Clinical guide to managing patients treated with Pradaxa

Transcription

1 Clinical guide to managing patients treated with Pradaxa Updated August 2013 Treatment with Pradaxa (dabigatran etexilate) requires no routine laboratory monitoring. 1 Routine coagulation tests (aptt, PT/INR) do not accurately indicate the anticoagulant effect of Pradaxa. 1 Assess renal function in all patients before commencing treatment; carefully consider the appropriate dose in patients with mild to moderate renal impairment. 1 Two approved doses of Pradaxa for dose selection specific to patients needs. 1 3 The Hemoclot direct thrombin inhibitor assay determines dabigatran plasma concentration and is commercially available. This guide is designed to provide you with some important information about Pradaxa, including how to manage patients in cases of surgery, bleeding or overdose, and how to measure the anticoagulant effect of Pradaxa. Clinical evidence for Pradaxa 2,3 The Randomized Evaluation of Long-term anticoagulation therapy (RE-LY) trial compared Pradaxa with warfarin in 18,113 patients with non-valvular atrial fibrillation (AF) and at least one additional risk factor for stroke. Pradaxa 150 mg bd 2,3 Pradaxa 110 mg bd 2,3 35% reduced risk of stroke or systemic embolism vs. warfarin (p<0.001) Similar rate of major bleeding vs. warfarin (3.32% vs. 3.57%, p=0.31) 59% reduced risk of intracranial bleeding vs. warfarin (p<0.001) Significantly reduced risk of total bleeding (16.56% vs %, p=0.002) and life-threatening bleeding (1.49% vs. 1.85%, p=0.03) vs. warfarin Significantly increased risk of major gastrointestinal bleeding vs. warfarin (1.56% vs. 1.07%, p=0.001) Similar rate of stroke or systemic embolism vs. warfarin (p<0.001 for non-inferiority) Significantly reduced risk of major bleeding vs. warfarin (2.87% vs. 3.57%, p=0.03) 70% reduced risk of intracranial bleeding vs. warfarin (p<0.001) Significantly reduced risk of total bleeding (14.74% vs %, p<0.001) and life-threatening bleeding (1.24% vs. 1.85%, p<0.001) vs. warfarin Similar rate of major gastrointestinal bleeding vs. warfarin (1.15% vs. 1.07%, p=0.52) As with all anticoagulants, Pradaxa should be used with caution, especially in patients who have conditions associated with an increased risk of bleeding. 1 It is important to be informed and prepared when managing patients who are taking Pradaxa for stroke prevention in non-valvular atrial fibrillation.

2 Choosing the right dose of Pradaxa Pradaxa offers the flexibility of two proven doses for stroke prevention in non-valvular AF 150 mg bd and 110 mg bd allowing prescribers to tailor therapy to their patients needs. 1 3 Before starting treatment, calculate creatinine clearance (CrCl) to determine the appropriate dose of Pradaxa. 1 Pradaxa is contraindicated in patients with severe renal impairment (CrCl <30 ml/min). 1 To calculate CrCl using the Cockcroft-Gault equation, please visit the downloads section of or use the following equation: (140 age) x weight (kg) x F CrCl (ml/min) = x serum creatinine (μmol/l) F = 1.0 for males and 0.85 for females. Initiating and switching patients to Pradaxa Initiating Pradaxa (anticoagulant naïve) Commence treatment with first Pradaxa dose; no dose titration or bridging is required. 1 Onset of anticoagulant effect begins shortly after dosing, with peak plasma concentrations achieved within hours. 1,4 Simultaneous initiation of treatment with oral verapamil is contraindicated. 1 Switching from low molecular weight heparin (LMWH) to Pradaxa Pradaxa should be given 0 2 hours before the next scheduled dose of LMWH would be due. 1 Switching from continuous treatment with intravenous unfractionated heparin (IV UFH) to Pradaxa Pradaxa should be given at the time IV UFH is stopped. 1 Switching from warfarin to Pradaxa Stop warfarin and commence Pradaxa as soon as the patient s INR is <2. 1 Ensure patients do not continue warfarin in addition to Pradaxa; it is recommended that patients return their unused warfarin to their doctor or pharmacist for safe disposal. During treatment, kidney function should be assessed in: 1 Patients >75 years or those with moderate renal impairment (CrCl ml/min) at least once a year Clinical situations where a decline in kidney function is suspected, including low blood volume, dehydration and with certain co-medications

3 Pradaxa pharmacokinetics 1 Pradaxa is a direct thrombin inhibitor with a mean half-life of hours. It is eliminated unchanged primarily in the urine (85%). The rate of elimination by the kidney depends on the individual patient s kidney function: 85% is based on healthy volunteer studies (100 ml/min is normal). The half-life of Pradaxa is prolonged in cases of renal impairment. In addition, protein binding is low ( 35%). 1,5 Following oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran; C max is achieved hours post-administration. 1 There is a close correlation between plasma dabigatran concentration and degree of anticoagulant effect. 1 Coagulation tests and their interpretation Routine monitoring of the anticoagulant effect of Pradaxa is not required; however, testing may be required in specific circumstances, such as: surgery overdose bleeding. There is a close correlation between plasma dabigatran concentration and degree of anticoagulant effect. 1 Ecarin clotting time (ECT) ECT is: a specific assay for thrombin generation 7 a sensitive test that shows a direct linear relationship between dabigatran concentration and clotting time 1,7 not readily available in clinical practice. 1 Activated partial thromboplastin time (aptt) The assay targets the intrinsic pathway of the coagulation cascade. 7 Interpretation of coagulation assay results should consider time of Pradaxa administration relative to time of blood sampling. 1,6 Calibrated Hemoclot Thrombin Inhibitor assay There is a direct linear relationship between dabigatran concentration and clotting time. 7 The Hemoclot test can be used for the quantitative determination of dabigatran plasma levels and can be calibrated with dabigatran standards. 6 A result of >200 ng/ml hours after a dose of Pradaxa 150 mg bd is associated with a higher risk of bleeding. 8 Table 1 shows the expected plasma levels of Pradaxa after intake of approved doses. The Hemoclot test is available in Australia from Haematex (Tel: , aptt increases in a non-linear manner to dabigatran concentration and is less proportional at higher doses (>200 ng/ml). 1,7 A result >2.5 times the control is suggestive of excess anticoagulation. 1 In RE-LY, an aptt of > fold of normal range was associated with an increased risk of bleeding. 1 Thrombin time (TT) TT is a sensitive test that shows a direct linear relationship between dabigatran concentration and clotting time. 1,7 It directly assesses the activity of thrombin in a plasma sample. 7 An elevated TT provides useful information, but it alone does not predict the actual in vivo bleeding risk for an individual. The result depends on the coagulometer and the thrombin lot used for the measurement. 7 Routine coagulation tests (aptt, PT/INR) do not accurately indicate the anticoagulant effect of Pradaxa. 1 Table 1. Expected plasma levels of Pradaxa after dosing in patients with AF 8 Mean C max,ss (25 th 75 th percentile range) ~2 hours after dosing, ng/ml Mean C trough,ss (25 th 75 th percentile range) ~10 16 hours after dosing, ng/ml Pradaxa 150 mg bd 175 ( ) 91 (61 143) Pradaxa 110 mg bd 126 (85 200) 65 (43 102)

4 Perioperative management of Pradaxa Surgical interventions may require the temporary discontinuation of Pradaxa. Prior to invasive or surgical procedures 1 Pradaxa should be temporarily discontinued the timing of discontinuation is dependent on the patient s renal function (see Table 2). In patients at higher risk of bleeding or in major surgery where complete haemostasis may be required, consider stopping Pradaxa 2 4 days before surgery, depending on renal function. Clearance of Pradaxa in patients with renal insufficiency may take longer and should be considered in advance of any procedures. Pradaxa is contraindicated in patients with severe renal impairment (CrCl <30 ml/min), but should this occur Pradaxa should be stopped at least 5 days before major surgery. In cases of emergency surgery or intervention 1 Pradaxa should be temporarily discontinued. Surgery or intervention should be delayed until at least 12 hours after the last dose. If surgery cannot be delayed, there may be an increased risk of bleeding that should be weighed against the urgency of the intervention. After surgery, Pradaxa can be resumed when complete haemostasis is achieved. Do not restart Pradaxa in severe renal impairment (CrCl <30mL/min). Table 2. Discontinuing Pradaxa before invasive or surgical procedures 1 Renal function (CrCl in ml/min) Estimated half-life (hours) Stop Pradaxa 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) *For more details, refer to the Pradaxa Approved Product Information. Managing cases of overdose 1,7 In cases of poisoning or overdose, seek advice from the Poisons Information Centre, by phoning Overdose following administration of Pradaxa may lead to haemorrhagic complications due to its pharmacodynamic properties. 1 Dabigatran etexilate is a lipophilic molecule; therefore, adsorption by activated charcoal is expected. Preliminary in vitro data indicate that dabigatran etexilate can be successfully adsorbed by classical activated charcoal therapy. 7 It is advised that charcoal should be given within 1 2 hours of overdose before dabigatran etexilate is absorbed within the intestine. 7 Further removal of dabigatran from plasma via haemoperfusion over a charcoal filter is under evaluation although additional clinically relevant models are required before this can be recommended in patients. 7 In the event of haemorrhagic complications, refer to the following bleeding management section. Excessive anticoagulation requires the discontinuation of Pradaxa.

5 Managing cases of bleeding CARE guide to managing cases of bleeding with Pradaxa 6 * Cease Pradaxa delay next dose or discontinue as appropriate A ssess source of bleeding administer appropriate symptomatic treatment and maintain adequate diuresis Replace blood volume consider fresh whole blood or fresh frozen plasma, if required E mploy dialysis and/or consider coagulation factors only if required, in cases of severe or life-threatening bleeding * Note: The management of bleeding complications in patients receiving Pradaxa should be individualised according to the location and severity of the haemorrhage. See Figure below: Patient with bleeding on Pradaxa. 7 Bleeding can occur at any site during therapy and close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period. 1 An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. 1 In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. 1 Adequate diuresis must be maintained. 1 Appropriate standard treatment, such as surgical haemostasis as indicated, and blood volume replacement should be undertaken (consideration may be given to using fresh whole blood or fresh frozen plasma). 1 As protein binding is low, Pradaxa is dialysable; however, there is limited clinical experience in using dialysis in this setting. 1 Currently, there is no direct reversal agent available for Pradaxa, although one is in early stage of development. 9 The use of specific agents to reverse the anticoagulant effects of Pradaxa is based on a combination of pre-clinical data and anecdotal case reports. 7 Patient with bleeding on Pradaxa Mild bleeding Moderate to severe bleeding Life-threatening bleeding Delay next dose of Pradaxa or discontinue treatment as appropriate Symptomatic treatment Mechanical compression Surgical intervention Fluid replacement and haemodynamic support Blood product transfusion Oral charcoal application* (if Pradaxa ingestion <2 hours before) Haemodialysis Consideration of recombinant factor VIIa or PCC* Charcoal filtration* Adapted from van Ryn et al. Throm Haemost 2010; 103: *Recommendation is based only on limited non-clinical data; there is no experience in volunteers or patients.

6 PBS Information: Authority required (STREAMLINED AUTHORITY CODE 4269). Prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation and one or more risk factors for developing stroke or systemic embolism. Authority required. Prevention of venous thromboembolism in a patient undergoing total hip or knee replacement. Refer to PBS Schedule. Please review Product Information before prescribing. The Product Information can be accessed at PRADAXA (dabigatran etexilate) 110 mg and 150 mg capsules. MINIMUM PRODUCT INFORMATION. INDICATION: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke. CONTRAINDICATIONS: Known hypersensitivity to dabigatran, dabigatran etexilate or excipient (e.g. sunset yellow FCF CI15985); severe renal impairment (CrCL < 30mL/min); haemorrhagic manifestations, bleeding diathesis, spontaneous or pharmacological impairment of haemostasis; organ lesions at risk of clinically significant bleeding (including haemorrhagic stroke within the last 6 months, active peptic ulcer disease with recent bleeding); indwelling spinal or epidural catheter and during the first two hours after removal; hepatic impairment or liver disease expected to have any impact on survival; history of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding; gastrointestinal haemorrhage within the past year unless the cause has been permanently eliminated; conditions associated with increased risk of bleeding; concomitant treatment with systemic ketoconazole or dronedarone*; simultaneous initiation of treatment with dabigatran etexilate and oral verapamil; prosthetic heart valve replacement*. PRECAUTIONS: Haemorrhagic risk: moderate renal impairment (CrCL ml/min), congenital or acquired coagulation disorders, thrombocytopenia or functional platelet defects, active ulcerative gastrointestinal disease, recent gastrointestinal bleeding, recent biopsy or major trauma, brain, spinal or ophthalmic surgery, bacterial endocarditis, age 75 years, fibrinolytic agents*. Myocardial infarction. Concomitant administration with: acetylsalicylic acid, NSAIDs, clopidogrel, unfractionated heparins and heparin derivatives, low molecular weight heparins, fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, dextran, sulfinpyrazone, rivaroxaban, prasugrel, ticagrelor, vitamin K antagonists, selective serotonin re-uptake inhibitors, *selective serotonin norepinephrine re-uptake inhibitors, P-gp inhibitors: amiodarone, verapamil, itraconazole, tacrolimus, cyclosporin, ritonavir, tipranavir, nelfinavir, saquinavir, quinidine*, clarithromycin*, P-gp inducers. Surgical interventions may require temporary discontinuation and *anticoagulant monitoring is warranted; *clearance in patients with renal impairment may take longer. Not recommended in patients undergoing hip fracture surgery. Pregnancy (Category C). Lactation. Children. Patients < 50 kg. See full PI available at ADVERSE REACTIONS: Bleeding and signs of bleeding, dyspepsia, gastritis-like symptoms, diarrhoea, nausea, constipation, flatulence, dysphagia, nasopharyngitis, dyspnoea, cough, dyspnoea exertional, upper respiratory tract infection, bronchitis, pneumonia, influenza, sinusitis, urinary tract infection, dizziness, headache, syncope, atrial fibrillation, cardiac failure congestive, cardiac failure, palpitations, angina pectoris, hypertension, hypotension, rash, gout, arthralgia, back pain, pain in extremity, osteoarthritis, musculoskeletal pain, oedema peripheral, fatigue, asthenia, chest pain, chest discomfort, fall, abnormal liver function tests. Less common adverse reactions see full PI available at DOSAGE: Assess renal function *(Cockcroft-Gault method) prior to treatment initiation, in clinical situations that could lead to renal function decline and at least once a year in patients 75 years or with moderate renal impairment. Swallow capsule whole with water, with or without food. Recommended dose: 300 mg (one 150 mg capsule twice daily). Age 75 years: reduced dose of 220 mg (one 110 mg capsule twice daily). Moderate renal impairment, higher risk of bleeding: reduced dose of 220 mg (one 110 mg capsule twice daily) may be considered. Special populations see full PI available at *Please note changes in Product Information. References: 1. Pradaxa Approved Product Information, available at 2. Connolly SJ et al. N Engl J Med 2009; 361: Connolly SJ et al. N Engl J Med 2010; 363: Ezekowitz MD et al. Am Heart J 2009; 157: Blech S et al. Drug Metab Dispos 2008; 36: Hankey GJ and Eikelboom JW. Circulation 2011; 123: van Ryn J et al. Thromb Haemost 2010; 103: Data on file, Boehringer Ingelheim. 9. van Ryn J et al. JACC 2011; 57: E1130; poster number (abstract). Pradaxa is a registered trademark of Boehringer Ingelheim Pty Limited, ABN Waterloo Road, North Ryde NSW BIAPR0037. August 2013