1. Name Of The Medicinal Product
Angiox 250
2. Qualitative And Quantitative Composition
Each vial contains 250 mg bivalirudin.
After reconstitution 1 ml contains 50 mg bivalirudin.
After dilution 1 ml contains 5 mg bivalirudin.
For a full list of excipients see section 6.1.
3. Pharmaceutical Form
Powder for concentrate for solution for injection or infusion.
White to off-white lyophilised powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Angiox is indicated as 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 aspirin and clopidogrel.
4.2 Posology And Method Of Administration
Angiox should be administered by a physician experienced in either acute coronary care or in coronary intervention procedures.
Posology
Patients undergoing PCI, including primary PCI
The recommended dose of Angiox 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 1.75 mg/kg body weight/hour for at least the duration of the procedure. The infusion may be continued for up to 4 hours post-PCI as clinically warranted. After cessation of the 1.75 mg/kg /h infusion, a reduced infusion dose of 0.25 mg/kg/h may be continued for 4 – 12 hours as clinically necessary.
Patients should be carefully monitored following primary PCI for signs and symptoms consistent with myocardial ischaemia.
Patients with unstable angina/non-ST segment elevated myocardial infarction (UA/NSTEMI)
The recommended starting dose of Angiox for patients with ACS is an intravenous bolus of 0.1 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 of bivalirudin should be administered before the procedure and the infusion increased to 1.75 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 12 hours as clinically necessary.
For patients who proceed to coronary artery bypass graft (CABG) surgery off pump, the intravenous (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 1.75 mg/kg/h 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 1 hour prior to surgery after which the infusion should be discontinued and the patient treated with unfractionated heparin (UFH).
The safety and efficacy of a bolus only dose of Angiox has not been evaluated and is not recommended even if a short PCI procedure is planned.
The activated clotting time (ACT) may be used to assess bivalirudin activity.
In order to reduce the potential for low ACT values, the reconstituted and diluted product should be thoroughly mixed prior to administration and the bolus dose administered by a rapid intravenous push.
ACT values 5 minutes after bivalirudin bolus average 365 +/- 100 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 1.75 mg/kg infusion dose is properly administered.
The arterial sheath can be removed 2 hours after discontinuation of the bivalirudin infusion without further ACT monitoring.
Renal insufficiency
Angiox is contraindicated in patients with severe renal insufficiency (GFR<30 ml/min) and also in dialysis-dependent patients (see section 4.3).
In patients with mild or moderate renal insufficiency, the ACS dose (0.1 mg/kg bolus/0.25 mg/kg/h infusion) should not be adjusted.
Patients with moderate renal impairment (GFR 30-59 ml/min) undergoing PCI (whether being treated with bivalirudin for ACS or not) should receive a lower infusion rate of 1.4 mg/kg/h. The bolus dose should not be changed from the posology described under ACS or PCI above.
During PCI, monitoring of clotting time such as the ACT is recommended in patients with renal insufficiency.
The ACT should be checked at 5 minutes post bolus dose. If the 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.
Hepatic impairment
No dose adjustment is needed. Pharmacokinetic studies indicate that hepatic metabolism of bivalirudin is limited, therefore the safety and efficacy of bivalirudin have not been specifically studied in patients with hepatic impairment.
Elderly population
Caution should be exercised in the elderly due to age-related decrease in renal function.
Paediatric patients
There is no relevant indication for use of Angiox in children less than 18 years old.
Use with other anticoagulant therapy
In STEMI patients undergoing primary PCI, standard pre-hospital adjunctive therapy should include clopidogrel and may include the early administration of UFH (See section 5.1).
Patients can be started on Angiox 30 minutes after discontinuation of unfractionated heparin given intravenously, or 8 hours after discontinuation of low molecular weight heparin given subcutaneously.
Angiox can be used in conjunction with a GP IIb/IIIa inhibitor. Refer to section 5.1 for further information regarding the use of bivalirudin with or without a GP IIb/IIIa inhibitor.
Method of administration
Angiox is intended for intravenous (IV) use.
Angiox should be initially reconstituted to give a solution of 50 mg/ml bivalirudin. Reconstituted material should then be further diluted in a total volume of 50 ml to give a solution of 5 mg/ml bivalirudin.
Reconstituted and diluted product should be thoroughly mixed prior to administration.
Refer to section 6.6 for full instructions regarding the method of administration.
Angiox is administered as a weight based regimen consisting of an initial bolus (by rapid IV push) followed by an IV infusion.
4.3 Contraindications
Angiox is contraindicated in patients with:
• a known hypersensitivity to the active substance or to any of the excipients, or to hirudins
• active bleeding or increased risk of bleeding because of haemostasis disorders and/or irreversible coagulation disorders
• severe uncontrolled hypertension
• subacute bacterial endocarditis
• severe renal impairment (GFR<30 ml/min) and in dialysis-dependent patients.
4.4 Special Warnings And Precautions For Use
Angiox is not intended for intramuscular use. Do not administer intramuscularly.
Haemorrhage
Patients must be observed carefully for symptoms and signs of bleeding during treatment particularly if bivalirudin is combined with another anticoagulant (see section 4.5). Although most bleeding associated with bivalirudin occurs at the site of arterial puncture in patients undergoing PCI, haemorrhage can occur at any site during therapy. Unexplained decreases in haematocrit, haemoglobin or blood pressure may indicate haemorrhage. Treatment should be stopped if bleeding is observed or suspected.
There is no known antidote to bivalirudin but its effect wears off quickly (T½ is 35 to 40 minutes).
Co-administration with platelet inhibitors or anti-coagulants
Combined use of anti-coagulant medicines can be expected to increase the risk of bleeding (see section 4.5). When bivalirudin is combined with a platelet inhibitor or an anti-coagulant medicine, clinical and biological parameters of haemostasis should be regularly monitored.
In patients taking warfarin who are treated with bivalirudin, International Normalised Ratio (INR) monitoring should be considered to ensure that it returns to pre-treatment levels following discontinuation of bivalirudin treatment.
Hypersensitivity
Allergic type hypersensitivity reactions were reported uncommonly (
Treatment-emergent positive bivalirudin antibodies are rare and have not been associated with clinical evidence of allergic or anaphylactic reactions. Caution should be exercised in patients previously treated with lepirudin who had developed lepirudin antibodies.
Acute stent thrombosis
Acute stent thrombosis (<24 hours) has been observed in patients with STEMI undergoing primary PCI and has been managed by Target Vessel Revascularisation (TVR) (see sections 4.8 and 5.1). 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.
Brachytherapy
Intra-procedural thrombus formation has been observed during gamma brachytherapy procedures with Angiox.
Angiox should be used with caution during beta brachytherapy procedures.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interaction studies have been conducted with platelet inhibitors, including acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, eptifibatide, or tirofiban. The results do not suggest pharmacodynamic interactions with these medicinal products.
From the knowledge of their mechanism of action, combined use of anti-coagulant medicinal products (heparin, warfarin, thrombolytics or antiplatelet agents) can be expected to increase the risk of bleeding.
In any case, when bivalirudin is combined with a platelet inhibitor or an anticoagulant medicine, clinical and biological parameters of haemostasis should be regularly monitored.
4.6 Pregnancy And Lactation
Pregnancy
There are no or limited data from the use of bivalirudin in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).
Angiox should not be used during pregnancy unless the clinical condition of the woman requires treatment with bivalirudin.
Breastfeeding
It is unknown whether bivalirudin is excreted in human milk. Angiox should be administered with caution in breast-feeding mothers.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
In all clinical studies bleeding data were collected separately from adverse drug reactions and are summarised in Table 8 together with the bleeding definitions used for each study.
The HORIZONS Trial (Patients with STEMI undergoing primary PCI)
The following adverse reaction data are based on a clinical study of bivalirudin in patients with STEMI undergoing primary PCI; 1,800 patients were randomised to bivalirudin alone, 1,802 were randomised to heparin plus GP IIb/IIIa inhibitor. Serious adverse reactions were reported more frequently in the heparin plus GP IIb/IIIa group than the bivalirudin treated group.
A total of 55.1% of patients receiving bivalirudin experienced at least one adverse event and 8.7% experienced an adverse drug reaction. Adverse drug reactions for bivalirudin are listed by system organ class in Table 1.The incidence of stent thrombosis within the first 24 hours was 1.5% in patients receiving bivalirudin versus 0.3% in patients receiving UFH plus GP IIb/IIIa inhibitor (p=0.0002). Two deaths occurred after acute stent thrombosis, 1 in each arm of the study. The incidence of stent thrombosis between 24 hours and 30 days was 1. 2% in patients receiving bivalirudin versus 1.9% in patients receiving UFH plus GP IIb/IIIa inhibitor (p=0.1553). A total of 17 deaths occurred after subacute stent thrombosis, 3 in the bivalirudin arm and 14 in the UFH plus GP IIb/IIIa arm. There was no statistically significant difference in the rates of stent thrombosis between treatment arms at 30 days (p=0.3257) and 1 year (p=0.7754).
Platelets, bleeding and clotting
In the HORIZONS study both major and minor bleeding occurred commonly (
In the HORIZONS study, thrombocytopenia was reported in 26 (1. 6%) of bivalirudin-treated patients and in 67 (3.9%) of patients treated with heparin plus a GP IIb/IIIa inhibitor. All of these bivalirudin-treated patients received concomitant aspirin, all but 1 received clopidogrel and 15 also received a GP IIb/IIIa inhibitor.
Table 1. HORIZONS trial; adverse drug reaction data
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The ACUITY Trial (Patients with unstable angina/non-ST segment elevated myocardial infarction (UA/NSTEMI))
The following adverse reaction data are based on a clinical study of bivalirudin in 13,819 patients with ACS; 4,612 were randomised to bivalirudin alone, 4,604 were randomised to bivalirudin plus GP IIb/IIIa inhibitor and 4,603 were randomised to either unfractionated heparin or enoxaparin plus GP IIb/IIIa inhibitor. Adverse reactions were more frequent in females and in patients more than 65 years of age in both the bivalirudin and the heparin-treated comparator groups compared to male or younger patients.
Approximately 23.3% of patients receiving bivalirudin experienced at least one adverse event and 2.1% experienced an adverse reaction. Adverse event reactions for bivalirudin are listed by system organ class in Table 2.
Platelets, bleeding and clotting
In ACUITY, bleeding data were collected separately from adverse reactions.
ACUITY major bleeding was defined as any one of the following: intracranial, retroperitoneal, intraocular, access site haemorrhage requiring radiological or surgical intervention,
Major bleeding rates are shown in Table 8 for the IIT population and Table 10 for the per protocol population (patients receiving clopidogrel and aspirin). Both major and minor bleeds were significantly less frequent with bivalirudin alone than the heparin plus GP IIb/IIIa inhibitor and bivalirudin plus GP IIb/IIIa inhibitor groups. Similar reductions in bleeding were observed in patients who were switched to bivalirudin from heparin-based therapies (N = 2,078).
Major bleeding occurred most frequently at the sheath puncture site. Other less frequently observed bleeding sites with greater than 0.1% (uncommon) bleeding included “other” puncture site, retroperitoneal, gastrointestinal, ear, nose or throat.
Thrombocytopenia was reported in 10 bivalirudin-treated patients participating in the ACUITY study (0.1%). The majority of these patients received concomitant acetylsalicylic acid and clopidogrel, and 6 out of the 10 patients also received a GP IIb/IIIa inhibitor. Mortality among these patients was nil.
Table 2. ACUITY trial; adverse reaction data
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The REPLACE-2 Trial (Patients undergoing PCI)
The following adverse reaction data is based on a clinical study of bivalirudin in 6,000 patients undergoing PCI, half of whom were treated with bivalirudin (REPLACE-2). Adverse events were more frequent in females and in patients more than 65 years of age in both the bivalirudin and the heparin-treated comparator groups compared to male or younger patients.
Approximately 30% of patients receiving bivalirudin experienced at least one adverse event and 3% experienced an adverse reaction. Adverse reactions for bivalirudin are listed by system organ class in Table 3.
Platelets, bleeding and clotting
In REPLACE-2, bleeding data were collected separately from adverse events. Major bleeding rates for the intent-to-treat trial population is shown in Table 8.
Major bleeding was defined as the occurrence of any of the following: intracranial haemorrhage, retroperitoneal haemorrhage, blood loss leading to a transfusion of at least two units of whole blood or packed red blood cells, or bleeding resulting in a haemoglobin drop of more than 3 g/dl, or a fall in haemoglobin greater than 4 g/dl (or 12% of haematocrit) with no bleeding site identified. Minor haemorrhage was defined as any observed bleeding event that did not meet the criteria for a major haemorrhage. Minor bleeding occurred very commonly (
Both minor and major bleeds were significantly less frequent with bivalirudin than the heparin plus GP IIb/IIIa inhibitor comparator group. Major bleeding occurred most frequently at the sheath puncture site. Other less frequently observed bleeding sites with greater than 0.1% (uncommon) bleeding included “other” puncture site, retroperitoneal, gastrointestinal, ear, nose or throat.
In REPLACE-2 thrombocytopenia occurred in 20 bivalirudin-treated patients (0.7%). The majority of these patients received concomitant aspirin and clopidogrel, and 10 out of 20 patients also received a GP IIb/IIIa inhibitor. Mortality among these patients was nil.
Table 3. REPLACE-2 trial; adverse reaction data
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4.9 Overdose
Cases of overdose of up to 10 times the recommended dose have been reported in clinical trials. Single bolus doses of bivalirudin up to 7.5 mg/kg have also been reported. Bleeding has been observed in some reports of overdose.
In cases of overdose, treatment with bivalirudin should be immediately discontinued and the patient monitored closely for signs of bleeding.
In the event of major bleeding, treatment with bivalirudin should be immediately discontinued. There is no known antidote to bivalirudin, however, bivalirudin is haemo-dialysable.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Direct thrombin inhibitors, ATC code: B01AE06.
Angiox contains bivalirudin, a direct and specific thrombin inhibitor that binds both to the catalytic site and the anion-binding exosite of fluid-phase and clot-bound thrombin.
Thrombin plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework that stabilises the thrombus. Thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. Bivalirudin inhibits each of these thrombin effects.
The binding of bivalirudin to thrombin, and therefore its activity, is reversible as thrombin slowly cleaves the bivalirudin, Arg3-Pro4, bond, resulting in recovery of thrombin active site function. Thus, bivalirudin initially acts as a complete non-competitive inhibitor of thrombin, but transitions over time to become a competitive inhibitor enabling initially inhibited thrombin molecules to interact with other clotting substrates and to coagulation if required.
In vitro studies have indicated that bivalirudin inhibits both soluble (free) and clot-bound thrombin. Bivalirudin remains active and is not neutralised by products of the platelet release reaction.
In vitro studies have also shown that bivalirudin prolongs the activated partial thromboplastin time (aPTT) thrombin time (TT) and pro-thrombin time (PT) of normal human plasma in a concentration-dependent manner and that bivalirudin does not induce a platelet aggregation response against sera from patients with a history of Heparin-Induced Thrombocytopenia/Thrombosis Syndrome (HIT/HITTS).
In healthy volunteers and patients, bivalirudin exhibits dose- and concentration-dependent anticoagulant activity as evidenced as prolongation of the ACT, aPTT, PT, INR and TT. Intravenous administration of bivalirudin produces measurable anticoagulation within minutes.
The pharmacodynamic effects of bivalirudin may be assessed using measures of anticoagulation including the ACT. The ACT value is positively correlated with the dose and plasma concentration of bivalirudin administered. Data from 366 patients indicates that the ACT is unaffected by concomitant treatment with a GP IIb/IIIa inhibitor.
In clinical studies bivalirudin has been shown to provide adequate anticoagulation during PCI procedures.
The HORIZONS Trial (Patients with STEMI undergoing primary PCI)
The HORIZONS trial was a prospective, dual arm, single blind, randomised, multi-centre trial to establish the safety and efficacy of bivalirudin in patients with STEMI undergoing a primary PCI strategy with stent implantation with either a slow release paclitaxal-eluding stent (TAXUS™) or an otherwise identical uncoated bare metal stent (Express2™). A total of 3,602 patients were randomised to receive either bivalirudin (1,800 patients) or unfractionated heparin plus a GP IIb/IIIa inhibitor (1,802 patients). All patients received aspirin and clopidogrel with twice as many patients (approximately 64%) receiving a 600mg loading dose of clopidogrel than a 300mg loading dose of clopidogrel. Approximately 66% of patients were pre-treated with unfractionated heparin.
The dose of bivalirudin used in HORIZONS was the same as that used in the REPLACE-2 study (0.75 mg/kg bolus followed by a 1.75 mg/kg body weight/hour infusion). A total of 92.9% of patients treated underwent primary PCI as their primary management strategy.
The analysis and results for the HORIZONS trial at 30 days for the overall (ITT) population is shown in Table 4.Results at 1 year were consistent with results at 30 days.
Bleeding definitions and outcomes from the HORIZONS trial are shown in Table 8.
Table 4. HORIZONS 30-day study results (intent-to-treat population)
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