Composition and excipients:

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

Excipients and its quantities used in the product:

Tartaric acid, Acacia, Hypromellose, Dimeticone 350, Talc, Hydroxy propyl cellulose

 Pharmacological Properties:

Dabigatran etexilate, a prodrug of the potent, competitive, reversible direct thrombin inhibitor dabigatran. Since thrombin enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

Pharmacokinetics:

After oral administration, dabigatran etexilate is cleaved by esterase-catalyzed hydrolysis to the active principle dabigatran, and this is the predominant metabolic reaction. In pharmacokinetic studies, the absolute bioavailability of dabigatran is approximately 6.5 %. C_max is attained within 0.5 and 2 hours post administration. When administered on the first day of surgery, peak plasma concentrations were delayed to 6 hours. Low concentrations (34-35 %) of dabigatran are bound to plasma proteins. After multiple doses, dabigatran showed a half-life of about 12-14 hours indepedant of dose in healthy subjects.  Dabigatran is eliminated primarily in the unchanged form in the urine (85 %). Fecal excretion accounts for 6 % of the administered dose.

Indications:

Dabigatran (75 mg – 110 mg) is indicated for primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

Dabigatran (110 mg – 150 mg) is indicated for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more of the following risk factors:

• Previous stroke or transient ischemic attack
• Heart failure, New York Heart Association (NYHA) Class ≥ 2
• Age ≥ 75 years
• Diabetes mellitus, hypertension.

Dabigatran (110 mg – 150 mg) is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Contraindications:

– Hypersensitivity to the active substance or to any of the excipients.

– 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 hemorrhage, known or suspected esophageal 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), heparin derivatives (fondaparinux), oral anticoagulants (warfarin, rivaroxaban) except under specific circumstances of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.

– Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and dronedarone.

– Hepatic impairment or liver disease expected to have any impact on survival.

– Prosthetic heart valves requiring anticoagulant treatment

Pregnancy and Breast-feeding:

Pregnancy Category C.

Women of child-bearing potential should avoid pregnancy during treatment with Dabigatran.

There are limited amount of data from the use of Dabigatran in pregnant women. Therefore, this product should not be used during pregnancy unless clearly necessary.

Nursing should be discontinued during treatment with Dabigatran, because there are no clinical data of the effect of Dabigatran on infants during breast-feeding.

Warnings and Precautions:

Hepatic impairment: The use of Dabigatran is not recommended in patients with elevated liver enzymes >2 times the upper normal limit because of the absence of treatment experience in these populations.

Bleeding risk: Bleeding can occur at any site during therapy with Dabigatran. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site.

It is recommended to closely monitor patients clinically for signs of bleeding or anemia throughout the treatment period, especially if the risk factors are combined.  Factors which may increase the bleeding risk:

1- Diseases or procedures associated with an increased risk of bleeding (such as congenital or acquired coagulation disorders, thrombocytopenia or functional platelet defects, recent biopsy or major trauma, bacterial endocarditis, esophagitis, gastritis and gastroesophageal reflux).

2- Factors increasing dabigatran plasma levels include: patients weighing less than 50 Kg, patients with moderate renal impairment (30-50 ml/min CrCl) and patients co-administering Dabigatran with P-gp inhibitors (like verapamil, quinidine and amiodarone).

3- The elderly ≥75 years

4- Pharmacological treatment with (Aspirin, NSAID, clopidogrel, selective serotonin re-uptake inhibitors (SSRIs), selective serotonin norepinephrine re-uptake inhibitors (SNRIs), or other drugs which may impair hemostasis).

In the presence of these factors, Dabigatran should only be given if the benefit outweighs bleeding risks.

Patients who develop acute renal failure during therapy must discontinue this medication.

Generally, dabigatran does not require routine anticoagulant monitoring, but the measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors. INR false positive elevations have been reported in patients on dabigatran and this test should not be performed. Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but are not standardised and results should be interpreted with caution. When severe bleedings occur, treatment must be discontinued and the source of bleeding investigated.

Fibrinolytic use: The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient presents with a diluted thrombin time (dTT), escarin clotting time (ECT) or an activated partial thromboplastin time (aPTT) not exceeding the ULN according to the reference range.

Pre/Postoperative phase: Surgical interventions may require the temporary discontinuation of dabigatran etexilate, and anticoagulant monitoring is warranted. Caution should be exercised when treatment is temporarily discontinued. The following table summarizes discontinuation rules before invasive or surgical procedures.

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

If an acute intervention is required, it should be delayed if possible until at least 12 hours after the last dose of Dabigatran. If surgery cannot be delayed the risk of bleeding may be increased and it should be weighed against the urgency of intervention.

Dabigatran should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate hemostasis 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.

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

Renal function: It should be assessed by calculating the CrCL prior to initiation of treatment with dabigatran to exclude patients with severe renal impairment and when a decline in renal function is suspected during treatment. While on treatment, renal function should be assessed at least once a year or more frequently as needed in certain clinical situations where renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications especially in patients with mild to moderate renal impairment and in patients aged > 75 years).

Myocardial Infarction: In trials, the following groups had a very high risk of myocardial infarction during therapy: patients with previous myocardial infarction, patients ≥65 years with either diabetes or coronary artery disease, patients with left ventricular ejection fraction <40%, patients with moderate renal dysfunction, and patients concomitantly taking aspirin plus clopidogrel or clopidogrel alone.

Active cancer: The efficacy and safety of this drug have not been established in DVT/PE patients with active cancer.

Drug Interactions:

In patients with atrial fibrillation it was observed that the concomitant use of other oral or parenteral anticoagulants, aspirin or clopidogrel increases major bleeding rates with both dabigatran and warfarin.

There is limited data on concomitant administration of Dabigatran with the following drugs and may increase the risk of bleeding: unfractionated heparin and heparin derivatives (fondaparinux, desirudin), low molecular weight heparins (LMWH), thrombolytic agents, GPIIb/IIIa receptor antagonists, prasugrel, ticlopidine, ticagrelor, dextran, sulfinpyrazone, rivaroxaban and vitamin K antagonists. Unfractionated heparin can only be administered at doses necessary to maintain a patent central venous or arterial catheter.

Concomitant use of aspirin, clopidogrel, non steroidal anti-inflammatory drug (NSAID), selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs) increases the risk of bleeding.Close observation for signs of bleeding is recommended.

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Co-administration of P-gp inhibitors is expected to increase dabigatran plasma concentrations. Concomitant administration with the strong inhibitors such as systemic ketoconazole, cyclosporine, itraconazole and dronedarone is contraindicated. Concomitant administration with tacrolimus is not recommended. Caution is advised with mild to moderate inhibitors such as amiodarone, verapamil, quinidine, ticagrelor, posaconazole and clarithromycin.

Concomitant administration of P-gp inducers (such as rifampicin, St. John’s wort, carbamazepine, or phenytoin) is expected to result in decreased dabigatran plasma concentrations, and should be avoided.

No significant interactions were observed between dabigatran and cytochrome P450 enzymes or when dabigatranetexilate was concomitantly administered with digoxin, pantoprazole or ranitidine.

Protease inhibitors including ritonavir and its combinations with other protease inhibitors affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with dabigatran.

Side Effects:

Frequency	Primary VTE prevention after hip or knee replacement surgery	Stroke and SEE prevention in patients with arterial fibrillation	DVT/PE treatment and DVT/PE prevention
Common	Decreased hemoglobin, hepatic function abnormal/Liver function test abnormal.	Anemia, epistaxis, gastrointestinal hemorrhage, abdominal pain, diarrhea, dyspepsia, nausea, skin hemorrahage, genitourological hemorrhage, hematuria.	Epistaxis, gastrointestinal hemorrhage, dyspepsia, rectal hemorrhage, skin hemorrhage, genitourological hemorrhage, hematuria.
Uncommon	Anemia, decreased hematocrite, drug hypersensitivity, hematoma,  wound hemorrhage, epistaxis, gastrointestinal hemorrhage, diarrhea, nausea, rectal hemorrhage, hemorrhoidal hemorrhage, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzymes increased, hyperbilirubinemia, skin hemorrahage, hemarthrosis, genitourological hemorrhage, hematuria, traumatic hemorrhage, post procedural hematoma/ hemorrhage, post procedural discharge, wound secretion.	Decreased hemoglobin, thrombocytopenia, drug hypersensitivity, rash, pruritus, intracranial hemorrhage, hematoma, hemorrhage, hemoptysis, rectal hemorrhage, hemorrhoidal hemorrhage, gastrointestinal ulcer, esophageal ulcer,  gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagia, hepatic function abnormal/Liver function test abnormal,  alanine aminotransferase increased, aspartate aminotransferase increased.	Anemia, drug hypersensitivity, rash, pruritus, hematoma, hemorrhage, hemoptysis, abdominal pain, diarrhea, nausea, hemorrhoidal hemorrhage, gastrointestinal ulcer, esophageal ulcer, gastroesophagitis, gastroesophageal reflux disease, vomiting, hepatic function abnormal/Liver function test abnormal,  alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzymes increased, hemarthrosis, traumatic hemorrhage.

Dosage and Administration:

Capsules should be swallowed whole with water, with or without food.

Patients should not break, chew, or empty the pellets from the capsule since this may increase the risk of bleeding.

1- Primary prevention of venous thromboembolism following elective knee or hip replacement surgery: The recommended dose is 220 mg once daily (2 capsules of 110 mg taken together). Treatment should be initiated orally within 1 – 4 hours of completed surgery with a single capsule on the first day, and continuing with 2 capsules once daily thereafter.

Treatment duration: Treatment should continue for a total of 10 days in patients who had elective knee replacement surgery, and for a total of 28-35 days in patients who had elective hip replacement surgery.

For both surgeries, if hemostasis 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.

The following groups should be treated with caution: Elderly patients (≥75 years) and patients with moderate renal impairment (CrCL 30-50 ml/min), or patients concomitantly receiving mild to moderate P-gp inhibitors (such as quinidine, amiodarone or verapamil) (taken with Dabigatran at the same time), and the treatment should be initiated orally within 1 – 4 hours of completed surgery with a single 75 mg capsule on the first day, and continuing with 150 mg taken once daily as 2 capsules of 75 mg together, and treatment should continue as previously explained. When concomitantly use, P-gp inhibitors and Dabigatran should be taken at the same time.

In patients with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Dabigatran to 75 mg daily should be considered.

Conversion of therapies:

Converting patients		Recommendations
from	to
Dabigatran	parenteral anticoagulant	Wait 24 hours after the last dose of Dabigatran
parenteral anticoagulant	Dabigatran	Discontinue parenteral anticoagulant and give Dabigatran 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))

* Pediatric population:There is no relevant use of Dabigatran in the pediatric population in the indication.

* If a dose is missed, the patient should continue with the remaining daily doses at the same time of the next day. Never double a dose to make up for a missed dose.

2- Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation with one or more risk factors; Treatment of DVT and PE and prevention of recurrent DVT and PE:

The recommended daily dose of Dabigatran is 300 mg taken as one 150 mg capsule twice daily. In cases of DVT and PE Dabigatran should be initiated following treatment with a parenteral anticoagulant for at least 5 days.

Treatment duration: Therapy should be continued long term in patients of stroke and systemic embolism with non-valvular atrial fibrillation. In cases of DVT and PE, the duration of therapy should be individualized after careful assessment of the treatment benefit against the risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (recent surgery, trauma, imobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.

In case of intolerability to Dabigatran, patients should immediately consult their doctor.

In patients at high risk of bleeding, a dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When bleeding occurs, treatment should be interrupted. This reduced daily dose is recommended for patients aged 80 years or above (because of increased risk of bleeding) or patients receiving concomitant verapamil (the two drugs should be taken at the same time).

For the following groups, a daily dose 300 mg or 220 mg should be selected based on an individualized assessment of the thromboembolic risk and the risk of bleeding:  Patients 75-80 years; patients with moderate renal impairment; patients with gastritis, esophagitis, or gastroesophageal reflux.

Elderly patients between 75-80 years: They should be treated with a daily dose of 300 mg taken as one 150 mg capsule twice daily. A dose of 220 mg taken as one 110 mg capsule twice daily can be individually considered, at the discretion of the physician,when the thromboembolic risk is low and the bleeding risk is high.

Patients with moderate renal impairment: The recommended dose is 300 mg taken as one 150 mg capsule twice daily. Patients with high risk of bleeding, a dose reduction to 220 mg taken as one 110 mg capsule twice daily should be considered. Renal impairment requires close surveillance.

Conversion of therapies:

Converting patients		Recommendations
from	to
Dabigatran	parenteral anticoagulant	Wait 12 hours after the last dose of Dabigatran
parenteral anticoagulant	Dabigatran	Discontinue parenteral anticoagulant and give Dabigatran 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))
Vitamin K Antagonists (VKA)	Dabigatran	VKA stopped and Dabigatran can be given as soon as INR is < 2.0
Dabigatran	Vitamin K Antagonists	CrCL ≥ 50 ml/min, VKA to be started 3 days before discontinuing Dabigatran CrCL ≥ 30-< 50 ml/min, VKA to be started 2 days before discontinuing Dabigatran

Patients can stay on Dabigatran while being cardioverted.

Pediatric population: There is no relevant use of Dabigatran in the pediatric population in prevention of stroke and systemic embolism in patients with NVAF.

The safety to use in DVT/PE in children from birth to less than 18 years of age has not yet been established.

A missed 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.

Overdosage:

High doses expose the patient to increased risk of bleeding. There is no antidote to dabigatran. In the event of hemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. Appropriate supportive treatment, such as surgical hemostasis and blood volume replacement should be considered.

Dabigatran can be dialyzed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies.

How Supplied: Each box of Pradatran  contains  10  capsules in Al/Al blisters ( 1 blisters in a box ) or 30 capsules in Al/Al blisters ( 3 blisters in a box)  . Each blister contains 10capsules.

Storage Conditions: Store below 30°C, protect from moisture.