NoBlood

Jan B. Wade · #1 (**permalink**) 01-21-2004, 06:27 PM

Aggrastat(R), Added to Heparin, Reduced Complications From Unstable Angina, Regardless of Whether Patients Had Invasive Procedures or Received Medical Therapy Alone;.

PR Newswire, Nov 9, 1998

Researchers at American Heart Association Meeting Say Merck Drug Had

Consistent Benefits in Wide Range of Patients, Including Those With Diabetes

DALLAS, Nov. 9 /PRNewswire/ -- Patients treated with Merck's platelet blocker Aggrastat(R) (tirofiban HCl) along with heparin for unstable angina achieved reductions in the combination of death, new heart attack or refractory ischemia(1) for up to six months, regardless of whether they required angioplasty or other invasive procedures, or were managed with medical therapy alone.

These findings, as well as new data that showed Aggrastat, added to heparin, reduced the combined incidence of death and heart attack in diabetics with unstable angina, are from new analyses of the landmark PRISM-PLUS (the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited to very Unstable Signs and Symptoms) study presented this week at the American Heart Association's 71st Scientific Sessions.

Aggrastat, a new drug in a class of intravenous medicines called glycoprotein (GP) IIb/IIIa inhibitors, was approved by the U.S. Food and Drug Administration last May for the treatment of acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction) in combination with heparin -- the standard treatment for these conditions.

Although the PRISM-PLUS trial was not designed to provide definitive results in subsets of the overall population, this new analysis of the 1,570 patients evaluated in PRISM-PLUS compared the safety and efficacy of infusions (48 hours to 108 hours) of Aggrastat plus heparin to heparin alone in three subgroups of patients: those undergoing angioplasty/atherectomy/ stent implantation, those undergoing bypass surgery and those managed with medical therapy only.

"Data from this new analysis provide evidence that the long-term benefit of treatment with Aggrastat in patients presenting with acute coronary syndrome is not dependent on whether a patient undergoes an invasive procedure," said Eliav Barr, M.D., director, Clinical Research, Merck Research Laboratories, who presented the findings today. "Added to heparin, Aggrastat reduced the risk for these cardiac complications consistently across a wide spectrum of patients, and these effects were maintained at 30 days and 180 days, regardless of the treatment strategy selected for the management of the patients -- angioplasty, bypass surgery or medical therapy alone.

"The implication of this research is that treatment with Aggrastat should not be limited to patients who undergo angioplasty, but instead should be considered in all patients presenting with unstable angina in the emergency room setting," Barr said.

Unstable angina, which is characterized by chest pain at rest, and non-Q- wave MI, often defined as "small" heart attack, are associated with a 10 to 12 percent risk of heart attack or death within 30 days of the episode. Of the 1 million patients hospitalized in the United States for unstable angina each year, about 300,000 undergo angioplasty to stabilize the condition.

In PRISM-PLUS, treatment with Aggrastat plus heparin reduced the combined risk of death, new heart attack or refractory ischemia by 32 percent compared to heparin alone, at seven days.

Aggrastat Reduced the Combination of Serious Cardiac Events

Results showed that patients in each group who received Aggrastat plus heparin achieved important reductions in the combined incidences of readmission for unstable angina, refractory ischemia, heart attack or death at 30 days; these reductions were consistent with the overall findings from the PRISM-PLUS study.

-- Across all patient groups, Aggrastat reduced the combined incidences

of those complications by 22 percent (18.5 percent with Aggrastat

plus heparin vs. 22.3 percent with heparin alone) at 30 days.

-- Aggrastat also reduced the combined incidence of death and heart

attack consistently across all patient groups by 30 percent (8.7

percent with Aggrastat plus heparin vs. 11.9 percent with heparin

alone) at 30 days.

In the new analysis, an increase in the incidence of bleeding was seen in patients who received Aggrastat plus heparin, particularly in those who had angioplasty or atherectomy (3.1 percent with Aggrastat plus heparin vs. 2.0 percent with heparin alone). This result was consistent with the overall findings of PRISM-PLUS (1.4 percent with Aggrastat plus heparin vs. 0.8 percent with heparin alone).

Reduced Combined Incidence of Death and Heart Attack by 88 Percent in Diabetics

A separate analysis of patients from PRISM-PLUS who had diabetes demonstrated the benefit of Aggrastat added to heparin in these patients. Although the PRISM-PLUS study was not designed to definitively evaluate the efficacy of therapy with Aggrastat in this subgroup, researchers demonstrated that reduction in the composite endpoint of death, heart attack, refractory ischemia and readmission for unstable angina that occurred in these patients with the addition of Aggrastat to heparin was consistent with the benefit observed in the trial overall.

One striking finding of this analysis was that the addition of Aggrastat to heparin resulted in a marked reduction in the incidence of death and heart attack, the irreversible complications of unstable angina/non-Q-wave MI in diabetics.

-- At seven days, Aggrastat reduced the combined incidence of death or

heart attack by 88 percent (1.2 percent with Aggrastat plus heparin

vs. 9.3 percent with heparin alone).

-- Reductions in these complications were also seen at 30 days and at 180

days.

"Of all the patients treated for unstable angina, those with diabetes are known to be among those with the poorest outcomes associated with the condition," said Pierre Theroux, M.D., professor of medicine, Montreal Heart Institute, presenter of the research. "This analysis showed that treatment with Aggrastat plus heparin led to a dramatic, sustained reduction in the combined incidence of death and heart attack, particularly recurrent heart attacks, among patients with diabetes who present with unstable angina or non- Q-wave MI."

Three other analyses from PRISM-PLUS on the pathophysiology and diagnosis of acute coronary syndrome were also presented at the meeting.

Aggrastat works by interfering with the process of platelet aggregation, an early step in the formation of the blood clots which may ultimately block arteries. When given according to the recommended regimen, therapy with Aggrastat rapidly results in a high level of inhibition of platelet aggregation: by 30 minutes following initiation of Aggrastat, platelet aggregation is 90 percent inhibited. The inhibition is maintained during the course of therapy with Aggrastat.

Unstable angina and non-Q-wave MI are caused by a halt in blood flow in a coronary artery due to the presence of blood clots. Such blockages often evolve into a major (large) heart attack if left untreated. Clots are composed largely of platelets, a type of blood cell that is held together by fibrinogen, a protein that attaches to platelets at special sites called GP

IIb/IIIa receptors. Aggrastat was designed to attach to and block these receptors, thereby preventing fibrinogen from sticking to platelets and linking them together to form clots.

Because Aggrastat is a drug that affects the blood clotting system, it should not be used in patients who are at risk for bleeding complications such as active internal bleeding, intracranial hemorrhage and intracranial neoplasm. Aggrastat also should not be used in patients with a history of stroke or who have had a major surgical procedure within the past 30 days.

Aggrastat Generally Well Tolerated

Aggrastat was generally well tolerated in clinical studies. The most common drug-related adverse event reported during therapy with Aggrastat, when added to heparin, was bleeding. In PRISM-PLUS, the 773 patients treated with Aggrastat plus heparin compared to the 797 patients treated with heparin alone experienced some increase in the incidences of: major bleeding events (1.4 percent with Aggrastat added to heparin vs. 0.8 percent with heparin alone); minor bleeding events (10.5 percent with Aggrastat plus heparin vs. 8.0 percent with heparin alone); and bleeding events requiring transfusions (4.0 percent with Aggrastat plus heparin vs. 2.8 percent with heparin alone).

In clinical trials, 1.8 percent of patients treated with Aggrastat added to heparin experienced moderate or severe decreases in platelet counts versus 0.7 percent of patients treated with heparin alone. These counts returned to normal after Aggrastat was stopped.

Aggrastat, discovered and developed by Merck, is available in two formulations -- concentrate for injection and injection pre-mixed -- and dosage is flexible, allowing physicians to individualize therapy for a patient's weight and medical need.

Merck & Co., Inc. (NYSE: MRK), is a global research-driven pharmaceutical company that discovers, develops, manufactures and markets a broad range of human and animal health products, directly and through its joint ventures, and provides pharmaceutical benefit services through Merck-Medco Managed Care.

(1) Refractory ischemia is defined as continuous severe chest pain despite treatment.

Full prescribing information for Aggrastat(R) follows:

AGGRASTAT(R)

(TIROFIBAN HYDROCHLORIDE INJECTION PREMIXED)

AGGRASTAT(R)

(TIROFIBAN HYDROCHLORIDE INJECTION)

DESCRIPTION

AGGRASTAT* (tirofiban hydrochloride), a non-peptide antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, inhibits platelet aggregation.

Tirofiban hydrochloride monohydrate, a non-peptide molecule, is chemically described as N-(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate.

Its molecular formula is C22H36N2O5S.HCl.H2O and its structural formula is:

(MOLECULE HERE)

Tirofiban hydrochloride monohydrate is a white to off-white, non- hygroscopic, free-flowing powder, with a molecular weight of 495.08. It is very slightly soluble in water.

AGGRASTAT Injection Premixed is supplied as a sterile solution in water for injection, for intravenous use only, in plastic containers. Each 500 mL of the premixed, iso-osmotic intravenous injection contains 28.09 mg tirofiban hydrochloride monohydrate equivalent to 25 mg tirofiban (50 micro-g/mL) and the following inactive ingredients: 4.5 g sodium chloride, 270 mg sodium citrate dihydrate, and 16 mg citric acid anhydrous. The pH ranges from 5.5 to 6.5 and may have been adjusted with hydrochloric acid and/or sodium hydroxide.

The flexible container is manufactured from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.

AGGRASTAT Injection is a sterile concentrated solution for intravenous infusion after dilution and is supplied in a 50 mL vial. Each mL of the solution contains 0.281 mg of tirofiban hydrochloride monohydrate equivalent to 0.25 mg of tirofiban and the following inactive ingredients: 0.16 mg citric acid anhydrous, 2.7 mg sodium citrate dihydrate, 8 mg sodium chloride, and water for injection. The pH ranges from 5.5 to 6.5 and may have been adjusted with hydrochloric acid and/or sodium hydroxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

AGGRASTAT is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa 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, greater than 90 percent inhibition is attained by the end of the 30-minute infusion. Platelet aggregation inhibition is reversible following cessation of the infusion of AGGRASTAT.

Pharmacokinetics

Tirofiban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65 percent of an administered dose appearing in urine and about 25 percent 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 micro-g/mL. Unbound fraction in human plasma is 35 percent. 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 percent 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 percent of plasma clearance.

Special Populations

Gender

Plasma clearance of tirofiban in patients with coronary artery disease is similar in males and females.

Elderly

Plasma clearance of tirofiban is about 19 to 26 percent lower in elderly (greater than 65 years) patients with coronary artery disease than in younger (less than or equal to 65 years) patients.

Race

No difference in plasma clearance was detected in patients of different races.

Hepatic Insufficiency

In patients with mild to moderate hepatic insufficiency, plasma clearance of tirofiban is not significantly different from clearance in healthy subjects.

Renal Insufficiency

Plasma clearance of tirofiban is significantly decreased (greater than 50 percent) in patients with creatinine clearance less than 30 mL/min, including patients requiring hemodialysis (see DOSAGE AND ADMINISTRATION, Recommended Dosage). Tirofiban is removed by hemodialysis.

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 micro-g/kg/min, ex vivo platelet aggregation returns to near baseline in approximately 90 percent 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 greater than 70 percent inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to greater than 30 minutes.

In patients with unstable angina, a two-staged intravenous infusion regimen of AGGRASTAT (loading infusion of 0.4 micro-g/kg/min for 30 minutes followed by 0.1 micro-g/kg/min for up to 48 hours in the presence of heparin and aspirin), produces approximately 90 percent 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.

Clinical Trials

Three large-scale clinical studies were conducted to study the efficacy and safety of AGGRASTAT in the management of patients with Acute Coronary Syndrome (unstable angina/non-Q-wave myocardial infarction). Acute Coronary Syndrome is characterized by prolonged (greater than or equal to 10 minutes) or repetitive symptoms of cardiac ischemia occurring at rest or with minimal exertion, associated with either ischemic ST-T wave changes on electrocardiogram (ECG) or elevated cardiac enzymes. The definition includes "unstable angina" and "non-Q-wave myocardial infarction" but excludes myocardial infarction that is associated with Q-waves or non-transient ST-segment elevation. The three studies examined AGGRASTAT alone and as an addition to heparin, prior to and after angioplasty (if indicated) (PRISM- PLUS), in comparison to heparin in a similar population (PRISM), and in addition to heparin in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) or atherectomy (RESTORE). These trials are discussed in detail below.

PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management -- Patients Limited by Unstable Signs and Symptoms)

In the multi-center, randomized, parallel, double-blind PRISM-PLUS trial, the use of AGGRASTAT in combination with heparin (n equals 773) was compared to heparin alone (n equals 797) in patients with documented unstable angina/non-Q-wave myocardial infarction within 12 hours of entry into the study and initiation of treatment. All patients with unstable angina/non- Q-wave myocardial infarction had cardiac ischemia documented by ECG or had elevated cardiac enzymes. Patients who were medically managed or who subsequently underwent revascularization procedures were studied. The mean age of the population was 63 years; 32 percent of patients were female and approximately half of the population presented with non-Q-wave myocardial infarction. Exclusions included contraindications to anticoagulation (see CONTRAINDICATIONS), decompensated heart failure, platelet count less than 150,000/mm3, and creatinine greater than 2.5 mg/dL. In this study, patients were randomized to either AGGRASTAT (30 minute loading infusion of 0.4 micro- g/kg/min followed by a maintenance infusion of 0.10 micro-g/kg/min) and heparin (bolus of 5,000 units (U) followed by an infusion of 1,000 U/hr titrated to maintain an activated partial thromboplastin time (APTT) of approximately 2 times control), or heparin alone (bolus of 5,000 U followed by an infusion of 1,000 U/hr titrated to maintain an APTT of approximately 2 times control). All patients received concomitant aspirin unless contraindicated. Patients underwent 48 hours of medical stabilization on study drug therapy, and they were to undergo angiography before 96 hours (and, if indicated, angioplasty/atherectomy, while continuing on AGGRASTAT and heparin for 12-24 hours after the procedure). Some patients went on to coronary artery bypass grafting (CABG) after cessation of drug therapy. AGGRASTAT and heparin could be continued for up to 108 hours. On average, patients received AGGRASTAT for 71.3 hours. A third group of patients was initially randomized to AGGRASTAT alone (no heparin). This arm was stopped when the group was found, at an interim look, to have greater mortality than the other two groups. Note, however, that a direct comparison of heparin and tirofiban alone in the PRISM study (see below) did not show excess mortality.

The primary endpoint of the study was a composite of refractory ischemia, new myocardial infarction and death at 7 days after initiation of AGGRASTAT and heparin. At the primary endpoint, there was a 32 percent risk reduction in the overall composite. The components of the composite were examined separately (they total more than the composite because a patient could have more than one, e.g., by dying after having a new infarction). There was a 47 percent risk reduction in myocardial infarction and a 30 percent risk reduction in refractory ischemia. The results are shown in Table 1.

(TABLE 1 HERE)

The benefit seen at 7 days was maintained over time. At 30 days, the risk of the composite endpoint was reduced by 22 percent (p equals 0.029) and there was a 30 percent reduction in the composite of myocardial infarction and death (p equals 0.027). At 6 months, the risk of the composite endpoint was reduced by 19 percent (p equals 0.024). The risk reduction in the composite endpoint at 30 days and 6 months is shown in the Kaplan-Meier curve below.

(CHART HERE)

PRISM-PLUS was not designed to provide definitive results in subsets of the overall population. Nonetheless, results were examined for demographic (age, gender, race) subsets and for people who did and did not receive PTCA, atherectomy, or CABG.

In PRISM-PLUS, there was a consistent treatment effect in patients either greater or less than 65 years old, and in men and women. Too few non- Caucasians were enrolled to make a definite statement about racial differences in treatment effect.

Approximately 90 percent of patients in the PRISM-PLUS study underwent coronary angiography and 30 percent underwent angioplasty/atherectomy during the first 30 days of the study. The majority of these patients continued on study drug throughout these procedures. AGGRASTAT was continued for 12-24 hours (average 15 hours) after angioplasty/atherectomy. The effects of AGGRASTAT at Day 30 did not appear to differ among the sub-populations that did or did not receive PTCA or CABG, both prior to and after the procedure.

A sub-study in PRISM-PLUS of angiograms after 48 to 96 hours found that there was a significant decrease in the extent of angiographically apparent thrombus in patients treated with AGGRASTAT in combination with heparin compared to heparin alone. In addition, flow in the affected coronary artery was significantly improved.

PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management)

In the PRISM study, a randomized, parallel, double-blind, active control study, AGGRASTAT alone (n equals 1616) was compared to heparin (n equals 1616) alone as medical management in patients with unstable angina/non-Q-wave myocardial infarction. In this study, the drug was started within 24 hours of the time the patient experienced chest pain. The mean age of the population was 62 years; 32 percent of the population was female and 25 percent had non- Q-wave myocardial infarction on presentation. Thirty percent had no ECG evidence of cardiac ischemia. Exclusion criteria were similar to PRISM-PLUS. The primary, prospectively identified endpoint was the composite endpoint of refractory ischemia, myocardial infarction or death after a 48-hour drug infusion with AGGRASTAT. The results are shown in Table 2.

(TABLE 2 HERE)

In the PRISM study, no adverse effect of AGGRASTAT on mortality at either 7 or 30 days was detected. This result is in conflict with the PRISM-PLUS study, where the arm that included AGGRASTAT without heparin (n equals 345) was dropped at an interim analysis by the Data Safety Monitoring Committee due to increased mortality at 7 days. A pooled analysis of the data from these two trials (PRISM and PRISM-PLUS) demonstrated that the effect of AGGRASTAT alone on mortality (at 7 and 30 days) was comparable to that of heparin alone.

RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis)

The RESTORE study (n equals 2141) was a randomized, placebo-controlled comparison of AGGRASTAT and placebo, each added to heparin, in patients undergoing PTCA or atherectomy within 72 hours of presentation with unstable angina or acute myocardial infarction. The mean age of the population was 59 years; 27 percent were female. Two-thirds of patients underwent angioplasty for unstable angina and the remainder in association with acute myocardial infarction. Exclusions included anatomy not amenable to angioplasty, contraindications to anticoagulation (see CONTRAINDICATIONS), platelet count less than 150,000/mm3, and creatinine greater than 2.0 mg/dL. AGGRASTAT (with heparin) was initiated immediately prior to the angioplasty/atherectomy at a dose of 10 micro-g/kg bolus (over 3 minutes) followed by an infusion of 0.15 micor-g/kg/min along with a heparin bolus (bolus of 10,000 U, or 150 U/kg for patients less than 70 kg). The infusion dose of AGGRASTAT is 50 percent higher than the dose used in the PRISM-PLUS trial. AGGRASTAT was administered for a total of 36 hours. In general, heparin was to be discontinued at the conclusion of the angioplasty/atherectomy. Reasons for continued heparin included: imperfect outcome (e.g., large tear, intraluminal filling defect, or residual stenosis greater than 40 percent), large thrombus load, continuing rest angina through the procedure, abrupt closure or very active artery during the procedure, or side branch occlusion. The primary endpoint was the composite of all deaths, non-fatal myocardial infarctions, and all repeat revascularization procedures at 30 days. For results see Table 3. A sub-study in RESTORE of angiograms after approximately 6 months found that AGGRASTAT had no significant effect on the extent of coronary artery restenosis following angioplasty.

(TABLE 3 HERE)

The risk reduction in the composite endpoint at 180 days is shown in the Kaplan-Meier curve below.

(CHART HERE)

INDICATIONS AND USAGE

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 (for discussion of trial results and for definition of acute coronary syndrome see CLINICAL PHARMACOLOGY, Clinical Trials).

AGGRASTAT has been studied in a setting, as described in Clinical Trials, that included aspirin and heparin.

CONTRAINDICATIONS

AGGRASTAT is contraindicated in patients with:

-- known hypersensitivity to any component of the product

-- active internal bleeding or a history of bleeding diathesis within the

30 days

-- a history of intracranial hemorrhage, intracranial neoplasm,

arteriovenous malformation, or aneurysm

-- a history of thrombocytopenia following prior exposure to AGGRASTAT

-- history of stroke within 30 days or any history of hemorrhagic stroke

-- major surgical procedure or severe physical trauma within the previous

month

-- history, symptoms, or findings suggestive of aortic dissection

-- severe hypertension (systolic blood pressure greater than 180 mmHg

and/or diastolic blood pressure greater than 110 mmHg)

-- concomitant use of another parenteral GP IIb/IIIa inhibitor

-- acute pericarditis

WARNINGS

Bleeding is the most common complication encountered during therapy with AGGRASTAT. Administration of AGGRASTAT is associated with an increase in bleeding events classified as both major and minor bleeding events by criteria developed by the Thrombolysis in Myocardial Infarction Study group (TIMI).** Most major bleeding associated with AGGRASTAT occurs at the arterial access site for cardiac catheterization.

AGGRASTAT should be used with caution in patients with platelet count less than 150,000/mm3 and in patients with hemorrhagic retinopathy.

Because AGGRASTAT inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis. The safety of AGGRASTAT when used in combination with thrombolytic agents has not been established.

During therapy with AGGRASTAT, patients should be monitored for potential bleeding. When bleeding cannot be controlled with pressure, infusion of AGGRASTAT and heparin should be discontinued.

PRECAUTIONS

Bleeding Precautions

Percutaneous Coronary Intervention -- Care of the femoral artery access site: Therapy with AGGRASTAT is associated with increases in bleeding rates particularly at the site of arterial access for femoral sheath placement. Care should be taken when attempting vascular access that only the anterior wall of the femoral artery is punctured. Prior to pulling the sheath, heparin should be discontinued for 3-4 hours and activated clotting time (ACT) less than 180 seconds or APTT less than 45 seconds should be documented. Care should be taken to obtain proper hemostasis after removal of the sheaths using standard compressive techniques followed by close observation. While the vascular sheath is in place, patients should be maintained on complete bed rest with the head of the bed elevated 30 degrees and the affected limb restrained in a straight position. Sheath hemostasis should be achieved at least 4 hours before hospital discharge.

Minimize Vascular and Other Trauma: Other arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation and nasogastric tubes should be minimized. When obtaining intravenous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided.

Laboratory Monitoring: Platelet counts, and hemoglobin and hematocrit should be monitored prior to treatment, within 6 hours following the loading infusion, and at least daily thereafter during therapy with AGGRASTAT (or more frequently if there is evidence of significant decline). If the patient experiences a platelet decrease to less than 90,000/mm3, additional platelet counts should be performed to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, AGGRASTAT and heparin should be discontinued and the condition appropriately monitored and treated.

To monitor unfractionated heparin, APTT should be monitored 6 hours after the start of the heparin infusion; heparin should be adjusted to maintain APTT at approximately 2 times control.

Severe Renal Insufficiency

In clinical studies, patients with severe renal insufficiency (creatinine clearance less than 30 mL/min) showed decreased plasma clearance of AGGRASTAT. The dosage of AGGRASTAT should be reduced in these patients (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY, Clinical Trials).

Drug Interactions

AGGRASTAT has been studied on a background of aspirin and heparin.

The use of AGGRASTAT, in combination with heparin and aspirin, has been associated with an increase in bleeding compared to heparin and aspirin alone (see ADVERSE REACTIONS). Caution should be employed when AGGRASTAT is used with other drugs that affect hemostasis (e.g., warfarin). No information is available about the concomitant use of AGGRASTAT with thrombolytic agents (see PRECAUTIONS, Bleeding Precautions).

In a sub-set of patients (n equals 762) in the PRISM study, the plasma clearance of tirofiban in patients receiving one of the following drugs was compared to that in patients not receiving that drug. There were no clinically significant effects of co-administration of these drugs on the plasma clearance of tirofiban: acebutolol, acetaminophen, alprazolam, amlodipine, aspirin preparations, atenolol, bromazepam, captopril, diazepam, digoxin, diltiazem, docusate sodium, enalapril, furosemide, glyburide, heparin, insulin, isosorbide, lorazepam, lovastatin, metoclopramide, metoprolol, morphine, nifedipine, nitrate preparations, oxazepam, potassium chloride, propranolol, ranitidine, simvastatin, sucralfate and temazepam. Patients who received levothyroxine or omeprazole along with AGGRASTAT had a higher rate of clearance of AGGRASTAT. The clinical significance of this is unknown.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of AGGRASTAT has not been evaluated.

Tirofiban HCl was negative in the in vitro microbial mutagenesis and V-79 mammalian cell mutagenesis assays. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution and in vitro chromosomal aberration assays. There was no induction of chromosomal aberrations in bone marrow cells of male mice after the administration of intravenous doses up to 5 mg tirofiban/kg (about 3 times the maximum recommended daily human dose when compared on a body surface area basis).

Fertility and reproductive performance were not affected in studies with male and female rats given intravenous doses of tirofiban hydrochloride up to 5 mg/kg/day (about 5 times the maximum recommended daily human dose when compared on a body surface area basis).

Pregnancy

Pregnancy Category B

Tirofiban has been shown to cross the placenta in pregnant rats and rabbits. Studies with tirofiban HCl at intravenous doses up to 5 mg/kg/day (about 5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on a body surface area basis) have revealed no harm to the fetus. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether tirofiban is excreted in human milk. However, significant levels of tirofiban were shown to be present in rat milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of AGGRASTAT in pediatric patients (less than 18 years old) have not been established.

Use in the Elderly

Of the total number of patients in controlled clinical studies of AGGRASTAT, 42.8 percent were 65 years and over, while 11.7 percent were 75 and over. With respect to efficacy, the effect of AGGRASTAT in the elderly (greater than or equal to 65 years) appeared similar to that seen in younger patients (less than 65 years). Elderly patients receiving AGGRASTAT with heparin or heparin alone had a higher incidence of bleeding complications than younger patients, but the incremental risk of bleeding in patients treated with AGGRASTAT in combination with heparin compared to the risk in patients treated with heparin alone was similar regardless of age. The overall incidence of non-bleeding adverse events was higher in older patients (compared to younger patients) but this was true both for AGGRASTAT with

heparin and heparin alone. No dose adjustment is recommended for the elderly population (see DOSAGE AND ADMINISTRATION, Recommended Dosage).

ADVERSE REACTIONS

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 percent of the population was greater than 65 years of age and approximately 30 percent of patients were female.

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.

(TABLE HERE)

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 percent for AGGRASTAT in combination with heparin and 0.3 percent 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 percent and 0.1 percent, respectively. In the RESTORE study, the incidences of retroperitoneal bleeding reported for AGGRASTAT in combination with heparin, and the control group were 0.6 percent and 0.3 percent, respectively. The incidences of TIMI major gastrointestinal and genitourinary bleeding for AGGRASTAT in combination with heparin in the PRISM-PLUS study were 0.1 percent and 0.1 percent, respectively; the incidences in the RESTORE study for AGGRASTAT in combination with heparin were 0.2 percent and 0.0 percent, respectively.

The incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in PRISM-PLUS are shown below.

(TABLE HERE)

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.

(TABLE HERE)

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 (see DOSAGE AND ADMINISTRATION, Recommended Dosage).

NON-BLEEDING

The incidences of non-bleeding adverse events that occurred at an incidence of greater than 1 percent and numerically higher than control, regardless of drug relationship, are shown below:

(TABLE HERE)

Other non-bleeding side effects (considered at least possibly related to treatment) reported at a greater than 1 percent 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.)

Allergic Reactions/Readministration

No patients in the clinical database developed anaphylaxis and/or hives requiring discontinuation of the infusion of tirofiban. No information is available regarding the development of antibodies to tirofiban; very few patients received tirofiban twice.

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 percent) and hematocrit (2.2 percent) were observed in the group receiving AGGRASTAT compared to 3.1 percent and 2.6 percent, respectively, in the heparin group. Increases in the presence of urine and fecal occult blood were also observed (10.7 percent and 18.3 percent, respectively) in the group receiving AGGRASTAT compared to 7.8 percent and 12.2 percent, 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 less than 90,000/mm3 was 1.5 percent, compared with 0.6 percent in the patients who received heparin alone. The percentage of patients with a decrease of platelets to less than 50,000/mm3 was 0.3 percent, compared with 0.1 percent of the patients who received heparin alone.

OVERDOSAGE

In clinical trials, inadvertent overdosage with AGGRASTAT occurred in doses up to 5 times and 2 times the recommended dose for bolus administration and loading infusion, respectively. Inadvertent overdosage occurred in doses up to 9.8 times the 0.15 micro-g/kg/min maintenance infusion rate.

The most frequently reported manifestation of overdosage was bleeding, primarily minor mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization (see PRECAUTIONS, Bleeding Precautions).

Overdosage of AGGRASTAT should be treated by assessment of the patient's clinical condition and cessation or adjustment of the drug infusion as appropriate.

AGGRASTAT can be removed by hemodialysis.

DOSAGE AND ADMINISTRATION

AGGRASTAT Injection must first be diluted to the same strength as AGGRASTAT Injection Premixed, as noted under Directions for Use.

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.

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. Discard unused solution 24 hours following the start of infusion.

Directions for Use

AGGRASTAT Injection is first diluted to the same strength as AGGRASTAT Injection Premixed as follows: withdraw and discard 100 mL from a 500 mL bag of sterile 0.9 percent sodium chloride or 5 percent dextrose in water and replace this volume with 100 mL of AGGRASTAT Injection (from two 50 mL vials) or withdraw and discard 50 mL from a 250 mL bag of sterile 0.9 percent sodium chloride or 5 percent dextrose in water and replace this volume with 50 mL of AGGRASTAT Injection (from one 50 mL vial), to achieve a final concentration of 50 micro-g/mL. Mix well prior to administration.

AGGRASTAT Injection Premixed is supplied as 500 mL of 0.9 percent sodium chloride containing tirofiban hydrochloride 50 micro-g/mL. It is supplied in IntraVia*** containers (PL 2408 plastic). To open the IntraVia(TM) container, first tear off its dust cover. 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.

Recommended Dosage

In most patients, AGGRASTAT should be administered intravenously, at an initial rate of 0.4 micro-g/kg/min for 30 minutes and then continued at 0.1 micro-g/kg/min. Patients with severe renal insufficiency (creatinine clearance less than 30 mL/min) should receive half the usual rate of infusion (see PRECAUTIONS, Severe Renal Insufficiency and CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, Renal Insufficiency). The table below is provided as a guide to dosage adjustment by weight.

(TABLE HERE)

No dosage adjustment is recommended for elderly or female patients (see PRECAUTIONS, Use in the Elderly). 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.

HOW SUPPLIED

FOR INTRAVENOUS USE ONLY

No. 3713 -- AGGRASTAT Injection 12.5 mg per 50 mL (250 micro-g per mL) is a non-preserved, clear, colorless concentrated sterile solution for intravenous infusion after dilution and is supplied as follows:

NDC 0006-3713-50, 50 mL vials.

No. 3739 -- AGGRASTAT Injection Premixed 25 mg per 500 mL (50 micro-g per mL) is a clear, non-preserved, sterile solution premixed in a vehicle made iso-osmotic with sodium chloride, and is supplied as follows:

NDC 0006-3739-43, 500 mL single-dose IntraVia(TM) containers (PL 2408 Plastic).

Storage

AGGRASTAT Injection

Store at 25 degrees C (77 degrees F) with excursions permitted between 15-30 degrees C (59-86 degrees F) (see USP Controlled Room Temperature). Do not freeze. Protect from light during storage.

AGGRASTAT Injection Premixed

Store at 25 degrees C (77 degrees F) with excursions permitted between 15-30 degrees C (59-86 degrees F) (see USP Controlled Room Temperature). Do not freeze. Protect from light during storage.

AGGRASTAT (Tirofiban Hydrochloride Injection Premixed) is manufactured for: Merck & Co., Inc., West Point, PA 19486, USA
by: BAXTER HEALTHCARE CORPORATION
Deerfield, Illinois 60015 USA

AGGRASTAT (Tirofiban Hydrochloride Injection) is manufactured for:
Merck & Co., Inc., West Point, PA 19486, USA
by:BEN VENUE LABORATORIES
Bedford, Ohio 44146 USA

* Registered trademark of MERCK & CO., Inc., COPYRIGHT (C) MERCK & CO., Inc., 1998, All rights reserved.

** Bovill, E.G.; et al.: Hemorrhagic Events during Therapy with Recombinant Tissue-Type Plasminogen Activator, Heparin, and Aspirin for Acute Myocardial Infarction, Results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial, Annals of Internal Medicine, 115(4): 256-265, 1991.

*** Trademark of Baxter International, Inc.