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 bivalirudin for patients undergoing PCI is an intravenous bolus of 0.75 mg/kg body weight followed immediately by an intravenous infusion at a rate of 1.75 mg/kg body weight/hour for at least the duration of the procedure. The infusion of 1.75 mg/kg body weight/hour may be continued for up to 4 hours post-PCI as clinically warranted and further continued at a reduced infusion dose of 0.25 mg/kg/h for 4 – 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 bivalirudinfor patients with acute coronary syndrome (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 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 intravenous infusion for the duration of the surgery.
For patients who proceed to CABG surgery on pump, the intravenous 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 bivalirudin 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 bivalirudin.
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 intravenous equipment failures.
The arterial sheath can be removed 2 hours after discontinuation of the bivalirudin infusion without anticoagulation monitoring.
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. For further information regarding the use of bivalirudin with or without a GP IIb/IIIa inhibitor, please see section 5.1.
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 intravenous 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
Increased awareness due to high bleeding risk should be exercised in the elderly because of age-related decrease in renal function. Dose adjustments for this age group should be on the basis of renal function.
Paediatric patients
There is no relevant indication for use of Angiox in children less than 18 years old in all indications.
Method of administration
Angiox is intended for intravenous 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.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
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 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 following discontinuation of bivalirudin treatment.
Hypersensitivity
Allergic type hypersensitivity reactions we
