AGGRASTAT（TIROFIBAN HCL M-HYDRATE/NORMAL SALINE）盐酸替罗非班

药品英文名
Tirofiban
 
药品别名
欣维宁、AGGRASTAT、Tirofiban Hydrochloride
 
药物剂型
1.替罗非班注射剂：0.4mg/支。冷藏保存。
2.盐酸替罗非班注射液：12.5mg/50ml；12.5mg/250ml。
3.盐酸替罗非班氯化钠注射液：100ml(替罗非班5mg和氯化钠900mg)。密封，于室温保存。
 
药理作用
本品为一高效可逆性非肽类血小板表面糖蛋白(GP)Ⅱb/Ⅲa受体拮抗剂。纤维蛋白原和血小板GPⅡb/Ⅲa受体结合是血小板聚集的最终共同通路，血小板活化可诱导GPⅡb/Ⅲa受体发生构象变化，导致受体与纤维蛋白原的亲和力明显增加，结合的纤维蛋白原可使血小板发生交联，引起血小板聚集。因此，不论血栓形成的原因如何，血小板的活化、黏附和聚集是动脉血栓形成过程中的关键步骤，其中GPⅡb/Ⅲa受体在血小板聚集和血栓形成过程中起着重要作用。本品竞争性抑制纤维蛋白原和血小板GPⅡb/Ⅲa受体的结合，抑制血小板聚集、延长出血时间、抑制血栓形成。本品对各种刺激因素诱发的血小板聚集都有效，对急性冠状动脉综合征(不稳定性心绞痛、心肌梗死)和行冠状动脉内介入治疗的患者均有抑制血小板聚集的作用，其抑制作用与剂量成正比。由于本品强有力的抗血小板聚集作用，可使其延迟或抑制血栓形成，缩小形成血栓的大小；持续静滴可使血栓形成不易阻塞血管，并促进再灌注的形成。
 
药动学
静脉给药后5min起效，作用持续3～8小时。稳态分布容积范围为22～42L。在0.01～25µg/ml的浓度范围内，血浆蛋白结合率为65%，与药物浓度无关。多以原形经胆道和尿液排出。正常人单次静脉给药后，从尿液、粪便中可分别测到给药量的66%、23%。在正常人及冠心病患者中，药物血浆清除率分别为213～314ml/min、152～267ml/min，肾脏清除率分别占血浆清除率的39%～69%、39%，半衰期分别为1.4～1.8h、1.9～2.2h。65岁以上老年冠心病患者与年龄不超过65岁的患者相比，其血浆清除率约下降19%～26%。严重肾功能不全者(肌酐清除率小于30ml/min，包括需血液透析的患者)血浆清除率下降大于50%。轻中度肝功能不全者血浆清除率与正常人相比，无明显差异。药物可经血液透析清除。
 
适应证
用于冠脉缺血综合征患者行冠脉血管成形术或冠脉内斑块切除术，以防治相关的心脏缺血并发症。也用于不稳定性心绞痛或非Q波型心肌梗死患者(与肝素或阿司匹林联用)，预防心脏缺血事件的发生。
 
禁忌证
1.对本品过敏者禁用。
2.有活动性出血、血小板减少症及出血史者禁用。
3.有颅内出血、颅内肿瘤、动静脉畸形或动脉瘤及有急性心包炎史的患者禁用。
4.用本品前1个月内有中风史或有任何出血性中风发作者及行主要器官手术者或有严重外伤需手术治疗者禁用。
5.有分割性支脉瘤史、严重高血压以及同时服用其他静脉用GPⅡb/Ⅲa受体拮抗剂的患者禁用。
 
注意事项
1.当与肝素或阿司匹林合用时，可使出血时间更加延长。
2.由于替罗非班对血小板聚集的抑制作用是可逆性的，当停止给药3小时左右以后，出血时间可恢复到正常。
3.严重肾功能不全患者应用时其血浆清除率可降低50%以上，因此需减少用药剂量，减慢输注速率。
4.哺乳期妇女在用药期间应停止哺乳。
 
不良反应
常见不良反应有出血，如颅内出血、腹膜后出血和心包积血，其他不良反应尚有恶心、发热、头痛、皮疹或荨麻疹，血红蛋白、红细胞压积、血小板数目减少，尿粪隐血发生率增加。不良反应发生程度一般均较轻微，无需治疗，停药后即可消失。使用时必须严密观察出血等副作用，并监测出血时间。
 
用法用量
静脉给药。
1.冠脉血管成形术或冠脉内斑块切除术：宜与肝素联用，本品起始剂量为10µg/kg，于3分钟内静注后，以0.15µg/(kg·min)维持静滴36小时，然后停用肝素。
2.不稳定性心绞痛或非Q波型心肌梗死：与肝素联用，开始30min，以0.4µg/(kg·min)静滴，以后按0.1µg/(kg·min)维持静滴。在疗效研究中，本品与肝素联用持续滴注至少48h(平均71.3h，可达108h)。在血管造影术期间可持续滴注，并在冠脉血管成形术或冠脉内斑块切除术后持续滴注12～24h。
 
药物相应作用
1.与阿加曲班、阿司匹林、维生素A、软骨素、多昔单抗、低分子肝素、萃布地尼、尕古树脂、抗凝药、溶栓药合用，有增加出血的危险性。
2.与当归、茴香、山金车、小槲树、月见草、绣线菊、野甘菊、越橘、黑穗醋栗、墨角藻、睡菜、波多、琉璃苣、猫爪草、芹菜、姜黄素、大蒜、黄芪、辣椒辣素、生姜、蒲公英、银杏、丁香油、山楂、甘草、益母草、黄芩、卡瓦(Kava)、丹参、大黄、红花油合用，有增加出血的危险性。
3.本品与地西泮存在配伍禁忌。
4.可与硫酸阿托品、多巴酚丁胺、多巴胺、盐酸肾上腺素、呋塞米、利多卡因、盐酸咪达唑仑、硫酸吗啡、硝酸甘油、氯化钾、盐酸普萘洛尔、法莫替丁配伍使用。

DESCRIPTION

AGGRASTAT¹ (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:

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 of 100 mL or 250 mL. Each 100 mL of the premixed, iso-osmotic intravenous injection contains 5.618 mg tirofiban hydrochloride monohydrate equivalent to 5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 0.9 g sodium chloride, 54 mg sodium citrate dihydrate, and 3.2 mg citric acid anhydrous. Each 250 mL of the premixed, iso-osmotic intravenous injection contains 14.045 mg tirofiban hydrochloride monohydrate equivalent to 12.5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 2.25 g sodium chloride, 135 mg sodium citrate dihydrate, and 8 mg citric acid anhydrous.

The pH of the solution 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 lIb/lIla receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, AGGRASTAT inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner.

When given according to the recommended regimen, >90% inhibition is attained by the end of the 30-minute infusion. Platelet aggregation inhibition is reversible following cessation of the infusion of AGGRASTAT.

Pharmacokinetics

Tirofiban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. Metabolism appears to be limited.

Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 mcg/mL. Unbound fraction in human plasma is 35%. The steady state volume of distribution of tirofiban ranges from 22 to 42 liters.

In healthy subjects, the plasma clearance of tirofiban ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance. The recommended regimen of a loading infusion followed by a maintenance infusion produces a peak tirofiban plasma concentration that is similar to the steady state concentration during the infusion. In patients with coronary artery disease, the plasma clearance of tirofiban ranges from 152 to 267 mL/min; renal clearance accounts for 39% of plasma clearance.

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% lower in elderly (>65 years) patients with coronary artery disease than in younger (≤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 (>50%) in patients with creatinine clearance <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 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in approximately 90% of patients with coronary artery disease in 4 to 8 hours. The addition of heparin to this regimen does not significantly alter the percentage of subjects with >70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to >30 minutes.

In patients with unstable angina, a two-staged intravenous infusion regimen of AGGRASTAT (loading infusion of 0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min for up to 48 hours in the presence of heparin and aspirin), produces approximately 90% inhibition of ex vivo ADP-induced platelet aggregation with a 2.9-fold prolongation of bleeding time during the loading infusion. Inhibition persists over the duration of the maintenance infusion.

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 (≥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 lschemic 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=773) was compared to heparin alone (n=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% 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 <150,000/mm³, and creatinine >2.5 mg/dL. In this study, patients were randomized to either AGGRASTAT (30 minute loading infusion of 0.4 mcg/kg/min followed by a maintenance infusion of 0.10 mcg/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% 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% risk reduction in myocardial infarction and a 30% risk reduction in refractory ischemia. The results are shown in Table 1.

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

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% of patients in the PRISM-PLUS study underwent coronary angiography and 30% 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=1616) was compared to heparin (n=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% of the population was female and 25% 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.

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=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=2141) was a randomized, 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% 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 <150,000/mm³, and creatinine >2.0 mg/dL. AGGRASTAT (with heparin) was initiated immediately prior to the angioplasty/atherectomy at a dose of 10 mcg/kg bolus (over 3 minutes) followed by an infusion of 0.15 mcg/kg/min along with a heparin bolus (bolus of 10,000 U, or 150 U/kg for patients <70 kg). The infusion dose of AGGRASTAT is 50% 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 >40%), 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.

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

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 previous 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 >180 mmHg and/or diastolic blood pressure >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)². Most major bleeding associated with AGGRASTAT occurs at the arterial access site for cardiac catheterization. Fatal bleedings have been reported (see ADVERSE REACTIONS).

AGGRASTAT should be used with caution in patients with platelet count <150,000/mm³, in patients with hemorrhagic retinopathy, and in chronic hemodialysis patients.

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) <180 seconds or APTT <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° 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, epidural procedures, 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). In patients who have previously received GP IIb/IIIa receptor antagonists, consideration should be given to earlier monitoring of platelet count. If the patient experiences a platelet decrease to <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.

In addition, the activated partial thromboplastin time (APTT) should be determined before treatment and the anticoagulant effects of heparin should be carefully monitored by repeated determinations of APTT and the dose should be adjusted accordingly (see also DOSAGE AND ADMINISTRATION). Potentially life-threatening bleeding may occur especially when heparin is administered with other products affecting hemostasis, such as GP IIb/IIIa receptor antagonists. 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 <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=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 HCI 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 HCI 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 (<18 years old) have not been established.

Geriatric Use

Of the total number of patients in controlled clinical studies of AGGRASTAT, 42.8% were 65 years and over, while 11.7% were 75 and over. With respect to efficacy, the effect of AGGRASTAT in the elderly (≥65 years) appeared similar to that seen in younger patients (<65 years). Elderly patients receiving AGGRASTAT with heparin or heparin alone had a higher incidence of bleeding complications than younger patients, 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% of the population was >65 years of age and approximately 30% 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.

	PRISM-PLUS* (UAP/Non-Q-Wave MI Study)		RESTORE* (Angioplasty/Atherectomy Study)
Bleeding	AGGRASTAT† + Heparin‡ (n=773) %(n)	Heparin‡ (n=797) %(n)	AGGRASTAT§ + Heparin ¶ (n=1071) %(n)	Heparin¶ (n=1070) %(n)
Major Bleeding (TIMI Criteria)#	1.4 (11)	0.8 (6)	2.2 (24)	1.6 (17)
Minor Bleeding (TIMI Criteria)♠	10.5 (81)	8.0 (64)	12.0 (129)	6.3 (67)
Transfusions	4.0 (31)	2.8 (22)	4.3 (46)	2.5 (27)

Patients received aspirin unless contraindicated.

There were no reports of intracranial bleeding in the PRISM-PLUS study for AGGRASTAT in combination with heparin or in the heparin control group. The incidence of intracranial bleeding in the RESTORE study was 0.1% for AGGRASTAT in combination with heparin and 0.3% for the control group (which received heparin). In the PRISM-PLUS study, the incidences of retroperitoneal bleeding reported for AGGRASTAT in combination with heparin, and for the heparin control group were 0.0% and 0.1%, respectively. In the RESTORE study, the incidences of retroperitoneal bleeding reported for AGGRASTAT in combination with heparin, and the control group were 0.6% and 0.3%, respectively. The incidences of TIMI major gastrointestinal and genitourinary bleeding for AGGRASTAT in combination with heparin in the PRISM-PLUS study were 0.1% and 0.1%, respectively; the incidences in the RESTORE study for AGGRASTAT in combination with heparin were 0.2% and 0.0%, respectively.

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

The incidence rates of TIMI major bleeding (in some cases possibly reflecting hemodilution rather than actual bleeding) in patients undergoing CABG in the PRISM-PLUS and RESTORE studies within one day of discontinuation of AGGRASTAT are shown below.

Female patients and elderly patients receiving AGGRASTAT with heparin or heparin alone had a higher incidence of bleeding complications than male patients or younger patients. The incremental risk of bleeding in patients treated with AGGRASTAT in combination with heparin over the risk in patients treated with heparin alone was comparable regardless of age or gender. No dose adjustment is recommended for these populations (see DOSAGE AND ADMINISTRATION, Recommended Dosage).

NON-BLEEDING

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

Other non-bleeding side effects (considered at least possibly related to treatment) reported at a >1% rate with AGGRASTAT administered concomitantly with heparin were nausea, fever, and headache; these side effects were reported at a similar rate in the heparin group.

In clinical studies, the incidences of adverse events were generally similar among different races, patients with or without hypertension, patients with or without diabetes mellitus, and patients with or without hypercholesteremia.

The overall incidence of non-bleeding adverse events was higher in female patients (compared to male patients) and older patients (compared to younger patients). However, the incidences of non-bleeding adverse events in these patients were comparable between the AGGRASTAT with heparin and the heparin alone groups. (See above for bleeding adverse events.)

Allergic Reactions/Readministration

Although no patients in the clinical trial database developed anaphylaxis and/or hives requiring discontinuation of the infusion of tirofiban, anaphylaxis has been reported in post-marketing experience (see also Post-Marketing Experience, Hypersensitivity). No information is available regarding the development of antibodies to tirofiban.

Laboratory Findings

The most frequently observed laboratory adverse events in patients receiving AGGRASTAT concomitantly with heparin were related to bleeding. Decreases in hemoglobin (2.1%) and hematocrit (2.2%) were observed in the group receiving AGGRASTAT compared to 3.1% and 2.6%, respectively, in the heparin group. Increases in the presence of urine and fecal occult blood were also observed (10.7% and 18.3%, respectively) in the group receiving AGGRASTAT compared to 7.8% and 12.2%, respectively, in the heparin group.

Patients treated with AGGRASTAT, with heparin, were more likely to experience decreases in platelet counts than the control group. These decreases were reversible upon discontinuation of AGGRASTAT. The percentage of patients with a decrease of platelets to <90,000/mm³ was 1.5%, compared with 0.6% in the patients who received heparin alone. The percentage of patients with a decrease of platelets to <50,000/mm³ was 0.3%, compared with 0.1% of the patients who received heparin alone. Platelet decreases have been observed in patients with no prior history of thrombocytopenia upon readministration of GP IIb/IIIa receptor antagonists.

Post-Marketing Experience

The following additional adverse reactions have been reported in post-marketing experience: Bleeding: Intracranial bleeding, retroperitoneal bleeding, hemopericardium, pulmonary (alveolar) hemorrhage, and spinal-epidural hematoma. Fatal bleeding events have been reported;Body as a Whole: Acute and/or severe decreases in platelet counts which may be associated with chills, low-grade fever, or bleeding complications (see Laboratory Findings above);Hypersensitivity: Severe allergic reactions including anaphylactic reactions. The reported cases have occurred during the first day of tirofiban infusion, during initial treatment, and during readministration of tirofiban. Some cases have been associated with severe thrombocytopenia (platelet counts <10,000/mm³).

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 mcg/kg/min maintenance infusion rate.

The most frequently reported manifestation of overdosage was bleeding, primarily minor mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization (see 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. Any unused solution should be discarded.

Directions for Use

Prior to use, AGGRASTAT Injection (250 mcg/mL) must be diluted to the same strength as AGGRASTAT Injection Premixed (50 mcg/mL). This may be achieved, for example, using either of the following two methods:

1. If using a 500 mL bag of sterile 0.9% sodium chloride or 5% dextrose in water, withdraw and discard 100 mL from the bag and replace this volume with 100 mL of AGGRASTAT Injection from two 50 mL vials, OR
2. If using a 250 mL bag of sterile 0.9% sodium chloride or 5% dextrose in water, withdraw and discard 50 mL from the bag and replace this volume with 50 mL of AGGRASTAT Injection from one 50 mL vial.

Mix well prior to administration.

AGGRASTAT Injection Premixed is supplied as 100 mL or 250 mL of 0.9% sodium chloride containing 50 mcg/mL tirofiban. It is supplied in IntraVia³ containers (PL 2408 plastic). To open the IntraVia^® container, first tear off its foil overpouch. The plastic may be somewhat opaque because of moisture absorption during sterilization; the opacity will diminish gradually. Check for leaks by squeezing the inner bag firmly; if any leaks are found, the sterility is suspect and the solution should be discarded. Do not use unless the solution is clear and the seal is intact. Suspend the container from its eyelet support, remove the plastic protector from the outlet port, and attach a conventional administration set.

AGGRASTAT may be administered in the same intravenous line as dopamine, lidocaine, potassium chloride, and PEPCID^* (famotidine) Injection. AGGRASTAT should not be administered in the same intravenous line as diazepam.

Recommended Dosage

In most patients, AGGRASTAT should be administered intravenously, at an initial rate of 0.4 mcg/kg/min for 30 minutes and then continued at 0.1 mcg/kg/min.

Patients with severe renal insufficiency (creatinine clearance <30 mL/min) should receive half the usual rate of infusion (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.

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

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

AGGRASTAT Injection 12.5 mg per 50 mL (250 mcg per mL) is a non-preserved, clear, colorless concentrated sterile solution for intravenous infusion after dilution and is supplied as follows:

NDC 25208-001-01 50 mL vials.

AGGRASTAT Injection Premixed 5 mg tirofiban per 100 mL (50 mcg per mL) and 12.5 mg tirofiban per 250 mL (50 mcg per mL) are clear, non-preserved, sterile solutions premixed in a vehicle made iso-osmotic with sodium chloride, and are supplied as follows:

NDC 25208-002-01, 100 mL single-dose IntraVia^® containers (PL 2408 Plastic).

NDC 25208-002-02, 250 mL single-dose IntraVia^® containers (PL 2408 Plastic).

Storage

AGGRASTAT Injection

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

AGGRASTAT Injection Premixed

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

US Patent Nos: 5,292,756, 5,439,454, 5,849,843, and 5,998,019

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注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
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产地国家: 意大利
原产地英文商品名:
AGGRASTAT 250mcg/50ml/vial
原产地英文药品名:
TIROFIBAN HCL M-HYDRATE/NORMAL SALINE
原产地英文化合物名称:
N(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate
中文参考商品译名:
AGGRASTAT 250微克/50毫升/瓶
中文参考药品译名:
盐酸替罗非班 M-水合物/生理盐水
中文参考化合物名称:
N-(正丁基磺酰基)-O-[4-(4-哌啶基)丁基]-L-酪氨酸盐酸盐一水合物
生产厂家中文参考译名:
Iroko
生产厂家英文名:
Iroko
---------------------------------------------------------------
产地国家:新西兰
原产地英文商品名:
AGGRASTAT 0.25mg/ml 50ml/bag
原产地英文药品名:
TIROFIBAN HCL M-HYDRATE/NORMAL SALINE
原产地英文化合物名称:
N(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate
中文参考商品译名:
AGGRASTAT 0.25毫克/毫升 50毫升/袋
中文参考药品译名:
盐酸替罗非班 M-水合物/生理盐水
中文参考化合物名称:
N-(正丁基磺酰基)-O-[4-(4-哌啶基)丁基]-L-酪氨酸盐酸盐一水合物
生产厂家中文参考译名:
Aspen
生产厂家英文名:
Aspen
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产地国家: 美国
原产地英文商品名:
AGGRASTAT 12.5mg/2500ml/plast bag
原产地英文药品名:
TIROFIBAN HCL M-HYDRATE/NORMAL SALINE
原产地英文化合物名称:
N(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate
中文参考商品译名:
AGGRASTAT 12.5毫克/250毫升/塑胶袋
中文参考药品译名:
盐酸替罗非班 M-水合物/生理盐水
中文参考化合物名称:
N-(正丁基磺酰基)-O-[4-(4-哌啶基)丁基]-L-酪氨酸盐酸盐一水合物
生产厂家中文参考译名:
MEDICURE
生产厂家英文名:
MEDICURE
-----------------------------------------------------------------
产地国家: 美国
原产地英文药品名:
TIROFIBAN HCL M-HYDRATE/NORMAL SALINE
原产地英文化合物名称:
N(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate
中文参考商品译名:
AGGRASTAT 5毫克/100毫升/塑胶袋
中文参考药品译名:
盐酸替罗非班 M-水合物/生理盐水
中文参考化合物名称:
N-(正丁基磺酰基)-O-[4-(4-哌啶基)丁基]-L-酪氨酸盐酸盐一水合物
生产厂家中文参考译名:
MEDICURE
生产厂家英文名:
MEDICURE