Antithrombotic

Bivalirudin

Each vial contains 250 mg bivalirudin. After reconstitution 1 ml contains 50 mg bivalirudin. After dilution 1 ml contains 5 mg bivalirudin.

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

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.

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.

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.

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.

Angiox is administered as a weight based regimen consisting of an initial bolus (by rapid IV push) followed by an IV infusion.

There is no relevant indication for use of Angiox in children less than 18 years old.

Caution should be exercised in the elderly due to age-related decrease in renal function.

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. 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. 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.

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). 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.

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 (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 8. 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.

Table 1. HORIZONS trial; adverse drug reaction data

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, 5 cm diameter haematoma at puncture 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 for bleeding or use of any blood product transfusion. Minor bleeding was defined as any observed bleeding 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 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

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 (1/10) and major bleeding occurred commonly (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 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

The Medicines Company

(POM)

13 February 2012