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1 ANGIOX (bivalirudin) 250 mg powder for concentrate for solution for injection or infusion EUROPEAN Dosing and Administration Information AX/IE/07204/03

2 Instructions for administration ANGIOX is intended for use as an intravenous bolus followed by an intravenous infusion This dosing regimen has been evaluated in all pivotal trials and is based on the following properties of bivalirudin: the pharmacology of bivalirudin is predictable (linear PK/PD profile) plasma levels as achieved by the 0.75 mg/kg bolus plus.75 mg/kg/h infusion are required for adequate anticoagulation And, the half life of bivalirudin is very short (approximately 25 minutes)

3 Bivalirudin: pharmacology profile ACUITY trial: Bivalirudin ACS dosing regimen Modeled plasma levels Estimated Mean Plasma Concentration (mcg/ml) Initial Dose PCI Dose Shown to provide adequate anticoagulation in PCI (6.5 mcg/ml) mg/kg bolus B +.75 mg/kg/h infusion I* 2 Initial 0. mg/kg B mg/kg/h I; At the time of PCI 0.5 mg/kg B +.75 mg/kg/h I 3 = 25-minutes half-life B I BB II Elapsed Time From Start of Bivalirudin Bolus (Hours) Dose used in the ACUITY trial. The initial dose in ACUITY trial was derived from TIMI 7, & pilot TIMI 8 trials. The PCI dose was derived from phase 2 Topol dose ranging study and validated in REPLACE- & REPLACE-2. 2 Lincoff AM et al. JAMA 2003; 289: Stone G et al. Am Heart J. 2004;48: Topol et al. Circulation 993; 87:622.

4 ANGIOX the need for a bolus and infusion In the ImproveR registry bolus only dosing (one or more bolus doses, without infusion) was observed in EU clinical practice 5. Bolus only dosing was associated with increased in-hospital ischaemic events (MACE). The infusion dose should be initiated immediately after the bolus dose is administered, ensuring delivery to the patient prior to the procedure, and continued uninterrupted for the duration of the procedure. Failure to initiate the infusion following the bolus will result in a plasma concentration that is below the required level within minutes. The safety and efficacy of a bolus only dose of bivalirudin without the subsequent infusion has not been evaluated and is not recommended even if a short PCI procedure is planned. 5 Madsen JK et al. EuroIntervention 2008:3(5):60 6

5 ImproveR Registry 5 An observational study of Angiox use in patients undergoing PCI. 26.3% of patients received a single bolus dose no subsequent infusion 7.% of patients received a double bolus dose no subsequent infusion Bolus only dosing associated with in-hospital ischaemic events (MACE) UFH/LMWH <24h after PCI (n=069) Age >65 years (n=2230) Angiox double bolus (n=268)* STEMI (n=407) PCI >45 minutes (n=074) Coumarins (n=99) GP IIb/IIIa inhibitors (n=79) 5 Madsen JK et al. EuroIntervention 2008:3:60 6 Odds ratio [95% CI] Ischaemic events less frequent Ischaemic events more frequent

6 Instructions for administration PCI, including Primary PCI ANGIOX should be used with acetylsalicylic acid and clopidogrel. The recommended dose of bivalirudin for patients undergoing PCI is an intravenous bolus of 0.75 mg/kg body weight followed immediately by an intravenous infusion at a rate of.75 mg/kg body weight/hour for at least the duration of the procedure. The infusion of.75 mg/kg body weight/hour may be continued for up to 4 hours post-pci as clinically warranted and further continued at a reduced infusion dose of 0.25 mg/kg/h for 4-2 hours as clinically necessary. Please refer to the Angiox Dosing card provided for additional dosing information.

7 Instructions for administration Treatment of Acute Coronary Syndromes (ACS) ANGIOX should be used with acetylsalicylic acid and clopidogrel. The recommended starting dose of bivalirudin for patients with ACS is an intravenous bolus of 0. mg/kg followed by an infusion of 0.25 mg/kg/h. Patients who are to be medically managed may continue the infusion of 0.25 mg/kg/h for up to 72 hours. If the patient proceeds to PCI, an additional bolus of 0.5 mg/kg should be administered and the infusion increased to.75 mg/kg/h for the duration of the procedure. Following PCI, the reduced infusion dose of 0.25 mg/kg/h may be resumed for 4 to 2 hours as clinically necessary. Please refer to the Angiox Dosing card provided for additional dosing information.

8 Instructions for administration Treatment for Acute coronary syndromes (ACS) continued For patients who proceed to coronary artery bypass graft (CABG) surgery off pump, the IV infusion of bivalirudin should be continued until the time of surgery. Just prior to surgery, a 0.5 mg/kg bolus dose should be administered followed by a.75 mg/kg/h IV infusion for the duration of the surgery. For patients who proceed to CABG surgery on pump, the IV infusion of bivalirudin should be continued until hour prior to surgery after which the infusion should be discontinued and the patient treated with unfractionated heparin. Please refer to the Angiox Dosing card provided for additional dosing information.

9 Instructions for administration Other considerations Increased awareness due to high bleeding risk should be exercised in the elderly because of age-related decrease in renal function. Dose adjustments for this age group should be on the basis of renal function. Patients should be carefully monitored following primary PCI for signs and symptoms consistent with myocardial ischaemia. Please refer to the Angiox Dosing card provided for additional dosing information.

10 Instructions for administration Other considerations (continued) An increase in the activated clotting time (ACT) may be used as an indication that a patient has received bivalirudin. ACT values 5 minutes after bivalirudin bolus average 365 +/- 00 seconds. If the 5-minute ACT is less than 225 seconds, a second bolus dose of 0.3 mg/kg should be administered. Once the ACT value is greater than 225 seconds, no further monitoring is required provided the.75mg/kg/h infusion dose is properly administered. Where insufficient ACT increase is observed, the possibility of medication error should be considered, for example inadequate mixing of Angiox or intravenous equipment failures. The arterial sheath can be removed 2 hours after discontinuation of the bivalirudin infusion without anticoagulation monitoring. Please refer to the Angiox Dosing card provided for additional dosing information.

11 ANGIOX & renal impairment ANGIOX is contraindicated in patients with severe renal insufficiency (GFR<30ml/min) and also in dialysis-dependent patients. The ACS treatment dose (0.mg/kg bolus/0.25mg/kg/h infusion) should not be adjusted for patients with mild or moderate renal insufficiency. Patients with moderate renal impairment (GFR ml/min) undergoing PCI (whether being treated with bivalirudin for ACS or not) should receive a lower infusion rate of.4 mg/kg/h. The bolus dose should not be changed. Patients with renal impairment should be carefully monitored for clinical signs of bleeding during PCI, as clearance of bivalirudin is reduced in these patients. If the 5-minute ACT is less than 225 seconds, a second bolus dose of 0.3 mg/kg should be administered and the ACT re-checked 5 minutes after the administration of the second bolus dose. NOTE: Where insufficient ACT increase is observed, the possibility of medication error should be considered, for example inadequate mixing of Angiox or IV equipment failures. CrCl = creatinine clearance.

12 ANGIOX: Instructions for preparation & administration ANGIOX is intended for IV injection and infusion after reconstitution and dilution. Angiox should not be used without dilution. To each 250 mg vial add 5 ml of Sterile Water for Injections. Swirl until all material is completely dissolved and the solution is clear. Withdraw 5 ml from the vial, and further dilute in a total volume of 50ml of glucose 5% solution for injection, or sodium chloride 9mg/ml (0.9%) solution for injection to give a final bivalirudin concentration of 5mg/ml. Withdraw bolus and infusion dose from diluted bag using weight-based dosing Any unused product or waste material should be disposed of in accordance with local requirements

13 ANGIOX Reconstitution Swirl the vial make sure all material is dissolved. This may take several minutes. Visually inspect the vial for particulate matter and discolouration. ANGIOX vials with visible particulate matter should not be used. The reconstituted/diluted solution will be a clear to slightly opalescent, colourless to slightly yellow solution. Before Reconstitution After addition of Diluent Completely Dissolved Ensure all the liquid is withdrawn from the reconstituted vial Shake the infusion bag after adding reconstituted ANGIOX to it to ensure adequate mixing To ensure appropriate administration of bivalirudin, the completely dissolved, reconstituted and diluted product should be thoroughly mixed prior to administration

14 ANGIOX administration Aseptic procedures should be used for the preparation and administration of Angiox. STEP : Withdraw the bolus dose from the IV infusion bag Choose a syringe with a volume large enough to administer bolus in one push (based on weight-based dosing chart) STEP 2: Administer bolus at IV port closest to the catheter insertion site The bolus dose should be administered by a rapid intravenous push to ensure that the entire bolus reaches the patient before the start of the procedure Be sure that all the bolus reaches the patient in a rapid manner STEP 3: Prepare and hang the IV infusion bag. STEP 4: Intravenous infusion lines should be primed with bivalirudin to ensure continuity of drug infusion after delivery of the bolus On an infusion pump, set the infusion dose according to patient weight The infusion dose should be initiated immediately after the bolus dose is administered, ensuring delivery to the patient prior to the procedure, and continued uninterrupted for the duration of the procedure

15 ANGIOX: IV line incompatibilities No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets Bivalirudin was tested with 98 medications and was found to be incompatible with the medications listed in the table below 6-7 Incompatibilities may result in haze formation, microparticulate formation, or gross precipitation 6 Alteplase Chlorpromazine HCl Reteplase Amiodarone HCl Diazepam Streptokinase Amphotericin B Prochlorperazine edisylate Vancomycin HCl 6 Trissel LA et al. Int J Pharm Compd. 2002;6: Hartman CA et al. Am J HealthSyst Pharm. 2004;6:774, 776.

16 ANGIOX: IV line incompatibilities The six drugs in the table below show dose-concentration incompatibilities with bivalirudin 6-7 Drugs with dose concentration incompatibilities Compatible concentrations Incompatible concentrations Dobutamine HCl 4 mg/ml 2.5 mg/ml Famotidine 2 mg/ml 0 mg/ml Haloperidol lactate 0.2 mg/ml 5 mg/ml Labetalol HCl 2 mg/ml 5 mg/ml Lorazepam 0.5 mg/ml 2 mg/ml Promethazine HCl 2 mg/ml 25 mg/ml 6 Trissel LA et al. Int J Pharm Compd. 2002;6: Hartman CA et al. Am J HealthSyst Pharm. 2004;6:774, 776.

17 Stability of ANGIOX Lyophilised powder 4 years Do not store above 25 C Reconstituted solution Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8 o C. Store in a refrigerator (2 o C-8 o C). Do not freeze Diluted solution Chemical and physical in-use stability has been demonstrated for 24 hours at 25 o C. Do not freeze From a microbiological point of view, the product should be used immediately If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 8 o C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions

18 Switching to ANGIOX For patients started on unfractionated heparin administered IV before PCI For patients started on LMWH administered SC before PCI Wait until UFH has been discontinued for 30 minutes before starting ANGIOX for PCI Wait 8 hours after the last LMWH dose before starting ANGIOX for PCI

19 Reporting of Adverse Events Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: ; Fax: Website: medsafety@hpra.ie. Adverse events should also be reported to The Medicines Company by medical.information@themedco.com or phone or +353 (0)

20 Contact The Medicines Company Tel: or +353 (0) Live 24/7 support is available Request medical information Report product complaints Report all safety information incl. adverse events

21 Abbreviated Prescribing Information Abbreviated Prescribing Information for ANGIOX (bivalirudin) 250mg powder for concentrate for solution for injection or infusion: Please refer to the full Summary of Product Characteristics when prescribing Angiox. Legal classification: Medicinal product subject to restricted medical prescription Presentation: Each vial contains 250mg bivalirudin, mannitol and sodium hydroxide. Indications: An anticoagulant in adult patients undergoing percutaneous coronary intervention (PCI) including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. Angiox is also indicated for the treatment of adult patients with unstable angina/non-st segment elevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention. Angiox should be administered with acetylsalicylic acid and clopidogrel. Dose and administration: For intravenous (IV) use, should be administered by a physician experienced in either acute coronary care or in coronary intervention procedures. Adults/Elderly: Increased awareness due to high bleeding risk should be exercised in the elderly because of decrease in renal function. PCI/primary PCI: Initial IV bolus of 0.75 mg/kg body weight followed immediately by IV infusion of.75 mg/kg body weight/hour for at least the duration of the procedure or up to 4 hours post-procedure as clinically warranted and further continued at a reduced infusion dose of 0.25 mg/kg/h for 4 2 hours as clinically necessary. Acute coronary syndromes (ACS): Starting dose is an IV bolus of 0. mg/kg followed by an IV infusion of 0.25 mg/kg/h. Medically managed patients may continue the infusion of 0.25 mg/kg/h for up to 72 hours. If proceeding to PCI, an additional bolus of 0.5 mg/kg should be administered and the infusion increased to.75 mg/kg/h for PCI duration. Following PCI, the 0.25 mg/kg/h IV infusion dose may be resumed for 4 to 2 hours as clinically necessary. For patients who proceed to CABG refer to the full prescribing information. The safety and efficacy of a bolus dose of Angiox without the subsequent infusion has not been evaluated and is not recommended even if a short PCI procedure is planned. Refer to full prescribing information for instructions regarding method of administration and ACT monitoring. Hepatic impairment: No dose adjustment needed. Renal insufficiency: Refer to the full prescribing information and see contraindications if GFR<30ml/min. Monitoring of clinical signs of bleeding and dose adjustments are recommended in this group. Children and adolescents: No indication. Contraindications: In patients with: a known hypersensitivity to bivalirudin, the excipients, or to hirudins; active/increased risk of bleeding; severe uncontrolled hypertension; subacute bacterial endocarditis; severe renal impairment (GFR<30ml/min) and dialysis-dependent patients. Special Warnings and Precautions for Use: Haemorrhage: Observe patients for bleeding, stop treatment if bleeding is observed or suspected. Consider INR monitoring in patients taking warfarin. Hypersensitivity: Anaphylaxis, including anaphylactic shock with fatal outcome has been reported very rarely in post-marketing experience. Caution in patients who have developed lepirudin antibodies. Intra-procedural thrombus formation has been observed during γ-brachytherapy procedures, use caution during β-brachytherapy procedures. Acute stent thrombosis has been observed in patients with STEMI undergoing primary PCI and has been managed by Target Vessel Revascularisation. Patients should remain for at least 24 hours in a facility capable of managing ischaemic complications and should be carefully monitored following primary PCI for signs and symptoms consistent with myocardial ischaemia. Interactions: Start Angiox 30 minutes after discontinuation of UFH, or 8 hours after LMWH given subcutaneously. When combining anticoagulants, clinical and biological parameters of haemostasis should be regularly monitored. Pregnancy and Lactation: Do not use during pregnancy unless clearly necessary, and administer with caution in breast-feeding mothers. Undesirable effects (including reports with fatal outcome): Major and minor bleeding at any site, thrombosis (including coronary artery thrombosis, stent thrombosis and catheter thrombosis), haemoglobin decreased, access site haemorrhage, vessel puncture site haematoma and ecchymosis are the most common adverse reactions. The following adverse reactions have also been reported rarely or uncommonly; increased INR, thrombocytopenia, anaemia, myocardial infarction, cardiac tamponade, pericardial haemorrhage, ear haemorrhage, intraocular haemorrhage, gastrointestinal haemorrhage (including haematemesis, malaena, oesophageal haemorrhage, anal haemorrhage), peritoneal haemorrhage, retroperitoneal haemorrhage, gingival haemorrhage, hypersensitivity including anaphylactic reaction and shock, reperfusion injury, contusion, headache, intracranial haemorrhage, bradycardia, haematoma, hypotension, arteriovenous fistula, vascular pseudoaneurysm, haematuria, epistaxis, haemoptysis, pharyngeal haemorrhage, nausea, vomiting, urticaria, rash, chest pain, back pain, groin pain, injection site pain/reactions, angina pectoris, ventricular tachycardia, pulmonary haemorrhage and dyspnoea. Compartment syndrome has been reported in post-marketing experience. Overdose: Discontinue treatment immediately and monitor patient for signs of bleeding. There is no antidote to bivalirudin; however it is haemo-dialysable. Bleeding has been observed in some reports of overdose. Pack size: 0 vials. Cost: 3,00 for pack of 0. Shelf-life/Storage: 4 years, do not store above 25ºC. Legal category: POM. Marketing authorisation number: EU//04/289/00. Marketing authorisation holder: The Medicines Company UK Ltd., 5L Milton Park, Abingdon, Oxfordshire, OX4 4SA, UK. Product Licence Holder: The Medicines Company UK Ltd. Date of latest revision of brief prescribing information: June 204. Further information including full prescribing information is available from: The Medicines Company UK Ltd., 5L Milton Park, Abingdon, Oxfordshire, OX4 4SA, UK. +44 (0) Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via: IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: , Fax: , website: imbpharmacovigilance@imb.ie. Adverse events should be reported to: The Medicines Company, Tel: or +353 (0) ; medical.information@themedco.com June 204 AX/IE/07204/0