Pradaxa

Overdose

Pradaxa 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. A calibrated quantitative dTT test or repetitive dTT measurements allow prediction of the time by when certain dabigatran levels will be reached , also in case additional measures e.g. dialysis have been initiated.

Excessive anticoagulation may require interruption of Pradaxa 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.

Management of bleeding complications

In the event of haemorrhagic complications, Pradaxa 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 prescribers discretion.

For situations when rapid reversal of the anticoagulant effect of Pradaxa is required the specific reversal agent (Praxbind, idarucizumab) antagonizing the pharmacodynamic effect of Pradaxa is available.

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.

Shelf life

Blister and bottle

3 years

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

Pradaxa price

Average cost of Pradaxa 110 mg per unit in online pharmacies is from 0.84$ to 3.02$, per pack from 67$ to 544$.

Incompatibilities

Not applicable.

List of excipients

Capsule content

Tartaric acid

Acacia

Hypromellose

Dimeticone 350

Talc

Hydroxypropylcellulose

Capsule shell

Carrageenan

Potassium chloride

Titanium dioxide

Indigo carmine (E132)

Hypromellose

Black printing ink

Shellac

Iron oxide black (E172)

Potassium hydroxide

Undesirable effects

Summary of the safety profile

The safety of Pradaxa has been evaluated in ten phase III studies including 23,393 patients exposed to Pradaxa (see Table 10).

Table 10: Number of patients studied, maximum daily dose in phase III studies

Indication	Number of patients treated with Pradaxa	Maximum daily dose
Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery	6,684	220 mg
Stroke and systemic embolism prevention in patients with atrial fibrillation	6,059 5,983	300 mg 220 mg
DVT/PE treatment (RE-COVER, RE-COVER II)	2,553	300 mg
DVT/PE prevention (RE-MEDY, RE-SONATE)	2,114	300 mg

In total, about 9 % of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days) , 22 % of patient with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14 % of patient 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 patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4% of patients in the DVT/PE prevention trial RE-MEDY and in 10.5% of patient in the DVT/PE prevention trial RE-SONATE.

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 given in tables 12-16 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 from the primary VTE prevention studies after hip or knee replacement surgery, the study in the prevention of thromboembolic stroke , and systemic embolism in patients with atrial fibrillation and the studies in DVT/PE treatment and in DVT/PE prevention. They are ranked under headings of 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.	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
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
Musculoskeletal and connective tissue disorders
Haemarthrosis	Uncommon	Rare	Uncommon
Renal and urinary disorders
Genitourological haemorrhage, including haematuria	Uncommon	Common	Common
General disorders and administration site conditions
Injection site haemorrhage	Rare	Rare	Rare
Catheter site haemorrhage	Rare	Rare	Rare
Bloody discharge	Rare	-
Injury, poisoning and procedural complications
Traumatic haemorrhage	Uncommon	Rare	Uncommon
Incision site haemorrhage	Rare	Rare	Rare
Post procedural haematoma	Uncommon	-	-
Post procedural haemorrhage	Uncommon	-
Anaemia postoperative	Rare	-	-
Post procedural discharge	Uncommon	-	-
Wound secretion	Uncommon	-	-
Surgical and medical procedures
Wound drainage	Rare	-	-
Post procedural drainage	Rare	-	.

Description of selected adverse reactions

Bleeding reactions

Due to the pharmacological mode of action, the use of Pradaxa 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 Pradaxa 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. 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 Pradaxa. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient. A specific reversal agent for dabigatran, idarucizumab, is available in case of uncontrollable bleeding.

Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery

The table 12 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 12: Number (%) of patients experiencing the adverse reaction bleeding

	Pradaxa 150 mg once daily N (%)	Pradaxa 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 13 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 13: Bleeding events in a study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation

	Pradaxa 110 mg twice daily	Pradaxa 150 mg twice daily	Warfarin
Subjects randomized	6,015	6,076	6,022
Major bleeding	347 (2.92 %)	409 (3.40 %)	426 (3.61 %)
Intracranial bleeding	27 (0.23 %)	39 (0.32 %)	91 (0.77 %)
GI bleeding	134 (1.13 %)	192 (1.60 %)	128 (1.09 %)
Fatal bleeding	26 (0.22 %)	30 (0.25 %)	42 (0.36 %)
Minor bleeding	1,566 (13.16 %)	1,787 (14.85 %)	1,931 (16.37 %)
Any bleeding	1,759 (14.78 %)	1,997 (16.60 %)	2,169 (18.39 %)

Subjects randomized to Pradaxa 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 Pradaxa had also a statistically significant lower total bleed rate. Subjects randomized to 110 mg Pradaxa twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81 [p=0.0027]). Subjects randomized to 150 mg Pradaxa 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 Pradaxa therapy.

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

Table 14 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). In the pooled studies the primary safety endpoints of major bleeding, major or clinically relevant bleeding and any bleeding were significantly lower than warfarin at a nominal alpha level of 5 %.

Table 14: Bleeding events in the studies RE-COVER and RE-COVER II testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)

	Pradaxa 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 Pradaxa or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events, which occurred during Pradaxa therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.

Table 15 shows bleeding events in pivotal study RE-MEDY testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). Some bleeding events (MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of 5% in patients receiving Pradaxa as compared with those receiving warfarin.

Table 15: Bleeding events in study RE-MEDY testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE)

	Pradaxa 150 mg twice daily	Warfarin	Hazard ratio vs warfarin (95% Confidence Interval)
Treated patients	1,430	1,426
Major 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 16 shows bleeding events in pivotal study RE-SONATE testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (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 Pradaxa.

Table 16: Bleeding events in study RE-SONATE testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE)

	Pradaxa 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

Paediatric population (DVT/PE)

In the clinical study 1160.88 in total, 9 adolescent patients (age 12 to < 18 years) with diagnosis of primary VTE received an initial oral dose of dabigatran etexilate of 1.71 (± 10 %) mg/kg bodyweight. Based on dabigatran concentrations as determined by the diluted thrombin time test and clinical assessment, the dose was adjusted to the target dose of 2.14 (± 10%) mg/kg bodyweight of dabigatran etexilate. On treatment 2 (22.1 %) patients experienced mild related adverse events (gastrooesophageal reflux / abdominal pain; abdominal discomfort) and 1 (11.1 %) patient experienced a not related serious adverse event (recurrent VTE of the leg) in the post treatment period > 3 days after stop of dabigatran etexilate.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows c

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 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.

Pharmacotherapeutic group

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

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 is considered to be associated with an increased risk of bleeding.

Primary Prevention of Venous Thromboembolism 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) ,

- 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 deep vein thrombosis (DVT) and pulmonary embolism (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.

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 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 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 17). Better results were seen with the 220 mg dose where the point estimate of Major VTE was slightly better than enoxaparin (table 17).

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 17.

Data for the total VTE and all cause mortality endpoint are shown in table 18.

Data for adjudicated major bleeding endpoints are shown in table 19 below.

Table 17: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and the RE-NOVATE orthopaedic surgery studies.

Trial	Pradaxa 220 mg once daily	Pradaxa 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

Table 18: Analysis of total VTE and all cause mortality during the treatment period in the RE-NOVATE and the RE-MODEL orthopaedic surgery studies.

Trial	Pradaxa 220 mg once daily	Pradaxa 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 19: Major bleeding events by treatment in the individual RE-MODEL and the RE-NOVATE studies.

Trial	Pradaxa 220 mg once daily	Pradaxa 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 (Randomized Evaluation of Long-term anticoagulant therapy) a multi-centre, multi-national, randomized 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 randomized, 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 randomized 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.

Tables 20-22 display details of key results in the overall population:

Table 20: Analysis of first occurrence of stroke or systemic embolism (primary endpoint) during the study period in RE-LY.

	Pradaxa 110 mg twice daily	Pradaxa 150 mg twice daily	Warfarin
Subjects randomized	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 21: Analysis of first occurrence of ischemic or haemorrhagic strokes during the study period in RE-LY.

	Pradaxa 110 mg twice daily	Pradaxa 150 mg twice daily	Warfarin
Subjects randomized	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

Table 22: Analysis of all cause and cardiovascular survival during the study period in RE-LY.

	Pradaxa 110 mg twice daily	Pradaxa 150 mg twice daily	Warfarin
Subjects randomized	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 23-25 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 23: Hazard Ratio and 95 % CI for stroke/sytemic embolism by subgroups

Endpoint	Pradaxa 110 mg twice daily vs. Warfarin	Pradaxa 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.

Table 24: Hazard Ratio and 95 % CI for major bleeds by subgroups

Endpoint	Pradaxa 110 mg twice daily vs. Warfarin	Pradaxa 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.

Patients who underwent Percutaneous coronary intervention (PCI) with stenting

A prospective, randomized, 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

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 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.

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 observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as shown in table 28.

Special populations

Renal insufficiency

In phase I studies 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.

Table 28: 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 randomized 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 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 30-50 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.

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.

Hepatic impairment

No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls.

Body weight

The dabigatran trough concentrations were about 20 % lower in 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. Limited clinical data in 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.

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).

Date of revision of the text

07 June 2018

Marketing authorisation holder

Boehringer Ingelheim International GmbH

Binger Str. 173

D-55216 Ingelheim am Rhein

Germany

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.

Nature and contents of container

Cartons containing 10 x 1, 30 x 1 or 60 x 1 hard capsules in perforated aluminium unit dose blisters.

Multipack containing 3 packs of 60 x 1 hard capsules (180 hard capsules) in perforated aluminium unit dose blisters.

Multipack containing 2 packs of 50 x 1 hard capsules (100 hard capsules) in perforated aluminium unit dose blisters.

Carton containing 6 blister strips (60 x 1) in perforated aluminium unit dose white blisters.

Polypropylene bottle with a screw cap containing 60 hard capsules.

Not all pack sizes may be marketed.

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

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. 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).

Effects on ability to drive and use machines

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

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.

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 18 March 2008

Date of latest renewal: 08 January 2018