Practical guide to Pradaxa in NVAF

Practical guide to Pradaxa in NVAF Pradaxa (dabigatran etexilate) is indicated for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and at least one additional risk factor for stroke. 1 NVAF occurs in the absence of a prosthetic valve or haemodynamically relevant valve disease requiring surgical intervention. Pradaxa is contraindicated in patients with a prosthetic heart valve replacement. 1 Dosing guide Pradaxa 110 mg bd may be considered for patients <75 years with: 1 a potentially higher risk of major bleeding or moderate renal impairment (CrCl 30 50 ml/min) Pradaxa is contraindicated in patients with severe renal impairment (CrCl <30 ml/min). 1 Estimating equations such as egfr are less accurate in people with extremes of body size or muscle mass. Calculation of CrCl using the Cockcroft-Gault formula is recommended. 1 Cockcroft-Gault formula: (140 age) x weight (kg) x F CrCl (ml/min) = 0.8136 x serum creatinine (μmol/l) Pradaxa nline F = 1.0 for males and 0.85 for females. Scan the QR code or visit www.tiny.cc/creatininecalc for an online creatinine clearance calculator

Initiating and switching patients to Pradaxa Initiating Pradaxa (anticoagulant naïve) Commence treatment with first Pradaxa dose; no dose titration or bridging is required 1 Switching from warfarin to Pradaxa Stop warfarin First Pradaxa dose as soon as INR <2 1 Switching from rivaroxaban or apixaban to Pradaxa Last dose of previous anticoagulant Pradaxa can be initiated when the next dose of anticoagulant is due 2 In patients with impaired renal function or those taking a reduced dose of rivaroxaban or apixaban, a longer time interval between cessation and initiating Pradaxa may be needed. 2 Please refer to the dosing section or the Approved Product Information for information on dose selection with Pradaxa. 1 Switching from low molecular weight heparin (LMWH) to Pradaxa 0 2 hours before next dose of LMWH 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 Stop IV UFH Pradaxa should be given at the time IV UFH is stopped 1

Monitoring treatment with Pradaxa Routine coagulation monitoring is not required for patients taking Pradaxa due to predictable pharmacokinetics and pharmacodynamics. 1 Coagulation testing may be considered in the following situations: 1 Peri-procedural setting Suspected overdose Emergency situations Interpretation of coagulation assay results should consider time of Pradaxa administration relative to time of blood sampling. 1,3 Table 1. Coagulation tests and their interpretation Quantitative Sensitive assay that can be used to measure the pharmacodynamic effects of Pradaxa Diluted thrombin time (dtt; Hemoclot Thrombin Inhibitor assay) 1,4,5 Direct linear relationship with Pradaxa concentration Interpreting results: trough dtt >200 ng/ml associated with a higher risk of bleeding 6 The Hemoclot test is available from Haematex (Tel: 02 9482 2288, http://haematex.com) Semi-quantitative May show false prolonged measures in first 2 3 days after surgery Activated partial thromboplastin time (aptt) 1 Non-linear relationship to Pradaxa concentration Interpreting results: aptt >2.0 3.0-fold greater than normal range at trough associated with increased bleeding risk Direct linear relationship with Pradaxa concentration Thrombin time (TT) 1,4 Very sensitive, but not suitable for measuring high Pradaxa concentrations as the maximum measurement time of the coagulometer may be exceeded Prone to inter-laboratory variability INR testing is not recommended for monitoring anticoagulant activity of Pradaxa.

Interrupting therapy Surgical interventions or invasive procedures that carry a bleeding risk may require the temporary discontinuation of Pradaxa. Table 2 classifies interventions according to bleeding risk. Prior to elective invasive or surgical procedures 1 Pradaxa should be temporarily discontinued the timing of discontinuation is dependent on the patient s renal function (see Table 3). Table 2. Classification of elective surgical intervention according to bleeding risk 2 Interventions not necessarily requiring discontinuation of anticoagulation Dental interventions Extraction of 1 to 3 teeth Paradontal surgery Incision of abscess Implant positioning Ophthalmology Cataract or glaucoma intervention Endoscopy without surgery Superficial surgery (e.g. abscess incision, small dermatologic excisions, etc.) Interventions with low bleeding risk Endoscopy with biopsy Prostate or bladder biopsy Electrophysiological study or radiofrequency catheter ablation for supraventricular tachycardia (including left-sided ablation via single transseptal puncture) Angiography Pacemaker or ICD implantation (unless complex anatomical setting, e.g. congenital heart disease) Interventions with high bleeding risk Complex left-sided ablation (pulmonary vein isolation; VT ablation) Spinal or epidural anaesthesia; lumbar diagnostic puncture Thoracic surgery Abdominal surgery Major orthopaedic surgery Liver biopsy Transurethral prostate resection Kidney biopsy For each patient, individual factors relating to bleeding and thromboembolic risk need to be taken into account, and be discussed with the intervening physician. Adapted from Heidbuchel H et al. 2013. 2 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. Treatment can be resumed after complete haemostasis is achieved. 1

Table 3. 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. 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. 1 Managing cases of bleeding "[Pradaxa] offers an alternative to warfarin with similar or superior efficacy, carrying similar or lower risk for major bleeding events (especially intracranial hemorrhage), that can be managed satisfactorily with simple measures (drug discontinuation, transfusion of red cell concentrates) with a trend to lower mortality after such bleeding events compared to warfarin." 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 Adequate diuresis must be maintained. 1 In the RE-LY trial, the overall resources required to manage bleeding with Pradaxa were not greater than with warfarin. 8 Check haemodynamic status, basic coagulation tests (aptt) to assess anticoagulation effect Mild bleeding Delay next dose of Pradaxa or discontinue treatment as appropriate Moderate to severe bleeding Symptomatic treatment Mechanical compression Surgical intervention Fluid replacement and haemodynamic support Blood product transfusion Oral charcoal application* (if Pradaxa ingestion <2 hours before) Haemodialysis Life-threatening bleeding Consideration of recombinant factor VIIa or PCC* Charcoal filtration* *Recommendation is based only on limited non-clinical data; there is no experience in volunteers or patients. Adapted from van Ryn et al. 2010. 4

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 www.boehringer-ingelheim.com.au/pi 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 30-50 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 www.boehringer-ingelheim.com.au/pi. 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 www.boehringer-ingelheim.com.au/pi. 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 www.boehringer-ingelheim.com.au/pi. *Please note changes in Product Information. References: 1. Pradaxa Approved Product Information, available at www.boehringer-ingelheim.com.au/pi. 2. Heidbuchel H et al. Europace 2013;15:625 51. 3. Hankey GJ and Eikelboom JW. Circulation 2011;123:1436 50. 4. van Ryn J et al. Thromb Haemost 2010;103:1116 27. 5. Stangier and Feuring. Blood Coagul Fibrinolysis 2012,23:138 143. 6. Data on file, Boehringer Ingelheim. 7. Majeed A et al. Circulation 2013; CIRCULATIONAHA.113.002332 [Epub ahead of print]. 8. Food and Drug Administration Cardio-Renal Advisory Committee 2010. Dabigatran for AF. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/ CardiovascularandRenalDrugsAdvisoryCommittee/UCM247244.pdf (accessed 02/10/12). Pradaxa is a registered trademark of Boehringer Ingelheim Pty Limited, abn 52 000 452 308 78 Waterloo Road, North Ryde NSW 2113. BIAP0204. November 2013.