Medicinal Products

ANGIOX 250 mg

Generic drug of the therapeutic class: Haemostasis and blood
Active ingredients: Bivalirudin
laboratory: The Medicines Company UK

Powder for concentrate for solution for injection IV or infusion
Box of 2 vials of 250 mg
All forms

Indication

Angiox is indicated as an anticoagulant in adult patients undergoing percutaneous coronary intervention (PCI), particularly in patients with ST segment elevation myocardial infarction (ST + IDM) undergoing primary PCI. Angiox is also indicated for the treatment of adult patients with unstable angina / non-ST segment elevation myocardial infarction (AI / IDM ST-) who require urgent or early intervention.

Angiox should be given with aspirin and clopidogrel.

Dosage ANGIOX 250 mg Powder for concentrate for solution for injection IV or for infusion Box of 2 vials of 250 mg

Angiox should be given by a physician specialized in the treatment of acute coronary syndrome or in coronary intervention procedures.

Dosage

Patients undergoing percutaneous coronary intervention (PCI), including primary PCI

The recommended dose of Angiox for patients receiving PCI is an intravenous bolus of 0.75 mg / kg body weight immediately followed by an intravenous infusion at a rate of 1.75 mg / kg body weight / hour for at least the entire duration of the procedure. Infusion may continue for up to 4 hours after PCI, if clinically justified. At the end of the 1.75 mg / kg / h infusion, a reduced dose of 0.25 mg / kg / h may be continued for 4 to 12 hours, depending on clinical need.

After primary PCI, patients should be closely monitored for signs or symptoms of myocardial ischemia.

Patients with unstable angina / ST-segment elevation myocardial infarction (AI / IDM ST-)

For patients with ACS, the recommended starting dose is an intravenous bolus of 0.1 mg / kg followed by an infusion of 0.25 mg / kg / h.

Patients undergoing conservative medical treatment may continue the 0.25 mg / kg / h infusion for 72 hours.

If the patient requires PCI, an additional bolus of 0.5 mg / kg of bivalirudin should be given before the procedure and the infusion increased to 1.75 mg / kg / h during the procedure. After PCI, infusion at 0.25 mg / kg / h may be maintained for 4 to 12 hours if clinically justified.

For patients with coronary bypass without CPB, intravenous (IV) infusion of bivalirudin should be maintained until intervention. Just prior to the operation, an intravenous bolus of 0.5 mg / kg should be administered followed by an infusion of 1.75 mg / kg / hr during the procedure.

For coronary bypass CABG patients, bivalirudin infusion should be maintained up to 1 hour before the operation, after which the infusion should be stopped and the patient treated with unfractionated heparin ( UFH).

In the absence of safety and efficacy data, it is not recommended to administer a single bolus of Angiox, even in the context of a short PKI.

Activated clotting time (ACT) can be used to evaluate the activity of bivalirudin.

In order to decrease the risk of low ACT values, the reconstituted and diluted product should be thoroughly mixed before use and then administered as a rapid intravenous boost bolus.

The ACT values, 5 minutes after the bivalirudin bolus, averaged 365 +/- 100 seconds. If the ACT obtained after 5 minutes is less than 225 seconds, a second bolus dose of 0.3 mg / kg should be administered.

As soon as the ACT value exceeds 225 seconds, further checks are no longer necessary provided that the 1.75 mg / kg infusion dose is given correctly.

The arterial introducer may be removed 2 hours after discontinuation of bivalirudin infusion without additional control of ACT.

Renal failure

Angiox is contraindicated in patients with severe renal impairment (GFR <30 ml / min) and in dialysis patients (see section 4.3 ).

In patients with mild-to-moderate renal impairment, it is not necessary to adjust the SCA dose (0.1 mg / kg bolus, 0.25 mg / kg / h infusion).

In patients with moderate renal impairment (GFR 30-59 ml / min) receiving PCI (whether treated with bivalirudin for SCA or not), the infusion rate should be lowered to 1.4 mg / kg / h. The bolus administered should be in accordance with the SCA or ICP dosage form described above.

Control of coagulation time is recommended during PCI in patients with renal impairment.

The ACT should be checked 5 minutes after the bolus. If the ACT is less than 225 seconds, a second bolus of 0.3 mg / kg should be given and ACT should be checked 5 minutes after the second bolus administration.

Hepatic insufficiency

No adjustment of the dose is necessary. Pharmacokinetic studies show 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 because of decreased renal function associated with age.

Pediatric patients

There is no relevant indication for the use of Angiox in children under 18 years of age.

Use with another anticoagulant treatment

In patients with ST + IDM receiving primary PCI, standard adjuvant treatment prior to hospitalization should include clopidogrel and may also include early administration of UFH (see section 5.1 Pharmacodynamic properties ).

Patients may be referred to Angiox 30 minutes after discontinuation of unfractionated heparin, administered intravenously, or 8 hours after discontinuation of low molecular weight heparin administered subcutaneously.

Angiox can be used in combination with a GPIIb / IIIa inhibitor. See Pharmacodynamic properties for more information on the use of bivalirudin with or without GP IIb / IIIa inhibitor.

Administration mode

Angiox is intended for intravenous (IV) use.

Angiox must initially be reconstituted to obtain a 50 mg / ml solution of bivalirudin. The reconstituted product should then be further diluted to a total volume of 50 ml to give a 5 mg / ml solution of bivalirudin.

The reconstituted and diluted product should be thoroughly mixed before administration.

See the topic Instructions for Use, Handling, and Disposal for all instructions regarding the mode of administration.

Angiox is given as an initial bolus (rapid IV boost), followed by IV infusion, in a weight-based dosing regimen.

Against indications

Angiox is contraindicated in patients:

• with known hypersensitivity to bivalirudin or any of the excipients of the product, or to hirudins;

• have active bleeding or an increased risk of bleeding due to hemostasis disorders and / or irreversible bleeding disorders;

• with uncontrolled severe hypertension

• with subacute bacterial endocarditis.

• with severe renal impairment (GFR <30 ml / min) and in dialysis patients.

Angiox side effects

Adverse reactions reported with bivalirudin in the HORIZONS, ACUITY, and REPLACE-2 trials or in post-marketing surveillance are reported by organ-system in Table 1.

In all clinical studies, bleeding data were collected separately from adverse reaction data; they are summarized in Table 6, which also gives the definitions of bleeding used for each study.

The HORIZONS study (ST + IDM patients with primary PCI)

The following data are from a clinical study conducted with bivalirudin in patients with ST + IDM receiving primary PCI; 1800 patients were randomized to receive bivalirudin alone and 1802 patients to receive heparin plus a GPIIb / IIIa inhibitor. Adverse events were more common in the heparin plus GP IIb / IIIa inhibitor group than in the bivalirudin group.

A total of 55.1% of patients receiving bivalirudin experienced at least one adverse event and 8.7% experienced a drug-related adverse event. The adverse effects of bivalirudin are listed by system organ class in Table 1. The incidence of stent thrombosis in the first 24 hours (thrombosis of early or acute stents) was 1.5% in patients receiving bivalirudin and 0.3% in those receiving UFH plus GP IIb / IIIa inhibitor (p = 0.0002). Two patients died after early stent thrombosis, one patient in each arm of the study. The incidence of stent thrombosis occurring between 24 hours and 30 days (subacute stent thrombosis) was 1.2% in patients receiving bivalirudin and 1.9% in those receiving UFH plus a GP inhibitor IIb / IIIa (p = 0.1553). A total of 17 patients died after subacute stent thrombosis, 3 in the bivalirudin arm and 14 in the HNF plus GP IIb / IIIa inhibitor arm. There was no statistically significant difference in stent thrombosis rates between the treated arms at 30 days (p = 0.3257) and at 1 year (p = 0.7754).

Blood platelets, bleeding and coagulation

In the HORIZONS study, major and minor bleeding were common (≥ 1/100 and <1/10). The incidence of major and minor bleeding was significantly lower in patients treated with bivalirudin than in those treated with heparin plus a GP IIb / IIIa inhibitor. The incidence of major bleeding is shown in Table 6. The most common major bleeding occurred at the puncture site. The most commonly observed adverse effects are hematomas <5 cm at the puncture site.

In the HORIZONS study, thrombocytopenia was reported in 26 patients (1.6%) treated with bivalirudin and 67 patients (3.9%) treated with heparin plus a GP IIb / IIIa inhibitor. . In the bivalirudin group, all of these patients received concomitant aspirin therapy, all but one received clopidogrel and 15 patients received a GP IIb / IIIa inhibitor.

The ACUITY Clinical Study - Patients With Unstable Angina / ST-segment-free Myocardial Infarction (AI / IDM ST-)

The following data are based on a clinical study conducted with bivalirudin in 13, 819 patients with ACS; 4612 were treated with bivalirudin alone, 4604 were treated with bivalirudin plus GP IIb / IIIa inhibitor and 4603 treated with unfractionated heparin or with enoxaparin plus GPIIb inhibitor / IIIa. Adverse events were more common in women and patients over 65 than in males or younger patients in both the bivalirudin and heparin comparator groups.

Approximately 23.3% of patients receiving bivalirudin experienced at least one adverse event and 2.1% experienced an adverse reaction. Adverse events for bivalirudin are listed by organ system class in Table 1.

Blood platelets, bleeding and coagulation

In ACUITY, bleeding data were collected separately from those for adverse events.

In ACUITY, major bleeding was defined as one of the following events: intracranial, retroperitoneal, intraocular or access site hemorrhage requiring radiological or surgical intervention, puncture site hematoma ≥5 cm, reduction in hemoglobin ≥ 4 g / dl without manifest source of bleeding, reduction in hemoglobin ≥ 3 g / dl with obvious source of bleeding, reintervention due to bleeding or transfusion of blood product . Minor bleeding was defined as all observed bleeding events that did not meet the criteria for major bleeding. Minor bleeding was reported very frequently (≥ 1/10) and major bleeding frequently (≥ 1/100 and <1/10).

The major bleeding rates are shown in Table 6 for the ITT population and in Table 7 for the per protocol population (patients receiving clopidogrel and aspirin). Significant decreases in the frequency of major and minor bleeding were observed in patients in the Bivalidurine group alone compared to patients in the heparin plus GP IIb / IIIa group and Bivalidurine plus GP IIb / IIIa inhibitor. Similar reductions in bleeding frequency were observed in patients who started heparin therapy and switched to bivalirudin (n = 2078).

The most common major bleeding occurred at the puncture site. Other sites of less frequent bleeding, but with more than 0.1% bleeding (infrequent), were "other" puncture site, retroperitoneal site, gastrointestinal tract, ear, nose, or throat.

In the ACUITY trial, cases of thrombocytopenia were reported in 10 patients treated with bivalirudin (0.1%). The majority of these patients had concomitant treatment with acetylsalicylic acid and clopidogrel, and 6 of them also received GP IIb / IIIa inhibitors. The mortality rate in this group is zero.

The REPLACE-2 Clinical Study (Patients with PCI)

The following data are based on a clinical study (REPLACE 2) conducted with bivalirudin in 6, 000 patients undergoing PCI, half of whom were treated with bivalirudin. Adverse events were more common in women and patients over 65 years of age than in males or younger patients in both bivalirudin and heparin groups.

Approximately 30% of patients receiving bivalirudin experienced at least one adverse event and 3% experienced an adverse reaction to the drug. Adverse events for bivalirudin are listed by organ system class in Table 1.

Blood platelets, bleeding and coagulation

In REPLACE 2, bleeding data were collected separately from those for adverse events. The major bleeding rates for the intention-to-treat population participating in the trials are shown in Table 6.

Major bleeding has been defined as the occurrence of any of the following: intracranial hemorrhage, retroperitoneal hemorrhage, loss of blood requiring the transfusion of at least two units of whole blood or concentrated red blood cells, or bleeding resulting in a fall in hemoglobin of more than 3 g / dl or a fall in hemoglobin greater than 4 g / dl (or 12% of the hematocrit) without an identified bleeding site. Minor bleeding was defined as any observed haemorrhagic event that did not meet the criteria for major bleeding. Minor bleeding was reported very frequently (≥ 1/10) and major bleeding frequently (≥ 1/100 and <1/10).

Both minor and major bleeding were significantly less frequent with bivalirudin compared to the heparin comparator group plus GP IIb / IIIa inhibitor. Major bleeding occurred most frequently at the puncture site. Other sites of less frequent bleeding but with a frequency of more than 0.1% bleeding (infrequent) were "other" puncture site, retroperitoneal site, gastrointestinal tract, ear, nose or throat.

In the REPLACE-2 study, thrombocytopenia was reported in 20 patients (0.7%) treated with bivalirudin. The majority of these patients received concomitant treatment with aspirin and clopidogrel, and 10 out of 20 patients also received a GP IIb / IIIa inhibitor. The mortality rate among these patients is zero.

Table 1. Adverse reactions reported with bivalirudin in HORIZONS, ACUITY and REPLACE-2 trials and in post-market surveillance

Classes of organ systems

Very common

(≥ 1/10)

Frequent (≥ 1/100 to <1/10)

Rare

(≥ 1/1000 to <1/100)

Rare

(≥ 1 / 10, 000 to <1/1000)

Very rare

(<1 / 10, 000)

Blood and lymphatic system disorders

Increase in hemoglobin

Thrombocytopenia, anemia

Increase in INR

Heart conditions

Myocardial infarction

Cardiac tamponade

Pericardial hemorrhage

Thrombosis

coronary arteriovenous

angor

bradycardia

Ventricular tachycardia

Chest pains

Affections of the ear and labyrinth

Atrial bleeding

Eye disorders

Intraocular hemorrhage

Gastrointestinal disorders

Gastrointestinal haemorrhage (including haematemesis, melena, esophageal haemorrhage, anal bleeding), retroperitoneal haemorrhage, gum bleeding, nausea

Hemorrhage

peritoneal,

hematoma

retroperitoneal,

vomiting

General disorders and site abnormalities

administration

Haemorrhage at the puncture site, vascular hematoma at the puncture site ≥ 5 cm, vascular hematoma at the puncture site <5 cm

Injection site reactions (discomfort at the injection site, pain at the injection site, reaction at the puncture site)

Injury, poisoning and procedural complications

Reperfusion injury (no reflux or slow reflux), contusion

Affections of

system

immune

Hypersensitivity, including reaction and shock

anaphylactic, some cases that led to death

Musculoskeletal and systemic disorders

Back pain, pain in the groin

Nervous system disorders

headaches

Intracranial hemorrhage

Renal and urinary disorders

hematuria

Respiratory, thoracic and mediastinal disorders

Epistaxis,

hemoptysis,

pharyngeal hemorrhage

Pulmonary hemorrhage

Dyspnea

Skin and subcutaneous tissue disorders

bruise

Rash, hives

Vascular disorders

Minor haemorrhage, all sites combined

Major haemorrhage, all sites combined, in some cases of fatal outcome

Hematoma, hypotension

Coronary stent thrombosis, in some cases fatal outcome c

Thrombosis,

In some cases of fatal outcome,

Fistula

arteriovenous,

Catheter thrombosis,

vascular pseudoaneurysm

Comparative syndrome

at. Adverse reactions identified in post-marketing surveillance b. Compartmental syndrome has been reported in post-marketing surveillance and has been considered a complication of forearm hematoma following radial administration of bivalirudin.

c. For more details on stent thrombosis, see the section on the HORIZONS trial (Patients with ST + IDM undergoing primary PCI) in the Adverse Reactions section. Also refer to the Warnings and Precautions for Instructions section for monitoring stent thrombosis.

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