ANGIOX 250mg concentrate powder for injection / infusion solution medication leaflet

Angiox 250 mg powder for concentrate for solution for injection or infusion.

Each vial contains 250 mg bivalirudin.

After reconstitution 1 ml contains 50 mg bivalirudin.

After dilution 1 ml contains 5 mg bivalirudin.

For the full list of excipients see section 6.1.

Powder for concentrate for solution for injection or infusion (powder for concentrate).

White to off-white lyophilised powder.

Angiox is indicated as an anticoagulant in adult patients undergoing percutaneous coronaryintervention (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 segmentelevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention.

Angiox should be administered with acetylsalicylic acid and clopidogrel.

Angiox should be administered by a physician experienced in either acute coronary care or in coronaryintervention procedures.

Patients undergoing PCI, including patients with ST-segment elevation myocardial infarction(STEMI) undergoing primary PCI

The recommended dose of bivalirudin for patients undergoing PCI is an intravenous bolus of0.75 mg/kg body weight followed immediately by an intravenous infusion at a rate of 1.75 mg/kgbody weight/hour for at least the duration of the procedure. The infusion of 1.75 mg/kg bodyweight/hour may be continued for up to 4 hours post-PCI and at a reduced dose of 0.25 mg/kg bodyweight/hour for an additional 4 - 12 hours as clinically necessary. In STEMI patients the infusion of1.75 mg/kg body weight/hour should be continued for up to 4 hours post-PCI and continued at areduced dose of 0.25 mg/kg body weight/hour for an additional 4 - 12 hours as clinically necessary(see section 4.4).

Patients should be carefully monitored following primary PCI for signs and symptoms consistent withmyocardial ischaemia.

Patients with unstable angina/non-ST segment elevated myocardial infarction (UA/NSTEMI)

The recommended starting dose of bivalirudin for medically managed patients with acute coronarysyndrome (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 72hours. If the medically managed patient proceeds to PCI, an additional bolus of 0.5 mg/kg ofbivalirudin should be administered before the procedure and the infusion increased to 1.75 mg/kg/h forthe duration of the procedure. Following PCI, the reduced infusion dose of 0.25 mg/kg/h may beresumed for 4 to 12 hours as clinically necessary.

For patients who proceed to coronary artery bypass graft (CABG) surgery off pump, the intravenousinfusion of bivalirudin should be continued until the time of surgery. Just prior to surgery, a 0.5 mg/kgbolus dose should be administered followed by a 1.75 mg/kg/h intravenous infusion for the duration ofthe surgery.

For patients who proceed to CABG surgery on pump, the intravenous infusion of bivalirudin should becontinued until 1 hour prior to surgery after which the infusion should be discontinued and the patienttreated with unfractionated heparin (UFH).

To ensure appropriate administration of bivalirudin, the completely dissolved, reconstituted anddiluted product should be thoroughly mixed prior to administration (see section 6.6). The bolus doseshould be administered by a rapid intravenous push to ensure that the entire bolus reaches the patientbefore the start of the procedure.

Intravenous infusion lines should be primed with bivalirudin to ensure continuity of drug infusion afterdelivery of the bolus.

The infusion dose should be initiated immediately after the bolus dose is administered, ensuringdelivery to the patient prior to the procedure, and continued uninterrupted for the duration of theprocedure. The safety and efficacy of a bolus dose of bivalirudin without the subsequent infusion hasnot been evaluated and is not recommended even if a short PCI procedure is planned.

An increase in the activated clotting time (ACT) may be used as an indication that a patient hasreceived bivalirudin.

ACT values 5 minutes after bivalirudin bolus average 365 +/- 100 seconds. If the 5-minute ACT is lessthan 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 the1.75 mg/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 withoutanticoagulation monitoring.

Use with other anticoagulant therapy

In STEMI patients undergoing primary PCI, standard pre-hospital adjunctive therapy should includeclopidogrel 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 givenintravenously, or 8 hours after discontinuation of low molecular weight heparin given subcutaneously.

Angiox can be used in conjunction with a GP IIb/IIIa inhibitor. For further information regarding theuse of bivalirudin with or without a GP IIb/IIIa inhibitor, please see section 5.1.

Angiox is contraindicated in patients with severe renal insufficiency (GFR<30 ml/min) and also indialysis-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/hinfusion) should not be adjusted.

Patients with moderate renal impairment (GFR 30-59 ml/min) undergoing PCI (whether being treatedwith bivalirudin for ACS or not) should receive a lower infusion rate of 1.4 mg/kg/h. The bolus doseshould not be changed from the posology described under ACS or PCI above.

Patients with renal impairment should be carefully monitored for clinical signs of bleeding during PCI,as clearance of bivalirudin is reduced in these patients (see section 5.2)

If the 5-minute ACT is less than 225 seconds, a second bolus dose of 0.3 mg/kg should beadministered and the ACT re-checked 5 minutes after the administration of the second bolus dose.

Where insufficient ACT increase is observed, the possibility of medication error should be considered,for example inadequate mixing of Angiox or intravenous equipment failures.

No dose adjustment is needed. Pharmacokinetic studies indicate that hepatic metabolism of bivalirudinis limited, therefore the safety and efficacy of bivalirudin have not been specifically studied in patientswith hepatic impairment.

Increased awareness due to high bleeding risk should be exercised in the elderly because ofage-related decrease in renal function. Dose adjustments for this age group should be on the basis ofrenal function.

There is currently no indication for the use of Angiox in children less than 18 years old and norecommendation on a posology can be made. Currently available data are described in sections 5.1and 5.2.

Angiox is intended for intravenous use.

Angiox should be initially reconstituted to give a solution of 50 mg/ml bivalirudin. Reconstitutedmaterial should then be further diluted in a total volume of 50 ml to give a solution of 5 mg/mlbivalirudin.

Reconstituted and diluted product should be thoroughly mixed prior to administration.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

Angiox is contraindicated in patients with:

- a known hypersensitivity to the active substance or to any of the excipients listed in section 6.1,or to hirudins

- active bleeding or increased risk of bleeding because of haemostasis disorders and/orirreversible coagulation disorders

- severe uncontrolled hypertension

- subacute bacterial endocarditis

- severe renal impairment (GFR<30 ml/min) and in dialysis-dependent patients

Angiox is not intended for intramuscular use. Do not administer intramuscularly.

Patients must be observed carefully for symptoms and signs of bleeding during treatment particularlyif bivalirudin is combined with another anticoagulant (see section 4.5). Although most bleedingassociated 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, haemoglobinor blood pressure may indicate haemorrhage. Treatment should be stopped if bleeding is observed orsuspected.

There is no known antidote to bivalirudin but its effect wears off quickly (T½ is 25 ± 12 minutes).

Prolonged post PCI infusions of bivalirudin at recommended doses have not been associated with anincreased rate of bleeding (see section 4.2).

Co-administration with platelet inhibitors or anti-coagulants

Combined use of anti-coagulant medicinal products 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 followingdiscontinuation of bivalirudin treatment.

Allergic type hypersensitivity reactions were reported uncommonly (≥1/1,000 to ≤1/100) in clinicaltrials. Necessary preparations should be made to deal with this. Patients should be informed of theearly signs of hypersensitivity reactions including hives, generalised urticaria, tightness of chest,wheezing, hypotension and anaphylaxis. In the case of shock, the current medical standards for shocktreatment should be applied. Anaphylaxis, including anaphylactic shock with fatal outcome has beenreported very rarely (≤1/10,000) in post-marketing experience (see section 4.8).

Treatment-emergent positive bivalirudin antibodies are rare and have not been associated with clinicalevidence of allergic or anaphylactic reactions. Caution should be exercised in patients previouslytreated 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). Themajority of these cases were non-fatal. This increased risk of acute stent thrombosis was observedduring the first 4 hours following the end of the procedure among patients who either discontinued theinfusion of bivalirudin at the end of the procedure or received a continued infusion at the reduced doseof 0.25 mg/kg/h (see section 4.2). Patients should remain for at least 24 hours in a facility capable ofmanaging ischaemic complications and should be carefully monitored following primary PCI for signsand 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.

Excipient

Angiox contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium-free”.

Interaction studies have been conducted with platelet inhibitors, including acetylsalicylic acid,ticlopidine, clopidogrel, abciximab, eptifibatide, or tirofiban. The results do not suggestpharmacodynamic 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 ofbleeding.

In any case, when bivalirudin is combined with a platelet inhibitor or an anticoagulant, clinical andbiological parameters of haemostasis should be regularly monitored.

There are no or limited data from the use of bivalirudin in pregnant women. Animal studies areinsufficient 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 requirestreatment with bivalirudin.

It is unknown whether bivalirudin is excreted in human milk. Angiox should be administered withcaution in breast-feeding mothers.

Angiox has no or negligible influence on the ability to drive and use machines.

- The most frequent serious and fatal adverse reactions are major haemorrhage (access site andnon access-site bleeding, including intracranial haemorrhage) and hypersensitivity, includinganaphylactic shock. Coronary artery thrombosis and coronary stent thrombosis with myocardialinfarction, and catheter thrombosis have each been reported rarely. Administration errors maylead to fatal thrombosis.

- In patients receiving warfarin, INR is increased by administration of bivalirudin.

Adverse reactions for bivalirudin from HORIZONS, ACUITY, REPLACE-2 trials and post-marketingexperience are listed by system organ class in Table 1.

Table 1. Adverse reactions for bivalirudin from HORIZONS, ACUITY, REPLACE-2 trialsand post-marketing experience

Very Rare

System organ common Common Uncommon (≥1/10,000 to Very rareclass (≥1/10) (≥1/100 to <1/10) (≥1/1,000 to <1/100) <1/1,000) ( <1/10,000)

Blood and Haemoglobin Thrombocytopenialymphatic system decreased Anaemiadisorders

Immune system Hypersensitivity,disorders includinganaphylactic reactionand shock, includingreports with fataloutcome

Nervous system Headache Intracranialdisorders haemorrhage

Eye disorders Intraocularhaemorrhage

Ear and labyrinth Ear haemorrhagedisorders

Cardiac disorders Cardiactamponade,

Pericardialhaemorrhage,

Myocardialinfarction,

Coronary arterythrombosis,

Bradycardia,

Ventriculartachycardia’

Angina pectoris,

Chest pain

Vascular disorders Minor Major Haematoma, Coronary stent Compartmenta, bhaemorrha haemorrhage at Hypotension thrombosis syndromege at any any site including including reportssite reports with fatal with fatalcoutcome outcome

Thrombosisincluding reportswith fataloutcome,

Arteriovenousfistula,

Catheterthrombosis,

Vascularpseudoaneurysm

Very Rare

System organ common Common Uncommon (≥1/10,000 to Very rareclass (≥1/10) (≥1/100 to <1/10) (≥1/1,000 to <1/100) <1/1,000) ( <1/10,000)

Respiratory, Epistaxis, Pulmonarythoracic and Haemoptysis, haemorrhagemediastinal a

Pharyngeal Dyspnoeadisordershaemorrhage

Gastrointestinal Gastrointestinal Peritonealdisorders haemorrhage haemorrhage,(including Retroperitonealhaematemesis, haematoma,melaena, Vomitingoesophagealhaemorrhage, analhaemorrhage),

Retroperitonealhaemorrhage,

Gingivalhaemorrhage,

Nausea

Skin and Ecchymosis Rash, Urticariasubcutaneoustissue disorders

Musculoskeletal Back pain,and connective Groin paintissue disorders

Renal and urinary Haematuriadisorders

General disorders Access site Injection siteand administration haemorrhage, reactionssite conditions Vessel puncture (Injection sitesite haematoma discomfort,>5 cm, Injection sitepain, Puncture

Vessel puncturesite reaction)site haematoma<5 cmd

Investigations INR increased

Injury, poisoning Reperfusionand procedural injury (no orcomplications slow reflow),

Contusion

a. ADRs identified in post-marketing experience

b. Compartment syndrome has been reported as a complication of forearm haematoma following administrationof bivalirudin via the radial access route in post-marketing experience

c. Further detail regarding stent thrombosis is provided in section 4.8: The HORIZONS Trial (Patients with

STEMI undergoing primary PCI). For instructions for monitoring acute stent thrombosis, see section 4.4.

d. Section 4.4 describes precautions for INR monitoring when bivalirudin is co-administered with warfarin.

In all clinical studies bleeding data were collected separately from adverse reactions and aresummarised in Table 6 together with the bleeding definitions used for each study.

The HORIZONS Trial (Patients with STEMI undergoing primary PCI)

Platelets, bleeding and clotting

In the HORIZONS study both major and minor bleeding occurred commonly (1/100 and <1/10). Theincidence of major and minor bleeding was significantly less in patients treated with bivalirudin versuspatients treated with heparin plus a GP IIb/IIIa inhibitor. The incidence of major bleeding is shown in

Table 6. Major bleeding occurred most frequently at the sheath puncture site. The most frequent eventwas a haematoma <5 cm at puncture site.

In the HORIZONS study, thrombocytopenia was reported in 26 (1. 6%) of bivalirudin-treated patientsand in 67 (3.9%) of patients treated with heparin plus a GP IIb/IIIa inhibitor. All of these bivalirudin-treated patients received concomitant acetylsalicylic acid, all but 1 received clopidogrel and 15 alsoreceived a GP IIb/IIIa inhibitor.

The ACUITY Trial (Patients with unstable angina/non-ST segment elevated myocardial infarction(UA/NSTEMI))

The following data are based on a clinical study of bivalirudin in 13,819 patients with ACS; 4,612were randomised to bivalirudin alone, 4,604 were randomised to bivalirudin plus GP IIb/IIIa inhibitorand 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 thebivalirudin 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 and2.1% experienced an adverse reaction. Adverse event reactions for bivalirudin are listed by systemorgan class in Table 1.

Platelets, bleeding and clotting

In ACUITY, bleeding data were collected separately from adverse reactions.

Major bleeding was defined as any one of the following: intracranial, retroperitoneal, intraocular,access site haemorrhage requiring radiological or surgical intervention, ≥5 cm diameter haematoma atpuncture site, reduction in haemoglobin concentration of ≥4 g/dl without an overt source of bleeding,reduction in haemoglobin concentration of ≥3 g/dl with an overt source of bleeding, re-operation forbleeding or use of any blood product transfusion. Minor bleeding was defined as any observedbleeding event that did not meet the criteria as major. Minor bleeding occurred very commonly(1/10) and major bleeding occurred commonly (1/100 and <1/10).

Major bleeding rates are shown in Table 6 for the IIT population and Table 7 for the per protocolpopulation (patients receiving clopidogrel and acetylsalicylic acid). Both major and minor bleeds weresignificantly less frequent with bivalirudin alone than the heparin plus GP IIb/IIIa inhibitor andbivalirudin plus GP IIb/IIIa inhibitor groups. Similar reductions in bleeding were observed in patientswho were switched to bivalirudin from heparin-based therapies (N = 2,078).

Major bleeding occurred most frequently at the sheath puncture site. Other less frequently observedbleeding 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 6out of the 10 patients also received a GP IIb/IIIa inhibitor. Mortality among these patients was nil.

The REPLACE-2 Trial (Patients undergoing PCI)

The following data is based on a clinical study of bivalirudin in 6,000 patients undergoing PCI, half ofwhom were treated with bivalirudin (REPLACE-2). Adverse events were more frequent in femalesand in patients more than 65 years of age in both the bivalirudin and the heparin-treated comparatorgroups 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 1.

Platelets, bleeding and clotting

In REPLACE-2, bleeding data were collected separately from adverse events. Major bleeding rates forthe intent-to-treat trial population are shown in Table 6.

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 orpacked red blood cells, or bleeding resulting in a haemoglobin drop of more than 3 g/dl, or a fall inhaemoglobin greater than 4 g/dl (or 12% of haematocrit) with no bleeding site identified. Minorhaemorrhage was defined as any observed bleeding event that did not meet the criteria for a majorhaemorrhage. Minor bleeding occurred very commonly (1/10) and major bleeding occurredcommonly (1/100 and <1/10).

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 sheathpuncture 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 ofthese patients received concomitant acetylsalicylic acid and clopidogrel, and 10 out of 20 patients alsoreceived a GP IIb/IIIa inhibitor. Mortality among these patients was nil.

Acute cardiac events

The HORIZONS Trial (Patients with STEMI undergoing primary PCI)

The following data are based on a clinical study of bivalirudin in patients with STEMI undergoingprimary PCI; 1,800 patients were randomised to bivalirudin alone, 1,802 were randomised to heparinplus 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 systemorgan class in Table 1.The incidence of stent thrombosis within the first 24 hours was 1.5% in patientsreceiving 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 stentthrombosis between 24 hours and 30 days was 1. 2% in patients receiving bivalirudin versus 1.9% inpatients receiving UFH plus GP IIb/IIIa inhibitor (p=0.1553). A total of 17 deaths occurred aftersubacute stent thrombosis, 3 in the bivalirudin arm and 14 in the UFH plus GP IIb/IIIa arm. There wasno statistically significant difference in the rates of stent thrombosis between treatment arms at30 days (p=0.3257) and 1 year (p=0.7754).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Cases of overdose of up to 10 times the recommended dose have been reported in clinical trials. Singlebolus doses of bivalirudin up to 7.5 mg/kg have also been reported. Bleeding has been observed insome reports of overdose.

In cases of overdose, treatment with bivalirudin should be immediately discontinued and the patientmonitored closely for signs of bleeding.

In the event of major bleeding, treatment with bivalirudin should be immediately discontinued. Thereis no known antidote to bivalirudin, however, bivalirudin is haemo-dialysable.

Pharmacotherapeutic group: antithrombotic agents, Direct thrombin inhibitors, ATC code: B01AE06.

Angiox contains bivalirudin, a direct and specific thrombin inhibitor that binds both to the catalyticsite 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 fibrinmonomers 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, promotingfurther 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 slowlycleaves 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 timeto become a competitive inhibitor enabling initially inhibited thrombin molecules to interact with otherclotting 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 serafrom patients with a history of Heparin-Induced Thrombocytopenia/Thrombosis Syndrome(HIT/HITTS).

In healthy volunteers and patients, bivalirudin exhibits dose- and concentration-dependentanticoagulant activity as evidenced as prolongation of the ACT, aPTT, PT, INR and TT. Intravenousadministration of bivalirudin produces measurable anticoagulation within minutes.

The pharmacodynamic effects of bivalirudin may be assessed using measures of anticoagulationincluding the ACT. The ACT value is positively correlated with the dose and plasma concentration ofbivalirudin administered. Data from 366 patients indicates that the ACT is unaffected by concomitanttreatment with a GP IIb/IIIa inhibitor.

In clinical studies bivalirudin has been shown to provide adequate anticoagulation during PCIprocedures.

The HORIZONS Trial (Patients with STEMI undergoing primary PCI)

The HORIZONS trial was a prospective, dual arm, single blind, randomised, multi-centre trial toestablish the safety and efficacy of bivalirudin in patients with STEMI undergoing a primary PCIstrategy with stent implantation with either a slow release paclitaxel-eluding stent (TAXUS™) or anotherwise identical uncoated bare metal stent (Express2™). A total of 3,602 patients were randomisedto receive either bivalirudin (1,800 patients) or unfractionated heparin plus a GP IIb/IIIa inhibitor(1,802 patients). All patients received acetylsalicylic acid and clopidogrel with twice as many patients(approximately 64%) receiving a 600mg loading dose of clopidogrel than a 300mg loading dose ofclopidogrel. 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 patientstreated 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 shownin Table 2.Results at 1 year were consistent with results at 30 days.

Bleeding definitions and outcomes from the HORIZONS trial are shown in Table 6.

Table 2. HORIZONS 30-day study results (intent-to-treat population)

Endpoint Bivalirudin Unfractionated heparin + GP Relative p-(%) IIb/IIIa inhibitor (%) Risk value*[95% CI]

N = 1,800 N = 1,80230 day Composite

MACE 5.4 5.5 0.98 0.8901[0.75, 1.29]

Major bleeding 5.1 8.8 0.58 <0.0001[0.45, 0.74]

Ischaemic Components

All cause death 2.1 3.1 0.66 0.0465[0.44, 1.0]

Reinfarction 1.9 1.8 1.06 0.8003[0.66, 1.72]

Ischaemic target vessel 2.5 1.9 1.29 0.2561revascularisation [0.83,1.99]

Stroke 0.8 0.7 1.17 0.6917[0.54, 2.52]

*Superiority p-value. Major Adverse Cardiac/Ischaemic Events (MACE) was defined as theoccurrence of any of the following; death, reinfarction, stroke or ischaemic target vesselrevascularisation. Major bleeding was defined using the ACUITY bleeding scale.

ACUITY Trial (Patients with unstable angina/non-ST segment elevated myocardial infarction(UA/NSTEMI)

The ACUITY trial was a prospective, randomised open-label, trial of bivalirudin with or without

GP IIb/IIIa inhibitor (Arms B and C respectively) versus unfractionated heparin or enoxaparin with

GP IIb/IIIa inhibitor (Arm A) in 13,819 high risk ACS patients.

In Arms B and C of the ACUITY trial, the recommended dose of bivalirudin was an initial post-randomisation intravenous bolus of 0.1 mg/kg followed by a continuous intravenous infusion of0.25 mg/kg/h during angiography or as clinically warranted.

For patients undergoing PCI, an additional intravenous bolus of 0.5 mg/kg bivalirudin wasadministered and the rate of intravenous infusion increased to 1.75 mg/kg/h.

In Arm A of the ACUITY trial, UFH or enoxaparin was administered in accordance with the relevantguidelines for the management of ACS in patients with UA and NSTEMI. Patients in Arms A and Bwere also randomised to receive a GP IIb/IIIa inhibitor either upfront at the time of randomization(prior to angiography) or at the time of PCI. A total of 356 (7.7%) of patients randomised to Arm Calso received a GP IIb/IIIa inhibitor.

High risk patient characteristics of the ACUITY population that mandated angiography within72 hours were balanced across the three treatment arms. Approximately 77% of patients had recurrentischaemia, approximately 70% had dynamic ECG changes or elevated cardiac biomarkers,approximately 28% had diabetes and approximately 99% of patients underwent angiography within72 hours.

Following angiographic assessment, patients were triaged to either medical management (33%), PCI(56%) or CABG (11%). Additional anti-platelet therapy utilised in the study included acetylsalicylicacid and clopidogrel.

The primary analysis and results for ACUITY at 30-days and 1 year for the overall (ITT) populationand for the patients that received acetylsalicylic acid and clopidogrel as per protocol (pre-angiographyor pre-PCI) are shown in Tables 3 and 4.

Table 3. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemicendpoint and its components for the overall population (ITT)

Overall population (ITT)

Arm A Arm B

Arm C

UFH/enox bival +GP B - A C - Abival+GP IIb/IIIa IIb/IIIa Risk diff. Risk diff.aloneinhibitor inhibitor (95% CI) (95% CI)(N=4,612)(N=4,603) (N=4,604)%% %30-day

Composite 7.3 7.7 0.48 7.8 0.55ischaemia (-0.60, 1.55) (-0.53, 1.63)

Death 1.3 1.5 0.17 1.6 0.26(-0.31, 0.66) (-0.23, 0.75)

MI 4.9 5.0 0.04 5.4 0.45(-0.84, 0.93) (-0.46, 1.35)

Unplanned 2.3 2.7 0.39 2.4 0.10revasc. (-0.24, 1.03) (-0.51, 0.72)1-year

Composite 15.3 15.9 0.65 16.0 0.71ischaemia (-0.83, 2.13) (-0.77, 2.19)

Death 3.9 3.8 0.04 3.7 -0.18(-0.83, 0.74) (-0.96, 0.60)

MI 6.8 7.0 0.19 7.6 0.83(-0.84, 1.23) (-0.22, 1.89)

Unplanned 8.1 8.8 0.78 8.4 0.37revasc. (-0.36, 1.92) (-0.75, 1.50)

Table 4. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemicendpoint and its components for patients that received acetylsalicylic acid andclopidogrel as per protocol*

Patients receiving acetylsalicylic acid & clopidogrel as per protocol*

Arm A Arm B

Arm C

UFH/enox bival +GP B - A C - Abival+GP IIb/IIIa IIb/IIIa Risk diff. Risk diff.aloneinhibitor inhibitor (95% CI) (95% CI)(N=2,911)(N=2,842) (N=2,924)%% %30-day

Composite 7.4 7.4 0.03 7.0 -0.35ischaemia (-1.32, 1.38) (-1.68, 0.99)

Death 1.4 1.4 -0.00 1.2 -0.14(-0.60, 0.60) (-0.72, 0.45)

MI 4.8 4.9 0.04 4.7 -0.08(-1.07, 1.14) (-1.18, 1.02)

Unplanned 2.6 2.8 0.23 2.2 -0.41revasc. (-0.61, 1.08) (-1.20, 0.39)1-year

Composite 16.1 16.8 0.68 15.8 -0.35ischaemia (-1.24, 2.59) (-2.24, 1.54)

Death 3.7 3.9 0.20 3.3 -0.36(-0.78, 1.19) (-1.31, 0.59)

MI 6.7 7.3 0.60 6.8 0.19(-0.71, 1.91) (-1.11, 1.48)

Unplanned 9.4 10.0 0.59 8.9 -0.53revasc. (-0.94, 2.12) (-2.02, 0.96)

*clopidogrel pre-angiography or pre-PCI

The incidence of both ACUITY-scale and TIMI-scale bleeding events up to day 30 for the intent-to-treat population is presented in Table 6. The incidence of both ACUITY-scale and TIMI-scalebleeding events to day 30 for the per protocol population are presented in Table 7. The advantage ofbivalirudin over UFH/enoxaparin plus GP IIb/IIIa inhibitor in terms of bleeding events was onlyobserved in the bivalirudin monotherapy arm.

The REPLACE-2 Trial (Patients undergoing PCI)

The 30-day results based on quadruple and triple endpoints from a randomized, double-blind trial ofover 6,000 patients undergoing PCI (REPLACE-2) are shown in Table 5. Bleeding definitions andoutcomes from the REPLACE-2 trial are shown in Table 6.

Table 5. REPLACE-2 study results: 30-day endpoints (intent-to-treat and per-protocolpopulations

Intent-to-treat Per-protocolheparinheparin GPbivalirudin bivalirudin

Endpoint  GP IIb/IIIa

IIb/IIIa(N=2,994) inhibitor (N=2,902)inhibitor% (N=3,008) %(N=2,882)%%

Quadruple endpoint 9.2 10.0 9.2 10.0

Triple endpoint* 7.6 7.1 7.8 7.1

Components:

Death 0.2 0.4 0.2 0.4

Myocardial Infarction 7.0 6.2 7.1 6.4

Major bleeding** (based on non- 2.4 4.1 2.2 4.0

TIMI criteria - see section 4.8)

Urgent revascularisation 1.2 1.4 1.2 1.3

* excludes major bleeding component. **p0.001

Table 6. Major bleeding rates in clinical trials of bivalirudin 30 day endpoints for intent-to-treat populations

Bivalirudin (%) Bival + UFH/Enox + GP IIb/IIIa

GP inhibitor (%)

IIb/IIIainhibitor(%)

REPLACE- ACUITY HORIZONS ACUITY REPLACE- ACUITY HORIZONS2 2

N = 2,994 N = 4,612 N = 1,800 N = 4,604 N = 3,008 N = 4,603 N = 1,802

Protocoldefined 2.4 3.0 5.1 5.3 4.1 5.7 8.8majorbleeding

TIMI

Major 0.4 0.9 1.8 1.8 0.8 1.9 3.2(non-

CABG)

Enoxaparin was used as comparator in ACUITY only.

Table 7. ACUITY trial; bleeding events up to day 30 for the population of patients whoreceived acetylsalicylic acid and clopidogrel as per protocol*

UFH/enox + GP IIb/IIIa Bival + GP IIb/IIIa Bival aloneinhibitor (N= 2,842) % inhibitor (N=2,924) (N=2,911) %%

ACUITY scale major 5.9 5.4 3.1bleeding

TIMI scale major 1.9 1.9 0.8bleeding

*clopidogrel pre-angiography or pre-PCI

Bleeding Definitions

REPLACE-2 major bleeding was defined as the occurrence of any of the following: intracranialhaemorrhage, retroperitoneal haemorrhage, blood loss leading to a transfusion of at least two units ofwhole blood or packed red blood cells, or bleeding resulting in a haemoglobin drop of more than3 g/dl, or a fall in haemoglobin greater than 4 g/dl (or 12% of haematocrit) with no bleeding siteidentified. ACUITY major bleeding was defined as any one of the following: intracranial,retroperitoneal, intraocular, access site haemorrhage requiring radiological or surgical intervention,≥5 cm diameter haematoma at puncture site, reduction in haemoglobin concentration of ≥4 g/dlwithout an overt source of bleeding, reduction in haemoglobin concentration of ≥3 g/dl with an overtsource of bleeding, re-operation for bleeding, use of any blood product transfusion. Major bleeding inthe HORIZONS study was also defined using the ACUITY scale. TIMI major bleeding wasdefined as intracranial bleeding or a decrease in haemoglobin concentration ≥5 g/dl.

Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia-thrombosissyndrome (HIT/HITTS)

Clinical trials in a small number of patients have provided limited information about the use of Angioxin patients with HIT/HITTS.

In clinical study TMC-BIV-07-01, the pharmacodynamic response as measured by ACT wasconsistent with adult studies. The ACT increased in all patients - from neonates to older children aswell as adults- with increasing bivalirudin concentrations. The ACT vs concentration data suggest atrend for a lower concentration response curve for adults as compared to older children (6 years to< 16 years) and younger children (2 years to <6 years), and for older children compared to infants(31 days to <24 months) and neonates (birth to 30 days). Pharmacodynamic models indicated that thiseffect is due to a higher baseline ACT in neonates and infants than in older children. However, themaximal ACT values for all groups (adults and all paediatric groups) converge at a similar level nearan ACT of 400 seconds. The clinical utility of ACT in neonates and children should be consideredwith caution considering their developmental haematological state.

Thrombotic (9/110, 8.2%) and major bleeding events (2/110, 1.8%) were observed in the study. Otherfrequently reported adverse events were decreased pedal pulse, catheter site haemorrhage, abnormalpulse, and nausea (8.2%, 7.3%, 6.4% and 5.5%, respectively). Five patients had a post-baseline nadirplatelet count of <150,000 cells/mm , representing a ≥50% decrease in platelets from baseline. All 5events were associated with additional cardiac procedures employing heparin anticoagulation (n=3) orwith infections (n=2). A population pharmacokinetic/pharmacodynamic analysis, and an Exposure and

Adverse Event Assessment Model based on the data from this study determined that in paediatricpatients, use of the adult dosing with plasma levels similar to that achieved in adults was associatedwith lower levels of thrombotic events with no impact on bleeding events (see section 4.2).

The pharmacokinetic properties of bivalirudin have been evaluated and found to be linear in patientsundergoing Percutaneous Coronary Intervention and in patients with ACS.

The bioavailability of bivalirudin for intravenous use is complete and immediate. The mean steady-state concentration of bivalirudin following a constant intravenous infusion of 2.5 mg/kg/h is12.4 µg/ml.

Bivalirudin is rapidly distributed between plasma and extracellular fluid. The steady-state volume ofdistribution is 0.1 l/kg. Bivalirudin does not bind to plasma proteins (other than thrombin) or to redblood cells.

As a peptide, bivalirudin is expected to undergo catabolism to its constituent amino acids, withsubsequent recycling of the amino acid in the body pool. Bivalirudin is metabolized by proteases,including thrombin. The primary metabolite resulting from the cleavage of Arg3-Pro4 bond of the N-terminal sequence by thrombin is not active because of the loss of affinity to the catalytic active site ofthrombin. About 20% of bivalirudin is excreted unchanged in the urine.

The concentration-time profile following intravenous administration is well described by a two-compartment model. Elimination follows a first order process with a terminal half-life of 25  12minutes in patients with normal renal function. The corresponding clearance is about3.4  0.5 ml/min/kg.

Hepatic Insufficiency

The pharmacokinetics of bivalirudin have not been studied in patients with hepatic impairment but arenot expected to be altered because bivalirudin is not metabolized by liver enzymes such as cytochrome

P-450 isozymes.

Renal Insufficiency

The systemic clearance of bivalirudin decreases with glomerular filtration rate (GFR). The clearanceof bivalirudin is similar in patients with normal renal function and those with mild renal impairment.

Clearance is reduced by approximately 20% in patients with moderate or severe renal impairment, and80% in dialysis-dependent patients (Table 8).

Table 8. Pharmacokinetic parameters for bivalirudin in patients with normal and impairedrenal function

Renal function (GFR) Clearance Half-life (minutes)(ml/min/kg)

Normal renal function (≥ 90ml/min) 3.4 25

Mild renal impairment (60-89 ml/min) 3.4 22

Moderate renal impairment (30-59 ml/min) 2.7 34

Severe renal impairment (10-29 ml/min) 2.8 57

Dialysis dependent patients (off-dialysis) 1.0 3.5 hours

Pharmacokinetics have been evaluated in elderly patients as part of a renal pharmacokinetic study.

Dose adjustments for this age group should be on the basis of renal function, see section 4.2.

There are no gender effects in the pharmacokinetics of bivalirudin.

In a clinical trial of 110 paediatric patients (neonates to <16 years of age) undergoing percutaneousintravascular procedures, the safety, pharmacokinetic and pharmacodynamic profile of bivalirudin wasevaluated [TMC-BIV-07-01]. The approved adult weight-based intravenous bolus dose of 0.75 mg/kgfollowed by an infusion of 1.75 mg/kg/hour was studied and pharmacokinetic/pharmacodynamicanalysis found a response similar to that of adults, although weight-normalized clearance (ml/min/kg)of bivalirudin was higher in neonates than in older children and decreased with increasing age.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety,pharmacology, repeated dose toxicity, genotoxicity, or toxicity to reproduction.

Toxicity in animals upon repeated or continuous exposure (1 day to 4 weeks at exposure levels of upto 10 times the clinical steady state plasma concentration) was limited to exaggerated pharmacologicaleffects. Comparison of the single and repeated dose studies revealed that toxicity was related primarilyto duration of exposure. All the undesirable effects, primary and secondary, resulting from excessivepharmacological activity were reversible. Undesirable effects that resulted from prolongedphysiological stress in response to a non-homeostatic state of coagulation were not seen after shortexposure comparable to that in clinical use, even at much higher doses.

Bivalirudin is intended for short-term administration and therefore no data on the long-termcarcinogenic potential of bivalirudin are available. However, bivalirudin was not mutagenic orclastogenic in standard assays for such effects.

Mannitol

Sodium hydroxide 2% (for pH adjustment)

The following medicinal products should not be administered in the same intravenous line asbivalirudin since they result in haze formation, micro-particulate formation or gross precipitation;alteplase, amiodarone HCl, amphotericin B, chlorpromazine hydrochloride (HCl), diazepam,prochlorperazine edisylate, reteplase, streptokinase and vancomycin HCl.

The following six medicinal products show dose-concentration incompatibilities with bivalirudin.

Table 9 summarises compatible and incompatible concentrations of these compounds. The medicinalproducts incompatible with bivalirudin at higher concentrations are: dobutamine hydrochloride,famotidine, haloperidol lactate, labetalol hydrochloride, lorazepam and promethazine HCl.

Table 9. Medicinal products with dose concentration incompatibilities to bivalirudin.

Medicinal products with dose Compatible concentrations Incompatible concentrationsconcentration incompatibilities

Dobutamine HCl 4 mg/ml 12.5 mg/ml

Famotidine 2 mg/ml 10 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

4 years

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at2-8°C. Store in a refrigerator (2°C-8°C). Do not freeze.

Diluted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

Do not store above 25°C. Do not freeze.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2-8°C unless reconstitution/dilution has taken place incontrolled and validated aseptic conditions.

Do not store above 25°C.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Angiox is supplied as a lyophilised powder in 10 ml single use glass vials (Type 1) closed with a butylrubber stopper and sealed with a crimped aluminum seal.

Angiox is available in packs of 10 vials.

Instructions for preparation

Aseptic procedures should be used for the preparation and administration of Angiox.

Add 5 ml sterile water for injections to one vial of Angiox and swirl gently until completely dissolvedand the solution is clear.

Withdraw 5 ml from the vial, and further dilute in a total volume of 50 ml of glucose 5% solution forinjection, or sodium chloride 9 mg/ml (0.9%) solution for injection to give a final bivalirudinconcentration of 5 mg/ml.

The reconstituted/diluted solution should be inspected visually for particulate matter anddiscolouration. Solutions containing particulate matter should not be used.

The reconstituted/diluted solution will be a clear to slightly opalescent, colourless to slightly yellowsolution.

Any unused product or waste material should be disposed of in accordance with local requirements.

The Medicines Company UK Ltd115L Milton Park

Abingdon

Oxfordshire

OX14 4SA

UNITED KINGDOM

EU/1/04/289/001

Date of first authorisation: 20.09.2004

Date of latest renewal: 23.06.2014

Detailed information on this medicinal product is available on the web site of the European Medicines

Agency http://www.ema.europa.eu