Dabigatran Etexilate Mesylate Capsule 150mg Taj Pharma

1. Name of the medicinal product

Dabigatran Etexilate Mesylate Capsule 75mg Taj Pharma
Dabigatran Etexilate Mesylate Capsule 110mg Taj Pharma
Dabigatran Etexilate Mesylate Capsule 150mg Taj Pharma

2. Qualitative and quantitative composition

a) Dabigatran Etexilate Mesylate Capsule 75mg Taj Pharma
Each hard gelatin capsule contains:
Dabigatran Etexilate Mesylate 86.48mg
Equivalent to Dabigatran Etexilate 75mg
Excipients Q.S.

b) Dabigatran Etexilate Mesylate Capsule 110mg Taj Pharma
Each hard gelatin capsule contains:
Dabigatran Etexilate Mesylate 126.83mg
Equivalent to Dabigatran Etexilate 110mg
Excipients Q.S.

c) Dabigatran Etexilate Mesylate Capsule 150mg Taj Pharma
Each hard gelatin capsule contains:
Dabigatran Etexilate Mesylate 172.95mg
Equivalent to Dabigatran Etexilate 150mg
Excipients Q.S.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Hard gelatin capsule.

4. Clinical particulars

• Therapeutic indications

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

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

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

• Posology and method of administration

Posology

Primary prevention of Venous Thromboembolism in Orthopaedic Surgery

The recommended doses of Dabigatran Taj Pharma etexilate mesylate capsule 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

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

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

Assessment of renal function prior to and during Dabigatran Taj Pharma etexilate mesylate capsule treatment

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

• Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Dabigatran Taj Pharma etexilate mesylate capsule to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min) (see sections 4.3, 4.4 and 5.2).
• Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).

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

Missed dose

It is recommended to continue with the remaining daily doses of Dabigatran Taj Pharma etexilate mesylate capsule at the same time of the next day.

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

Discontinuation of Dabigatran Taj Pharma etexilate mesylate capsule

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

Switching

Dabigatran Taj Pharma etexilate mesylate capsule treatment to parenteral anticoagulant:

It is recommended to wait 24 hours after the last dose before switching from Dabigatran Taj Pharma etexilate mesylate capsule to a parenteral anticoagulant (see section 4.5).

Parenteral anticoagulants to Dabigatran Taj Pharma etexilate mesylate capsule:

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

Special populations

Renal impairment

Treatment with Dabigatran Taj Pharma etexilate mesylate capsule in patients with severe renal impairment (CrCL < 30 mL/min) is contraindicated (see section 4.3).

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

Concomitant use of Dabigatran Taj Pharma etexilate mesylate capsule with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil

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

In patients with moderate renal impairment and concomitantly treated with verapamil, a dose reduction of Dabigatran Taj Pharma etexilate mesylate capsule to 75mg 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 > 75 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see section 5.2), but close clinical surveillance is recommended (see section 4.4).

Gender

No dose adjustment is necessary (see section 5.2).

Paediatric population

There is no relevant use of Dabigatran Taj Pharma etexilate mesylate capsule 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.

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

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

The recommended doses of Dabigatran Taj Pharma etexilate mesylate capsule in the indications SPAF, DVT and PE are shown in table 2.

Table 2: Dose recommendations for SPAF, DVT and PE

For DVT/PE the recommendation for the use of Dabigatran Taj Pharma etexilate mesylate capsule 220mg taken as one 75mg capsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in this clinical setting. See further down and sections 4.4, 4.5, 5.1 and 5.2.

In case of intolerability to Dabigatran Taj Pharma etexilate mesylate capsule, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and systemic embolism associated with atrial fibrillation or for DVT/PE.

Assessment of renal function prior to and during Dabigatran Taj Pharma etexilate mesylate capsule treatment

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

• Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Dabigatran Taj Pharma etexilate mesylate capsule to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min) (see sections 4.3, 4.4 and 5.2).
• Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
• Additional requirements in patients with mild to moderate renal impairment and in patients aged over 75 years:
• Renal function should be assessed during treatment with Dabigatran Taj Pharma etexilate mesylate capsule at least once a year or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).

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

Duration of use

The duration of use of Dabigatran Taj Pharma etexilate mesylate capsule in the indications SPAF, DVT and PE are shown in table 3.

Table 3: Duration of use for SPAF and DVT/PE

Missed dose

A forgotten Dabigatran Taj Pharma etexilate mesylate capsule dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.

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

Discontinuation of Dabigatran Taj Pharma etexilate mesylate capsule

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

Switching

Dabigatran Taj Pharma etexilate mesylate capsule treatment to parenteral anticoagulant:

It is recommended to wait 12 hours after the last dose before switching from Dabigatran Taj Pharma etexilate mesylate capsule to a parenteral anticoagulant (see section 4.5).

Parenteral anticoagulants to Dabigatran Taj Pharma etexilate mesylate capsule:

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

Dabigatran Taj Pharma etexilate mesylate capsule treatment to Vitamin K antagonists (VKA):

The starting time of the VKA should be adjusted based on CrCL as follows:

• CrCL ≥ 50 mL/min, VKA should be started 3 days before discontinuing Dabigatran Taj Pharma etexilate mesylate capsule
• CrCL ≥ 30-< 50 mL/min, VKA should be started 2 days before discontinuing Dabigatran Taj Pharma etexilate mesylate capsule

Because Dabigatran Taj Pharma etexilate mesylate capsule can impact the International Normalized Ratio (INR), the INR will better reflect VKA’s effect only after Dabigatran Taj Pharma etexilate mesylate capsule has been stopped for at least 2 days. Until then, INR values should be interpreted with caution.

VKA to Dabigatran Taj Pharma etexilate mesylate capsule:

The VKA should be stopped. Dabigatran Taj Pharma etexilate mesylate capsule can be given as soon as the INR is < 2.0.

Cardioversion (SPAF)

Patients can stay on Dabigatran Taj Pharma etexilate mesylate capsule while being cardioverted.

Catheter ablation for atrial fibrillation (SPAF)

There are no data available for 75mg twice daily Dabigatran Taj Pharma etexilate mesylate capsule treatment.

Percutaneous coronary intervention (PCI) with stenting (SPAF)

Patients with non valvular atrial fibrillation who undergo a PCI with stenting can be treated with Dabigatran Taj Pharma etexilate mesylate capsule in combination with antiplatelets after haemostasis is achieved (see section 5.1).

Special populations

Elderly

For dose modifications in this population see table 2 above.

Patients at risk of bleeding

Patients with an increased bleeding risk (see sections 4.4, 4.5, 5.1 and 5.2) should be closely monitored clinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient (see table 2 above). A coagulation test (see section 4.4) may help to identify patients with an increased bleeding risk caused by excessive Dabigatran Taj Pharma etexilate mesylate capsule exposure. When excessive Dabigatran Taj Pharma etexilate mesylate capsule exposure is identified in patients at high risk of bleeding, a reduced dose of 220mg taken as one 75mg capsuletwice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted.

For subjects with gastritis, esophagitis, or gastroesophageal reflux, a dose reduction may be considered due to the elevated risk of major gastro-intestinal bleeding (see table 2 above and section 4.4).

Renal impairment

Treatment with Dabigatran Taj Pharma etexilate mesylate capsule in patients with severe renal impairment (CrCL < 30 mL/min) is contraindicated (see section 4.3).

No dose adjustment is necessary in patients with mild renal impairment (CrCL 50- ≤ 80 mL/min). For patients with moderate renal impairment (CrCL 30-50 mL/min) the recommended dose of Dabigatran Taj Pharma etexilate mesylate capsule is also 300mg taken as one 150mg capsule twice daily. However, for patients with high risk of bleeding, a dose reduction of Dabigatran Taj Pharma etexilate mesylate capsule to 220mg taken as one 75mg capsule twice daily should be considered (see sections 4.4 and 5.2). Close clinical surveillance is recommended in patients with renal impairment.

Concomitant use of Dabigatran Taj Pharma etexilate mesylate capsule with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil

No dose adjustment is necessary for concomitant use of amiodarone or quinidine (see sections 4.4, 4.5 and 5.2).

Dose reductions are recommended for patients who receive concomitantly verapamil (see table 2 above and sections 4.4 and 4.5). In this situation Dabigatran Taj Pharma etexilate mesylate capsule and verapamil should be taken at the same time.

Weight

No dose adjustment is necessary (see section 5.2), but close clinical surveillance is recommended in patients with a body weight < 50 kg (see section 4.4).

Gender

No dose adjustment is necessary (see section 5.2).

Paediatric population

There is no relevant use of Dabigatran Taj Pharma etexilate mesylate capsule in the paediatric population for the indication of prevention of stroke and systemic embolism in patients with NVAF.

For the indication DVT/PE, the safety and efficacy of Dabigatran Taj Pharma etexilate mesylate capsule in children from birth to less than 18 years of age have not yet been established. Currently available data are described in section 4.8 and 5.1, but no recommendation on a posology can be made.

Method of administration

Dabigatran Taj Pharma etexilate mesylate capsule is for oral use.

The capsules can be taken with or without food. Dabigatran Taj Pharma etexilate mesylate capsule 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).

• Contraindications

• 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 and dronedarone (see section 4.5)
• Prosthetic heart valves requiring anticoagulant treatment (see section 5.1).
  • Special warnings and precautions for use

Haemorrhagic risk

Dabigatran Taj Pharma etexilate mesylate capsule 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 Dabigatran Taj Pharma etexilate mesylate capsule. 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 Taj Pharma etexilate mesylate capsule is required, the specific reversal agent (Praxbind, idarucizumab) is available (see section 4.9).

In clinical trials, Dabigatran Taj Pharma etexilate mesylate capsule was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (≥ 75 years) for the 150mg twice daily dose regimen. Further risk factors (see also table 4) comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux.

Risk factors

Table 4 summarises factors which may increase the haemorrhagic risk.

Table 4: Factors which may increase the haemorrhagic risk.

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. Dabigatran Taj Pharma etexilate mesylate capsule 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 4 above). Particular caution should be exercised when Dabigatran Taj Pharma etexilate mesylate capsule 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 Dabigatran Taj Pharma etexilate mesylate capsule

Patients who develop acute renal failure must discontinue Dabigatran Taj Pharma etexilate mesylate capsule (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 should be either considered or 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 Dabigatran Taj Pharma etexilate mesylate capsule does not, in general, require routine anticoagulant monitoring, the measurement of Dabigatran Taj Pharma etexilate mesylate capsule related anticoagulation may be helpful to detect excessive-high exposure to Dabigatran Taj Pharma etexilate mesylate capsule in the presence of additional risk factors.

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

Table 5 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see section 5.1)

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

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

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

Surgery and interventions

Patients on Dabigatran Taj Pharma etexilate mesylate capsule who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore, surgical interventions may require the temporary discontinuation of Dabigatran Taj Pharma etexilate mesylate capsule.

Patients can stay on Dabigatran Taj Pharma etexilate mesylate capsule while being cardioverted. There are no data available for 75mg twice daily Dabigatran Taj Pharma etexilate mesylate capsule treatment in patients undergoing catheter ablation for atrial fibrillation (see section 4.2).

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

Emergency surgery or urgent procedures

Dabigatran Taj Pharma etexilate mesylate capsule should be temporarily discontinued. When rapid reversal of the anticoagulation effect is required the specific reversal agent (Praxbind, idarucizumab) to Dabigatran Taj Pharma etexilate mesylate capsule is available.

Reversing Dabigatran Taj Pharma etexilate mesylate capsule therapy exposes patients to the thrombotic risk of their underlying disease. Dabigatran Taj Pharma etexilate mesylate capsule 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

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

Elective surgery

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

Table 6 summarises discontinuation rules before invasive or surgical procedures.

Table 6: Discontinuation rules before invasive or surgical procedures

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

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

Postoperative phase

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

Patients at risk for bleeding or patients at risk of overexposure, notably patients with 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 Dabigatran Taj Pharma etexilate mesylate capsule available in these patients and therefore they should be treated with caution.

Hip fracture surgery

There is no data on the use of Dabigatran Taj Pharma etexilate mesylate capsule in patients undergoing hip fracture surgery. Therefore treatment is not recommended.

Hepatic impairment

Patients with elevated liver enzymes > 2 ULN were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule plasma concentrations, and should be avoided (see sections 4.5 and 5.2).

Patients with antiphospholipid syndrome

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

Myocardial Infarction (MI)

In the phase III study RE-LY (SPAF, see section 5.1) the overall rate of MI was 0.82, 0.81, and 0.64 % / year for Dabigatran Taj Pharma etexilate mesylate capsule etexilate 75mg twice daily, Dabigatran Taj Pharma etexilate mesylate capsule etexilate 150mg twice daily and warfarin, respectively, an increase in relative risk for Dabigatran Taj Pharma etexilate mesylate capsule of 29 % and 27 % compared to warfarin. Irrespective of therapy, the highest absolute risk of MI was seen in the following subgroups, with similar relative risk: patients with previous MI, patients ≥ 65 years with either diabetes or coronary artery disease, patients with left ventricular ejection fraction < 40 %, and patients with moderate renal dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly taking ASA plus clopidogrel or clopidogrel alone.

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

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

Active Cancer Patients (DVT/PE)

The efficacy and safety have not been established for DVT/PE patients with active cancer.

• Interaction with other medicinal products and other forms of interaction

Transporter interactions

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

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

Table 7: Transporter interactions

Anticoagulants and antiplatelet aggregation medicinal products

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

From the data collected in the phase III study RE-LY (see section 5.1) it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both Dabigatran Taj Pharma etexilate mesylate capsule etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another (see section 4.3). Furthermore, concomitant use of antiplatelets, ASA or clopidogrel approximately doubled major bleeding rates with both Dabigatran Taj Pharma etexilate mesylate capsule etexilate and warfarin (see section 4.4).

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

Table 8: Interactions with anticoagulants and antiplatelet aggregation medicinal products

Other interactions

Table 9: Other interactions

Interactions linked to Dabigatran Taj Pharma etexilate mesylate capsule etexilate and Dabigatran Taj Pharma etexilate mesylate capsule metabolic profile

Dabigatran Taj Pharma etexilate mesylate capsule etexilate and Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule.

• Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should avoid pregnancy during treatment with Dabigatran Taj Pharma etexilate mesylate capsule.

Pregnancy

There is limited amount of data from the use of Dabigatran Taj Pharma etexilate mesylate capsule in pregnant women.

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

Dabigatran Taj Pharma etexilate mesylate capsule should not be used during pregnancy unless clearly necessary.

Breast-feeding

There are no clinical data of the effect of Dabigatran Taj Pharma etexilate mesylate capsule on infants during breast-feeding.

Breast-feeding should be discontinued during treatment with Dabigatran Taj Pharma etexilate mesylate capsule.

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 70mg/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

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

• Undesirable effects

Summary of the safety profile

The safety of Dabigatran Taj Pharma etexilate mesylate capsule has been evaluated in ten phase III studies including 23,393 patients exposed to Dabigatran Taj Pharma etexilate mesylate capsule (see Table 10).

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

In total, about 9 % of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days), 22 % of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14 % of patients treated for DVT/PE and 15 % of patients treated for DVT/PE prevention experienced adverse reactions.

The most commonly reported events are bleedings occurring in approximately 14 % of patients treated short-term for elective hip or knee replacement surgery, 16.6 % in patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism, and in 14.4 % of 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 patients 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 provided 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 System Organ Class (SOC) and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Table 11: Adverse reactions

Description of selected adverse reactions

Bleeding reactions

Due to the pharmacological mode of action, the use of Dabigatran Taj Pharma etexilate mesylate capsule may be associated with an increased risk of occult or overt bleeding from any tissue or organ. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. In the clinical studies mucosal bleedings (e.g. gastrointestinal, genitourinary) were seen more frequently during long term Dabigatran Taj Pharma etexilate mesylate capsule treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit is of value to detect occult bleeding. The risk of bleedings may be increased in certain patient groups e.g. those patients with moderate renal impairment and/or on concomitant treatment affecting haemostasis or strong P-gp inhibitors (see section 4.4 Haemorrhagic risk). Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock.

Known bleeding complications such as compartment syndrome and acute renal failure due to hypoperfusion have been reported for Dabigatran Taj Pharma etexilate mesylate capsule. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient. A specific reversal agent for Dabigatran Taj Pharma etexilate mesylate capsule, idarucizumab, is available in case of uncontrollable bleeding (see Section 4.9).

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

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

Subjects randomized to Dabigatran Taj Pharma etexilate mesylate capsule 75mg twice daily or 150mg twice daily had a significantly lower risk for life-threatening bleeds and intracranial bleeding compared to warfarin [p < 0.05]. Both dose strengths of Dabigatran Taj Pharma etexilate mesylate capsule had also a statistically significant lower total bleed rate. Subjects randomized to 75mg Dabigatran Taj Pharma etexilate mesylate capsule twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81 [p=0.0027]). Subjects randomized to 150mg Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule is due to GI bleeding, typically seen within the first 3-6 months following initiation of Dabigatran Taj Pharma etexilate mesylate capsule 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)

Bleeding events for both treatments are counted from the first intake of Dabigatran Taj Pharma etexilate mesylate capsule or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events, which occurred during Dabigatran Taj Pharma etexilate mesylate capsule 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 Dabigatran Taj Pharma etexilate mesylate capsule 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)

*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 Dabigatran Taj Pharma etexilate mesylate capsule.

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

*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 Taj Pharma etexilate mesylate capsule etexilate of 1.71 (± 10 %)mg/kg bodyweight. Based on Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule etexilate.

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.

• Overdose

Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule levels will be reached (see section 5.1), also in case additional measures e.g. dialysis have been initiated.

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

Management of bleeding complications

In the event of haemorrhagic complications, Dabigatran Taj Pharma etexilate mesylate capsule 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 Dabigatran Taj Pharma etexilate mesylate capsule is required the specific reversal agent (Praxbind, idarucizumab) antagonizing the pharmacodynamic effect of Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule, but data on their usefulness in clinical settings and also on the possible risk of rebound thromboembolism is very limited. Coagulation tests may become unreliable following administration of suggested coagulation factor concentrates. Caution should be exercised when interpreting these tests. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet medicinal products have been used. All symptomatic treatment should be given according to the physician’s judgement.

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

5. Pharmacological properties
   • Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors, Mechanism of action

Dabigatran Taj Pharma etexilate mesylate capsule etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After oral administration, Dabigatran Taj Pharma etexilate mesylate capsule etexilate is rapidly absorbed and converted to Dabigatran Taj Pharma etexilate mesylate capsule by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule after intravenous administration and of Dabigatran Taj Pharma etexilate mesylate capsule etexilate after oral administration in various animal models of thrombosis.

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

The calibrated quantitative diluted TT (dTT) test provides an estimation of Dabigatran Taj Pharma etexilate mesylate capsule plasma concentration that can be compared to the expected Dabigatran Taj Pharma etexilate mesylate capsule plasma concentrations. When the calibrated dTT assay delivers a Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of Dabigatran Taj Pharma etexilate mesylate capsule. 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 Taj Pharma etexilate mesylate capsule levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90^th percentile of Dabigatran Taj Pharma etexilate mesylate capsule trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see section 4.4, table 5) is considered to be associated with an increased risk of bleeding.

Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery

Steady state (after day 3) geometric mean Dabigatran Taj Pharma etexilate mesylate capsule peak plasma concentration, measured around 2 hours after 220mg Dabigatran Taj Pharma etexilate mesylate capsule etexilate administration, was 70.8 ng/mL, with a range of 35.2-162 ng/mL (25th–75th percentile range).The Dabigatran Taj Pharma etexilate mesylate capsule geometric mean trough concentration, measured at the end of the dosing interval (i.e. 24 hours after a 220mg Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule etexilate 150mg QD, the Dabigatran Taj Pharma etexilate mesylate capsule 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 220mg Dabigatran Taj Pharma etexilate mesylate capsule etexilate once daily,

• the 90^thpercentile of Dabigatran Taj Pharma etexilate mesylate capsule 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^thpercentile 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 220mg Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule peak plasma concentration, measured around 2 hours after 150mg Dabigatran Taj Pharma etexilate mesylate capsule etexilate administration twice daily, was 175 ng/mL, with a range of 117-275 ng/mL (25^th-75^th percentile range). The Dabigatran Taj Pharma etexilate mesylate capsule geometric mean trough concentration, measured at trough in the morning, at the end of the dosing interval (i.e. 12 hours after the 150mg Dabigatran Taj Pharma etexilate mesylate capsule evening dose), was on average 91.0 ng/mL, with a range of 61.0-143 ng/mL (25^th-75^th percentile range).

For patients with NVAF treated for prevention of stroke and systemic embolism with 150mg Dabigatran Taj Pharma etexilate mesylate capsule etexilate twice daily,

• the 90^thpercentile of Dabigatran Taj Pharma etexilate mesylate capsule 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 90^thpercentile 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 90^thpercentile 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 150mg Dabigatran Taj Pharma etexilate mesylate capsule etexilate twice daily, the Dabigatran Taj Pharma etexilate mesylate capsule geometric mean trough concentration, measured within 10−16 hours after dose, at the end of the dosing interval (i.e. 12 hours after the 150mg Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule etexilate 150mg twice daily,

• the 90th percentile of Dabigatran Taj Pharma etexilate mesylate capsule 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 150mg Dabigatran Taj Pharma etexilate mesylate capsule 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 Dabigatran Taj Pharma etexilate mesylate capsule 75mg or 75mg within 1-4 hours of surgery followed by 150mg or 220mg once daily thereafter, haemostasis having been secured, or enoxaparin 40mg 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 Dabigatran Taj Pharma etexilate mesylate capsule 220mg and 150mg 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 150mg dose was slightly worse than enoxaparin (table 17). Better results were seen with the 220mg 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 Taj Pharma etexilate mesylate capsule 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.

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.

Table 19: Major bleeding events by treatment in the individual RE-MODEL and the RE-NOVATE studies.

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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule etexilate (75mg and 150mg 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule etexilate, at a dose of 75mg 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 150mg 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 Taj Pharma etexilate mesylate capsule etexilate 75mg twice daily and 150mg 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 Taj Pharma etexilate mesylate capsule 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.

% refers to yearly event rate

Table 21: Analysis of first occurrence of ischemic or haemorrhagic strokes during the study period in RE-LY.

% refers to yearly event rate

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

% 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/systemic embolism by subgroups

For the primary safety endpoint of major bleeding there was an interaction of treatment effect and age. The relative risk of bleeding with Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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

RELY-ABLE (Long term multi-center extension of Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule etexilate was confirmed for both test doses 75mg b.i.d. and 150mg b.i.d.. No new safety findings were observed.

The rates of outcome events including, major bleed and other bleeding events were consistent with those seen in RE-LY.

Data from non-interventional studies

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

In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157-164] in more than 134,000 elderly patients with NVAF in the United States (contributing more than 37,500 patient-years of on-therapy follow-up time) Dabigatran Taj Pharma etexilate mesylate capsule etexilate (84 % patients treated with 150mg bid, 16 % patients treated with 75mg bid) was associated with a reduced risk of ischemic stroke (hazard ratio 0.80, 95 % confidence interval [CI] 0.67 – 0.96), intracranial haemorrhage (hazard ratio 0.34, CI 0.26 – 0.46), and mortality (hazard ratio 0.86, CI 0.77 – 0.96) and increased risk of gastrointestinal bleeding (hazard ratio 1.28, CI 1.14 – 1.44) compared to warfarin. No difference was found for major bleeding (hazard ratio 0.97, CI 0.88 – 1.07).

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

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 Taj Pharma etexilate mesylate capsule etexilate (75mg or 150mg bid) plus clopidogrel or ticagrelor (P2Y12 antagonist) vs. triple-therapy with warfarin (adjusted to a INR 2.0 – 3.0) plus clopidogrel or ticagrelor and aspirin was conducted in 2725 patients with non valvular atrial fibrillation who underwent a PCI with stenting (RE-DUAL PCI). Patients were randomized to Dabigatran Taj Pharma etexilate mesylate capsule etexilate 75mg bid dual-therapy, Dabigatran Taj Pharma etexilate mesylate capsule etexilate 150mg bid dual-therapy or warfarin triple-therapy. Elderly patients outside of the United States (≥80 years of age for all countries, ≥70 years of age for Japan) were randomly assigned to the Dabigatran Taj Pharma etexilate mesylate capsule etexilate 75mg dual-therapy group or the warfarin triple-therapy group. The primary endpoint was a combined endpoint of major bleeds based on ISTH definition or clinically relevant non-major bleeding event.

The incidence of the primary endpoint was 15.4 % (151 patients) in the Dabigatran Taj Pharma etexilate mesylate capsule etexilate 75mg dual-therapy group as compared with 26.9 % (264 patients) in the warfarin triple-therapy group (HR 0.52; 95% CI 0.42, 0.63; P<0.0001 for non-inferiority and P<0.0001 for superiority) and 20.2 % (154 patients) in the Dabigatran Taj Pharma etexilate mesylate capsule etexilate 150mg dual-therapy group as compared with 25.7 % (196 patients) in the corresponding warfarin triple-therapy group (HR 0.72; 95% CI 0.58, 0.88; P<0.0001 for non-inferiority and P=0.002 for superiority). As part of the descriptive analysis, TIMI (Thrombolysis In Myocardial Infarction) major bleeding events was lower in both Dabigatran Taj Pharma etexilate mesylate capsule etexilate dual-therapy groups than in the warfarin triple-therapy group: 14 events (1.4%) in the Dabigatran Taj Pharma etexilate mesylate capsule etexilate 75mg dual-therapy group as compared with 37 events (3.8%) in the warfarin triple-therapy group (HR 0.37; 95% CI 0.20, 0.68; P=0.002) and 16 events (2.1%) in the Dabigatran Taj Pharma etexilate mesylate capsule etexilate 150mg dual-therapy group as compared with 30 events (3.9%) in the corresponding warfarin triple-therapy group (HR 0.51; 95% CI 0.28, 0.93; P=0.03). Both Dabigatran Taj Pharma etexilate mesylate capsule etexilate dual-therapy groups had lower rates of intracranial hemorrhage than the corresponding warfarin triple-therapy group: 3 events (0.3%) in the 75mg Dabigatran Taj Pharma etexilate mesylate capsule etexilate dual-therapy group as compared with 10 events (1.0%) in the warfarin triple-therapy group (HR 0.30; 95% CI 0.08, 1.07; P=0.06) and 1 event (0.1%) in the 150mg Dabigatran Taj Pharma etexilate mesylate capsule etexilate dual-therapy group as compared with 8 events (1.0%) in the corresponding warfarin triple-therapy group (HR 0.12; 95% CI 0.02, 0.98; P=0.047). The incidence of the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, or systemic embolism) or unplanned revascularization in the two Dabigatran Taj Pharma etexilate mesylate capsule etexilate dual-therapy groups combined was non-inferior to the warfarin triple-therapy group (13.7% vs. 13.4% respectively; HR 1.04; 95% CI: 0.84, 1.29; P=0.0047 for non-inferiority).There were no statistical differences in the individual components of the efficacy endpoints between either Dabigatran Taj Pharma etexilate mesylate capsule etexilate dual-therapy groups and warfarin triple-therapy.

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

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

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

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

The duration of treatment with fixed dose of Dabigatran Taj Pharma etexilate mesylate capsule was 174.0 days without coagulation monitoring. For patients randomized to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) was 60.6 %.

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

Table 25: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of DVT and/or PE) until the end of post-treatment period for the pooled studies RE-COVER and RE-COVER II

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

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

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

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

Table 26: Analysis of the primary and secondary efficacy endpoints (VTE is a composite of DVT and/or PE) until the end of post-treatment period for the RE-MEDY study

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

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

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

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

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

A phase II study examined Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule etexilate than with warfarin. In the early post-operative patients, major bleeding manifested predominantly as haemorrhagic pericardial effusions, specifically in patients who started Dabigatran Taj Pharma etexilate mesylate capsule 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 Dabigatran Taj Pharma etexilate mesylate capsule in all subsets of the paediatric population for the granted indications (see section 4.2 for information on paediatric use).

The pharmacokinetics and pharmacodynamics of Dabigatran Taj Pharma etexilate mesylate capsule etexilate administered twice daily for three consecutive days (total 6 doses) at the end of standard anticoagulant therapy were assessed in an open-label safety and tolerability study in 9 stable adolescents (12 to < 18 years). All patients received an initial oral dose of 1.71 (± 10%)mg/kg of Dabigatran Taj Pharma etexilate mesylate capsule etexilate (80 % of the adult dose of 150mg/70 kg adjusted for the patient’s weight). Based on Dabigatran Taj Pharma etexilate mesylate capsule concentrations and clinical assessment, the dose was subsequently modified to a target dose of 2.14 (± 10 %)mg/kg of Dabigatran Taj Pharma etexilate mesylate capsule etexilate (100 % of the adult dose adjusted for the patient’s weight). In this small number of adolescents, Dabigatran Taj Pharma etexilate mesylate capsule etexilate capsules were apparently tolerated with only three mild and transient gastrointestinal adverse events reported by two patients. According to the relatively low exposure, coagulation at 72 hrs (presumed Dabigatran Taj Pharma etexilate mesylate capsule trough level at steady state or close to steady state conditions) was only slightly prolonged with aPTT at maximum 1.60 fold, ECT 1.86 fold, and Hemoclot^® TT (Anti-FIIa) 1.36 fold, respectively. Dabigatran Taj Pharma etexilate mesylate capsule plasma concentrations observed at 72 hrs were relatively low, between 32.9 ng/mL and 97.2 ng/mL at final doses between 100mg and 150mg (gMean dose normalized total Dabigatran Taj Pharma etexilate mesylate capsule plasma concentration of 0.493 ng/mL/mg).

• Pharmacokinetic properties

After oral administration, Dabigatran Taj Pharma etexilate mesylate capsule etexilate is rapidly and completely converted to Dabigatran Taj Pharma etexilate mesylate capsule, which is the active form in plasma. The cleavage of the prodrug Dabigatran Taj Pharma etexilate mesylate capsule etexilate by esterase-catalysed hydrolysis to the active principle Dabigatran Taj Pharma etexilate mesylate capsule is the predominant metabolic reaction. The absolute bioavailability of Dabigatran Taj Pharma etexilate mesylate capsule following oral administration of Dabigatran Taj Pharma etexilate mesylate capsule was approximately 6.5 %.

After oral administration of Dabigatran Taj Pharma etexilate mesylate capsule in healthy volunteers, the pharmacokinetic profile of Dabigatran Taj Pharma etexilate mesylate capsule in plasma is characterized by a rapid increase in plasma concentrations with C_max attained within 0.5 and 2.0 hours post administration.

Absorption

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

Food does not affect the bioavailability of Dabigatran Taj Pharma etexilate mesylate capsule etexilate but delays the time to peak plasma concentrations by 2 hours.

C_max 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 Taj Pharma etexilate mesylate capsule etexilate (see section 4.2).

Distribution

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

Biotransformation

Metabolism and excretion of Dabigatran Taj Pharma etexilate mesylate capsule were studied following a single intravenous dose of radiolabeled Dabigatran Taj Pharma etexilate mesylate capsule in healthy male subjects. After an intravenous dose, the Dabigatran Taj Pharma etexilate mesylate capsule-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 Taj Pharma etexilate mesylate capsule is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of total Dabigatran Taj Pharma etexilate mesylate capsule in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods. Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule after the oral administration of Dabigatran Taj Pharma etexilate mesylate capsule is approximately 2.7-fold higher in volunteers with moderate renal insufficiency (CrCL between 30 and 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 Taj Pharma etexilate mesylate capsule 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 28: Half-life of total Dabigatran Taj Pharma etexilate mesylate capsule in healthy subjects and subjects with impaired renal function.

Additionally, Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule etexilate 75mg 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 C_max compared to young subjects.

The effect by age on exposure to Dabigatran Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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 Taj Pharma etexilate mesylate capsule 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. In atrial fibrillation patients females had on average 30 % higher trough and post-dose concentrations. No dose adjustment is required (see section 4.2).

Ethnic origin

No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding Dabigatran Taj Pharma etexilate mesylate capsule 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).

• 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 Taj Pharma etexilate mesylate capsule.

An effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70mg/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 Taj Pharma etexilate mesylate capsule up to maximum doses of 200mg/kg.

Dabigatran Taj Pharma etexilate mesylate capsule, the active moiety of Dabigatran Taj Pharma etexilate mesylate capsule etexilate mesilate, is persistent in the environment.

6. Pharmaceutical particulars
   • List of excipients

Capsule content

Tartaric acid, Acacia, Hypromellose, Dimeticone 350, Talc, Hydroxypropylcellulose

Capsule shell

Carrageenan, Potassium chloride, Titanium dioxide, Indigo carmine, Hypromellose

Black printing ink

Shellac, Iron oxide black , Potassium hydroxide

• Incompatibilities

Not applicable.

• Shelf life

Blister and bottle

3 years

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

• 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

Each Cartons containing 30, 60, 90,120, 240, 360, 500 hard capsules in perforated aluminium unit dose blisters.

Each pack contains: 10, 15, 30, 50, 60 and 90 hard capsules.

Not all pack sizes may be marketed.

• Special precautions for disposal and other handling

When taking Dabigatran Taj Pharma etexilate mesylate capsule 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.

Manufactured by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Dabigatran Etexilate Mesylate Capsule 150mg Taj Pharma

Package leaflet: Information for the patient

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Dabigatran Taj Pharma etexilate mesylate capsule is and what it is used for
2. What you need to know before you take Dabigatran Taj Pharma etexilate mesylate capsule
3. How to take Dabigatran Taj Pharma etexilate mesylate capsule
4. Possible side effects
5. How to store Dabigatran Taj Pharma etexilate mesylate capsule
6. Contents of the pack and other information
7. What Dabigatran Taj Pharma etexilate mesylate capsule is and what it is used for

Dabigatran Taj Pharma etexilate mesylate capsule contains the active substance Dabigatran Taj Pharma etexilate and belongs to a group of medicines called anticoagulants. It works by blocking a substance in the body which is involved in blood clot formation.

Dabigatran Taj Pharma etexilate mesylate capsule is used in adults to:

• Prevent the formation of blood clots in the veins after knee or hip replacement surgery.
• Prevent blood clots in the brain (stroke) and other blood vessels in the body if you have a form of irregular heart rhythm called nonvalvular atrial fibrillation and at least one additional risk factor.
• Treat blood clots in the veins of your legs and lungs and to prevent blood clots from reoccurring in the vein of your legs and lungs.

2. What you need to know before you take Dabigatran Taj Pharma etexilate mesylate capsule

Do not take Dabigatran Taj Pharma etexilate mesylate capsule

• if you are allergic to Dabigatran Taj Pharma etexilate or any of the other ingredients of this medicine (listedin section 6).
• if you have severely reduced kidney function.
• if you are currently bleeding.
• if you have a disease in an organ of the body that increases the risk of serious bleeding (e.g. stomach ulcer, injury or bleeding in the brain, recent surgery of the brain or eyes).
• if you have an increased tendency to bleed. This may be inborn, of unknown cause or due to other medicines.
• if you are taking medicines to prevent blood clotting (e.g.warfarin, rivaroxaban, apixaban or heparin), except when changing anticoagulant treatment, while having a venous or arterial line
• and you get heparin through this line to keep it open or while your heart beat is being restored to normal by a procedure called catheter ablation for atrial fibrillation.
• if you have a severely reduced liver function or liver disease which could possibly cause death.
• if you are taking oral ketoconazole or itraconazole, medicines to treat fungal infections.
• if you are taking oral cyclosporine, a medicine to prevent organ rejection after transplantation.
• if you are taking dronedarone, a medicine used to treat abnormal heart beat.
• if you have received an artificial heart valve which requires permanent blood thinning.

Warnings and precautions

Talk to your doctor before taking Dabigatran Taj Pharma etexilate mesylate capsule. You may also need to talk to your doctor during treatment with Dabigatran Taj Pharma etexilate mesylate capsule if you experience symptoms or if you have to undergo surgery.

Tell your doctor if you have or have had any medical conditions or illnesses, in particular any of those included in the following list:

• if you have an increased bleeding risk, such as:
• if you have been recently bleeding.
• if you have had a surgical tissue removal (biopsy) in the past month.
• if you have had a serious injury (e.g. a bone fracture, head injury or any injury requiring surgical treatment).
• if you are suffering from an inflammation of the gullet or stomach.
• if you have problems with reflux of gastric juice into the gullet.
• if you are receiving medicines which could increase the risk of bleeding. See ‘Other medicines and Dabigatran Taj Pharma etexilate mesylate capsule’ below.
• if you are taking anti-inflammatory medicines such as diclofenac, ibuprofen,piroxicam.
• if you are suffering from an infection of the heart (bacterial endocarditis).
• if you know you have impaired kidney function, or you are suffering from dehydration
• (symptoms include feeling thirsty and passing reduced amounts of dark-coloured (concentrated) urine).
• if you are older than 75 years.
• if you weigh 50 kg or less.
• if you have had a heart attack or if you have been diagnosed with conditions that increase the risk to develop a heart attack.
• if you have a liver disease that is associated with changes in the blood tests. The use of Dabigatran Taj Pharma etexilate mesylate capsule is not recommended in this case.

Take special care with Dabigatran Taj Pharma etexilate mesylate capsule

• if you need to have an operation:

In this case Dabigatran Taj Pharma etexilate mesylate capsule will need to be stopped temporarily due to an increased bleeding risk during and shortly after an operation. It is very important to take Dabigatran Taj Pharma etexilate mesylate capsule before and after the operation exactly at the times you have been told by your doctor.

• if an operation involves a catheter or injection into your spinal column (e.g. for epidural or spinal anaesthesia or pain reduction):
• it is very important to take Dabigatran Taj Pharma etexilate mesylate capsule before and after the operation exactly at the times you have been told by your doctor.

Tell your doctor immediately if you get numbness or weakness of your legs or problems with your bowel or bladder after the end of anaesthesia, because urgent care is necessary.

• if you fall or injure yourself during treatment, especially if you hit your head. Please seek urgent medical attention. You may need to be checked by a doctor, as you may be at increased risk of bleeding.
• if you know that you have a disease called antiphospholipid syndrome (a disorder of the immune system that causes an increased risk of blood clots), tell your doctor who will decide if the treatment may need to be changed.

Children and adolescents

Dabigatran Taj Pharma etexilate mesylate capsule is not recommended in children and adolescents below 18 years old.

Other medicines and Dabigatran Taj Pharma etexilate mesylate capsule

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. In particular you should tell your doctor before taking Dabigatran Taj Pharma etexilate mesylate capsule, if you are taking one of the medicines listed below:

• Medicines to reduce blood clotting (e.g. warfarin, phenprocoumon, acenocoumarol, heparin,
• clopidogrel, prasugrel, ticagrelor, rivaroxaban, acetylsalicylic acid)
• Medicines to treat fungal infections (e.g. ketoconazole, itraconazole), unless they are only applied to the skin
• Medicines to treat abnormal heart beats (e.g. amiodarone, dronedarone, quinidine, verapamil).

If you are taking amiodarone, quinidine or verapamil containing medicines, your doctor may tell you to use a reduced dose of Dabigatran Taj Pharma etexilate mesylate capsule depending on the condition for which Dabigatran Taj Pharma etexilate mesylate capsule is prescribed to you. See section 3.

• Medicines to prevent organ rejection after transplantation (e.g. tacrolimus, cyclosporine)
• Anti-inflammatory and pain reliever medicines (e.g. acetylsalicylic acid, ibuprofen, diclofenac)
• John´s wort, a herbal medicine for depression
• Antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin-norepinephrine re-uptake inhibitors
• Rifampicin or clarithromycin (two antibiotics)
• Anti-viral medicines for AIDS (e.g. ritonavir)
• Certain medicines for treatment of epilepsy (e.g. carbamazepine, phenytoin)

Pregnancy and breast-feeding

The effects of Dabigatran Taj Pharma etexilate mesylate capsule on pregnancy and the unborn child are not known. You should not take Dabigatran Taj Pharma etexilate mesylate capsule if you are pregnant unless your doctor advises you that it is safe to do so. If you are a woman of child-bearing age, you should avoid becoming pregnant while you are taking Dabigatran Taj Pharma etexilate mesylate capsule.

You should not breast-feed while you are taking Dabigatran Taj Pharma etexilate mesylate capsule.

Driving and using machines

Dabigatran Taj Pharma etexilate mesylate capsule has no known effects on the ability to drive or use machines.

3. How to take Dabigatran Taj Pharma etexilate mesylate capsule

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Take Dabigatran Taj Pharma etexilate mesylate capsule as recommended for the following conditions:

Prevention of blood clot formation after knee or hip replacement surgery

The recommended dose is 220mg once a day (taken as 2 capsules of 75mg).

If your kidney function is decreased by more than half or if you are 75 years of age or older, the recommended dose is 150mg once a day (taken as 2 capsules of 75mg).

If you are taking amiodarone, quinidine or verapamil containing medicines the recommended dose is 150mg once a day (taken as 2 capsules of 75mg).

If you are taking verapamil containing medicines and your kidney function is decreased by more

than half, you should be treated with a reduced dose of 75mg Dabigatran Taj Pharma etexilate mesylate capsule because your bleeding risk may be increased.

For both surgery types, treatment should not be started if there is bleeding from the site of operation. If the treatment cannot be started until the day after surgery, dosing should be started with 2 capsules once a day.

After knee replacement surgery

You should start treatment with Dabigatran Taj Pharma etexilate mesylate capsule within 1-4 hours after surgery finishes, taking a single capsule. Thereafter two capsules once a day should be taken for a total of 10 days.

After hip replacement surgery

You should start treatment with Dabigatran Taj Pharma etexilate mesylate capsule within 1-4 hours after surgery finishes, taking a single capsule. Thereafter two capsules once a day should be taken for a total of 28-35 days.

Prevention of brain or body vessel obstruction by blood clot formation developing after abnormal heart beats and Treatment of blood clots in the veins of your legs and lungs including prevention of blood clots from re-occurring in the vein of your legs and lungs

The recommended dose is 300mg taken as one 150mg capsule twice a day.

If you are 80 years or older, the recommended dose of Dabigatran Taj Pharma etexilate mesylate capsule is 220mg taken as one 75mg capsuletwice a day.

If you are taking verapamil containing medicines, you should be treated with a reduced Dabigatran Taj Pharma etexilate mesylate capsule dose of 220mg taken as one 75mg capsuletwice a day, because your bleeding risk may be increased.

If you have a potentially higher risk for bleeding, your doctor may decide to prescribe a dose of

Dabigatran Taj Pharma etexilate mesylate capsule 220mg taken as one 75mg capsule twice a day.

You can continue to take Dabigatran Taj Pharma etexilate mesylate capsule if your heart beat needs to be restored to normal by a procedure called cardioversion. Take Dabigatran Taj Pharma etexilate mesylate capsule as your physician has told you.

If a medical device (stent) has been deployed in a blood vessel to keep it open in a procedure called percutaneous coronary intervention with stenting, you can be treated with Dabigatran Taj Pharma etexilate mesylate capsule after your physician has decided that normal control of blood coagulation is achieved. Take Dabigatran Taj Pharma etexilate mesylate capsule as your physician has told you.

How to take Dabigatran Taj Pharma etexilate mesylate capsule

Dabigatran Taj Pharma etexilate mesylate capsule can be taken with or without food. The capsule should be swallowed whole with a glass of water, to ensure delivery to the stomach. Do not break, chew, or empty the pellets from the capsule since this may increase the risk of bleeding.

Instructions for opening the blisters

The following pictogram illustrates how to take Dabigatran Taj Pharma etexilate mesylate capsule capsules out of the blister

Tear off one individual blister from the blister card along the perforated line

Peel off the backing foil and remove the capsule.

• Do not push the capsules through the blister foil.
• Do not peel off the blister foil until a capsuleis required.
• Instructions for the bottle
• Push and turn for opening.
• After removing the capsule, place the cap back on the bottle and tightly close the bottle right
• away after you take your dose.

Change of anticoagulant treatment

Without specific guidance from your doctor do not change your anticoagulant treatment.

If you take more Dabigatran Taj Pharma etexilate mesylate capsule than you should

Taking too much Dabigatran Taj Pharma etexilate mesylate capsule increases the risk of bleeding. Contact your doctor immediately if you have taken too many Dabigatran Taj Pharma etexilate mesylate capsule capsules. Specific treatment options are available.

If you forget to take Dabigatran Taj Pharma etexilate mesylate capsule

Prevention of blood clot formation after knee or hip replacement surgery

Continue with your remaining daily doses of Dabigatran Taj Pharma etexilate mesylate capsule at the same time of the next day.

Do not take a double dose to make up for a forgotten dose.

Prevention of brain or body vessel obstruction by blood clot formation developing after abnormal heart beats and treatment of blood clots in the veins of your legs and lungs including prevention of blood clots from re-occurring in the vein of your legs and lungs

A forgotten dose can still be taken up to 6 hours prior to the next due dose.

A missed dose should be omitted if the remaining time is below 6 hours prior to the next due dose.

Do not take a double dose to make up for a forgotten dose.

If you stop taking Dabigatran Taj Pharma etexilate mesylate capsule

Take Dabigatran Taj Pharma etexilate mesylate capsule exactly as prescribed. Do not stop taking Dabigatran Taj Pharma etexilate mesylate capsule without talking to your doctor first, because the risk of developing a blood clot could be higher if you stop treatment too early. Contact your doctor if you experience indigestion after taking Dabigatran Taj Pharma etexilate mesylate capsule.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Dabigatran Taj Pharma etexilate mesylate capsule affects blood clotting, so most side effects are related to signs such as bruising or bleeding.

Major or severe bleeding may occur, these constitute the most serious side effects and, regardless of location, may become disabling, life-threatening or even lead to death. In some cases these bleedings may not be obvious.

If you experience any bleeding event that does not stop by itself or if you experience signs of excessive bleeding (exceptional weakness, tiredness, paleness, dizziness, headache or unexplained swelling) consult your doctor immediately. Your doctor may decide to keep you under closer observation or change your medicine.

Tell your doctor immediately, if you experience a serious allergic reaction which causes difficulty in breathing or dizziness.

Possible side effects are listed below, grouped by how likely they are to happen.

Prevention of blood clot formation after knee or hip replacement surgery

Common (may affect up to 1 in 10 people):

• A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
• Unusual laboratory test results on liver function

Uncommon (may affect up to 1 in 100 people):

• Bleeding may happen from the nose, into the stomach or bowel, from penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), from piles, from the rectum, under the skin, into a joint, from or after an injury or after an operation
• Haematoma formation or bruising occurring after an operation
• Blood detected in the stools by a laboratory test
• A fall in the number of red cells in the blood
• A decrease in the proportion of red cells in the blood
• Allergic reaction
• Vomiting
• Frequent loose or liquid bowel movements
• Feeling sick
• Wound secretion (liquid exuding from the surgical wound)
• Liver enzymes increased
• Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Rare (may affect up to 1 in 1,000 people):

• Bleeding
• Bleeding may happen in the brain, from a surgical incision, from the site of entry of an injection or from the site of entry of a catheter into a vein
• Blood-stained discharge from the site of entry of a catheter into a vein
• Coughing of blood or blood stained sputum
• A fall in the number of platelets in the blood
• A fall in the number of red cells in the blood after an operation
• Serious allergic reaction which causes difficulty in breathing or dizziness
• Serious allergic reaction which causes swelling of the face or throat
• Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
• Sudden change of the skin which affects its colour and appearance
• Itching
• Ulcer in the stomach or bowel (incl. ulcer in the gullet)
• Inflammation of the gullet and stomach
• Reflux of gastric juice into the gullet
• Belly ache or stomach ache
• Indigestion
• Difficulty in swallowing
• Fluid exiting a wound
• Fluid exiting a wound after an operation

Not known (frequency cannot be estimated from the available data):

• Difficulty in breathing or wheezing

Prevention of brain or body vessel obstruction by blood clot formation developing after abnormal heart beats

Common (may affect up to 1 in 10 people):

• Bleeding may happen from the nose, into the stomach or bowel, from penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under the skin
• A fall in the number of red cells in the blood
• Belly ache or stomach ache
• Indigestion
• Frequent loose or liquid bowel movements
• Feeling sick

Uncommon (may affect up to 1 in 100 people):

• Bleeding
• Bleeding may happen from piles, from the rectum, or in the brain.
• Haematoma formation
• Coughing of blood or blood stained sputum
• A fall in the number of platelets in the blood
• A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
• Allergic reaction
• Sudden change of the skin which affects its colour and appearance
• Itching
• Ulcer in the stomach or bowel (incl. ulcer in the gullet)
• Inflammation of the gullet and stomach
• Reflux of gastric juice into the gullet
• Vomiting
• Difficulty in swallowing
• Unusual laboratory test results on liver function

Rare (may affect up to 1 in 1,000 people):

• Bleeding may happen into a joint, from a surgical incision, from an injury, from the site of entry of an injection or from the site of entry of a catheter into a vein
• Serious allergic reaction which causes difficulty in breathing or dizziness
• Serious allergic reaction which causes swelling of the face or throat
• Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
• A decrease in the proportion of red cells in the blood
• Liver enzymes increased
• Yellowing of the skin or whites of the eyes, caused by liver or blood problems

Not known (frequency cannot be estimated from the available data):

• Difficulty in breathing or wheezing

In a clinical trial the rate of heart attacks with Dabigatran Taj Pharma etexilate mesylate capsule was numerically higher than with warfarin. The overall occurence was low.

Treatment of blood clots in the veins of your legs and lungs including prevention of blood clots from re-occurring in the veins of your legs and/or lungs

Common (may affect up to 1 in 10 people):

• Bleeding may happen from the nose, into the stomach or bowel, from the rectum, from penis/vagina or urinary tract (incl. blood in the urine that stains the urine pink or red), or under the skin
• Indigestion

Uncommon (may affect up to 1 in 100 people):

• Bleeding
• Bleeding may happen into a joint or from an injury
• Bleeding may happen from piles
• A fall in the number of red cells in the blood
• Haematoma formation
• Coughing of blood or blood stained sputum
• Allergic reaction
• Sudden change of the skin which affects its colour and appearance
• Itching
• Ulcer in the stomach or bowel
• Inflammation of the gullet and stomach
• Reflux of gastric juice into the gullet
• Feeling sick
• Vomiting
• Belly ache or stomach ache
• Frequent loose or liquid bowel movements
• Unusual laboratory test results on liver function
• Liver enzymes increased

Rare (may affect up to 1 in 1,000 people):

• Bleeding may happen, from a surgical incision, or from the site of entry of an injection or from the site of entry of a catheter into a vein or from the brain
• A fall in the number of platelets in the blood
• Serious allergic reaction which causes difficulty in breathing or dizziness
• Serious allergic reaction which causes swelling of the face or throat
• Skin rash notable for dark red, raised, itchy bumps caused by an allergic reaction
• Difficulty in swallowing
• A decrease in the proportion of red cells in the blood

Not known (frequency cannot be estimated from the available data):

• Difficulty in breathing or wheezing
• A fall in the amount of haemoglobin in the blood (the substance in the red blood cells)
• A fall in the number of red cells in the blood
• Yellowing of the skin or whites of the eyes, caused by liver or blood problems

In the trial program the rate of heart attacks with Dabigatran Taj Pharma etexilate mesylate capsule was higher than with warfarin. The overall occurence was low. No imbalance in the rate of heart attacks was observed in patients treated with Dabigatran Taj Pharma versus patients treated with placebo.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. How to store Dabigatran Taj Pharma etexilate mesylate capsule

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, blister or bottle after

“EXP”. The expiry date refers to the last day of that month.

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

Bottle: Once opened, the medicine must be used within 4 months. Keep the bottle tightly closed.

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

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Dabigatran Taj Pharma etexilate mesylate capsule contains

• The active substance is Dabigatran Taj Pharma. Each hard capsule contains 75mg Dabigatran Taj Pharma etexilate (as mesilate).
• The other ingredients are tartaric acid, acacia, hypromellose, dimeticone 350, talc, and hydroxypropylcellulose.
• The capsuleshell contains carrageenan, potassium chloride, titanium dioxide, indigo carmine, and hypromellose.
• The black printing ink contains shellac, iron oxide black and potassium hydroxide.

What Dabigatran Taj Pharma etexilate mesylate capsule looks like and contents of the pack

Each Cartons containing 30, 60, 90,120, 240, 360, 500 hard capsules in perforated aluminium unit dose blisters.

Each pack contains: 10, 15, 30, 50, 60 and 90 hard capsules.

Not all pack sizes may be marketed.

Manufactured by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com