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  • Pradaxa
    / Boehringer Ingelheim


    Active Ingredient
    Dabigatran Etexilate 75, 110, 150 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Hard Capsules

    10 X 75 mg

    partial basket chart 16927

    Hard Capsules

    30 X 75 mg

    partial basket chart 84205 16928

    Hard Capsules

    10 X 110 mg

    partial basket chart 84207 16929

    Hard Capsules

    30 X 110 mg

    partial basket chart 84208 16930

    Hard Capsules

    60 X 110 mg

    partial basket chart 84209 16931

    Hard Capsules

    60 X 150 mg

    partial basket chart 26096 16932

    Dosage

    75 mg:
    Primary prevention of Venous Thromboembolism in Orthopaedic Surgery:
    The recommended dose of Pradaxa and the duration of therapy for primary prevention of venous thromboembolism in orthopaedic surgery are shown in table 1 at the attached doctor’s leaflet.
    110 mg:
    Primary prevention of Venous Thromboembolism in Orthopaedic Surgery (pVTEp orthopaedic surgery):
    Patients following elective knee replacement surgery: The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg.
    Treatment should be initiated orally within 1-4 hours of completed surgery with a single capsule of 110 mg and continuing with 2 capsules once daily thereafter for a total of 10 days.
    Patients following elective hip replacement surgery: The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg.
    Treatment should be initiated orally within 1-4 hours of completed surgery with a single capsule of 110 mg and continuing with 2 capsules once daily thereafter for a total of 28-35 days.
    For the following groups the recommended daily dose of Pradaxa is 150 mg taken once daily as 2 capsules of 75 mg.
    Treatment should be initiated orally within 1-4 hours of completed surgery with a single capsule of 75 mg and continuing with 2 capsules once daily thereafter for a total of 10 days (knee replacement surgery) or 28-35 days (hip replacement surgery):
    – Patients with moderate renal impairment (creatinine clearance (CrCL) 30-50 mL/min).
    – Patients who receive concomitant verapamil, amiodarone, quinidine.
    – Patients aged 75 or above.
    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.
    Prevention of stroke and SEE in adult patients with NVAF (SPAF): The recommended daily dose of Pradaxa is 300 mg taken as one 150 mg capsule twice daily. Therapy should be continued long term.
    Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE): The recommended daily dose of Pradaxa is 300 mg taken as one 150 mg capsule twice daily following treatment with a parenteral anticoagulant for at least 5 days. The duration of therapy should be individualised 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 (e.g. recent surgery, trauma, imobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.
    150 mg:
    Prevention of stroke and SEE in adult patients with NVAF (SPAF): 
    The recommended daily dose of Pradaxa is 300 mg taken as one 150 mg capsule twice daily. Therapy should be continued long term.
    Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE): The recommended daily dose of Pradaxa is 300 mg taken as one 150 mg capsule twice daily following treatment with a parenteral anticoagulant for at least 5 days. The duration of therapy should be individualised 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 (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.
    SPAF, DVT/PE: For the following groups the recommended daily dose of Pradaxa is 220 mg taken as one 110 mg capsule twice daily:
    – Patients aged 80 years or above
    – Patients who receive concomitant verapamil
    For the following groups the daily dose of Pradaxa of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding:
    – Patients between 75-80 years
    – Patients with moderate renal impairment
    – Patients with gastritis, esophagitis or gastroesophageal reflux
    – Other patients at increased risk of bleeding
    For DVT/PE the recommendation for the use of Pradaxa 220 mg taken as one 110 mg capsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in this clinical setting.
    See prescribing information for full details.


    Indications

    Pradaxa 75 mg: Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
    Pradaxa 110 mg: 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).
    Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
    Pradaxa 150 mg: Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF).
    Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.


    Contra-Indications

    – Hypersensitivity to the active substance or to any of the excipients.
    – 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 vascul 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, 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.
    – 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.
    – Prosthetic heart valves requiring anticoagulant treatment.


    Special Precautions

    Increased risk of stroke with discontinuation of Dabigatran: Discontinuing Dabigatran in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If Dabigatran must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.
    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 is not recommended in this population.
    Haemorrhagic risk: Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding and in situations with concomitant use of drugs affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy with dabigatran etexilate. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. Factors, such as decreased renal function (30-50 mL/min CrCL), age ≥ 75 years, low body weight < 50 kg, or mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, quinidine or verapamil) are associated with increased dabigatran plasma levels. The concomitant use of ticagrelor increases the exposure to dabigatran and may show pharmacodynamic interaction, which may result in an increased risk of bleeding. In a study of prevention of stroke and see in adult patients with NVAF, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding which was statistically significant for dabigatran etexilate 150 mg twice daily. This increased risk was seen in the elderly (≥ 75 years). Use of acetylsalicylic acid (ASA), clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux increase the risk of GI bleeding. In these atrial fibrillationpatients a dosage of 220 mg dabigatran given as 110 mg capsule twice daily should be considered. The administration of a PPI can be considered to prevent GI bleeding. Bleeding risk may be increased in patients concomitantly treated with selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs). Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined.  Factors which may increase the haemorrhagic risk – see prescribing information for full details.  Patients who develop acute renal failure must discontinue Dabigatran. Limited data is available in patients < 50 kg. When severe bleedings occur treatment must be discontinued and the source of bleeding investigated. Medicinal products that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Dabigatran. Use of fibrinolytic medicinal products for the treatment of acute ischemic strokeץ 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 ULN according to the local reference range.
    Interaction with P-gp inducers: Concomitant administration of P-gp inducers (such as rifampicin, St. John`s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran plasma concentrations, and should be avoided.
    Surgery and interventions: Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of dabigatran etexilate. Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer. This should be considered in advance of any procedures. In such cases a coagulation test may help to determine whether haemostasis is still impaired.
    Preoperative phase: discontinuation rules before invasive or surgical procedures – see prescribing information for full details. If an acute intervention is required, dabigatran etexilate 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.
    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 etexilate. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.
    Postoperative phase: Dabigatran etexilate should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 mL/min), should be treated with caution.
    Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events: There are limited efficacy and safety data for dabigatran available in these patients and therefore they should be treated with caution.
    Hip fracture surgery: There is no data on the use of Dabigatran in patients undergoing hip fracture surgery. Therefore treatment is not recommended.
    Myocardial Infarction (SPAF): 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.
    Myocardial Infarction (DVT/PE): In the RE-SONATE study, which compared dabigatran etexilate to placebo, the rate of MI was 0.1% for patients who received dabigatran 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.
    Colorants: Dabigatran hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions
    See prescribing information for full details.  


    Side Effects

    75 mg: In actively controlled VTE prevention trials 6,684 patients were treated with 150 mg or 220 mg Pradaxa daily.
    The most commonly reported events are bleedings occurring in approximately 14% of patients; the frequency of major bleeds (including wound site bleedings) is less than 2%.
    Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
    110 mg and 150 mg: The most commonly reported adverse reactions are bleedings occurring in total 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 SEE, and in 14,4% of patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4% of patients in the DVT/PE prevention trial RE-MEDY and in 10,5% of patient in the DVT/PE prevention trial RE-SONATE.
    See prescribing information for full details.


    Drug 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: 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 , and plateletet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone.
    UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter or during catheter ablation for atrial fibrillation.
    P-gp inhibitors: Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole, dronedarone, clarithromycin and ticagrelor) is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure. The following strong P-gp inhibitors are contraindicated: systemic ketoconazole, cyclosporine, itraconazole and dronedarone. Concomitant treatment with tacrolimus is not recommended. Caution should be exercised with mild to moderate P-gp inhibitors (e.g. amiodarone, posaconazole, quinidine, verapamil and ticagrelor).
    P-gp inducers: Concomitant administration of a P-gp inducer (such as rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be avoided.
    Other medicinal products affecting P-gp: 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.
    P-gp substrate: Digoxin: In a study performed with 24 healthy subjects, when Dabigatran was co-administered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.
    Co-medication with selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs): SSRIs and SNRIs increased the risk of bleeding in RE-LY in all treatment groups.
    Gastric pH: Pantoprazole: When Dabigatran was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Dabigatran in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Dabigatran. Ranitidine: Ranitidine administration together with Dabigatran had no clinically relevant effect on the extent of absorption of dabigatran.
    See prescribing information for full details.              


    Pregnancy and Lactation

    Pregnancy: There is limited amount of data from the use of Pradaxa in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Pradaxa should not be used during pregnancy unless clearly necessary.
    Lactation: There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breast-feeding should be discontinued during treatment with Pradaxa.


    Overdose

    Pradaxa doses beyond those recommended, expose the patient to increased risk of bleeding.
    In case of an overdose suspicion, coagulation tests can help to determine a bleeding risk. A calibrated quantitative dTT test or repetitive dTT measurements allow prediction of the time by when certain dabigatran levels will be reached, also in case additional measures e.g. dialysis have been initiated.
    Excessive anticoagulation may require interruption of Pradaxa treatment. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. As protein binding is low, dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies.
    Management of bleeding complications: In the event of haemorrhagic complications, Pradaxa treatment must be discontinued and the source of bleeding investigated. Depending on the clinical situation appropriate supportive treatment, such as surgical haemostasis and blood volume replacement, should be undertaken at the prescriber’s discretion.
    For situations when rapid reversal of the anticoagulant effect of Pradaxa is required the specific reversal agent (Praxbind, idarucizumab) antagonizing the pharmacodynamic effect of Pradaxa is
    available.
    Coagulation factor concentrates (activated or non-activated) or recombinant Factor VIIa may be taken into account. There is some experimental evidence to support the role of these medicinal products in reversing the anticoagulant effect of dabigatran, but data on their usefulness in clinical settings and also on the possible risk of rebound thromboembolism is very limited. Coagulation tests
    may become unreliable following administration of suggested coagulation factor concentrates.
    Caution should be exercised when interpreting these tests. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet medicinal products have been used. All symptomatic treatment should be given according to the physician’s judgement.
    Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.


    Manufacturer
    Boehringer Ingelheim GmbH
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