxa looks like and contents of the pack
Pradaxa is a hard capsule.
Pradaxa 75 mg hard capsules have an opaque, light blue-coloured cap and an opaque, cream-coloured body.
The Boehringer Ingelheim logo is printed on the cap and “R75” on the body of the capsule.
Pradaxa 110 mg hard capsules have an opaque, light blue-coloured cap and an opaque, cream-coloured body.
The Boehringer Ingelheim logo is printed on the cap and “R110” on the body of the capsule.
Pradaxa 75 mg and 110 mg hard capsules are available in packs containing 10 x 1, 30 x 1, 60 x 1 capsules in
aluminium perforated unit dose blisters.
Pradaxa 75 mg and 110 mg hard capsules are also available in polypropylene (plastic) bottles with 60 hard
capsules.
Not all pack sizes may be marketed.
52
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
53
For any information about this medicinal product, 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
Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11
България
Бьорингер Ингелхайм Фарма ГмбХ
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim Pharma GmbH
Eesti Filiaal
Tel: +372 60 80 940
Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-0
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp. z o.o.
Tel: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG,
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG,
organizačná zložka
Tel: +421 2 5810 1211
54
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 67 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim Pharma Ges mbH
Atstovybė Lietuvoje
Tel: +370 37 473922
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site:
55
Source: European Medicines Agency
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