Medicinal Products

AGRASTAT 50 μg / mL

Generic drug of the therapeutic class: Haemostasis and blood
Active ingredients: Tirofiban
laboratory: Correvio

Injection solution for IV infusion
Box of 1 bag of 250 ml
All forms

Indication

AGRASTAT is indicated for the prevention of early myocardial infarction in adults with acute coronary syndrome without persistent ST-segment elevation (SCA NST), whose last episode of chest pain occurred less than 12 years ago. hours and is accompanied by electrocardiographic changes and / or elevation of cardiac enzymes.

The patients most likely to benefit from treatment with AGRASTAT are those at high risk of developing myocardial infarction within 3-4 days after the onset of symptoms of the acute angina episode, for example those likely to benefit from early percutaneous coronary intervention.

AGRASTAT is also indicated for the reduction of the risk of major cardiovascular events in patients with acute myocardial infarction (ST + IDM) who require percutaneous coronary intervention (see sections Posology and method of administration and Properties). pharmacodynamics ).

The use of AGRASTAT is recommended in combination with aspirin (ASA) and unfractionated heparin.

Dosage AGRASTAT 50 μg / mL Solution for IV infusion Pack of 1 bag of 250 ml

This medicinal product is for hospital use only, for medical specialists with experience in the management of acute coronary syndromes.

AGRASTAT should be given with unfractionated heparin and oral antiplatelet therapy such as aspirin.

Dosage

In patients benefiting from an early invasive management strategy for acute coronary syndrome without persistent ST segment elevation (SCA NST) and in whom it is not intended to perform coronary angiography within 4 hours and At 48 hours after diagnosis, AGRASTAT is administered intravenously at an initial infusion rate of 0.4 microgram / kg / min for 30 minutes.

At the end of the initial infusion, administration of AGRASTAT should be continued at an infusion rate of 0.1 microgram / kg / min.

AGRASTAT should be administered concomitantly with unfractionated heparin (usually intravenous bolus of 50-60 units (IU) / kg at the start of AGRASTAT treatment, then at approximately 1000 IU / hour, adjusting with time activated thromboplastin (TCA) which must be greater than at least twice the value of the control), and in combination with oral antiplatelet therapy, including aspirin (ASA) (see section 5.1 ). contraindication.

In SCA NST patients for whom percutaneous coronary intervention is planned within the first four hours after diagnosis or in acute myocardial infarction (STS + MI) patients who require primary percutaneous coronary intervention, AGRASTAT should be administered in the form of an initial bolus of 25 micrograms / kg injected over a period of 3 minutes, followed by continuous infusion at a rate of 0.15 microgram / kg / min for 12 to 24 hours and up to 48 hours.

AGRASTAT should be administered with unfractionated heparin (see dosage above) and oral antiplatelet therapy, including aspirin (ASA) (see section 5.1 ), in the absence of contraindications.

The elderly

No dose adjustment is necessary for elderly patients (see Warnings and Precautions ).

Patients with severe renal impairment

In patients with severe renal impairment (creatinine clearance <30 ml / min), the dosage of AGRASTAT should be reduced by 50% (see sections Warnings and Precautions and Pharmacokinetic Properties ).

Pediatric population

The safety and efficacy of AGRASTAT have not been established in children under 18 years of age.

No data available.

Table 1 is provided as an indication for dosage adjustment based on weight.

Table 1 - Dosage

Charge rate 0.4 microgram / kg / min

Bolus of 25 micrograms / kg

Most patients

Severe renal insufficiency

Most patients

Severe renal insufficiency

Patient weight (kg)

Initial infusion rate for 30 min (ml / h)

Maintenance infusion rate (ml / h)

Initial infusion rate for 30 min (ml / h)

Maintenance infusion rate (ml / h)

Bolus (ml)

Maintenance infusion rate (ml / h)

Bolus (ml)

Maintenance infusion rate (ml / h)

30-37

16

4

8

2

17

6

8

3

38-45

20

5

10

3

21

7

10

4

46-54

24

6

12

3

25

9

13

5

55-62

28

7

14

4

29

11

15

5

63-70

32

8

16

4

33

12

17

6

71-79

36

9

18

5

38

14

19

7

80-87

40

10

20

5

42

15

21

8

88-95

44

11

22

6

46

16

23

8

96-104

48

12

24

6

50

18

25

9

105-112

52

13

26

7

54

20

27

10

113-120

56

14

28

7

58

21

29

10

121-128

60

15

30

8

62

22

31

11

129-137

64

16

32

8

67

24

33

12

138-145

68

17

34

9

71

25

35

13

146-153

72

18

36

9

75

27

37

13

Start and duration of treatment with AGRASTAT

In patients with an early invasive management strategy for SCA NST who are not scheduled for coronary angiography within 4 hours and up to 48 hours after diagnosis, 0.4 microgram / kg / min of AGRASTAT should be initiated as soon as the diagnosis is made.

The recommended duration of the maintenance infusion is at least 48 hours. The infusion of AGRASTAT and unfractionated heparin may be continued during coronary angiography, and should be continued for at least 12 hours, not exceeding 24 hours after percutaneous coronary intervention. The infusion should be stopped when the patient is clinically stable and no coronary intervention is planned by the attending physician. The total duration of treatment should not exceed 108 hours.

If a patient diagnosed with NTS SCA and managed with an invasive strategy has coronary angiography within 4 hours of diagnosis, AGRASTAT should be given as a 25 microgram / kg bolus at the beginning of the coronary intervention. percutaneous followed by continuous infusion for 12 to 24 hours and up to 48 hours.

In patients with acute myocardial infarction (IDM ST +) who require percutaneous coronary intervention, the initial bolus of 25 microgram / kg should be started as soon as possible after diagnosis.

Concomitant treatments (unfractionated heparin, oral platelet antiaggregant, including aspirin)

Treatment with unfractionated heparin should be started with an intravenous bolus of 50-60 IU / kg, followed by maintenance infusion at a rate of 1000 IU per hour. The dosage of heparin is adjusted to maintain the TCA at approximately twice the value of the control.

In the absence of a contraindication, all patients should receive an oral platelet antiaggregant, including aspirin, prior to initiation of AGRASTAT therapy (see section 5.1 Pharmacodynamic properties ). This treatment should be continued for at least the duration of the AGRASTAT infusion.

Most studies evaluating AGRASTAT treatment in addition to percutaneous coronary intervention have used aspirin in combination with clopidogrel as an oral antiplatelet therapy. The efficacy of the combination of AGRASTAT with prasugrel or ticagrelor has not been established in randomized controlled trials.

If percutaneous coronary intervention is required, heparin should be discontinued after this procedure, and the vest should be removed after restoration of adequate hemostasis, ie when ACT (Activated Clotting Time) is below at 180 seconds (usually 2 to 6 hours after stopping heparin).

Instructions on handling

Do not take the solution directly from the bag with a syringe.

How to use IntraVia Pouches

To open: tear off the overwrap or dust-proof plastic protector at the notch on the edge, and remove the IntraVia pocket . The plastic may exhibit some opacity due to the absorption of moisture during the sterilization process. This phenomenon is normal and does not affect the quality or safety of the solution. The opacity will gradually fade. Check for leaks by squeezing the inner bag. In case of leakage, discard the solution as sterility may be compromised.

Use only if the solution is clear and the pouch sealed.

Do not add other medication, and do not take solution directly from the pouch with a syringe.

CAUTION: Do not use plastic bags fitted in series. Such use could result in air embolism due to the residual air taken from the first bag, before the administration of the solution of the second bag is completed.

Preparation for administration

1. Hang the bag by the eyelet provided for this purpose.

2. Remove the plastic cover from the outlet on the bottom of the bag.

3. Connect the administration device. Refer to the complete instructions attached to this device.

Administer at the dosage indicated in Table 1.

Perform a visual check before use. Only clear solutions without particles can be used.

AGRASTAT should only be administered intravenously and can be injected through the same infusion line as unfractionated heparin.

It is recommended to administer AGRASTAT with a controlled rate infusion system using sterile equipment.

Care should be taken to ensure that the infusion of the loading dose is not continued beyond the recommended duration and to avoid any error in the calculation of the maintenance infusion rate based on the patient's weight.

Against indications

AGRASTAT is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients of the formulation mentioned in the Composition section, or who have developed thrombocytopenia when previously administered GP receptor antagonist IIb / IIIa.

Due to the fact that inhibition of platelet aggregation increases the risk of bleeding, AGRASTAT is contraindicated in patients with:

· A history of a stroke that is less than 30 days old or any history of a hemorrhagic stroke,

· A known history of intracranial pathology (eg tumor, arteriovenous malformation, aneurysm),

· Current or recent bleeding (in the 30 days prior to treatment), clinically significant (eg, gastrointestinal bleeding),

· Malignant hypertension,

· Experienced major trauma or major surgery in the last six weeks,

· Thrombocytopenia (platelet count <100, 000 / mm 3 ), platelet function disorders,

· Disorders of coagulation (for example time of Quick> 1.3 times normal or INR (International Normalized Ratio)> 1.5),

· Severe liver failure.

Agrastat side effects

Summary of the security profile

The most frequently reported adverse reaction during treatment with AGRASTAT, in concomitant use with heparin, aspirin, and other antiplatelet agents, was bleeding, usually minor mucocutaneous or minor bleeding at the puncture site.

Gastrointestinal, retroperitoneal, intracranial, hemorrhoidal and postoperative bleeding, including epidural hematoma in the spinal region, haemopericardium and pulmonary (alveolar) haemorrhage have also been reported. In the AGRASTAT pivotal studies, the TIMI major and intracranial bleeding rates were <2.2% and <0.1%, respectively. The most serious adverse effect was fatal bleeding.

In pivotal studies, administration of AGRASTAT was associated with thrombocytopenia (platelet count <90, 000 / mm 3 ), which occurred in 1.5% of patients treated with AGRASTAT and heparin. The incidence of severe thrombocytopenia (platelet count <50 000 / mm 3 ) was 0.3%. The most common adverse events observed with simultaneous administration of AGRASTAT and aspirin, other than bleeding, were nausea (1.7%), fever (1.5%) and headache (1%)., 1%).

Table summarizing the adverse effects

Table 2 presents a list of adverse events based on data from six double-blind controlled clinical trials (recruiting 1953 patients receiving AGRASTAT plus heparin), as well as from post-marketing data. .

Adverse reactions are presented in the table below according to organ system and frequency, using the following categories: very common (≥1 / 10); frequent (≥1 / 100 and <1/10); uncommon (≥ 1/1000 and <1/100); rare (≥ 1/10 000 and <1/1000); very rare (<1 / 10, 000); indeterminate frequency (can not be estimated from the available data). Due to the fact that adverse events occurring in post-marketing situations arise from spontaneous reports from a population of uncertain size, it is not possible to determine their exact incidence. Therefore, the frequency of these adverse reactions is classified as unknown.

Table 2: Adverse events observed in clinical trials and post-marketing.

ORGAN SYSTEM

Very common

Frequent

Rare

Not known frequency

Blood and lymphatic system disorders

Abrupt and / or severe reduction in the number of platelets (<20 000 / mm 3 )

Immune system disorders

Severe allergic reactions including anaphylactic reactions

Nervous system disorders

headaches

Intracranial bleeding, epidural intraspinal hematoma

Heart conditions

haemopericardium

Vascular disorders

hematoma

Respiratory, thoracic and mediastinal disorders

Hemoptysis, epistaxis

Pulmonary haemorrhage (alveolar)

Gastrointestinal disorders

nausea

Oral haemorrhage, gingival hemorrhage

Gastrointestinal haemorrhage, hematemesis

Retroperitoneal bleeding

Skin and subcutaneous tissue disorders

bruising

Renal and urinary disorders

hematuria

General disorders and administration site conditions

Fever

Injury, poisoning and procedural complications

Post operative bleeding *

Hemorrhage at the puncture point of the vessels

investigations

Occult bleeding in the stool or urine

Decreased hematocrit, hemoglobin, platelets (<90, 000 / mm 3)

Platelets <50, 000 / mm 3

* Mainly related to the catheterization site

bleeding

With an infusion of 0.4 microgram / kg / min, and with the bolus of 25 micrograms / kg, the rates of major bleeding complications are low and not significantly higher.

In the PRISM-PLUS study, which used the AGRASTAT infusion regimen at 0.4 microgram / kg / min, the incidence of major bleeds according to the TIMI classification was 1.4% for AGRASTAT in combination with heparin and 0.8% for heparin alone. The incidence of minor bleeding according to the TIMI classification was 10.5% for AGRASTAT in combination with heparin and 8.0% for heparin alone. The percentage of patients who received a transfusion was 4.0% for AGRASTAT in combination with heparin and 2.8% for heparin alone.

With the AGRASTAT bolus of 25 micrograms / kg, ADVANCE data show that the number of bleeds is low and does not appear to increase significantly compared to placebo. In both groups, no major bleeding according to the TIMI classification was observed and no transfusion occurred. The minor bleeds according to the TIMI classification with the AGRASTAT bolus of 25 micrograms / kg were 4% compared to 1% in the placebo group (p = 0.19).

In the ON-TIME 2 study, there was no significant difference in major bleeding according to the TIMI classification (3.4% vs. 2.9% p = 0.58) or minor bleeding according to the TIMI classification (5.9% vs. 4.4%, p = 0.206) between the bolus of 25 micrograms / kg of AGRASTAT and the control group.

The rates of major bleeding (2.4% vs. 1.6%, p = 0.44) or minor bleeding (4.8% vs. 6.2%, p = 0.4) according to the TIMI classification were not significantly different. between the 25 micrograms / kg dose of AGRASTAT and the standard dose of abciximab, which were compared in the MULTISTRATEGY study.

Based on an evaluation of reported hemorrhagic complications in a meta-analysis (n = 4076 SCA patients), the 25 microgram / kg bolus of AGRASTAT did not significantly increase the number of major bleeds or thrombocytopenia when it occurred. compared to placebo. The results of individual studies comparing the bolus of 25 micrograms / kg of AGRASTAT to abciximab, show no significant difference in major bleeding between the two treatments.

thrombocytopenia

A sudden drop in platelet count or thrombocytopenia occurred more frequently during AGRASTAT treatment than in the placebo group. These decreases were reversible after stopping AGRASTAT. Acute and severe decreases in platelet count (platelet count <20 000 / mm 3 ) were observed in patients without prior thrombocytopenia when re-administering GP IIb / IIIa receptor antagonists, and could be associated with chills, mild fever or hemorrhagic complications.

Analysis of studies comparing the 25 microgram / kg bolus versus abciximab showed a significant reduction in thrombocytopenia with AGRASTAT (0.45% vs. 1.7%, OR = 0.31; p = 0.004).

Allergic reactions

Severe allergic reactions (eg bronchospasm, urticaria) including anaphylactic reactions occurred during initial treatment (also on day one) and during re-administration of AGRASTAT. Some cases have been associated with severe thrombocytopenia (platelet count <10 000 / mm 3 ).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals declare any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (Ansm) and the network of Regional Pharmacovigilance Centers - Website: www.ansm.sante.fr.

Popular Posts

Category Medicinal Products, Next Article