Medicinal Products

AGRASTAT 250 μg / ml Concentrate for solution for infusion Box of 1 bottle of 50 ml

Generic drug of the therapeutic class: Haemostasis and blood
Active ingredients: Tirofiban
laboratory: Iroko Cardio (UK) Ltd

Solution for solution for IV infusion
All forms

Indication

- AGRASTAT is indicated for the prevention of early myocardial infarction in patients with unstable angina or Q-wave myocardial infarction whose last episode of chest pain occurred within the previous 12 hours and accompanied by electrocardiographic changes and / or elevation of cardiac enzymes.
- The patients most likely to benefit from AGRASTAT treatment are those who are 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 undergo early coronary angioplasty (see also posology and method of administration and pharmacodynamic properties).
- The use of AGRASTAT is recommended in combination with aspirin and unfractionated heparin.

Dosage AGRASTAT 250 μg / ml Concentrate for solution for infusion Box of 1 bottle of 50 ml

- This medicinal product is for hospital use only, for medical specialists with experience in the management of acute coronary syndromes.
- AGRASTAT concentrate for solution for infusion should be diluted before use.
- AGRASTAT is administered intravenously at an initial infusion rate of 0.4 μg / kg / min for 30 minutes.
- At the end of the initial infusion, administration of AGRASTAT should be continued at a maintenance rate of 0.1 μg / kg / min.
- AGRASTAT should be administered concomitantly with unfractionated heparin [usually in the 5000 bolus intravenous bolus (U) at the start of AGRASTAT treatment and then at approximately 1000 U per hour, adjusting for activated partial thromboplastin time ( TCA) which should be about double the control value], and in combination with aspirin (see pharmacodynamic properties, Study PRISM PLUS), in the absence of contraindication.
- No dosage adjustment is necessary in elderly patients (see also warnings and precautions for use).
PATIENTS WITH SEVERE RENAL INSUFFICIENCY:
- In cases of severe renal impairment (creatinine clearance <30 ml / min), the dose of AGRASTAT should be reduced by 50% (see also warnings and precautions for use and pharmacokinetic properties).
- The table below is provided as an indication for dose adjustment based on weight:
AGRASTAT concentrate for infusion should first be diluted to the same concentration as AGRASTAT solution for infusion, as indicated in the instructions for use.
Most patients: Initial infusion rate for 30 min / Maintenance infusion rate // Severe renal impairment: Initial infusion rate for 30 min / Maintenance infusion rate .
. 30-37 kg: 16 ml / h / 4 ml / h // 8 ml / h / 2 ml / h.
. 38-45 kg: 20 ml / hr / 5 ml / hr // 10 ml / hr / 3 ml / hr.
. 46-54 kg: 24 ml / h / 6 ml / h // 12 ml / h / 3 ml / h.
. 55-62 kg: 28 ml / h / 7 ml / h // 14 ml / h / 4 ml / h.
. 63-70 kg: 32 ml / h / 8 ml / h // 16 ml / h / 4 ml / h.
. 71-79 kg: 36 ml / h / 9 ml / h // 18 ml / h / 5 ml / h.
. 80-87 kg: 40 ml / h / 10 ml / h // 20 ml / h / 5 ml / h.
. 88-95 kg: 44 ml / h / 11 ml / h // 22 ml / h / 6 ml / h.
. 96-104 kg: 48 ml / h / 12 ml / h // 24 ml / h / 6 ml / h.
. 105-112 kg: 52 ml / h / 13 ml / h // 26 ml / h / 7 ml / h.
. 113-120 kg: 56 ml / h / 14 ml / h // 28 ml / h / 7 ml / h.
. 121-128 kg: 60 ml / h / 15 ml / h // 30 ml / h / 8 ml / h.
. 129-137 kg: 64 ml / h / 16 ml / h // 32 ml / h / 8 ml / h.
. 138-145 kg: 68 ml / h / 17 ml / h // 34 ml / h / 9 ml / h.
. 146-153 kg: 72 ml / h / 18 ml / h // 36 ml / h / 9 ml / h.
START AND DURATION OF TREATMENT WITH AGRASTAT:
- Optimally, administration of AGRASTAT should begin within 12 hours after the last episode of anginal pain. The recommended duration of treatment is at least 48 hours.
- The infusion of AGRASTAT and unfractionated heparin can be continued during coronary angiography, and should be maintained for at least 12 hours, not to exceed 24 hours after angioplasty or atherectomy.
- 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.
- Concomitant treatments (unfractionated heparin, aspirin):
. Treatment with unfractionated heparin should be started with an intravenous bolus of 5000 U, relayed by maintenance infusion at a rate of 1000 U per hour. The dosage of heparin is adjusted to maintain the TCA at about twice the control value.
. In the absence of contraindication, all patients should receive aspirin orally before starting treatment with AGRASTAT (see pharmacodynamic properties, Study PRISM PLUS). Aspirin should be continued for at least the duration of the AGRASTAT infusion.
. If coronary angioplasty is required, heparin should be discontinued after angioplasty, and the protective sheath of the catheter should be removed when coagulation is normal, for example, when the activated clotting time (ACT) is less than 180 seconds. (usually 2 to 6 hours after stopping heparin).
INSTRUCTIONS FOR HANDLING:
AGRASTAT concentrate must be diluted before use:
1. Take 50 ml of a 250 ml vial containing a sterile solution of 0.9% sodium chloride or 5% glucose and replace with 50 ml of AGRASTAT (from a 50 ml perforable vial) ) in order to obtain a concentration of 50 micrograms / ml. Mix well before use.
2. Administer according to the dosage indicated above.
- To the extent that the nature of the packaging and the solution permit, parenteral medicinal products should be examined before use for visible particles or discoloration.
- AGRASTAT should be administered only 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.
- It should be ensured that the infusion of the loading dose is not continued beyond the recommended duration, and to avoid any error in the calculation of the flow rate of the maintenance infusion according to the weight of the patient .

Against indications

CONTRAINDICATED:
- AGRASTAT is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients of the preparation, or who have developed thrombocytopenia in the previous administration of a GP IIb / IIIa receptor antagonist.
- As inhibition of platelet aggregation increases the risk of bleeding, AGRASTAT is contraindicated in patients with:
. a history of a stroke less than 30 days old or any history of a hemorrhagic stroke;
. known history of intracranial pathology (eg tumor, arteriovenous malformation, aneurysm);
. bleeding current or recent (within 30 days prior to treatment), clinically significant (eg, gastrointestinal bleeding);
. malignant hypertension;
. major trauma or major surgery in the last six weeks;
. thrombocytopenia (platelet count <100000 / mm3), platelet function disorders;
. coagulation disorders [eg time of Quick> 1.3 times normal or INR (International Normalized Ratio)> 1.5];
. severe hepatic insufficiency.
- Breast-feeding: There is no data on the passage of AGRASTAT in breast milk but it is known that it passes into milk in the rat. The possibility of side effects in breast-fed infants requires a choice between discontinuation of breastfeeding or treatment, depending on the importance of the drug to the mother.
NOT RECOMMENDED :
There is no experience with AGRASTAT in children. Therefore, the use of AGRASTAT is not recommended in these patients.

Agrastat side effects

- Bleeding:
. Bleeding is the most commonly reported treatment-related adverse event when using AGRASTAT (in combination with unfractionated heparin and aspirin). They were generally moderate.
. In the PRISM-PLUS study, the overall incidence of major bleeds according to the TIMI criteria (defined as a fall in hemoglobin greater than 50 g / L with or without an identified bleeding site, intracranial hemorrhage, or cardiac tamponade) in patients treated with AGRASTAT in combination with heparin was not significantly higher than in the control group. The incidence of major bleeds according to the TIMI criteria was 1.4% with AGRASTAT in combination with heparin and 0.8% in the control group (who received heparin). The incidence of minor bleeding according to the TIMI criteria (defined by a hemoglobin drop of more than 30 g / L with identified bleeding site, gross spontaneous hematuria, haematemesis or haemoptysis) was 10, 5% with AGRASTAT in combination with heparin and 8.0% in the control group. There was no evidence of intracranial bleeding with AGRASTAT in combination with heparin or the control group. The incidence of retroperitoneal bleeding reported with AGRASTAT in combination with heparin was 0.0% and 0.1% in the control group. The percentage of patients who received a transfusion (including red blood cell concentrates, fresh frozen plasma, whole blood and platelet concentrate) was 4.0% with AGRASTAT and 2.8% in the control group.
. AGRASTAT with unfractionated heparin and aspirin has been associated with gastrointestinal, hemorrhoidal and postoperative bleeding, epistaxis, gingivorrhage and superficial cutaneous bleeding, as well as hemorrhagic bleeding (hematoma) at vascular puncture sites (eg during cardiac catheterization) significantly more frequently than under the dual therapy with unfractionated heparin and aspirin.
- Adverse effects other than bleeding:
. With the combination of AGRASTAT and heparin, the most commonly observed treatment-related adverse events (other than bleeding) (incidence greater than 1%) were: nausea (1.7%), fever (1%), , 5%), and headache (1.1%); nausea, fever and headache occurred with incidences of 1.4%, 1.1% and 1.2%, respectively, in the control group.
. The incidence of non-hemorrhagic adverse events was higher in women (compared to men) and in older patients (compared to younger patients). However, the incidence of non-hemorrhagic adverse events was comparable in the AGRASTAT plus heparin group and the heparin-only group.
Frequent: (> 1/100, <1/10) .
. Nervous system disorders and psychiatric disorders :
Frequent : headache.
. Gastrointestinal disorders :
Frequent : nausea.
. General disorders and accidents related to the site of administration :
Frequent : fever.
- Investigations:
. The most common laboratory changes observed with AGRASTAT were bleeding: decreased hemoglobin and hematocrit, and increased cases of occult bleeding in urine and feces.
. A sudden drop in platelet count or thrombocytopenia occurred occasionally during treatment with AGRASTAT. The percentage of patients in whom the platelet count dropped below 90000 / mm3 was 1.5%. The percentage of patients in whom the platelet count dropped below 50000 / mm3 was 0.3%. These decreases were reversible after stopping AGRASTAT. Acute and severe decreases in platelet counts have been observed in patients with no prior history of thrombocytopenia when PG IIb / IIIa receptor antagonists are re-administered.
- The following other adverse reactions have been reported exceptionally since the drug was marketed; they come from spontaneous cases for which precise effects can not be determined.
. Blood and lymphatic system disorders :
Intracranial bleeding, retroperitoneal bleeding, hemopericardium, pulmonary (alveolar) hemorrhage, and epidural intraspinal hematoma. Fatal bleeding has been reported rarely.
Acute and / or severe (<20000 / mm3) decrease in platelet count that may be accompanied by chills, low fever, or bleeding-like complications (see Investigations above).
. Immune system disorders :
Severe allergic reactions (eg bronchospasm, urticaria) including anaphylactic reactions. The reported cases occurred during the initial treatment (also the first day) and during the readministration of tirofiban. Some cases have been associated with severe thrombocytopenia (platelet count <10000 / mm3).

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