Pradaxa

Pradaxa Thận trọng

dabigatran

Nhà sản xuất:

Boehringer Ingelheim
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Special Precautions
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 Pradaxa is not recommended in this population.
Haemorrhagic risk: As with all anticoagulants, PRADAXA 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 PRADAXA. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site.
For situation of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effects of dabigatran is required, the specific reversal agent (PRAXBIND, idarucizumab) is available (see Overdosage, Surgery and Interventions, and Pre-operative Phase as follows).
PRADAXA treatment does not require routine anticoagulant monitoring.
However, the measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.
The INR test is unreliable in patients on PRADAXA and false positive INR elevations have been reported. Therefore INR tests should not be performed.
Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but the tests are not standardised, and results should be interpreted with caution (see Pharmacology under Actions).
Table 11 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see Pharmacology under Actions). (See Table 11.)


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Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): In atrial fibrillation patients in RE-LY treated with 150 mg bid an aPTT of greater than 2.0-3.0 fold of normal range at trough was associated with an increased risk of bleeding.
Pharmacokinetic studies demonstrated an increase in drug exposure in patients with reduced renal function including age-related decline of renal function. PRADAXA is contraindicated in cases of severe renal impairment (CrCL <30 mL/min).
Patients who develop acute renal failure should discontinue PRADAXA.
Limited data is available in patients <50 kg (see Pharmacology: Pharmacokinetics under Actions).
When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see Overdosage).
Medicinal products that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Pradaxa (see Interactions).
Factors, such as decreased renal function (CrCL 30-50 mL/min), age ≥75 years, low body weight <50 kg, or mild to moderate P-gp-inhibitor comedication (e.g. amiodarone, quinidine or verapamil) are associated with increased dabigatran plasma levels. The presence of one or more than one of these factors may increase the risk of bleeding (see Dosage & Administration).
The concomitant use of PRADAXA with the following treatments has not been studied and may increase the risk of bleeding: unfractionated heparins (except at doses necessary to maintain patency of central venous or arterial catheter) and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, dextran, sulfinpyrazone, rivaroxaban, prasugrel, vitamin K antagonists, and the P-gp inhibitors, itraconazole, tacrolimus, cyclosporine, ritonavir, tipranavir, nelfinavir and saquinavir.
The concomitant use of dronedarone increases exposure of dabigatran and is not recommended (see Pharmacology: Pharmacokinetics under Actions).
The concomitant use of ticagrelor increases the exposure to dabigatran and may show pharmacodynamic interaction, which may result in an increased risk of bleeding.
Bleeding risk may be increased in patients concomitantly treated with selective serotonin re-uptake inhibitors (SSRI) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs).
Table 12 summarises factors which may increase the haemorrhagic risk. Please also refer to Contraindications. (See Table 12.)


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The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see Interactions), which significantly increase the risk of major bleeding requires a careful benefit risk assessment. Pradaxa should only be given if the benefit outweighs bleeding risks.
Use of fibrinolytic agents for the treatment of acute ischemic stroke: The use of fibrinolytic agents for the treatment of acute ischemic stroke may be considered if the patient presents with a thrombin time (TT), or Ecarin clotting time (ECT), or activated partial thromboplastin time (aPTT) not exceeding the upper limit of normal (ULN) according to the local reference range.
In situations where there is an increased haemorrhagic risk (e.g. recent biopsy or major trauma, bacterial endocarditis) close observation (looking for signs of bleeding or anaemia) is generally required.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with PRADAXA. There is limited evidence regarding the use of regular NSAID medication with half-lives of less than 12 hours during treatment with PRADAXA and this has not suggested additional bleeding risk.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): 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 fibrillation patients a dosage of 220 mg dabigatran given as 110 mg capsule twice daily should be considered and posology recommendations in Dosage & Administration be followed. The administration of a PPI can be considered to prevent GI bleeding.
Interaction with P-gp inducers: The concomitant use of PRADAXA with the strong P-gp inducer rifampicin reduces dabigatran plasma concentrations. Other P-gp inducers such as St. John's Wort (Hypericum perforatum) or carbamazepine, or phenytoin are also expected to reduce dabigatran plasma concentrations, and should be co-administered with caution (see Pharmacology: Pharmacokinetics under Actions and Interactions).
Surgery and Interventions: Patients on PRADAXA who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of PRADAXA (see also Pharmacology: Pharmacokinetics under Actions).
In case of emergency surgery or urgent procedures when rapid reversal of the anticoagulation effect is required the specific reversal agent (PRAXBIND, idarucizumab) to PRADAXA is available.
Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease.
PRADAXA treatment can be re-initiated 24 hours after administration of PRAXBIND (idarucizumab), if the patient is clinically stable and adequate hemostasis has been achieved.
Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see Pharmacology: Pharmacokinetics under Actions).
This should be considered in advance of any procedures. In such cases a coagulation test (see Pharmacology: Pharmacokinetics under Actions and Precautions) may help to determine whether haemostasis is still impaired.
Preoperative Phase: Due to an increased risk of bleeding PRADAXA may be stopped temporarily in advance of invasive or surgical procedures.
Emergency Surgery or Urgent Procedure: Dabigatran etexilate should be temporarily discontinued.
The specific reversal agent (PRAXBIND, idarucizumab) of PRADAXA is available for the rapid reversal of the anticoagulation effect (see Surgery and Interventions on previous text).
Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Pradaxa treatment can be re-initiated 24 hours after administration of Praxbind (idarucizumab), if the patient is clinically stable and adequate haemostasis has been achieved.
Subacute Surgery/Intervention: PRADAXA should be temporarily discontinued. An acute surgery/intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed there may be an increase in the risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention (for cardioversion see Dosage & Administration).
Elective Surgery/Intervention: If possible, PRADAXA should be discontinued at least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding or in major surgery where complete hemostasis may be required consider stopping PRADAXA 2-4 days before surgery. Clearance of dabigatran in patients with renal insufficiency may take longer. This should be considered in advance of any procedures (see Table 13 and also Pharmacology: Pharmacokinetics under Actions).


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PRADAXA is contraindicated in patients with severe renal dysfunction (CrCL <30 mL/min) but should this occur then PRADAXA should be stopped at least 5 days before major surgery (for cardioversion see Dosage & Administration).
Spinal Anesthesia/Epidural Anesthesia/Lumbar Puncture: Procedures such as spinal anesthesia may require complete hemostatic function.
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 1 hour should elapse before the administration of the first dose of PRADAXA. These patients require frequent observation for neurological signs and symptoms of spinal or epidural hematoma.
Postoperative phase: Resume treatment after complete haemostasis is achieved.
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 (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Patients with bioprosthetic valves: The use of dabigatran etexilate has not been evaluated in patients with bioprosthetic valves and use cannot be recommended for such patients.
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 Pradaxa in patients undergoing hip fracture surgery.
Therefore treatment is not recommended.
Myocardial Infarction: Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): In the phase III study RE-LY (see Pharmacology under Actions) the overall rate of myocardial infarction (MI) was 0.82, 0.81, and 0.64%/year for dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase in relative risk for dabigatran 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.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: In the three active controlled studies, a higher rate of MI was reported in patients who received dabigatran 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 etexilate to placebo, the rate of MI was 0.1% for patients who received dabigatran etexilate and 0.2% for patients who received placebo.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: In the three active controlled studies, a higher rate of MI was reported in patients who received dabigatran 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 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: Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: The efficacy and safety have not been established for DVT/PE patients with active cancer.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: The efficacy and safety have not been established for DVT/PE patients with active cancer.
Colorants: Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
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