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

Posology

 

Primary prevention of Venous Thromboembolism in Orthopaedic Surgery

The recommended doses of Pradaxa and the duration of therapy for primary prevention of venous thromboembolism in orthopaedic surgery are shown in table 1.

 

Table 1:    Dose recommendations and duration of therapy for primary prevention of venous thromboembolism in orthopaedic surgery

 

	Treatment initiation on the day of surgery 1-4 hours after completed surgery	Maintenance dose starting on the first day after surgery	Duration of maintenance dose
Patients following elective knee replacement surgery	single capsule of 110 mg Pradaxa	220 mg Pradaxa once daily taken as 2 capsules of 110 mg	10 days
Patients following elective hip replacement surgery			28-35 days
Dose reduction recommended
Patients with moderate renal impairment (creatinine clearance (CrCL 30-50 mL/min)	single capsule of 75 mg Pradaxa	150 mg Pradaxa once daily taken as 2 capsules of 75 mg	10 days (knee replacement surgery) or 28-35 days (hip replacement surgery)
Patients who receive concomitant verapamil*, amiodarone, quinidine
Patients aged 75 or above

*For patients with moderate renal impairment concomitantly treated with verapamil see Special populations

For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.

 

Assessment of renal function prior to and during Pradaxa treatment

In all patients and especially in the elderly (>75 years), as renal impairment may be frequent in this age group:

·             Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Pradaxa to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min) (see sections 4.3, 4.4 and 5.2).

·             Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products ).

The method to be used to estimate renal function (CrCL in mL/min) is the Cockcroft-Gault method.

 

Missed dose

 

It is recommended to continue with the remaining daily doses of Pradaxa at the same time of the next day.

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

 

Discontinuation of Pradaxa

 

Pradaxa treatment should not be discontinued without medical advice. Patients should be instructed to contact the treating physician if they develop gastrointestinal symptoms such as dyspepsia (see section 4.8).

 

Switching

 

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).

Parenteral anticoagulants to Pradaxa:

The parenteral anticoagulant should be discontinued and Pradaxa should be started 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5).

Special populations

 

Renal impairment

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

In patients with moderate renal impairment (CrCL 30-50 mL/min), a dose reduction is recommended (see table 1 above and sections 4.4 and 5.1).

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

 

Dosing should be reduced as indicated in table 1 (see also sections 4.4 and 4.5). In this situation Pradaxa and these medicinal products should be taken at the same time.

 

In patients with moderate renal impairment and concomitantly treated with verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.4 and 4.5).

 

Elderly

 

For elderly patients > 75 years, a dose reduction is recommended (see table 1 above and sections 4.4 and 5.1).

Weight

 

There is very limited clinical experience in patients with a body weight < 50 kg or > 110 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see section 5.2), but close clinical surveillance is recommended (see section 4.4).

Gender

 

No dose adjustment is necessary (see section 5.2).

 

Paediatric population

There is no relevant use of Pradaxa in the paediatric population for the indication of primary prevention of venous thromboembolic events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

 

Method of administration

Pradaxa is for oral use.

The capsules can be taken with or without food. Pradaxa should be swallowed as a whole with a glass of water, to facilitate delivery to the stomach.

 

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

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Patients with severe renal impairment (CrCL < 30 mL/min) • Active clinically significant bleeding • Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities • Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances. These are switching anticoagulant therapy (see section 4.2), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.5) • Hepatic impairment or liver disease expected to have any impact on survival • Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see section 4.5) • Prosthetic heart valves requiring anticoagulant treatment (see section 5.1).

Haemorrhagic risk

 

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

 

For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent (Praxbind, idarucizumab) is available (see section 4.9).

 

Use of platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux increase the risk of GI bleeding.

Risk factors

 

Table 2 summarises factors which may increase the haemorrhagic risk.

 

Table 2:    Factors which may increase the haemorrhagic risk.

 

Pharmacodynamic and kinetic factors	Age ≥ 75 years
Factors increasing dabigatran plasma levels	Major: ·              Moderate renal impairment (30-50 mL/min CrCL) ·              Strong P-gp inhibitors (see section 4.3 and 4.5) ·              Mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, verapamil, quinidine and ticagrelor; see section 4.5) Minor: ·              Low body weight (< 50 kg)
Pharmacodynamic interactions (see section 4.5)	·              ASA and other platelet aggregation inhibitors such as clopidogrel ·              NSAID ·              SSRIs or SNRIs ·              Other medicinal products which may impair haemostasis
Diseases / procedures with special haemorrhagic risks	·              Congenital or acquired coagulation disorders ·              Thrombocytopenia or functional platelet defects ·              Recent biopsy, major trauma ·              Bacterial endocarditis ·              Esophagitis, gastritis or gastroesophageal reflux

Limited data is available in patients < 50 kg (see section 5.2).

 

Precautions and management of the haemorrhagic risk

For the management of bleeding complications, see also section 4.9.

 

Benefit-risk assessment

 

The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see section 4.5), which significantly increase the risk of major bleeding requires a careful benefit-risk assessment. Pradaxa should only be given if the benefit outweighs bleeding risks.

 

Close clinical surveillance

Close observation for signs of bleeding or anaemia is recommended throughout the treatment period, especially if risk factors are combined (see table 2 above). Particular caution should be exercised when Pradaxa is co-administered with verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors) and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment (see section 4.5).

Close observation for signs of bleeding is recommended in patients concomitantly treated with NSAIDs (see section 4.5).

 

Discontinuation of Pradaxa

Patients who develop acute renal failure must discontinue Pradaxa (see also section 4.3).

 

When severe bleedings occur, treatment must be discontinued, the source of bleeding investigated and use of the specific reversal agent Praxbind (idarucizumab) may be considered (see section 4.9 Management of bleeding complications).

Dose reduction

 

A dose reduction is recommended as indicated in section 4.2.

Use of proton-pump inhibitors

 

The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding.

Laboratory coagulation parameters

 

Although Pradaxa does not in general require routine anticoagulant monitoring, the measurement of dabigatran related anticoagulation may be helpful to detect excessive high exposure to dabigatran in the presence of additional risk factors.

Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but results should be interpreted with caution due to inter-test variability (see section 5.1). The International Normalised Ratio (INR) test is unreliable in patients on Pradaxa and false positive INR elevations have been reported. Therefore INR tests should not be performed.

 

Table 3 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see section 5.1)

Table 3:    Coagulation test thresholds at trough that may be associated with an increased risk of bleeding.

 

Test (trough value)
dTT [ng/mL]	> 67
ECT [x-fold upper limit of normal]	No data
aPTT [x-fold upper limit of normal]	> 1.3
INR	Should not be performed

 

Use of fibrinolytic medicinal products for the treatment of acute ischemic stroke

 

The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient presents with a dTT, ECT or aPTT not exceeding the upper limit of normal (ULN) according to the local reference range.

Surgery and interventions

Patients on Pradaxa who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore, surgical interventions may require the temporary discontinuation of Pradaxa.

Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see section 5.2). This should be considered in advance of any procedures. In such cases a coagulation test (see sections 4.4 and 5.1) may help to determine whether haemostasis is still impaired.

 

Emergency surgery or urgent procedures

 

Pradaxa should be temporarily discontinued. When rapid reversal of the anticoagulation effect is required the specific reversal agent (Praxbind, idarucizumab) to Pradaxa is available.

 

Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Pradaxa treatment can be re-initiated 24 hours after administration of Praxbind (idarucizumab), if the patient is clinically stable and adequate haemostasis has been achieved.

 

Subacute surgery/interventions

 

Pradaxa should be temporarily discontinued. A surgery / intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention.

 

Elective surgery

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

Table 4 summarises discontinuation rules before invasive or surgical procedures.

 

Table 4:    Discontinuation rules before invasive or surgical procedures

 

Renal function (CrCL in mL/min)	Estimated half-life (hours)	Pradaxa should be stopped before elective surgery
		High risk of bleeding or major surgery	Standard risk
≥ 80	~ 13	2 days before	24 hours before
≥ 50-< 80	~ 15	2-3 days before	1-2 days before
≥ 30-< 50	~ 18	4 days before	2-3 days before (> 48 hours)

 

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

 

Procedures such as spinal anaesthesia may require complete haemostatic function.

The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least

2 hours should elapse before the administration of the first dose of Pradaxa. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.

 

Postoperative phase

Pradaxa should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.

Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 mL/min), should be treated with caution (see sections 4.4 and 5.1).

 

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

 

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

Hip fracture surgery

 

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

 

Hepatic impairment

 

Patients with elevated liver enzymes > 2 ULN were excluded in controlled clinical trials investigating the VTE prevention following elective hip or knee replacement surgery. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population. Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see section 4.3).

Interaction with P-gp inducers

 

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

Patients with antiphospholipid syndrome

 

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

Transporter interactions

 

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

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

Table 5:    Transporter interactions

 

P-gp inhibitors
Concomitant use contraindicated (see section 4.3)
Ketoconazole	Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazole once daily.
Dronedarone	When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg.
Itraconazole, cyclosporine	Based on in vitro results a similar effect as with ketoconazole may be expected.
Glecaprevir / pibrentasvir	The concomitant use of dabigatran etexilate with the fixed-dose combination of the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure of dabigatran and may increase the risk of bleeding.
Concomitant use not recommended
Tacrolimus	Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-

 

	gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors.
Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4)
Verapamil	When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigatran were increased but the magnitude of this change differs depending on timing of administration and formulation of verapamil (see sections 4.2 and 4.4). The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to the dabigatran etexilate intake (increase of Cmax by about 2.8-fold and AUC by about 2.5-fold). The effect was progressively decreased with administration of an extended release formulation (increase of Cmax by about 1.9-fold and AUC by about 1.7-fold) or administration of multiple doses of verapamil (increase of Cmax by about 1.6-fold and AUC by about 1.5-fold). There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increase of Cmax by about 1.1-fold and AUC by about 1.2-fold). This is explained by completed dabigatran absorption after 2 hours.
Amiodarone	When Pradaxa was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 1.6-fold and 1.5-fold, respectively. In view of the long half-life of amiodarone the potential for an interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4).
Quinidine	Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1,000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUCτ,ss and Cmax,ss were increased on average by 1.53-fold and 1.56-fold, respectively with concomitant quinidine (see sections 4.2 and 4.4).
Clarithromycin	When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 1.19-fold and Cmax by about 1.15-fold was observed.
Ticagrelor	When a single dose of 75 mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and Cmax were increased by 1.73-fold and 1.95-fold, respectively. After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is 1.56-fold and 1.46- fold for Cmax and AUC, respectively. Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUCτ,ss and Cmax,ss by 1.49-fold and 1.65-fold, respectively, compared with dabigatran etexilate given alone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mg dabigatran etexilate (in steady state), the increase of dabigatran AUCτ,ss and Cmax,ss was reduced to 1.27-fold and 1.23-fold, respectively, compared with dabigatran etexilate given alone. This staggered intake is the recommended administration for start of ticagrelor with a loading dose. Concomitant administration of 90 mg ticagrelor b.i.d. (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUCτ,ss and Cmax,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate given alone.
Posaconazole	Posaconazole also inhibits P-gp to some extent but has not been clinically studied.

 

	Caution should be exercised when Pradaxa is co-administered with posaconazole.
P-gp inducers
Concomitant use should be avoided.
e.g. rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin	Concomitant administration is expected to result in decreased dabigatran concentrations. Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5 % and 67 %, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.
Protease inhibitors such as ritonavir
Concomitant use not recommended
e.g. ritonavir and its combinations with other protease inhibitors	These affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with Pradaxa.
P-gp substrate
Digoxin	In a study performed with 24 healthy subjects, when Pradaxa was co-administered with digoxin, no changes on digoxin and no clinically relevant changes on dabigatran exposure have been observed.

 

Anticoagulants and antiplatelet aggregation medicinal products

 

There is no or only limited experience with the following treatments which may increase the risk of bleeding when used concomitantly with Pradaxa: anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic medicinal products, and vitamin K antagonists, rivaroxaban or other oral anticoagulants (see section 4.3), and antiplatelet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see section 4.4).

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

 

Table 6:    Interactions with anticoagulants and antiplatelet aggregation medicinal products

 

NSAIDs	NSAIDs given for short-term analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use, NSAIDs increased the risk of bleeding by approximately 50 % on both dabigatran etexilate and warfarin.
Clopidogrel	In young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUCτ,ss and Cmax,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUCτ,ss and Cmax,ss were increased by about 30-40 % (see section 4.4) .
ASA	Co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively (see section 4.4).
LMWH	The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin.

 

Other interactions

 

Table 7:    Other interactions

 

Selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs)
SSRIs, SNRIs	SSRIs and SNRIs increased the risk of bleeding in all treatment groups of a phase III clinical trial comparing dabigatran to warfarin for stroke prevention in atrial fibrillation patients (RE-LY).
Substances influencing gastric pH
Pantoprazole	When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran AUC of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.
Ranitidine	Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran.

 

Interactions linked to dabigatran etexilate and dabigatran metabolic profile

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

Women of childbearing potential

 

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

The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including Pradaxa should be assessed in females of reproductive potential and those with abnormal uterine bleeding

 

Pregnancy

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

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

 

Pradaxa should not be used during pregnancy unless clearly necessary. Breast-feeding

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

Fertility

 

No human data available.

 

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

 

 

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

Summary of the safety profile

 

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

 

The most commonly reported events are bleedings occurring in approximately 14 % of patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %.

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

 

Tabulated list of adverse reactions

 

Table 8 shows the adverse reactions ranked under headings of System Organ Classes (SOC) and

 

frequency using the following convention: very common (³ 1/10), common (³ 1/100 to < 1/10), uncommon (³ 1/1,000 to < 1/100), rare (³ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Table 8:    Adverse reactions

 

SOC / Preferred term	Frequency
Blood and lymphatic system disorders
Haemoglobin decreased	Common
Anaemia	Uncommon
Haematocrit decreased	Uncommon
Thrombocytopenia	Rare
Neutropenia	Not known
Agranulocytosis	Not known
Immune system disorder
Drug hypersensitivity	Uncommon
Anaphylactic reaction	Rare
Angioedema	Rare
Urticaria	Rare
Rash	Rare
Pruritus	Rare
Bronchospasm	Not known
Nervous system disorders
Intracranial haemorrhage	Rare
Vascular disorders
Haematoma	Uncommon
Wound haemorrhage	Uncommon
Haemorrhage	Rare
Respiratory, thoracic and mediastinal disorders
Epistaxis	Uncommon
Haemoptysis	Rare
Gastrointestinal disorders
Gastrointestinal haemorrhage	Uncommon
Rectal haemorrhage	Uncommon
Haemorrhoidal haemorrhage	Uncommon
Diarrhoea	Uncommon
Nausea	Uncommon
Vomiting	Uncommon
Gastrointestinal ulcer, including oesophageal ulcer	Rare
Gastroesophagitis	Rare
Gastroesophageal reflux disease	Rare
Abdominal pain	Rare
Dyspepsia	Rare
Dysphagia	Rare
Hepatobiliary disorders
Hepatic function abnormal/ Liver function Test abnormal	Common
Alanine aminotransferase increased	Uncommon
Aspartate aminotransferase increased	Uncommon
Hepatic enzyme increased	Uncommon
Hyperbilirubinaemia	Uncommon
Skin and subcutaneous tissue disorder
Skin haemorrhage	Uncommon
Alopecia	Not known
Musculoskeletal and connective tissue disorders

 

Haemarthrosis	Uncommon
Renal and urinary disorders
Genitourological haemorrhage, including	Uncommon

 

haematuria
General disorders and administration site conditions
Injection site haemorrhage	Rare
Catheter site haemorrhage	Rare
Bloody discharge	Rare
Injury, poisoning and procedural complications
Traumatic haemorrhage	Uncommon
Post procedural haematoma	Uncommon
Post procedural haemorrhage	Uncommon
Post procedural discharge	Uncommon
Wound secretion	Uncommon
Incision site haemorrhage	Rare
Anaemia postoperative	Rare
Surgical and medical procedures
Wound drainage	Rare
Post procedural drainage	Rare

 

Description of selected adverse reactions

 

Bleeding reactions

 

Due to the pharmacological mode of action, the use of 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 (see section 4.4 Haemorrhagic risk). Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock.

Known bleeding complications such as compartment syndrome and acute renal failure due to hypoperfusion have been reported for 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 (see Section 4.9).

The table 9 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 9:    Number (%) of patients experiencing the adverse reaction bleeding

 

	Pradaxa 150 mg N (%)	Pradaxa 220 mg N (%)	Enoxaparin N (%)
Treated	1,866(100.0)	1,825(100.0)	1,848(100.0)
Major bleeding	24 (1.3)	33 (1.8)	27 (1.5)
Any bleeding	258(13.8)	251(13.8)	247(13.4)

Agranulocytosis and neutropenia

 

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

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

TO REPORT ANY SIDE EFFECT(S):

•   Saudi Arabia:

-           The National Pharmacovigilance Centre (NPC):

· Fax: +966-11-205-7662

· SFDA Call Center: 19999

· E-mail: npc.drug@sfda.gov.sa

· Website: https://ade.sfda.gov.sa

•   Other countries:

-           Please contact the relevant competent authority.

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 (see sections 4.4 and 5.1). A calibrated quantitative dTT test or repetitive dTT measurements allow prediction of the time by when certain dabigatran levels will be reached (see section 5.1), also in case additional measures e.g. dialysis have been initiated.

 

Excessive anticoagulation may require interruption of 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 (see section 5.2).

 

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 prescriber’s 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 (see section 4.4).

 

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

 

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

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 90^th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see section 4.4, table 3) is considered to be associated with an increased risk of bleeding.

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 (25^th-75^th 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 (25^th-75^th 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 (25^th-75^th percentile range).

 

In patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily,

 

·             the 90^th percentile of dabigatran plasma concentrations was 67 ng/mL, measured at trough (20-28 hours after the previous dose) (see section 4.4 and 4.9),

·             the 90^th 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.

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 10). Better results were seen with the 220 mg dose where the point estimate of Major VTE was slightly better than enoxaparin (table 10).

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 10.

 

Data for the total VTE and all cause mortality endpoint are shown in table 11. Data for adjudicated major bleeding endpoints are shown in table 12 below.

 

Table 10: 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	Pradaxa 150 mg	Enoxaparin 40 mg
RE-NOVATE (hip)
N	909	888	917
Incidences (%)	28 (3.1)	38 (4.3)	36 (3.9)
Risk ratio over enoxaparin	0.78	1.09
95 % CI	0.48, 1.27	0.70, 1.70
RE-MODEL (knee)
N	506	527	511
Incidences (%)	13 (2.6)	20 (3.8)	18 (3.5)
Risk ratio over enoxaparin	0.73	1.08
95 % CI	0.36, 1.47	0.58, 2.01

 

Table 11: 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	Pradaxa 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 12: Major bleeding events by treatment in the individual RE-MODEL and the RE-NOVATE studies

 

Trial	Pradaxa 220 mg	Pradaxa 150 mg	Enoxaparin 40 mg
RE-NOVATE (hip)
Treated patients N	1,146	1,163	1,154
Number of MBE N(%)	23 (2.0)	15 (1.3)	18 (1.6)
RE-MODEL (knee)
Treated patients N	679	703	694
Number of MBE N(%)	10 (1.5)	9 (1.3)	9 (1.3)

 

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

 

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

 

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

 

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Pradaxa in all subsets of the paediatric population in prevention of thromboembolic events for the granted indication (see section 4.2 for information on paediatric use).

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 (see section 4.2).

Distribution

 

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

 

Biotransformation

 

Metabolism and excretion of dabigatran were studied following a single intravenous dose of radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived radioactivity was eliminated primarily in the urine (85 %). Faecal excretion accounted for 6 % of the administered dose. Recovery of the total radioactivity ranged from 88-94 % of the administered dose by 168 hours post dose.

 

Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of total dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 mL/min corresponding to the glomerular filtration rate.

 

Elimination

 

Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as shown in table 13.

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 (see sections 4.2, 4.3 and 4.4).

Table 13: 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.

Elderly patients

Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60 % in the AUC and of more than 25 % in Cmax compared to young subjects.

 

The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31 % higher trough concentration for subjects ≥ 75 years and by about 22 % lower trough level for subjects

< 65 years compared to subjects between 65 and 75 years (see sections 4.2 and 4.4).

 

Hepatic impairment

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

Body weight

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

< 50 kg are available.

 

Gender

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

Ethnic origin

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

 

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).

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.

 

Capsule content

Tartaric acid

Acacia

Hypromellose

Dimeticone 350

Talc

Hydroxypropylcellulose

Capsule shell

Carrageenan

Potassium chloride

Titanium dioxide

Hypromellose

 

Black printing ink

Shellac

Iron oxide black (E172)

Potassium hydroxide

Not applicable.

Blister and bottle 3 years Once the bottle is opened, the medicinal product must be used within 4 months.

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.

Cartons containing 10 x 1, 30 x 1 or 60 x 1 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.

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