ATC Class:B01AC17

VA Class:BL117

AHFS Class:

• Platelet-aggregation Inhibitors 20:12.18

Generic Name(s):

• Tirofiban

Chemical Name:

• N -(butylsulfonyl)-4-[4-(4-piperidyl)butoxy]-l-phenylalanine monohydrochloride monohydrate

Molecular Formula:

• C₂₂H₃₆N₂O₅S

Tirofiban hydrochloride, a selective, competitive platelet-aggregation inhibitor,1,15,22 has been referred to as a platelet glycoprotein (GP) IIb/IIIa-receptor inhibitor.

Non-ST-Segment-Elevation Acute Coronary Syndromes

Tirofiban is used with anticoagulant therapy (e.g., heparin [referring throughout this monograph to unfractionated heparin], low molecular weight heparin), aspirin, and a P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) to reduce the risk of acute cardiac ischemic events (death and/or myocardial infarction [MI]) in patients with unstable angina or non-ST-segment-elevation MI (NSTEMI) (i.e., non-ST-segment-elevation acute coronary syndromes [NSTE ACS]), both in patients who are to receive medical management and those undergoing percutaneous coronary intervention (PCI) (e.g., percutaneous transluminal coronary angioplasty [PTCA], stent placement, atherectomy).1,5,6,21,91,994,995,1100 The goal of therapy in these patients is to maintain myocardial perfusion by inhibiting further platelet aggregation and thus preventing the progression of a nonocclusive thrombus to an occlusive thrombus.10,25 In clinical trials of tirofiban, NSTE ACS was defined by prolonged symptoms of cardiac ischemia (at least 10 minutes' duration within the previous 12-24 hours) occurring at rest or with minimal exertion that were associated with transient ST-segment changes (i.e., elevation or depression), T-wave inversion, or increased cardiac [MB] fraction of creatine kinase [CK, creatine phosphokinase, CPK]); patients who had MI associated with Q waves or persistent ST-segment elevation (exceeding 20 minutes) were not included in these studies.1,5,6,91 NSTEMI and unstable angina clinically may be indistinguishable at initial presentation and are managed similarly.9,65,67,77,81 Most of the patients in clinical trials of tirofiban received concomitant therapy with aspirin and IV heparin,1,5,6,11,14 and the efficacy and safety of tirofiban without adjunctive heparin and/or aspirin therapy have not been established.1,6,33,35,38,40,44,48,91

Platelet glycoprotein (GP) IIb/IIIa-receptor inhibitors are used as an adjunct to standard therapeutic measures for managing NSTE ACS.7,53,73,77,81,994,995 These measures include therapy with aspirin and a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor), nitrates (e.g., nitroglycerin), anticoagulant therapy (e.g., low molecular weight heparin, heparin), and β-blockers followed by either conservative medical management or early aggressive management, such as angiographic evaluation and revascularization procedures (e.g., PCI, coronary artery bypass grafting [CABG], coronary artery stent implantation) as required.1,5,6,7,48,53,98,994,995 Several meta-analyses of studies indicate that adjunctive therapy with a GP IIb/IIIa-receptor inhibitor can reduce the incidence of cardiac ischemic events, including subsequent MI and death, in patients with NSTE ACS.5,6,11,35,36,42,46,51,71,72,73,80,83,84,85,91 The benefits of GP IIb/IIIa-receptor inhibitors on mortality principally occur early during therapy (i.e., the first 48-96 hours).8,23,30,36,51,80,81,91

The benefit of aspirin for secondary prevention of ischemic events in patients with NSTE ACS has been demonstrated in several studies and pooled analyses.7,48,57,59,62,63,73,76 Many clinicians recommend that all patients with NSTE ACS receive aspirin as soon as possible after hospital admission and then continued indefinitely unless they have documented hypersensitivity or other definite contraindications (e.g., active or recent major bleeding, peptic ulcer disease).7,98,991,1100 (See Non-ST-Segment-Elevation Acute Coronary Syndromes under Thrombosis: Coronary Artery Disease and Myocardial Infarction, in Uses in Aspirin 28:08.04.24.) The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) state that in patients with NSTE ACS in whom an initial invasive management strategy is planned, an additional antiplatelet agent (either clopidogrel or a GP IIb/IIIa-receptor inhibitor given IV) should be administered prior to diagnostic angiography (“upstream”) as an adjunct to aspirin therapy.991 Eptifibatide or tirofiban is the preferred GP IIb/IIIa-receptor inhibitor for this use; abciximab is indicated only if there is no appreciable delay before angiography and PCI is likely to be performed.991

Randomized controlled studies, including a meta-analysis of 16 randomized trials involving approximately 10,000 patients with ST-segment-elevation MI (STEMI) undergoing primary PCI, generally have failed to demonstrate benefits of GP IIb/IIIa-receptor blockade similar to those observed in patients with NSTE ACS.994,1016 ACCF, AHA, the Society for Cardiovascular Angiography and Interventions (SCAI), and other experts currently do not recommend the routine use of GP IIb/IIIa-receptor inhibitors in patients with STEMI undergoing PCI; however, selective use of these drugs as an adjunct to heparin may be reasonable in certain high-risk patients (e.g., those with large anterior MI and/or large thrombus).994,1016 Studies evaluating the use of GP IIb/IIIa-receptor inhibitors in patients with NSTE ACS undergoing PCI have demonstrated reductions in ischemic outcomes, particularly in patients with high-risk features (e.g., elevated troponin); therefore, ACCF/AHA/SCAI states that it may be useful to administer a GP IIb/IIIa-receptor inhibitor at the time of PCI as an adjunct to heparin therapy in such high-risk patients who are not receiving bivalirudin and who are not adequately pretreated with clopidogrel.994 Regarding the choice of GP IIb/IIIa-receptor inhibitor in patients undergoing PCI, abciximab, “double-bolus” eptifibatide (i.e., two 180-mcg/kg direct IV injections given 10 minutes apart), and high-dose tirofiban (25 mcg/kg by direct IV injection) all have been shown to produce a high degree of platelet inhibition and reduce ischemic complications.994

In patients with NSTE ACS with elevated troponin concentrations who were managed with conservative medical therapy, GP IIb/IIIa-receptor inhibitors were equally effective in men and women.109 However, in women with NSTE ACS who are not at high risk for acute cardiac ischemic events (e.g., no elevated troponin concentrations) and are managed with a conservative strategy, eptifibatide and tirofiban appear to show little benefit and may possibly have detrimental effects; these agents are not recommended by AHA in women at lower risk for adverse cardiac events.109

The current labeled indication for tirofiban is based principally on the results of 3 large, randomized controlled studies evaluating the efficacy of tirofiban alone or in combination with heparin in patients with NSTE ACS, including those who subsequently underwent PCI.1,5,6,11,12,44 All patients in these studies also received aspirin (300-325 mg daily) for at least 48 hours after randomization (indefinitely in some patients) or within 12 hours prior to PCI unless the drug was contraindicated.1,5,6,11,14,21,91 In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms [PRISM-PLUS]) study, therapy with tirofiban (IV loading dose of 0.4 or 0.6 mcg/kg per minute given over 30 minutes followed by continuous IV infusion of 0.1 mcg/kg per minute for 48-108 hours) plus adjusted-dose heparin reduced the incidence of ischemic events compared with adjusted-dose heparin alone in patients with NSTE ACS.1,6 All patients received aspirin 325 mg daily unless the drug was contraindicated.1,6 Patients who received medical management alone (i.e., those not undergoing PCI) were given an IV loading dose of heparin sodium (5000 units) followed by an IV infusion (1000 units/hour) that was titrated to a target activated partial thromboplastin time (aPTT) of twice the control value.1,6 In patients undergoing PCI after at least 48 hours of medical management, the infusion of heparin sodium or heparin placebo was discontinued and an IV loading dose of heparin sodium (5000-7500 units) was administered, followed by an IV infusion (1000 units/hour) that was titrated with additional IV injections of heparin sodium as needed.1,6 Overall, patients in each group received the study drug(s) for an average of about 71 hours.8 Patients undergoing PCI received the study drug(s) for an average of 76 hours, of which an average of 15.4 hours was after PCI.6

Beneficial effects of therapy with tirofiban and heparin were evident within 48 hours of initiating the tirofiban infusion and persisted for up to 6 months.1,6,8,44 The combined incidence of nonfatal MI or death at 48 hours in patients receiving tirofiban plus heparin was reduced by 66% (from 2.6 to 0.9%).6,8 The combined incidence of death, nonfatal MI, or refractory ischemia at 7 days (the primary composite end point) in patients receiving tirofiban plus heparin was reduced by 32% (from 17.9% to 12.9%); relative reductions of 47 and 30% occurred in the individual incidences of MI and refractory ischemia, respectively.1,6,8 The incidences of the composite end point at 30 days and 6 months, which also included hospital readmissions for unstable angina in patients receiving tirofiban and heparin, were reduced by 22% (from 22.3% to 18.5%) and 19% (from 32.1% to 27.7%), respectively, compared with heparin therapy alone.1,6,8 Data from a substudy of patients in PRISM-PLUS indicate that troponin I concentrations, a sensitive marker of myocardial injury or ischemia,89,96 were reduced to a greater extent in patients receiving tirofiban and heparin than in those receiving heparin alone.9,13,48 In another substudy of PRISM-PLUS, a reduction in angiographically evident thrombus formation was accompanied by an increase in blood flow to the affected coronary artery in patients receiving tirofiban and heparin.1 The incidence of major hemorrhage was similar in patients receiving tirofiban plus heparin (4%) or heparin alone (3%).6 Death occurred in 1.9% of each study group; no intracranial hemorrhages or hemorrhage-related deaths occurred in either group.6

An initial third arm of the PRISM-PLUS study that included patients receiving tirofiban alone (without heparin) was discontinued prematurely because of unexpected excess mortality at 7 days (4.6%) compared with that in patients receiving heparin alone (1.1%);1,6,8 however, similar increases in the incidences of refractory ischemia, MI, or the composite end point did not occur.6 Also, another randomized study (Platelet Receptor Inhibition in Ischemic Syndrome Management [PRISM]) in which tirofiban therapy was compared with heparin therapy in patients with NSTE ACS demonstrated reductions in the composite end point of death, MI, or refractory ischemia at 48 hours and in mortality at 30 days.1,5,6 The PRISM-PLUS study included more high-risk patients than did the PRISM study (based on a higher percentage of patients with baseline ST-segment changes on ECG),6,8 and it has also been suggested that the large proportion (70%) of patients receiving IV heparin prior to randomization in the PRISM-PLUS study may have increased the likelihood of heparin rebound (i.e., ischemic events, including death, associated with recent or current heparin therapy in patients receiving concomitant aspirin).5,6,39,86 It has been suggested that the small number of events involved (16 of 345 patients receiving tirofiban alone versus 4 of 350 receiving heparin alone)6,8 also makes it possible that the higher incidence of death in PRISM-PLUS in patients receiving tirofiban alone compared with that in the PRISM study was attributable to chance.6,21,91 However, other variables potentially influencing the efficacy of tirofiban monotherapy (without heparin) include differences in the severity of NSTE ACS;5,6,8,32,33,38,39,40,46 the extent of use of PCI, angiography, or CABG;5,8,10,33,40,46 and the duration of the tirofiban infusion.6,8,33,40,91 Alternatively, concomitant thrombin inhibition (e.g., heparin, a low molecular weight heparin) may be needed for optimal efficacy of tirofiban, especially in high-risk patients with more severe NSTE ACS.6,91,97,98 Pooled analysis of data from the PRISM and PRISM-PLUS studies reportedly indicates that the effect of tirofiban therapy alone on mortality at 7 and 30 days was comparable to that of heparin therapy alone.1

The efficacy of tirofiban in reducing composite clinical events associated with NSTE ACS in the PRISM-PLUS study was not affected by age or gender; the effect of race on efficacy could not be determined from the small number of non-white patients studied.1,6 Subgroup analyses indicated that beneficial effects of tirofiban and aspirin and heparin were particularly evident in patients receiving β-adrenergic blocking agents prior to study entry; benefit appeared to be consistent for all other factors studied (e.g., age, gender prior treatment with aspirin or heparin).6 While evaluation of patients who did or did not undergo PCI was not based on a randomized cohort, the incidence of the composite end point at 30 days in patients undergoing PCI was reduced from 15.3% in patients receiving heparin alone to 8.8% in patients receiving tirofiban and heparin (45% reduction).6,8,91

In the Platelet Receptor Inhibition in Ischemic Syndrome Management [PRISM] study, therapy with tirofiban (IV loading dose of 0.6 mcg/kg per minute for 30 minutes followed by continuous IV infusion of 0.15 mcg/kg per minute for 48 hours) reduced the incidence of ischemic events compared with heparin sodium therapy (5000 units IV loading dose followed by 1000 units per hour for 48 hours, adjusted to achieve an aPTT of twice the control value).5 All patients received aspirin 300-325 mg before randomization and daily thereafter for at least 48 hours unless contraindicated.1,5 Approximately 25% of the patients in the PRISM study had evidence of NSTEMI, while 30% had no electrocardiographic evidence of cardiac ischemia (ST-segment depression).1,5,10,33,40

Beneficial effects of tirofiban were apparent during infusion of the drug but diminished thereafter.1,5,91 The combined incidence of death, nonfatal MI, or refractory ischemia at 48 hours (the primary composite end point) was reduced by 33% in patients receiving tirofiban compared with those receiving heparin; reductions in the incidence of these end-point events at 7 and 30 days (10 and 8%, respectively) were no longer statistically significant.1,5,39,44,46 However, the effect of tirofiban on survival became more pronounced with time; death was less common at 30 days (risk reduction of 38%) in tirofiban-treated patients than in those who received heparin (2.3 versus 3.6% of patients, respectively).1,5,21 In patients treated with medical therapy alone (i.e., not undergoing PCI), the rate of death or MI at 30 days was reduced by 42% (from 6.2%, with heparin to 3.6% with tirofiban).5 The incidence of major bleeding was similar in both treatment groups.5

In the Randomized Efficacy Study of Tirofiban for Outcome and Restenosis (RESTORE) study, therapy with tirofiban (IV loading dose of 10 mcg/kg followed by continuous IV infusion of 0.15 mcg/kg per minute for 36 hours, beginning immediately prior to coronary intervention) reduced the incidence of early ischemic events in patients at high risk for abrupt closure of the affected coronary artery who underwent urgent or emergency PCI, although this reduction was not sustained.1,11,12,37,44 Patients considered at high risk for abrupt closure of coronary blood vessels included those with NSTE ACS or acute STEMI.11 All patients were receiving adjunctive therapy with low-dose aspirin (325 mg within 12 hours before the procedure) and heparin sodium (IV loading dose of 10,000 units in patients weighing at least 70 kg or 150 units/kg in those weighing less than 70 kg) prior to PCI.1,11,37,44 Additional heparin sodium was administered during the procedure as required to maintain an activated clotting time (ACT) of 300-400 seconds; heparin generally was discontinued after completion of PCI.1,11,37,44

Beneficial effects of tirofiban were most apparent during infusion of the drug and for several days after drug administration but declined thereafter.1,11,12 The relative risk reduction in the primary composite clinical end point of death, nonfatal MI, or additional surgical interventions (e.g., recurrent ischemia, complications, or procedural failure of initial PCI necessitating CABG, coronary artery stent implantation, or repeat PCI) at 48 hours was 38% (from 8.7% in placebo recipients to 5.4% in those receiving tirofiban); however, the reduction in these clinical events was no longer statistically significant at 30 days (16% relative risk reduction) or 6 months (11% relative risk reduction), principally because of nonemergency CABG and repeat PCI procedures.11,12,22,37,41,42,44,46 In an angiographic substudy of the RESTORE study, tirofiban had no effect on the angiographic measurements of restenosis at 6 months.37,41 The incidence of major bleeding complications or thrombocytopenia were similar in patients receiving tirofiban or placebo.11

Administration

Tirofiban hydrochloride is administered by IV infusion using either the diluted injection concentrate or the premixed injection in plastic (IntraVia™) containers.1 Tirofiban hydrochloride injection concentrate for IV infusion must be diluted to the same concentration as the premixed injection (50 mcg/mL of tirofiban) before administration .1 The injection concentrate is prepared for infusion by withdrawing and discarding 50 or 100 mL of solution from a 250- or 500-mL bag, respectively, of 0.9% sodium chloride or 5% dextrose injection and replacing this volume with 50 mL (12.5 mg of tirofiban) or 100 mL (25 mg of tirofiban) of tirofiban hydrochloride injection to achieve a final tirofiban concentration of 50 mcg/mL.1,21 The solution should be mixed well prior to infusion.1 Any unused drug solution should be discarded.1

The plastic container of the premixed injection may be somewhat opaque because of moisture absorption during sterilization; this opacity will diminish gradually.1 The container of the premixed injection should be checked for minute leaks by firmly squeezing the bag.1 The premixed injection should be discarded if the seal is not intact,1 leaks are found, or the solution is cloudy1 or contains a precipitate.21,91 Additives should not be introduced into the injection container.1 The plastic IV containers should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container if the first container is empty.1

In clinical trials, almost all patients receiving tirofiban also received concomitant aspirin and/or heparin.1,5,6,11 Tirofiban and heparin may be administered through the same IV line.1

Parenteral tirofiban hydrochloride solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.21

Dosage

Dosage of tirofiban hydrochloride is expressed in terms of tirofiban.1

Non-ST-Segment-Elevation Acute Coronary Syndromes

For reducing the risk of death, nonfatal myocardial infarction (MI), and/or refractory ischemia/repeat revascularization procedures in patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS) who are receiving medical therapy alone, an IV loading dose consisting of 0.4 mcg/kg of tirofiban per minute for 30 minutes is given as soon as possible after diagnosis, followed by continuous IV infusion of tirofiban 0.1 mcg/kg per minute for at least 24-48 hours.21,91 Patients receiving tirofiban who undergo percutaneous coronary intervention (PCI) should receive the same IV loading dose of tirofiban (0.4 mcg/kg per minute for 30 minutes) followed by continuous IV infusion of 0.1 mcg/kg per minute given during angiography and for 12-24 hours after angioplasty or atherectomy.1,20,21,91 In the PRISM-PLUS study, the tirofiban infusion was continued in combination with heparin for 48-108 hours.1,20 In patients who require coronary artery bypass grafting (CABG), tirofiban should be discontinued at least 4-6 hours before the procedure.21,91 While females and geriatric patients had a higher incidence of adverse effects (both hemorrhagic and nonhemorrhagic) in clinical trials of tirofiban1,20 (see Cautions), the manufacturer does not recommend dosage adjustments for tirofiban in female or geriatric patients.1,20

Adjunctive Antithrombotic Therapy

Adjunctive antithrombotic therapy with aspirin and heparin was used in most patients with NSTE ACS receiving tirofiban therapy in clinical trials.1,5,6,11,14 In the 3 large, randomized controlled studies evaluating the efficacy of tirofiban, patients received aspirin (300-325 mg daily) for at least 48 hours after randomization or within 12 hours prior to PCI, unless the drug was contraindicated; some patients received aspirin indefinitely.1,5,6,11,14 For additional details regarding aspirin dosage regimens in patients with ACS, see Non-ST-Segment-Elevation Acute Coronary Syndromes under Dosage: Thrombosis, in Dosage and Administration in Aspirin 28:08.04.24.

The American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and Society of Cardiovascular Angiography and Interventions (SCAI) recommend that aspirin 325 mg be given prior to PCI in patients not already receiving maintenance therapy with aspirin.994 Patients already receiving maintenance therapy with aspirin should receive a dose of 81-325 mg of aspirin before the procedure.994 For additional details regarding aspirin dosage regimens in patients undergoing PCI, see Percutaneous Coronary Intervention and Revascularization Procedures under Dosage: Thrombosis, in Dosage and Administration in Aspirin 28:08.04.24.

In addition to aspirin, ACC/AHA/SCAI recommends administration of a loading dose of a P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in patients undergoing PCI with stent placement.994

In clinical trials with tirofiban in patients not undergoing PCI, an initial 5000-unit IV loading dose of heparin sodium was given, followed by IV infusion of 1000 units/hour and dosage titration to achieve a target activated partial thromboplastin time (aPTT) of twice the control value.1,5,6 In patients undergoing PCI after at least 48 hours of medical management with tirofiban and heparin in the PRISM-PLUS study, an IV loading dose of heparin sodium (5000-7500 units) was administered, followed by an IV infusion (1000 units/hour) that was titrated to an aPTT approximately 2 times the control value with additional IV injections of heparin sodium as needed.1,6 In the RESTORE trial, patients at high risk for abrupt closure of the affected coronary artery who underwent urgent or emergency PCI received heparin sodium as an IV loading dose (10,000 units in patients weighing at least 70 kg or 150 units/kg in those weighing less than 70 kg) prior to PCI.1,11,37,44 Additional heparin sodium was administered during the procedure as required to maintain an activated clotting time (ACT) of 300-400 seconds; heparin generally was discontinued after completion of PCI.1,11,37,44 Since tirofiban and other GP IIb/IIIa-receptor inhibitors may have additive effects on ACT in patients receiving one of these drugs concomitantly with heparin, the dosage of heparin required to maintain an appropriate ACT during such concomitant GP IIb/IIIa-receptor inhibitor therapy may be lower than with heparin monotherapy.56 Clinical experience from other studies with GP IIb/IIIa-receptor inhibitors (e.g., abciximab) and expert guidelines suggest that use of lower dosages of concomitant IV heparin sodium (e.g., 50-70 units/kg) given 6 hours prior to PCI and targeted to an ACT of at least 200 seconds may provide similar reductions in ischemic coronary events as dosages for higher target ACTs with less risk of major bleeding.1,18,35,44,53,71,74,77,80,81,95,96,994 In women and geriatric patients undergoing PCI and receiving adjunctive therapy with a GP IIb/IIIa-receptor inhibitor and heparin, a lower dosage of heparin should be considered to decrease the risk of minor bleeding that has been observed compared with that in men.109

Postprocedural use of heparin generally is not recommended while GP IIb/IIIa-receptor inhibitor therapy is given.6,11,42,52,53

Dosage in Renal and Hepatic Impairment

Plasma clearance of tirofiban may be decreased substantially (more than 50%) in patients with severe renal impairment (i.e., creatinine clearance of 30 mL/minute or less), including patients requiring hemodialysis.1 These patients should receive half the usual rate of infusion of tirofiban.1

In patients with mild to moderate hepatic impairment, plasma clearance of tirofiban is similar to that in healthy individuals;1,20 information on plasma clearance in patients with severe hepatic impairment is not available since these patients were excluded from participation in clinical trials of tirofiban.21 Metabolism of tirofiban appears to be limited, and the manufacturer does not make specific recommendations for dosage adjustment in patients with hepatic impairment.1,20

The most frequent and severe adverse effect of tirofiban therapy is bleeding.1,20 Bleeding is an extension of the pharmacologic action of tirofiban and was classified in clinical trials principally according to criteria of the Thrombolysis in Myocardial Infarction (TIMI) study groups.1,21,88,91 Minor bleeding generally was defined as spontaneous gross hematuria, hematemesis, hemoptysis, or observed blood loss with a decrease in hemoglobin concentration exceeding 3 but less than 5 g/dL; major bleeding was defined as intracranial bleeding, cardiac tamponade, or a hemoglobin decrease exceeding 5 g/dL with or without an observed bleeding site.1,11,14,20,22,52,88,91 Almost all patients receiving tirofiban in clinical trials received concomitant therapy with heparin and/or aspirin;1,5,6,11,41 therefore, the contribution of tirofiban to the incidence of bleeding complications in these trials is difficult to determine.1,91

Approximately 30% of patients in clinical trials of tirofiban were female, and 43% were older than 65 years of age.1 Patients in these trials received tirofiban for up to 116 hours.1 Females (compared with males) and geriatric (compared with younger) patients receiving tirofiban plus heparin or heparin alone had a higher incidence of adverse effects (both hemorrhagic and nonhemorrhagic).1,20 However, the incremental risk of hemorrhage and the incidence of nonhemorrhagic adverse effects in patients treated with tirofiban and heparin versus heparin alone were comparable regardless of age or gender.1 The incidence of adverse effects was not affected by race or the presence of underlying hypertension, diabetes mellitus, or hypercholesterolemia.1,20

Hematologic Effects

Effects on Hemostasis

Administration of tirofiban is associated with a small increase in major and minor bleeding complications compared with heparin and/or aspirin therapy.1,21,91 Major bleeding events (as defined by TIMI criteria) occurred in about 1.4 or 0.8% of patients receiving tirofiban plus heparin or heparin monotherapy, respectively, in the PRISM-PLUS study,1,6 in about 2.4 or 2.1% of patients receiving tirofiban plus heparin or heparin monotherapy, respectively, in the RESTORE study,1,11 and in 0.4% of each respective treatment group in the PRISM study.5 Major bleeding episodes, including fatalities, have been reported during postmarketing experience.1 Bleeding complications resulted in discontinuance of tirofiban in 3.5 or 1.3% of patients receiving tirofiban plus heparin or heparin alone, respectively, in PRISM-PLUS.6 Spontaneous (i.e., unrelated to catheter or other puncture sites) bleeding occurred at retroperitoneal, genitourinary, or GI sites in 0, 0.1, or 0.1%, respectively, of patients during therapy with tirofiban plus heparin in the PRISM-PLUS study,1,6,20 and in 0.6%, 0%, or 0.2%, respectively, of patients receiving this drug combination in the RESTORE study.1,11 During postmarketing experience, pulmonary (alveolar) hemorrhage, spinal-epidural hematoma, and hemopericardium have been reported in patients receiving tirofiban.1 Blood transfusions were required in 4 versus 2.8% of patients receiving tirofiban and heparin or heparin alone, respectively, in the PRISM-PLUS study1,6,20 and in 4.3 versus 2.5% of patients receiving these respective therapies in the RESTORE study.1,11,20

Most major bleeding in clinical trials of tirofiban occurred at the arterial access site for femoral sheath placement in patients undergoing revascularization procedures.1 In patients undergoing PCI (e.g., percutaneous transluminal coronary angioplasty [PTCA]) in the PRISM-PLUS study, the incidences of major bleeding prior to PCI, following angiography (performed in 89.8% of the patients),6 and following PCI were 0.3, 1.3, and 2.5%, respectively, in patients receiving tirofiban plus heparin and 0.1, 0.7, and 2.2%, respectively, in patients receiving heparin monotherapy.1,6,20 The incidence of major bleeding (in some instances possibly reflecting hemoglobin decreases related to hemodilution rather than actual bleeding) in patients receiving tirofiban plus heparin or heparin monotherapy and undergoing coronary artery bypass grafting (CABG) within 1 day of discontinuance of study drug was 17.2 or 35.4%, respectively, in the PRISM-PLUS study and 25 or 37.5%, respectively, in the RESTORE study.1,20

Therapy with GP IIb/IIIa-receptor inhibitors, including tirofiban, has not been associated with an increased risk of intracranial hemorrhage.1,44 Intracranial hemorrhage occurred in 0.1 or 0.3% of patients receiving tirofiban and heparin or heparin alone, respectively, in the RESTORE study, and was not reported in patients receiving these therapies in the PRISM-PLUS study.1,20 The incidence of intracranial hemorrhage in patients receiving tirofiban or heparin in the PRISM study was 0.1% in each group.5 Retroperitoneal bleeding1 or hemopericardium1 has been reported during postmarketing experience in patients receiving tirofiban.1

Minor bleeding episodes occurred in about 10.5 or 8% of patients receiving tirofiban plus heparin or heparin monotherapy, respectively, in the PRISM-PLUS study1,6 and in 12 or 6.3% of patients receiving tirofiban plus heparin or heparin alone, respectively, in the RESTORE study.1,11

Other Hematologic Effects

Decreases in platelet count or thrombocytopenia occurs occasionally (2.3% overall) after therapy with GP IIb/IIIa-receptor inhibitors.50,52 Thrombocytopenia associated with administration of a GP IIb/IIIa-receptor inhibitor generally occurs within hours or days after administration of the drug.37,43,44,45 Decreases in platelet counts have been observed in patients with no prior history of thrombocytopenia following readministration of GP IIb/IIIa-receptor inhibitors.1 Severe thrombocytopenia (i.e., platelet count less than 20,000/mm³)77,81,85 has been reported more frequently with abciximab than with tirofiban.18,30,32,35,37,44,50,53 However, a preliminary report based on pooled data from clinical trials indicates that the incidence of thrombocytopenia is not appreciably different among GP IIb/IIIa-receptor inhibitors (i.e., abciximab, eptifibatide, tirofiban), although the absolute risk of thrombocytopenia appears to increase (but not synergistically) with concomitant use of heparin.50 In controlled clinical trials of tirofiban, the incidence of thrombocytopenia (defined as platelet counts less than 90,000/mm³) was increased in patients receiving tirofiban plus heparin (1.5%) compared with heparin monotherapy (0.6%), respectively; reductions in platelet count to less than 50,000/mm³) were observed in 0.3 or 0.1% of patients receiving tirofiban plus heparin or heparin alone, respectively, in clinical trials.1 In the PRISM study, the incidence of thrombocytopenia also was increased in patients receiving tirofiban versus those receiving heparin; platelet counts returned to normal several days after cessation of therapy without any other clinical sequelae.5,32,43 Decreased platelet counts associated with chills and a low-grade fever have been reported with tirofiban during postmarketing experience.1

Reductions in hemoglobin or hematocrit were reported in 2.1 or 2.2%, respectively, of patients receiving tirofiban plus heparin and in 3.1 or 2.6%, respectively, of patients receiving heparin in controlled clinical trials.1 Microscopic hematuria or occult blood in the stool was noted in 10.7 or 18.3%, respectively, of patients receiving tirofiban plus heparin and in 7.8 or 12.2%, respectively, of those receiving heparin monotherapy in clinical trials.1,21

Cardiovascular Effects

Adverse cardiovascular effects that occurred in greater than 1% of patients receiving tirofiban plus heparin in clinical trials were bradycardia (4%) or dissection of the coronary artery (5%).1 Edema/swelling or vasovagal reactions were reported in 2% of patients receiving tirofiban and heparin in these trials.1

Dermatologic and Sensitivity Reactions

Sweating was reported in 2% of patients receiving tirofiban and heparin in controlled clinical trials.1,20 Anaphylaxis and/or urticaria requiring discontinuance of therapy was not reported in clinical trials of tirofiban, but anaphylaxis and other severe allergic reactions have been reported during postmarketing experience.1,21 Such reactions have occurred on the first day of tirofiban infusion, during initial treatment, and during readministration of the drug.1 Some severe allergic reactions have been associated with severe thrombocytopenia (platelet counts less than 10,000/mm³).1

Therapy with some platelet-aggregation inhibitors (e.g., abciximab) has been associated with development of antibodies to the drug;15,23,25,26,27,52 limited information indicates that no antibodies to tirofiban have developed, but very few patients have received the drug on more than one occasion.1,52,84,91 However, as a nonpeptide GP IIb/IIIa-receptor inhibitor, tirofiban is expected to be less immunogenic than the monoclonal antibody abciximab.15,21,91

Other Adverse Effects

Pelvic pain occurred in 6%, leg pain in 3%, and dizziness in 3% of patients receiving tirofiban plus heparin in clinical trials.1,20 Other adverse effects reported in greater than 1% of patients receiving tirofiban plus heparin in clinical trials include headache, nausea, and fever.1,20

Precautions and Contraindications

The administration of tirofiban in patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS) has been associated with a small increase in the frequency of major bleeding compared with heparin and aspirin therapy alone.1,5,6,11,21,91 Bleeding with platelet glycoprotein (GP) IIb/IIIa-receptor inhibitors can be reduced by adherence to strict anticoagulation guidelines, the use of a short course of low-dose, weight-adjusted heparin, and in patients undergoing PCI, early arterial sheath removal and careful patient and access site management.1,18,53,71,91 Prior to administration of tirofiban, preexisting hemostatic abnormalities should be identified by obtaining determinations of hematocrit and hemoglobin; these parameters should then be monitored within 6 hours following the loading infusion and at least daily thereafter during therapy.1,11,20,35,43,44 In patients receiving heparin concomitantly with tirofiban, the extent of heparin anticoagulation (as assessed by activated clotting time [ACT] or aPTT) should be monitored closely to minimize bleeding, which may be potentially life-threatening.1,30,52,70 The aPTT should be monitored 6 hours after the start of the heparin infusion and be maintained at 50-70 seconds or approximately 2 times the control value unless PCI is to be performed.1,6,30 In addition, the ACT should be measured in patients undergoing PCI.21,52,70 Current guidelines of the American College of Chest Physicians (ACCP) and other experts and risk-benefit analyses in trials with GP IIb/IIIa-receptor inhibitors suggest that heparin dosing should be adjusted to maintain the ACT at 200 seconds or greater during PCI in patients receiving GP IIb/IIIa-receptor inhibitors.52,53,77,80,81 (See Adjunctive Antithrombotic Therapy under Dosage: Non-ST-Segment-Elevation Acute Coronary Syndromes, in Dosage and Administration.) Routine use of postprocedural heparin generally is not recommended during GP IIb/IIIa-receptor inhibitor therapy.6,11,42,52,53 After PCI, the aPTT should be checked prior to arterial sheath removal, and the sheath should not be removed unless the aPTT is less than 45 seconds or the ACT is less than 180 seconds.1,30,41,53,70 Tirofiban should be used with caution in patients with hemorrhagic retinopathy, anemia (hemoglobin concentration less than 10-12 g/dL) and in those requiring chronic hemodialysis.1,20,91

Platelet counts should be determined prior to treatment with tirofiban and periodically (e.g., within the first 6 hours of the loading infusion and daily thereafter) during concomitant tirofiban and heparin therapy.1,11,20,43,44 should be used with caution in patients with a platelet count less than 150,000/mm³.1,20 If a patient experiences a reduction in platelet count to less than 90,000/mm³, additional platelet counts should be performed to exclude the possibility of pseudothrombocytopenia.1,18,90 The possibility of heparin-induced thrombocytopenia also should be considered in the differential diagnosis of thrombocytopenia in patients receiving GP IIb/IIIa-receptor inhibitors concomitantly with heparin.1,20,35,37,52 If thrombocytopenia is confirmed, tirofiban should be discontinued and the condition appropriately monitored and treated.1,52 Thrombocytopenia is usually reversible following discontinuance of GP IIb/IIIa-receptor inhibitors and anticoagulant (heparin) therapy; however, platelet transfusions should be considered for the management of severe thrombocytopenia.35,37,43,52

To minimize the possibility of bleeding associated with the use of tirofiban, particularly at the site of femoral artery sheath placement in patients undergoing PCI, precautions in the placement, maintenance, and removal of the vascular access sheath should be observed.1,18,35,37,42,46,52 Placement of a femoral venous sheath should be avoided if possible.18,52 When inserting the femoral artery sheath, care should be taken so that only the anterior wall of the femoral artery is punctured; a Seldinger (through and through) technique for puncture of the artery should be avoided.1,18,20,52,77,81 Appropriate precautions should be observed while the vascular access sheath is in place (e.g., complete bed rest, elevation of the head of the bed no more than 30°, restraint of the limb in which the vascular access sheath is inserted, frequent monitoring of the vascular access site and the distal pulse in the involved limb).1,18,19,20,52 The femoral artery sheath may be removed during treatment with tirofiban, provided at least 3-4 hours have elapsed since heparin therapy was discontinued and its effects largely have reversed (as indicated by an aPTT of less than 45 seconds or an ACT of less than 180 seconds).1,11,14,20,30,41,52,53,70

Both heparin and tirofiban therapy should be discontinued and sheath hemostasis achieved with standard compressive techniques at least 4 hours before hospital discharge.1,20 Pressure (e.g., using manual compression or a mechanical hemostatic device) should be applied to the femoral artery for at least 20-30 minutes after sheath removal;18,19 after hemostasis, a pressure dressing should be applied.18 Any hematoma that forms should be measured and monitored for enlargement.18

Careful monitoring of all potential bleeding sites should be undertaken during and following treatment with platelet aggregation inhibitors.1,18,20,21,91 Needle punctures (e.g., arterial, IM, IV, lumbar, subcutaneous, intradermal), cutdown sites, and use of nasotracheal intubation, nasogastric tubes, urinary catheterization,1,18,20 and automatic blood pressure cuffs18 should be minimized during and following treatment with tirofiban.1,18 Establishment of IV access at noncompressible sites (e.g., in subclavian or jugular veins) should be avoided;1,18,20 an indwelling venipuncture device (e.g., heparin lock) should be considered for drawing blood; documentation and monitoring of vascular puncture sites should occur; and dressings should gently and carefully be removed.18 The manufacturer states that any occurrence of serious bleeding that cannot be controlled by pressure on the bleeding site should result in discontinuance of tirofiban and concomitantly administered heparin therapy.1,20

Because tirofiban increases the risk of bleeding, the drug is contraindicated in patients with active internal bleeding (including microscopic hematuria or a positive test for occult fecal blood) or a history of bleeding diathesis (e.g., GI or genitourinary bleeding, elevated hemostatic indices, recent noncompressible vascular punctures)1,5,6,14,20,21,91 within the previous 30 days;1,20,21,91 a history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm;1,52 a history of thrombocytopenia following prior exposure to tirofiban;1,5,6,11,20,52 history of stroke within 30 days or any history of hemorrhagic stroke;1,5,6,11,14,20,52 recent (within 1 month) major surgery or severe physical trauma;1,5,20,52 history, symptoms, or findings suggestive of aortic dissection;1,20 severe uncontrolled hypertension (systolic or diastolic blood pressure exceeding 180 or 110 mm Hg, respectively);1,5,20 concomitant therapy with another parenteral GP IIb/IIIa-receptor inhibitor;1,20 or acute pericarditis.1,20 Tirofiban also is contraindicated in patients with a known hypersensitivity to any component of the commercially available preparation.1,20

Pediatric Precautions

Safety and efficacy of tirofiban in pediatric patients younger than 18 years of age have not been determined.1,20

Geriatric Precautions

Safety and efficacy of tirofiban in geriatric patients have not been specifically studied to date; however, in large clinical trials, approximately 43% of patients were 65 years of age or older, while 11.7% were 75 years of age or older.1 Clinical experience generally has not revealed age-related differences in response to tirofiban therapy.1 Plasma clearance of tirofiban is about 19-26% lower in geriatric patients (exceeding 65 years of age) with coronary artery disease than in younger patients.1 While the incidence of bleeding complications was higher in geriatric patients receiving either heparin plus tirofiban or heparin monotherapy, the incremental risk of bleeding among patients receiving these 2 regimens was similar regardless of age.1 The overall incidence of nonhemorrhagic adverse effects was higher in older patients compared with younger patients receiving either treatment regimen (heparin or tirofiban plus heparin).1 In the RESTORE study, the loading dose of IV heparin was weight-adjusted in patients weighing less than 70 kg1,11 because of concern for an increased risk for bleeding in these patients.30 However, the manufacturer recommends no dosage adjustment for tirofiban in geriatric patients.1

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was seen at the chromosomal or gene level when tirofiban was evaluated in several in vitro and in vivo test systems.1 The drug was not directly genotoxic in the in vitro alkaline elution or chromosomal aberration assay.1 Tirofiban did not induce chromosomal aberrations in bone marrow cells of male mice given the drug IV at dosages of up to 5 mg/kg daily (about 3 times the maximum recommended daily human dosage based on body surface area).1

Studies have not been performed to date to evaluate the carcinogenic potential of tirofiban.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies using IV tirofiban dosages of up to 5 mg/kg daily in rats and rabbits (representing about 5 and 13 times, respectively, the recommended maximum daily human dosage based on body surface area) have not revealed evidence of harm to the fetus.1 However, animal reproduction studies are not always predictive of human response.1 There are no adequate or controlled studies to date using tirofiban in pregnant women, and the drug should be used during pregnancy only when clearly needed.1

Fertility

Reproduction studies of tirofiban in male and female rats given up to 5 mg/kg daily IV (representing about 5 times the recommended maximum daily human dosage based on body surface area) have not revealed evidence of impaired fertility or reproductive performance.1

Lactation

It is not known if tirofiban is distributed into milk in humans; however, the drug is distributed into milk in rats.1 Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or tirofiban, taking into account the importance of the drug to the woman.1

Drugs Affecting Hemostasis

Almost all patients receiving tirofiban in clinical trials have received concomitant therapy with heparin and/or aspirin,1,5,6,11,41 and such concomitant therapy has been associated with a small increase in bleeding complications compared with that in patients receiving aspirin and heparin alone.1 (See Effects on Hemostasis under Cautions: Hematologic Effects.) Caution should be observed when tirofiban is used with other drugs that affect hemostasis, including thrombolytic agents, oral anticoagulants (e.g., warfarin), nonsteroidal anti-inflammatory agents (NSAIAs), dipyridamole, ticlopidine, and clopidogrel;1,20,21,91 some clinicians also recommend against concomitant use of tirofiban and IV dextran.91

In several studies evaluating pharmacokinetic and pharmacodynamic interactions with tirofiban in healthy individuals, the pharmacokinetics of tirofiban were not affected by pretreatment with aspirin (325 mg administered 1 and 24 hours prior to tirofiban) or ticlopidine (200 mg once daily for 4 days).1,4,22 However, aspirin or ticlopidine may enhance the inhibition of platelet aggregation produced by tirofiban.3,4,22 In healthy individuals and in patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS), bleeding time was prolonged by the combination of tirofiban and aspirin compared with tirofiban or aspirin therapy alone; aPTT was not affected (compared with baseline values).4,5,6,22 (See Pharmacology.)

No information is available concerning the use of tirofiban concomitantly with thrombolytic agents.1

Other Drugs

Data from a large clinical study (the PRISM study) indicate that concomitant administration of tirofiban and levothyroxine or omeprazole was associated with a higher clearance of tirofiban; the clinical importance of this effect is not known.1 Concomitant administration of the following drugs in the same study was not associated with clinically important effects 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, lorazepam, lovastatin, metoclopramide, metoprolol, morphine, nifedipine, nitrate preparations, oxazepam, potassium chloride, propranolol, ranitidine, simvastatin, sucralfate, or temazepam.1

Acute Toxicity

Limited information is available on the acute toxicity of tirofiban.1 In general, overdosage of tirofiban in humans may be expected to produce effects that are extensions of the pharmacologic and adverse effects of the drug, predominantly bleeding.1 (See Cautions: Hematologic Effects.) The most frequently reported manifestation of overdosage was bleeding, principally minor bleeding at mucocutaneous and cardiac catheterization sites.1 Inadvertent overdosage with tirofiban has occurred in doses of up to twice those recommended for an IV loading infusion and up to 9.8 times higher than the recommended maintenance infusion dosage of 0.15 mcg/kg per minute.1 In the event of overdosage, tirofiban therapy should be discontinued or the dosage adjusted and the patient's clinical status monitored as appropriate.1 Tirofiban is removed by hemodialysis.1

Pharmacology

Platelet Aggregation and Thrombosis

Tirofiban is a selective, competitive, reversible inhibitor of platelet aggregation that is used in combination with heparin to reduce the risk of acute ischemic events (death and/or myocardial infarction [MI]) associated with non-ST-segment-elevation acute coronary syndromes (NSTE ACS), including those undergoing percutaneous coronary intervention (PCI) (e.g., percutaneous transluminal coronary angioplasty [PTCA], atherectomy).1,5,6,8,9,10,11,12,14,22,91 Because of its mechanism of action, tirofiban, like abciximab and eptifibatide, has been referred to as a platelet glycoprotein (GP) IIb/IIIa-receptor inhibitor. Platelet adhesion,2 activation,4 and aggregation4 are key processes leading to the formation of platelet-rich (“white”) coronary artery thrombi and the development of acute coronary artery syndromes and ischemic complications associated with PCI.23,27 White thrombus formation is triggered by vascular injury (e.g., from PCI procedures), plaque rupture, or denudation of endothelium that exposes the subendothelial matrix of the vessel to circulating platelets.9,10,12,14,25,26,27,44,45,46 Upon exposure of the vessel subendothelium, potent thrombogenic stimuli (e.g., thrombin, collagen) present in both subendothelium and plaque, and/or high-shear stress, stimulate platelet adhesion and activation.25,26,31,32,33,46,47

Activated platelets release intracellular granules consisting of vasoactive substances that are part of an autostimulatory feedback loop for platelet aggregation;25,26,27,28,29,32,47 these substances include thromboxane A₂,27,32,47 serotonin,25,26,32 and adenosine diphosphate (ADP);26,32,47 adhesive glycoproteins such as fibrinogen, fibronectin, and von Willebrand's factor;25,26 and plasminogen activator inhibitor-1 (PAI-1).29 Regardless of the initial stimulus for platelet activation, the final common pathway to platelet aggregation and thrombosis involves activation of the receptor function of the GP IIb/IIIa complex (also known as α_IIbβ₃).2,4,25,26,31,32,34,37,44,46 Inactive GP IIb/IIIa receptors undergo a conformational change14,16,22,25,32,33,35,43,44,45,46,47 on the surface of activated platelets to accept soluble fibrinogen,2,14,22,32,35,45 von Willebrand's factor,2,14,22,32,45 and other ligands (e.g., fibronectin, vitronectin, thrombospondin).2,22,23,26,27,32,91 Some of these adhesive ligands form cross-links to other GP IIb/IIIa on surfaces of adjacent activated platelets, causing aggregation and white thrombus formation.14,22,23,25,26,27,29 In addition, fibrinogen bound to the vessel wall24,27,31,43 or to other platelet aggregates can activate GP IIb/IIIa receptors on unstimulated platelets and recruit these platelets to growing white thrombi.27,31

Progression of NSTE ACS to ST-segment-elevation MI (STEMI) or sudden death occurs when obstructive platelet-rich thrombi grow to become occlusive thrombi in the absence of adequate perfusion beyond the obstruction through collateral blood vessels.9,25,33,48,51,91 Fibrin and erythrocytes comprise the outer layer of occlusive red thrombi that are formed on the surface of the platelet-rich inner core of the thrombus.25,33,51 While thrombolytic therapy effectively dissolves the occluding fibrin-rich portion of the thrombus, this process releases clot-bound thrombin and re-exposes the underlying disrupted plaque, which rereleases potent thrombogenic stimuli.25,29,33,51 These newly released thrombogenic stimuli then activate platelets, leading to platelet aggregation.25,29,31,51 In addition, activated platelets secrete a variety of factors (e.g., PAI-1, fibrinogen, factor V) associated with rethrombosis or thrombin production and bind factors Xa, VIIIa, and IXa, which are involved in further thrombin production.29,32,46,47,51,55,91 Platelet reactivity also may increase after thrombolysis.33 It has been suggested that use of platelet-aggregation inhibitors concomitantly with thrombolytic therapy may counter the thrombogenic activity of these agents and minimize the risk of reocclusion.10,25,29

Inhibition of Platelet Aggregation

Tirofiban reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand's factor, and other adhesive ligands to resting and active GP IIb/IIIa receptors.1,43,45 Inhibition of platelet aggregation by tirofiban and other GP IIb/IIIa-receptor inhibitors occurs in a dose- and concentration-dependent manner via an increase in GP IIb/IIIa receptor occupancy (as determined by the ex vivo platelet aggregation assay for tirofiban using sodium citrate as the anticoagulant in blood samples); platelet aggregation is nearly completely abolished at receptor occupancy exceeding 80%.1,2,6,11,14,15,20,22,37 Sodium citrate reportedly does not affect binding of tirofiban to the GP IIb/IIIa receptor.21 Some platelet-aggregation inhibitors such as aspirin, ticlopidine, and clopidogrel prevent platelet aggregation by preventing platelet activation in response to one or more agonists (e.g., thromboxane A₂, adenosine diphosphate);4,9,22 agonists not affected by these drugs may continue to induce platelet aggregation.22,25 However, GP IIb/IIIa-receptor inhibitors such as abciximab, eptifibatide, and tirofiban prevent platelet aggregation regardless of the initial stimulus.2,4,22,25 Some in vitro data suggest that inhibition of platelet aggregation by tirofiban can be overcome by an increase in the concentration of fibrinogen, indicating reversible, competitive binding to the GP IIb/IIIa receptor.1,2,15,22,43 However, tirofiban or other GP IIb/IIIa-receptor inhibitors do not appear to be effective in displacing fibrinogen cross-links from GP IIb/IIIA receptors in established thrombi when the bond between fibrinogen and GP IIb/IIIa receptors becomes irreversible.28

In vitro binding studies in platelets and human endothelial cells demonstrate that tirofiban is selective in binding to the platelet GP IIb/IIIa receptor; concentrations of the drug needed to inhibit the attachment of human endothelial cells to vitronectin or fibronectin receptors are approximately 1000-fold or greater than those required for inhibiting the attachment of platelets to fibrinogen.11,16,17,22,24

Following the recommended IV loading infusion of tirofiban (0.4 mcg/kg per minute for 30 minutes) in patients with NSTE ACS receiving concomitant heparin and aspirin, inhibition of platelet aggregation exceeded 90% at the end of the infusion.1,20 Addition of heparin to tirofiban therapy (0.1 mcg/kg per minute by IV infusion) does not alter the percentage of individuals with platelet aggregation inhibition exceeding 70%.1

Hemostatic Effects

Since the effect of tirofiban on platelet aggregation is rapidly reversible following cessation of the infusion, the drug has a modest effect on hemostatic indices (e.g., bleeding times).1,2 Normal hemostasis is restored more rapidly than with abciximab, a monoclonal antibody that dissociates very slowly from the GP IIb/IIIa receptor.8,31,32,35,74,91

In healthy individuals1,4 and patients with coronary artery disease,1,6,14 tirofiban prolongs bleeding time in a dose-dependent manner.6,14,15 Following administration of tirofiban as a loading infusion (0.4 mcg/kg per minute for 30 minutes) concomitantly with heparin and aspirin in patients with NSTE ACS, bleeding time was prolonged to 2.9 times that of baseline values.1 During continuous infusion of tirofiban (0.1 mcg/kg per minute) with concomitant heparin and aspirin in patients with NSTE ACS, bleeding time exceeded 20-30 minutes.1,6,14 However, in patients with NSTE ACS receiving heparin titrated to an aPTT twice the control value, addition of tirofiban did not alter the aPTT.6 When administered without heparin in patients with NSTE ACS in several large clinical trials (the Platelet Receptor Inhibitor in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms [PRISM-PLUS] study and the Platelet Receptor Inhibition in Ischemic Syndrome Management [PRISM] study), tirofiban and aspirin prolonged bleeding time to less than 20 minutes and aPTT was not affected (compared with baseline values).5,6 In patients with coronary artery disease receiving tirofiban, ex vivo adenosine diphosphate (ADP)-induced platelet aggregation using sodium citrate as an anticoagulant in blood samples was restored toward baseline values in approximately 90% of patients within 4-8 hours after discontinuance of the infusion.1,20,91

Pharmacokinetics

The pharmacokinetics of tirofiban are linear, and plasma concentrations are proportional to dose following IV infusions of 0.05-0.4 mcg/kg per minute for 1 hour or 0.1-0.2 mcg/kg per minute for 4 hours in healthy individuals.1,4,22 Concomitant administration of aspirin1,4,22 or ticlopidine3 does not appear to affect the pharmacokinetics of tirofiban.1,3,4,22 (See Drug Interactions: Drugs Affecting Hemostasis.)

Absorption

Information concerning plasma concentrations resulting from recommended loading and maintenance infusion dosages of tirofiban is not available.21 In a study in healthy individuals, plasma tirofiban concentrations of 10.9 and 20.7 ng/mL were reported after infusion of 0.1 mcg/kg per minute of tirofiban for 1 and 4 hours, respectively.4

Tirofiban has a rapid onset and short duration of action.11,14,20 In patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS) receiving the recommended tirofiban regimen consisting of an IV loading infusion of 0.4 mcg/kg per minute for 30 minutes followed by 0.1 mcg/kg per minute for up to 48 hours, approximately 90% inhibition of ex vivo adenosine diphosphate (ADP)-induced platelet aggregation was achieved by the end of the loading infusion, with inhibition persisting for the duration of the maintenance infusion.1,20,21 Platelet function returned to near baseline levels in approximately 90% of these patients within 4-8 hours following discontinuance of the tirofiban infusion.1,20

In a randomized study in a limited number of patients with NSTE ACS undergoing PCI,87 administration of the recommended regimen of tirofiban (0.4 mcg/kg per minute IV for 30 minutes followed by 0.1 mcg/kg per minute by IV infusion) for 20-24 hours was associated with a delayed onset and reduced intensity of platelet-aggregation inhibition (as measured by rapid platelet function assay [RPFA] or light transmission aggregometry using 20 µmol ADP) compared with that produced by recommended regimens of abciximab (0.25-mg/kg IV loading dose followed by 0.125 mcg/kg per minute, up to a maximum infusion rate of 10 mcg/minute, for 12 hours)18,87 or eptifibatide (180-mcg/kg IV loading dose followed by 2 mcg/kg per minute by IV infusion for 20-24 hours).30,87,91 The delayed onset of action of tirofiban was attributed to its comparatively long loading infusion duration (30 minutes)87 since in another study, maximal inhibition of platelet aggregation (96%) occurred within 5 minutes after infusion of a 10-mcg/kg IV loading dose over 3 minutes.11 The diminished intensity of platelet-aggregation inhibition was related in part to the strength of the agonist (20 µ M ) used in the platelet-aggregation assay, which is identical to that used in clinical trials of abciximab and eptifibatide but exceeds the concentration used in clinical trials of tirofiban (5 µ M ).14,87,91,92,93

Distribution

Tirofiban is approximately 65% bound to plasma proteins, and protein binding is independent of plasma drug concentration4 over the range of 0.01-25 mcg/mL.1,20 The steady-state volume of distribution of tirofiban ranges from 22-42 L.1,20 It is not known whether tirofiban is distributed into milk or crosses the placenta in humans; however, the drug is distributed into milk in rats and crosses the placenta in pregnant rats and rabbits.1,20

Elimination

Following administration in healthy individuals, plasma concentrations of tirofiban decline in a biphasic manner.4,22 The half-life of tirofiban averages approximately 1.2-2 hours.1,3,4,15,20,22,91 Tirofiban is cleared from the plasma mainly by renal excretion; metabolism of the drug appears to be limited.1,20

About 65 and 25% of a single dose of tirofiban is excreted in urine and feces, respectively, principally as unchanged parent drug.1,20 Plasma clearance of tirofiban in healthy individuals ranges from 213-314 mL/minute, with renal clearance accounting for 39-69% of plasma clearance.1,20 In patients with coronary artery disease, the plasma clearance of tirofiban ranges from 152-267 mL/minute1,20 and does not appear to be influenced by gender or race;20 renal clearance in these patients accounts for 39% of plasma clearance.1,20 Plasma clearance is about 19-26% lower in geriatric patients (those exceeding 65 years of age) with coronary artery disease than in younger patients.20 Plasma clearance appears to be independent of dose in healthy individuals4,22 and is not appreciably affected by mild to moderate hepatic insufficiency.1,20 In patients with renal impairment (creatinine clearance less than 30 mL per minute), including those requiring hemodialysis, plasma clearance of tirofiban is decreased by greater than 50% compared with that in individuals with normal renal function.1,20 Tirofiban is removed by hemodialysis.1,20

Chemistry and Stability

Chemistry

Tirofiban hydrochloride, a synthetic nonpeptide tyrosine derivative,2,12,14,15,22 is a selective, competitive platelet-aggregation inhibitor.1,15,22 Tirofiban, like abciximab and eptifibatide, has been referred to as a platelet glycoprotein (GP) IIb/IIIa-receptor inhibitor.

Tirofiban is produced by the addition of an n -butylsulfonyl group to the C-terminus and a 4-(piperidin-4-yl)butyloxy group to the N -terminus of tyrosine; these modifications increase the potency of the drug's inhibitory effect on platelet aggregation.2,16

The final step in platelet aggregation involves the binding of fibrinogen to the activated, membrane-bound platelet glycoprotein complex, GP IIb/IIIa,1,2,4,16,22 principally through a recognition site on the C-terminal peptide of the γ chain of fibrinogen that is structurally similar to the amino acid sequence arginine-glycine-aspartate (RGD).2,16,22,23,26,27 Other adhesive glycoproteins (e.g., von Willebrand's factor, fibronectin, vitronectin) appear to bind to activated GP IIb/IIIa through the RGD sequence.2,22,26,91 Unlike other GP IIb/IIIa-receptor inhibitors such as abciximab, which is an antibody to the GP IIb/IIIa receptor, and eptifibatide, which is a peptide mimetic of the GP IIb/IIIa receptor binding site, tirofiban is a nonpeptide amino acid derivative that mimics the geometric, stereotactic, and charge characteristics of the RGD binding site on the GP IIb/IIIa receptor.12,16,17 Molecular modeling studies suggest that the piperidine nitrogen of tirofiban replaces the basic guanidino moiety of arginine, the aromatic ring of tyrosine replaces the glycine residue, and the tyrosine carboxyl group substitutes for the carboxyl group of aspartic acid on the GP IIb/IIIa receptor binding site.16,17 In addition, the butylsulfonyl group of tirofiban appears to enhance potency of the drug by interacting with another site (exosite) on the GP IIb/IIIa receptor to which peptide mimetics (e.g., eptifibatide) do not bind.16,17

Tirofiban is commercially available as the hydrochloride salt, which is monohydrated; potency of tirofiban hydrochloride is expressed in terms of tirofiban, calculated on the anhydrous basis.1,20,21

Tirofiban hydrochloride monohydrate occurs as a white to off-white powder and is very slightly soluble in water1,20 and freely soluble (exceeding 100 mg/mL) in alcohol.21 The drug has pK_a values of 3.6 and 11.1.1,20 Tirofiban hydrochloride is commercially available as a clear, colorless, sterile injection concentrate and as a clear, sterile premixed IV solution in water for injection that has been made iso-osmotic with sodium chloride.1 Tirofiban hydrochloride injections contain sodium citrate dihydrate and citric acid anhydrous as buffers;1,20,21,22 the injections contain no preservatives.1,20 Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH of the injections to 5.5-6.5.1,20 When tirofiban hydrochloride injection concentrate is diluted extemporaneously with 0.9% sodium chloride or 5% dextrose injection, the pH of the resulting IV solution is approximately 6.20 The osmolality of tirofiban hydrochloride injection concentrate after dilution or of the premixed IV solution is approximately 280 or 300 mOsm/kg, respectively.20

Each mL of tirofiban hydrochloride injection concentrate contains 0.281 mg of tirofiban hydrochloride monohydrate equivalent to 0.25 mg of tirofiban base (250 mcg/mL of tirofiban).1,20 Each 500 mL of tirofiban hydrochloride injection premixed contains 28.09 mg of tirofiban hydrochloride monohydrate equivalent to 25 mg of tirofiban base (50 mcg/mL of tirofiban).1

Stability

Commercially available premixed tirofiban hydrochloride in 0.9% sodium chloride injection is provided in a flexible plastic (Intravia^®) container fabricated from specially formulated, multilayered plastic (PL 2408).1 Premixed tirofiban hydrochloride injection or injection concentrate is stable for 18 or 24 months, respectively, following the date of manufacture when stored unopened as directed.20 Solutions in contact with the plastic container can leach out some of the container's chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic container materials has been supported by USP biological tests.1,21

Dopamine, lidocaine, potassium chloride, and famotidine injection may be administered in the same IV line with tirofiban hydrochloride injection;1 tirofiban should not be administered in the same IV line as diazepam.1

Unused portions of tirofiban hydrochloride IV solutions should be discarded since these solutions contain no preservatives.1 Tirofiban hydrochloride injections should be stored at a temperature between 15 and 30°C and should be protected from light during stora freezing should be avoided.1,20

1. Medicure Pharma. Aggrastat^® (tirofiban hydrochloride) injection premixed and injection prescribing information. Somerset, NJ; 2007 Nov.

2. Anon. Tirofiban hydrochloride. Drugs Future . 1995; 20:897-901.

3. Umemura K, Kondo K, Ikeda Y et al. Enhancement by ticlopidine of the inhibitory effect on in vitro platelet aggregation of the glycoprotein IIb/IIIa inhibitor tirofiban. Thromb Haemost . 1997; 78: 1381-4.

4. Barrett JS, Murphy G, Peerlinck K et al. Pharmacokinetics andpharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men. Clin Pharmacol Ther . 1994; 56:377-88. [PubMed 7955799]

5. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med . 1998; 338:1498-1505. [PubMed 9599104]

6. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med . 1998; 338:1488-97. [PubMed 9599103]

7. Agency for Health Care Policy and Research. Diagnosing and managing unstable angina. 1994. (AHCPR publication no. 94-0603)

8. Chesebro JH, Badimon JJ. Platelet glycoprotein IIb/IIIa receptor blockade in unstable coronary disease. N Engl J Med . 1998; 338:1539-41. [PubMed 9593795]

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