Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1396
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Integrilin (Injection)
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The safety and efficacy of eptifibatide has been established in clinical studies that employed concomitant use of heparin and aspirin. Different dose regimens of eptifibatide were used in the major clinical studies .<br/>Acute Coronary Syndrome: The recommended adult dosage of eptifibatide in patients with acute coronary syndrome and normal renal function is an intravenous bolus of 180��g/kg as soon as possible following diagnosis, followed by a continuous infusion of 2.0��g/kg/min until hospital discharge or initiation of CABG surgery, up to 72 hours. If a patient is to undergo a percutaneous coronary intervention (PCI) while receiving eptifibatide, the infusion should be continued up to hospital discharge, or for up to 18 to 24 hours after the procedure, whichever comes first, allowing for up to 96 hours of therapy.<br/>Patients with Creatinine Clearance Less Than 50 mL/min: The recommended adult dosage of eptifibatide in patients with acute coronary syndrome with an estimated creatinine clearance (using the Cockcroft-Gault equation)<50 mL/min is an intravenous bolus of 180��g/kg as soon as possible following diagnosis, immediately followed by a continuous infusion of 1.0��g/kg/min.<br/>Percutaneous Coronary Intervention (PCI): The recommended adult dosage of eptifibatide in patients with normal renal function is an intravenous bolus of 180��g/kg administered immediately before the initiation of PCI followed by a continuous infusion of 2.0��g/kg/min and a second 180-��g/kg bolus 10 minutes after the first bolus. Infusion should be continued until hospital discharge, or for up to 18 to 24 hours, whichever comes first. A minimum of 12 hours of infusion is recommended.<br/>Patients with Creatinine Clearance Less Than 50 mL/min: The recommended adult dose of eptifibatide in patients with an estimated creatinine clearance (using the Cockcroft-Gault equation)<50 mL/min is an intravenous bolus of 180��g/kg administered immediately before the initiation of the procedure, immediately followed by a continuous infusion of 1.0��g/kg/min and a second 180-��g/kg bolus administered 10 minutes after the first. In patients who undergo coronary artery bypass graft surgery, eptifibatide infusion should be discontinued prior to surgery.<br/>Aspirin and Heparin Dosing Recommendations: In the clinical trials that showed eptifibatide to be effective, most patients received concomitant aspirin and heparin. The recommended aspirin and heparin doses to be used are as follows:<br/>Acute Coronary Syndrome:<br/>PCI:<br/>Instructions for Administration: INTEGRILIN is to be administered by volume according to patient weight. Patients should receive INTEGRILIN according to the following table:
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Eptifibatide is a cyclic heptapeptide containing six amino acids and one mercaptopropionyl (des-amino cysteinyl) residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N-(aminoiminomethyl)-N-(3-mercapto-1-oxopropyl-L-lysylglycyl-L-��-aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic (1���6)-disulfide. Eptifibatide binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation. The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is: INTEGRILIN(eptifibatide) Injection is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use with an empirical formula of CHNOSand a molecular weight of 831.96. Each 10-mL vial contains 2 mg/mL of eptifibatide and each 100-mL vial contains either 0.75 mg/mL of eptifibatide or 2 mg/mL of eptifibatide. Each vial of either size also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.
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Mechanism of Action: Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet.<br/>Pharmacodynamics: Infusion of eptifibatide into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5.0��g/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of eptifibatide that inhibit aggregation prevented acute thrombosis with only a modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatide, with complete inhibition at 2.0��g/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model). Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI) and/or undergoing percutaneous coronary interventions. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, eptifibatide inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of eptifibatide was observed immediately after administration of a 180-��g/kg intravenous bolus. Table 1 shows the effects of dosing regimens of eptifibatide used in the IMPACT II and PURSUIT studies on ex vivo platelet aggregation induced by 20��M ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied. The eptifibatide dosing regimen used in the ESPRIT study included two 180-��g/kg bolus doses given 10 minutes apart combined with a continuous 2.0��g/kg/min infusion. When administered alone, eptifibatide has no measurable effect on prothrombin time (PT) or activated partial thromboplastin time (aPTT) . There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.<br/>Pharmacokinetics: The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250��g/kg and infusion rates from 0.5 to 3.0��g/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of a single 180-��g/kg bolus combined with an infusion produces an early peak level, followed by a small decline prior to attaining steady state (within 4���6 hours). This decline can be prevented by administering a second 180-��g/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma. In patients with moderate to severe renal insufficiency (creatinine clearance<50 mL/min using the Cockcroft-Gault equation), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels approximately doubled .<br/>Special Populations: Patients in clinical studies were older (range 20���94 years) than those in the clinical pharmacology studies. Elderly patients with coronary artery disease demonstrated higher plasma levels and lower total body clearance of eptifibatide when given the same dose as younger patients. Limited data are available on lighter weight (<50 kg) patients over 75 years of age. No studies have been conducted in patients with hepatic impairment. Males and females have not demonstrated any clinically significant differences in the pharmacokinetics of eptifibatide.
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INTEGRILIN (eptifibatide) Injection is supplied as a sterile solution in 10-mL vials containing 20 mg of eptifibatide (NDC 0085-1177-01) and 100-mL vials containing either 75 mg of eptifibatide (NDC 0085-1136-01) or 200 mg of eptifibatide (NDC 0085-1177-02). Vials should be stored refrigerated at 2�����8��C (36�����46��F). Vials may be transferred to room temperature storagefor a period not to exceed 2 months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with a "DISCARD BY" date (2 months from the transfer date or the labeled expiration date, whichever comes first). Do not use beyond the labeled expiration date. Protect from light until administration. Discard any unused portion left in the vial.
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There has been only limited experience with overdosage of eptifibatide. There were 8 patients in the IMPACT II study, 9 patients in the PURSUIT study, and no patients in the ESPRIT study who received bolus doses and/or infusion doses more than double those called for in the protocols. None of these patients experienced an intracranial bleed or other major bleeding. Eptifibatide was not lethal to rats, rabbits, or monkeys when administered by continuous intravenous infusion for 90 minutes at a total dose of 45 mg/kg (about 2 to 5 times the recommended maximum daily human dose on a body surface area basis). Symptoms of acute toxicity were loss of righting reflex, dyspnea, ptosis, and decreased muscle tone in rabbits, and petechial hemorrhages in the femoral and abdominal areas of monkeys. From in vitro studies, eptifibatide is not extensively bound to plasma proteins and thus may be cleared from plasma by dialysis.
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Eptifibatide
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Integrilin (Injection)
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A total of 16,782 patients were treated in the Phase III clinical trials (PURSUIT, ESPRIT, and IMPACT II). These 16,782 patients had a mean age of 62 years (range 20���94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUIT, IMPACT II, and ESPRIT, data from the three studies were not pooled.<br/>Bleeding: The incidences of bleeding events and transfusions in the PURSUIT, IMPACT II, and ESPRIT studies are shown in Table 8. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding events consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al. The majority of major bleeding events in the ESPRIT study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and eptifibatide groups, respectively). Bleeding at "other" locations occurred in 0.2% and 0.4% of patients, respectively. In the PURSUIT study, the greatest increase in major bleeding in eptifibatide-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% vs 1.3%). Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in eptifibatide-treated patients compared to placebo-treated patients. Among patients experiencing a major bleed in the IMPACT II study, an increase in bleeding on eptifibatide versus placebo was observed only for the femoral artery access site (3.2% vs 2.8%). Table 9 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUIT study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRIT is not presented as every patient underwent PCI in the ESPRIT study and only 11 patients underwent CABG. In the PURSUIT and ESPRIT studies, the risk of major bleeding with eptifibatide increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg. Bleeding adverse events resulting in discontinuation of the study drug were more frequent among patients receiving eptifibatide than placebo (4.6% vs 0.9% in ESPRIT, 8% vs 1% in PURSUIT, 3.5% vs 1.9% in IMPACT II).<br/>Intracranial Hemorrhage and Stroke: Intracranial hemorrhage was rare in the PURSUIT, IMPACT II, and ESPRIT clinical studies. In the PURSUIT study, 3 patients in the placebo group, 1 patient in the group treated with eptifibatide 180/1.3 and 5 patients in the group treated with eptifibatide 180/2.0 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving eptifibatide 180/1.3, 0.7% in patients receiving eptifibatide 180/2.0, and 0.8% in placebo patients. In the IMPACT II study, intracranial hemorrhage was experienced by 1 patient treated with eptifibatide 135/0.5, 2 patients treated with eptifibatide 135/0.75 and 2 patients in the placebo group. The overall incidence of stroke was 0.5% in patients receiving 135/0.5 eptifibatide, 0.7% in patients receiving eptifibatide 135/0.75 and 0.7% in the placebo group. In the ESPRIT study, there were 3 hemorrhagic strokes, 1 in the placebo group, and 2 in the eptifibatide group. In addition there was 1 case of cerebral infarction in the eptifibatide group.<br/>Thrombocytopenia: In the PURSUIT and IMPACT II studies, the incidence of thrombocytopenia (<100,000/mmor���50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with eptifibatide and placebo. In the ESPRIT study, the incidence was 0.6% in the placebo group and 1.2% in the eptifibatide group.<br/>Allergic Reactions: In the PURSUIT study, anaphylaxis was reported in 7 patients receiving placebo (0.15%) and 7 patients receiving eptifibatide 180/2.0 (0.16%). In the IMPACT II study, anaphylaxis was reported in 1 patient (0.08%) on placebo and in no patients on eptifibatide. In the IMPACT II study, 2 patients (1 patient [0.04%] receiving eptifibatide and 1 patient [0.08%] receiving placebo) discontinued study drug because of allergic reactions. In the ESPRIT study, there were no cases of anaphylaxis reported. There were 3 patients who suffered an allergic reaction, 1 on placebo and 2 on eptifibatide. In addition, 1 patient in the placebo group was diagnosed with urticaria. The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide was nonantigenic in 412 patients receiving a single administration of eptifibatide (135-��g/kg bolus followed by a continuous infusion of either 0.5��g/kg/min or 0.75��g/kg/min), and in 21 subjects to whom eptifibatide (135-��g/kg bolus followed by a continuous infusion of 0.75��g/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to eptifibatide at higher doses has not been evaluated.<br/>Other Adverse Reactions: In the PURSUIT and ESPRIT studies, the incidence of serious nonbleeding adverse events was similar in patients receiving placebo or eptifibatide (19% and 19%, respectively, in PURSUIT; 6% and 7%, respectively, in ESPRIT). In PURSUIT, the only serious nonbleeding adverse event that occurred at a rate of at least 1% and was more common with eptifibatide than placebo (7% vs 6%) was hypotension. Most of the serious nonbleeding events consisted of cardiovascular events typical of an unstable angina population. In the IMPACT II study, serious nonbleeding events that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and eptifibatide-treated patients. Discontinuation of study drug due to adverse events other than bleeding was uncommon in the PURSUIT, IMPACT II, and ESPRIT studies, with no single event occurring in>0.5% of the study population (except for "other" in the ESPRIT study). In the PURSUIT study, nonbleeding adverse events leading to discontinuation occurred in the eptifibatide and placebo groups in the following body systems with an incidence of���0.1%: cardiovascular system (0.3% and 0.3%), digestive system (0.1% and 0.1%), hemic/lymphatic system (0.1% and 0.1%), nervous system (0.3% and 0.4%), urogenital system (0.1% and 0.1%), and whole body system (0.2% and 0.2%). In the ESPRIT study, the following nonbleeding adverse events leading to discontinuation occurred in the eptifibatide and placebo groups with an incidence of���0.1%: "other" (1.2% and 1.1%). In the IMPACT II study, nonbleeding adverse events leading to discontinuation occurred in the 135/0.5 eptifibatide and placebo groups in the following body systems with an incidence of���0.1%: whole body (0.3% and 0.1%), cardiovascular system (1.4% and 1.4%), digestive system (0.2% and 0%), hemic/lymphatic system (0.2% and 0%), nervous system (0.3% and 0.2%), and respiratory system (0.1% and 0.1%).<br/>Post-Marketing Experience: The following adverse events have been reported in post-marketing experience, primarily with eptifibatide in combination with heparin and aspirin: cerebral, GI, and pulmonary hemorrhage. Fatal bleeding events have been reported. Acute profound thrombocytopenia has been reported.
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INTEGRILIN is indicated: In the IMPACT II, PURSUIT and ESPRIT studies of eptifibatide, most patients received heparin and aspirin .
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Integrilin
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