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 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.

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).

To ensure appropriate administration of bivalirudin, the completely dissolved, reconstituted and diluted product should be thoroughly mixed prior to administration (see section 6.6). 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.

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

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. The safety and efficacy of a bolus dose of Angiox without the subsequent infusion has not been eva luated 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 has received Angiox.

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/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 i.v. equipment failures.

The arterial sheath can be removed 2 hours after discontinuation of the bivalirudin infusion without anticoagulation 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.

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 be administered 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 i.v. equipment failures.

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.

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.

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 (T_½ 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 (≥1/1,000 to ≤1/100) in clinical trials. Necessary preparations should be made to deal with this. Patients should be informed of the early 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 shock treatment should be applied. Anaphylaxis, including anaphylactic shock with fatal outcome has been reported 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 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.

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.

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.

No studies on the effects on the ability to drive and use machines have been performed.

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

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

The HORIZONS Trial (Patients with STEMI undergoing primary PCI)

The following 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 (≥1/100 and <1/10). The incidence of major and minor bleeding was significantly less in patients treated with bivalirudin versus patients 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 event was a haematoma <5 cm at puncture site.

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.

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; 4,6