Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4274
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AGGRASTAT (Injection, Solution, Concentrate)
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AGGRASTAT Injection must first be diluted to the same strength as AGGRASTAT Injection Premixed, as noted under Directions for Use.<br/>Use with Aspirin and Heparin: In the clinical studies, patients received aspirin, unless it was contraindicated, and heparin. AGGRASTAT and heparin can be administered through the same intravenous catheter.<br/>Precautions: AGGRASTAT is intended for intravenous delivery using sterile equipment and technique. Do not add other drugs or remove solution directly from the bag with a syringe. Do not use plastic containers in series connections; such use can result in air embolism by drawing air from the first container if it is empty of solution. Any unused solution should be discarded.<br/>Directions for Use: Prior to use, AGGRASTAT Injection (250 mcg/mL) must be diluted to the same strength as AGGRASTAT Injection Premixed (50 mcg/mL). This may be achieved, for example, using either of the following two methods: Mix well prior to administration. AGGRASTAT Injection Premixed is supplied as 100 mL or 250 mL of 0.9% sodium chloride containing 50 mcg/mL tirofiban. It is supplied in IntraVia��containers (PL 2408 plastic). To open the IntraVia container, first tear off its foil overpouch. The plastic may be somewhat opaque because of moisture absorption during sterilization; the opacity will diminish gradually. Check for leaks by squeezing the inner bag firmly; if any leaks are found, the sterility is suspect and the solution should be discarded. Do not use unless the solution is clear and the seal is intact. Suspend the container from its eyelet support, remove the plastic protector from the outlet port, and attach a conventional administration set. AGGRASTAT may be administered in the same intravenous line as dopamine, lidocaine, potassium chloride, and PEPCID(famotidine) Injection. AGGRASTAT should not be administered in the same intravenous line as diazepam.<br/>Recommended Dosage: In most patients, AGGRASTAT should be administered intravenously, at an initial rate of 0.4 mcg/kg/min for 30 minutes and then continued at 0.1 mcg/kg/min. Patients with severe renal insufficiency (creatinine clearance<30 mL/min) should receive half the usual rate of infusion .The table below is provided as a guide to dosage adjustment by weight. AGGRASTAT Injection must first be diluted to the same strength as AGGRASTAT Injection Premixed, as noted under Directions for Use. No dosage adjustment is recommended for elderly or female patients . In PRISM-PLUS, AGGRASTAT was administered in combination with heparin for 48 to 108 hours. The infusion should be continued through angiography and for 12 to 24 hours after angioplasty or atherectomy.
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Mechanism of Action: AGGRASTAT is a reversible antagonist of fibrinogen binding to the GP lIb/lIla receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, AGGRASTAT inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the recommended regimen,>90% inhibition is attained by the end of the 30-minute infusion. Platelet aggregation inhibition is reversible following cessation of the infusion of AGGRASTAT.<br/>Pharmacokinetics: Tirofiban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. Metabolism appears to be limited. Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 mcg/mL. Unbound fraction in human plasma is 35%. The steady state volume of distribution of tirofiban ranges from 22 to 42 liters. In healthy subjects, the plasma clearance of tirofiban ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance. The recommended regimen of a loading infusion followed by a maintenance infusion produces a peak tirofiban plasma concentration that is similar to the steady state concentration during the infusion. In patients with coronary artery disease, the plasma clearance of tirofiban ranges from 152 to 267 mL/min; renal clearance accounts for 39% of plasma clearance.<br/>Special Populations:<br/>Gender: Plasma clearance of tirofiban in patients with coronary artery disease is similar in males and females.<br/>Elderly: Plasma clearance of tirofiban is about 19 to 26% lower in elderly (>65 years) patients with coronary artery disease than in younger (���65 years) patients.<br/>Race: No difference in plasma clearance was detected in patients of different races.<br/>Hepatic Insufficiency: In patients with mild to moderate hepatic insufficiency, plasma clearance of tirofiban is not significantly different from clearance in healthy subjects.<br/>Renal Insufficiency: Plasma clearance of tirofiban is significantly decreased (>50%) in patients with creatinine clearance<30 mL/min, including patients requiring hemodialysis .Tirofiban is removed by hemodialysis.<br/>Pharmacodynamics: AGGRASTAT inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug. Following discontinuation of an infusion of AGGRASTAT, 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in approximately 90% of patients with coronary artery disease in 4 to 8 hours. The addition of heparin to this regimen does not significantly alter the percentage of subjects with>70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to>30 minutes. In patients with unstable angina, a two-staged intravenous infusion regimen of AGGRASTAT (loading infusion of 0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min for up to 48 hours in the presence of heparin and aspirin), produces approximately 90% inhibition of ex vivo ADP-induced platelet aggregation with a 2.9-fold prolongation of bleeding time during the loading infusion. Inhibition persists over the duration of the maintenance infusion.
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FOR INTRAVENOUS USE ONLY AGGRASTAT Injection 12.5 mg per 50 mL (250 mcg per mL) is a non-preserved, clear, colorless concentrated sterile solution for intravenous infusion after dilution and is supplied as follows: NDC 25208-001-01 50 mL vials. AGGRASTAT Injection Premixed 5 mg tirofiban per 100 mL (50 mcg per mL) and 12.5 mg tirofiban per 250 mL (50 mcg per mL) are clear, non-preserved, sterile solutions premixed in a vehicle made iso-osmotic with sodium chloride, and are supplied as follows: NDC 25208-002-01, 100 mL single-dose IntraVia containers (PL 2408 Plastic). NDC 25208-002-02, 250 mL single-dose IntraVia containers (PL 2408 Plastic). Storage AGGRASTAT Injection Store at 25��C (77��F) with excursions permitted between 15-30��C (59-86��F) (see USP Controlled Room Temperature). Do not freeze. Protect from light during storage. AGGRASTAT Injection Premixed Store at 25��C (77��F) with excursions permitted between 15-30��C (59-86��F) (see USP Controlled Room Temperature). Do not freeze. Protect from light during storage. US Patent Nos: 5,292,756, 5,439,454, 5,849,843, and 5,998,019 AGGRASTAT (Tirofiban Hydrochloride Premixed) is manufactured for:MEDICURE INTERNATIONAL, INC.by:BAXTER HEALTHCARE CORPORATIONDeerfield, IL 60015, USADistributed by:MEDICURE PHARMA, INC.Somerset, NJ 08873 USA AGGRASTAT (Tirofiban Hydrochloride Injection) is manufactured for:MEDICURE INTERNATIONAL, INC.by:BEN VENUE LABORATORIESBedford, OH 44146 USADistributed by:MEDICURE PHARMA, INC.Somerset, NJ 08873 USA Issued October 2007Printed in USA07-19-54-779
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tirofiban hydrochloride
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AGGRASTAT (Injection, Solution, Concentrate)
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In clinical trials, 1946 patients received AGGRASTAT in combination with heparin and 2002 patients received AGGRASTAT alone. Duration of exposure was up to 116 hours. 43% of the population was>65 years of age and approximately 30% of patients were female.<br/>BLEEDING: 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 TIMI criteria in the PRISM-PLUS and RESTORE studies are shown below. There were no reports of intracranial bleeding in the PRISM-PLUS study for AGGRASTAT in combination with heparin or in the heparin control group. 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 heparin control group were 0.0% 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. The incidences of TIMI major gastrointestinal and genitourinary bleeding for AGGRASTAT in combination with heparin in the PRISM-PLUS study were 0.1% and 0.1%, respectively; the incidences in the RESTORE study for AGGRASTAT in combination with heparin were 0.2% and 0.0%, respectively. The incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in PRISM-PLUS are shown below. The incidence rates of TIMI major bleeding (in some cases possibly reflecting hemodilution rather than actual bleeding) in patients undergoing CABG in the PRISM-PLUS and RESTORE studies within one day of discontinuation of AGGRASTAT are shown below. 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. 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 .<br/>NON-BLEEDING: The incidences of non-bleeding adverse events that occurred at an incidence of>1% and numerically higher than control, regardless of drug relationship, are shown below: Other non-bleeding side effects (considered at least possibly related to treatment) reported at a>1% rate with AGGRASTAT administered concomitantly with heparin were nausea, fever, and headache; these side effects were reported at a similar rate in the heparin 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 non-bleeding adverse events was higher in female patients (compared to male patients) and older patients (compared to younger patients). However, the incidences of non-bleeding adverse events in these patients were comparable between the AGGRASTAT with heparin and the heparin alone groups. (See above for bleeding adverse events.)<br/>Allergic Reactions/Readministration: Although no patients in the clinical trial database developed anaphylaxis and/or hives requiring discontinuation of the infusion of tirofiban, anaphylaxis has been reported in post-marketing experience (see also Post-Marketing Experience, Hypersensitivity). No information is available regarding the development of antibodies to tirofiban.<br/>Laboratory Findings: The most frequently observed laboratory adverse events in patients receiving AGGRASTAT concomitantly with heparin were related to bleeding. Decreases in hemoglobin (2.1%) and hematocrit (2.2%) were observed in the group receiving AGGRASTAT compared to 3.1% and 2.6%, respectively, in the heparin group. Increases in the presence of urine and fecal occult blood were also observed (10.7% and 18.3%, respectively) in the group receiving AGGRASTAT compared to 7.8% and 12.2%, respectively, in the heparin group. 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/mmwas 1.5%, compared with 0.6% in the patients who received heparin alone. The percentage of patients with a decrease of platelets to<50,000/mmwas 0.3%, compared with 0.1% of the patients who received heparin alone. Platelet decreases have been observed in patients with no prior history of thrombocytopenia upon readministration of GP IIb/IIIa receptor antagonists.<br/>Post-Marketing Experience: The following additional adverse reactions have been reported in post-marketing experience: Bleeding: Intracranial bleeding, retroperitoneal bleeding, hemopericardium, pulmonary (alveolar) hemorrhage, and spinal-epidural hematoma. Fatal bleeding events have been reported;Body as a Whole: Acute and/or severe decreases in platelet counts which may be associated with chills, low-grade fever, or bleeding complications (see Laboratory Findings above);Hypersensitivity: Severe allergic reactions including anaphylactic reactions. The reported cases have occurred during the first day of tirofiban infusion, during initial treatment, and during readministration of tirofiban. Some cases have been associated with severe thrombocytopenia (platelet counts<10,000/mm).
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AGGRASTAT, in combination with heparin, is indicated for the treatment of acute coronary syndrome, including patients who are to be managed medically and those undergoing PTCA or atherectomy. In this setting, AGGRASTAT has been shown to decrease the rate of a combined endpoint of death, new myocardial infarction or refractory ischemia/repeat cardiac procedure . AGGRASTAT has been studied in a setting, as described in Clinical Trials, that included aspirin and heparin.
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AGGRASTAT
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