Aggrastat

Aggrastat

tirofiban

Manufacturer:

Aspen

Distributor:

Zuellig
Full Prescribing Info
Contents
Tirofiban HCl.
Action
Aggrastat (tirofiban HCl, MSD), a nonpeptide antagonist of the platelet GP IIb/IIIa receptor, is a platelet aggregation inhibitor.
Indications/Uses
Aggrastat, in combination with heparin, is indicated for patients with unstable angina or non-Q-wave myocardial infarction to prevent cardiac ischemic events and is also indicated for patients with coronary ischemic syndromes undergoing coronary angioplasty or atherectomy to prevent cardiac ischemic complications related to abrupt closure of the treated coronary artery. (See Dosage & Administration.)
Dosage/Direction for Use
The vial of Aggrastat (concentrate) must be diluted prior to administration (see Instructions for Use).
Aggrastat is for IV use only using sterile equipment. Aggrastat may be co-administered with heparin through the same line.
Aggrastat is recommended for use with a calibrated infusion device. Care should be taken to avoid a prolonged loading infusion. Care should also be taken in calculating the bolus dose and infusion rates based on patient weight.
In clinical studies, patients received aspirin, unless contraindicated.
Unstable Angina Pectoris or Non-Q-Wave Myocardial Infarction: Aggrastat should be administered IV, in combination with heparin, at the initial infusion rate of 0.4 mcg/kg/min for 30 min. Upon completion of the initial infusion, Aggrastat should be continued at a maintenance infusion rate of 0.1 mcg/kg/min. Table 1 is provided as a guide to dosage adjustment by weight. (See Table 1.)

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In the study that demonstrated efficacy, Aggrastat, in combination with heparin was generally continued for a minimum of 48 hrs and up to 108 hrs on average, patients received Aggrastat for 71.3 hrs. This infusion can be continued through angiography and should be continued up to 12-24 hrs post-angioplasty/atherectomy. Arterial sheaths should be removed when the patient's activated clotting time is <180 sec or 2-6 hrs following cessation of heparin.
Angioplasty/Atherectomy: In patients in whom Aggrastat is initiated in the setting of angioplasty/atherectomy, Aggrastat should be administered IV, in combination with heparin, as an initial bolus of 10 mcg/kg administered over 3 min followed by a maintenance infusion rate of 0.15 mcg/kg/min. Table 2 is provided as a guide to dosage adjustment by weight. (See Table 2.)

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The Aggrastat maintenance infusion should be administered for 36 hrs. Upon completion of the procedure, heparin should be discontinued and arterial sheaths should then be removed when the patient's activated clotting time is <180 sec.
Patients with Severe Renal Insufficiency: As specified in Tables 1 and 2, the dosage of Aggrastat should be decreased by 50% in patients with severe renal insufficiency [creatinine clearance (CrCl) <30 mL/min]. (See Severe Renal Insufficiency under Precautions.)
Other Patient Populations: No dosage adjustment is recommended for elderly patients (see Use in the elderly under Precautions) or female patients.
Overdosage
In clinical trials, inadvertent overdosage with tirofiban occurred in doses up to 5 times and 2 times the recommended dose for bolus administration and loading infusion, respectively. Inadvertent overdosage occurred in doses up to 9.8 times the 0.15 mcg/kg/min maintenance infusion rate.
The most frequently reported manifestation of overdosage was bleeding, primarily minor mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization (see Bleeding Precautions under Precautions).
Overdosage of tirofiban should be treated by assessment of the patient's clinical condition and cessation or adjustment of the drug infusion as appropriate.
Aggrastat can be removed by hemodialysis.
Contraindications
Hypersensitivity to any of the excipients of Aggrastat.
Since inhibition of platelet aggregation increases the risk of bleeding, Aggrastat is contraindicated in patients with active internal bleeding; a history of intracranial hemorrhage; intracranial neoplasm, arteriovenous malformation or aneurysm; and in patients who developed thrombocytopenia following prior exposure to Aggrastat.
Special Precautions
Aggrastat should be used with caution in the following patients: Recent (<1 year) bleeding, including a history of gastrointestinal bleeding or genitourinary bleeding of clinical significance; known coagulopathy, platelet disorder or history of thrombocytopenia; platelet count <150,000 cells/mm3; history of cerebrovascular disease within 1 year; major surgical procedure or severe physical trauma within 1 month; history, symptoms or findings suggestive of aortic dissection; severe uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg); acute pericarditis; hemorrhagic retinopathy.
Bleeding Precautions: Because Aggrastat inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis. The safety of Aggrastat when used in combination with thrombolytic agents has not been established.
During therapy with Aggrastat, patients should be monitored for potential bleeding. When treatment of bleeding is required, discontinuation of the drug should be considered. Consideration may also be given to transfusions.
Femoral Artery Access Site: Aggrastat is associated with minor increases in bleeding rates particularly at the site of arterial access for femoral sheath placement. Care should be taken when attempting vascular access that only the anterior wall of the femoral artery is punctured, avoiding a Seldinger (through and through) technique for obtaining sheath access. Care should be taken to obtain proper hemostasis after removal of the sheaths followed by close observation.
Laboratory Monitoring: Platelet counts, and hemoglobin and hematocrit should be monitored prior to treatment, within 6 hrs following the bolus or loading infusion, and at least daily thereafter during therapy with Aggrastat (or more frequently if there is evidence of significant decline). If the patient experiences a platelet count decrease to <90,000 cells/mm3, additional platelet counts should be performed to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, Aggrastat and heparin should be discontinued and the condition appropriately monitored and treated.
The anticoagulant effects of heparin should be carefully monitored and the dose should be adjusted accordingly.
Severe Renal Insufficiency: In clinical studies, patients with severe renal insufficiency (CrCl <30 mL/min) demonstrated decreased plasma clearance of Aggrastat. The dosage of Aggrastat should be reduced in these patients (see Dosage & Administration).
Use in pregnancy: There are no adequate and well-controlled studies in pregnant women. Aggrastat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in lactation: It is not known whether Aggrastat is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Use in children: Safety and effectiveness in children have not been established.
Use in the elderly: In clinical studies, the efficacy of Aggrastat in the elderly (≥65 years) was comparable to that seen in younger patients (<65 years). Elderly patients receiving Aggrastat with heparin or heparin alone had a higher incidence of bleeding complications than younger patients. The incremental risk of bleeding in patients treated with Aggrastat in combination with heparin over the risk in patients treated with heparin alone was comparable regardless of age. The overall incidence of nonbleeding adverse events was higher in older patients (compared to younger patients); however, the incidence of nonbleeding adverse events in these patients was comparable between the Aggrastat with heparin and the heparin alone groups. No dose adjustment is recommended (see Other Patient Populations under Dosage & Administration).
Use In Pregnancy & Lactation
Use in pregnancy: There are no adequate and well-controlled studies in pregnant women. Aggrastat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in lactation: It is not known whether Aggrastat is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Side Effects
The most common drug-related adverse event reported during therapy with Aggrastat when used concomitantly with heparin and aspirin was bleeding (usually reported by the investigators as oozing or mild). The incidences of major and minor bleeding using the Thrombolysis in Myocardial Infarction (TIMI) criteria in the Platelet Receptor Inhibition for Ischemic Syndrome Management - Patients Limited by Unstable Signs and Symptoms (PRISM PLUS) and Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) studies are shown as follows: See Table 3.

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There were no reports of intracranial bleeding in the PRISM PLUS study for Aggrastat in combination with heparin or in the control group (which received heparin). The incidence of intracranial bleeding in the RESTORE study was 0.1% for Aggrastat in combination with heparin and 0.3% for the control group (which received heparin). In the PRISM PLUS study, the incidences of retroperitoneal bleeding reported for Aggrastat in combination with heparin, and for the control group were 0% and 0.1%, respectively. In the RESTORE study, the incidences of retroperitoneal bleeding reported for Aggrastat in combination with heparin and the control group were 0.6% and 0.3%, respectively.
Female patients and elderly patients receiving Aggrastat with heparin or heparin alone had a higher incidence of bleeding complications than male patients or younger patients, respectively. The incremental risk of bleeding in patients treated with Aggrastat in combination with heparin over the risk in patients treated with heparin alone was comparable regardless of age or gender. No dose adjustment is recommended for these populations (see Other Patient Populations under Dosage & Administration).
Patients treated with Aggrastat, with heparin, were more likely to experience decreases in platelet counts than the control group. These decreases were reversible upon discontinuation of Aggrastat. The percentage of patients with a decrease of platelets to <90,000 cells/mm3 was 1.5%. The percentage of patients with a decrease of platelets to <50,000 cells/mm3 was 0.3%.
The most frequent drug-related nonbleeding side effects reported with Aggrastat, administered concomitantly with heparin, occurring at an incidence of >1% were nausea (1.7%), fever (1.5%) and headache (1.1%); nausea, fever and headache occurred at an incidence of 1.4%, 1.1% and 1.2%, respectively, in the control group.
In clinical studies, the incidences of adverse events were generally similar among different races, patients with or without hypertension, patients with or without diabetes mellitus, and patients with or without hypercholesteremia.
The overall incidence of nonbleeding adverse events was higher in female patients (compared to male patients) and older patients (compared to younger patients). However, the incidences of nonbleeding adverse events in these patients were comparable between the Aggrastat with heparin and the heparin alone groups. (See previous text for bleeding adverse events.)
The following additional adverse reactions have been reported in post-marketing experience:
Body as a Whole: Decreased platelet counts (see previous text) associated with chills and low-grade fever.
Laboratory Test Findings: The most frequently observed laboratory adverse events in patients receiving Aggrastat concomitantly with heparin were related to bleeding. Decreases in hemoglobin and hematocrit, and platelet count were observed. Increases in the presence of urine and fecal occult blood were also observed.
Drug Interactions
Aggrastat has been studied on a background of aspirin and heparin.
The use of Aggrastat, in combination with heparin and aspirin, has been associated with an increase in bleeding compared to heparin and aspirin alone (see Side Effects). Caution should be employed when Aggrastat is used with other drugs that affect hemostasis (eg, warfarin) (see Bleeding Precautions under Precautions).
Aggrastat has been used concomitantly in clinical studies with β-blockers, calcium-channel blockers, nonsteroidal anti-inflammatory agents (NSAIDs) and nitrate preparations without evidence of clinically significant adverse interactions.
In a subset of patients (n=762) in the PRISM study, the plasma clearance of tirofiban in patients receiving one of the following drugs was compared to that in patients not receiving that drug. There were no clinically significant interactions of these drugs on the plasma clearance of tirofiban: Acebutolol, acetaminophen, alprazolam, amlodipine, aspirin preparations, atenolol, bromazepam, captopril, diazepam, digoxin, diltiazem, docusate sodium, enalapril, furosemide, glyburide, heparin, insulin, isosorbide, levothyroxine, lorazepam, lovastatin, metoclopramide, metoprolol, morphine, nifedipine, nitrate preparations, omeprazole, oxazepam, potassium chloride, propranolol, ranitidine, simvastatin, sucralfate and temazepam.
Caution For Usage
Instructions for Use and Handling: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use, whenever solution and container permit.
The vial of Aggrastat (concentrate) must be diluted prior to administration.
Directions for Preparation of Aggrastat Solution for Infusion from Concentrate:
1. Withdraw 50 mL from a 250-mL bag of sterile 0.9% saline or 5% dextrose in water and replace it with Aggrastat 50 mL (from one 50-mL vial) to achieve a concentration of 50 mcg/mL. Mix well before administration.
2. Administer according to the appropriate dosage calculations.
3. Any unused IV solution should be discarded.
Aggrastat may be administered in the same IV line as dopamine, lidocaine, potassium chloride and Pepcid injection.
Storage
Concentrate for Infusion: Store between 15-30°C. Do not freeze. Protect from light.
ATC Classification
B01AC17 - tirofiban ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
Presentation/Packing
Infusion conc 250 mcg/mL x 50 mL x 1's.
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