Angiox 250mg powder for concentrate for solution for injection or infusion Ref.[2569] Active ingredients: Bivalirudin

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.

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.

4 years.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2‑8°C.

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

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

Lyophilised powder: Do not store above 25°C.

Reconstituted solution: Store in a refrigerator (2–8°C). Do not freeze.

Diluted solution: Do not store above 25°C. Do not freeze.

Angiox is supplied as a lyophilised powder in 10 ml single use glass vials (Type 1) closed with a butyl rubber 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 dissolved and the solution is clear.

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

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

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

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