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【药品名称】
通用名称：注射用盐酸替罗非班
英文名称：Tirofiban Hydrochloride for Injection
【成份】
化学名称：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
分子式：C22H36N2O5S·HCl·H2O
分子量：495.08
辅料：甘露醇
【性状】
本品为白色或类白色疏松块状物或粉末。
【适应症】
本品与肝素联用，适用于不稳定型心绞痛或非Q波心肌梗塞患者，预防心脏缺血事件，同时也适用于冠脉缺血综合征患者进行冠脉血管成形术或冠脉内斑块切除术，以预防与经治冠脉突然闭塞有关的心脏缺血并发症。
【规格】12.5mg、5mg（以C22H36N2O5S计）。
【用法用量】
将本品溶于0.9%氯化钠注射液或5%葡萄糖注射液中，终浓度为50μg/ml。
本品仅供静脉使用，需用无菌设备。本品可与肝素联用，从同一液路输入。
建议用有刻度的输液器输入本品。必须注意避免长时间负荷输入。还应注意根据患者体重计算静脉推注剂量和滴注速率。
临床研究中的患者除有禁忌症外，均服用了阿司匹林。
不稳定型心绞痛或非Q波心肌梗塞
本品与肝素联用由静脉输注，起始30分钟滴注速率为0.4μg/kg/min，起始输注量完成后，继续以0.1μg/kg/min的速率维持滴注。
在验证疗效的研究中，盐酸替罗非班注射液与肝素联用滴注一般至少持续48小时，并可达108小时。患者平均接受盐酸替罗非班注射液71.3小时。
在血管造影术期间可持续滴注，并在血管成形术/动脉内斑块切除术后持续滴注12-24小时。当患者激活凝血时间小于180秒或停用肝素后2-6小时应撤去动脉鞘管。
血管成形术/动脉内斑块切除术
对于血管成形术/动脉内斑块切除术患者开始接受本品时，本品应与肝素联用由静脉输注，起始推注剂量为10μg/kg，在3分钟内推注完毕，而后以0.15μg/kg/min的速率维持滴注。
本品维持量滴注应持续36小时。以后，停用肝素。如果患者激活凝血时间小于180秒应撤掉动脉鞘管。
严重肾功能不全患者：如上面调整剂量表所特别指出的，对于严重肾功能不全的患者（肌酐清除率小于30ml/min），本品的剂量应减少50%（参见注意事项，严重肾功能不全，药代动力学，患者的特点，肾功能不全）。
其他患者：对于老年患者（参见老年患者用药）或女性患者不推荐调整剂量。
使用说明
1、根据上表按体重调整适当的给药速度。
2、任何剩余溶液都须丢弃。
本品可以与下列注射药物在同一条静脉输液管路中使用，如硫酸阿托品、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、盐酸普萘洛尔及法莫替丁。但是本品不能与地西泮（安定Diazepam）在同一条静脉输液管路中使用。
【不良反应】
根据文献资料，盐酸替罗非班与肝素和阿司匹林联合治疗时，与药物有关的最常见不良事件是出血（研究者的报告通常是渗出或轻度出血）。
+除有禁忌症外，患者均接受阿司匹林治疗。
+血红蛋白下降大于50g/L，伴或不伴有一个确定部位的出血、颅内出血或心包填塞。
§血红蛋白下降大于30g/L，伴有已知部位的出血、自发性肉眼血尿、呕血或咯血。
在PRISM-PLUS研究中盐酸替罗非班与肝素联合治疗组或对照组（接受肝素治疗）均未报告有颅内出血。在RESTORE研究中颅内出血的发生率在盐酸替罗非班与肝素联合治疗组为0.1%，而对照组（接受肝素治疗）为0.3%。在PRISM-PLUS研究中，腹膜后出血的发生率在盐酸替罗非班与肝素联合治疗组和对照组分别为0.0%和0.1%。在RESTORE研究中，腹膜后出血的发生率在盐酸替罗非班与肝素联合治疗组和对照组分别为0.6%和0.3%。
接受盐酸替罗非班与肝素联合治疗或肝素单独治疗的女性和老年患者分别较男性和年轻患者有较高的出血并发症。不考虑年龄和性别因素，接受盐酸替罗非班与肝素联合治疗的患者与肝素单独治疗的患者相比，其出血的危险性增加相似。对这些人群不需调整剂量（参见用法用量，其他患者）。
接受盐酸替罗非班和肝素联合治疗的患者较对照组更易出现血小板计数下降。这种下降在中断盐酸替罗非班治疗后可逆转。血小板下降到小于90,000/mm3的患者百分比为1.5%。血小板下降到小于50,000/mm3的患者百分比为0.3%。血小板下降见于无血小板减少症病史并再次使用血小板糖蛋白IIb/IIIa受体拮抗剂的患者。
在盐酸替罗非班和肝素联合治疗组最常见的（发生率大于1%）与药物相关的非出血性不良反应有恶心（1.7%）、发热（1.5%）和头痛（1.1%）；在对照组中它们的发生率分别为1.4%、1.1%、1.2%。
在临床研究中，不良事件的发生率在不同的种族、有无高血压、糖尿病或高胆固醇血症的患者中通常是相似的。
非出血性不良事件的总发生率在女性患者（与男性患者相比）和老年患者（与年轻患者相比）中较高。但是，这些患者的非出血性不良事件的发生率在盐酸替罗非班与肝素联合治疗组和肝素单独治疗组是相似的（参见上述的出血性不良事件）。
以下不良事件在上市后也有报道：
出血：颅内出血、腹膜后出血、心包积血、肺（肺泡）出血和脊柱硬膜外血肿，致死性出血罕见。
全身：急性和/或严重血小板计数减少可伴有寒战、轻度发热或出血并发症。
超敏感性：严重变应性反应包括过敏性反应。在替罗非班输注第一天，初次治疗时以及再次使用时均有过敏性病例发生的报导。有些病例伴有严重的血小板减少症（血小板计数<10,000/mm3）。
实验室化验结果：
接受盐酸替罗非班与肝素联合治疗的患者最常见的实验室不良事件与出血相关。发现有血红蛋白、血球压积和血小板计数下降。也可见尿和大便隐血增加。
【禁忌】
盐酸替罗非班禁用于对其任何成份过敏的患者。
由于抑制血小板聚集可增加出血的危险，所以盐酸替罗非班禁用于有活动性内出血、颅内出血史、颅内肿瘤、动静脉畸形及动脉瘤的患者；也禁用于那些以前使用盐酸替罗非班出现血小板减少的患者。
【注意事项】
盐酸替罗非班应慎用于下列患者：
1、近期（1年内）出血，包括胃肠道出血或有临床意义的泌尿生殖道出血
2、已知的凝血障碍、血小板异常或血小板减少病史
3、血小板计数小于150,000/ mm3
4、1年内的脑血管病史
5、1个月内的大的外科手术或严重躯体创伤史
6、近期硬膜外的手术
7、 病史、症状或检查结果显示为壁间动脉瘤。
8、严重的未控制的高血压（收缩压大于180mmHg和/或舒张压大于110mmHg）
9、急性心包炎
10、出血性视网膜病
11、慢性血液透析
出血的预防
因为盐酸替罗非班抑制血小板聚集，所以与其它影响止血的药物合用时应当谨慎。盐酸替罗非班与溶栓药物联用的安全性尚未确定。
盐酸替罗非班治疗期间，应监测患者有无潜在的出血。当出血需要治疗时，应考虑停止使用盐酸替罗非班。也要考虑是否需要输血。
曾有报道发生致命性出血（见不良反应）。
股动脉穿刺部位：盐酸替罗非班可轻度增加出血的发生率，特别是在股动脉鞘管穿刺部位。当要进行血管穿刺时要注意确保只穿刺股动脉的前壁，避免用Seldinger（穿透）技术使鞘管进入。鞘管拔出后要注意正确止血并密切观察。
实验室监测：在盐酸替罗非班治疗前、推注或负荷输注后6小时内以及治疗期间至少每天要监测血小板计数、血红蛋白和血球压积（如果证实有显著下降需更频繁监测）。在原先接受过血小板糖蛋白IIb/IIIa受体拮抗剂的患者应当考虑尽早监测血小板计数。如果患者的血小板计数下降到小于90,000/mm3，则需要再进行血小板计数以排除假性血小板减少。如果已证实有血小板减少，则需停用盐酸替罗非班和肝素，并进行适当的监测和治疗。
此外，在治疗前应测定活化部分凝血酶原时间（APTT），并且应当反复测定APTT仔细监测肝素的抗凝效应并据此调整剂量（见用法用量）。有可能发生潜在致命性出血，特别是肝素与影响止血的其它产品如血小板糖蛋白IIb/IIIa受体拮抗剂联用时尤其可能。
严重肾功能不全
在临床研究中，已证明有严重肾功能不全（肌酐清除率<30ml/min）的患者其替罗非班血浆清除率下降。对于这样的患者应减少替罗非班的剂量（参见用法用量）。
【警示语】由于抑制血小板聚集可增加出血的危险，所以盐酸替罗非班禁用于有活动性内出血、颅内出血史、颅内肿瘤、动静脉畸形及动脉瘤的患者；也禁用于那些以前使用盐酸替罗非班出现血小板减少的患者。
【孕妇及哺乳期妇女用药】
对于妊娠妇女尚没有进行适当且对照良好的研究。在妊娠期间，盐酸替罗非班只可用于已证明对胎儿潜在的益处大于潜在的危险时。
尚不知盐酸替罗非班是否从人的乳汁排泌。因许多药物可以分泌到人乳汁中，而且可能对哺乳的婴儿产生不良反应，所以要根据此药对母亲的重要性来决定是中断哺乳还是中断药物治疗。
【儿童用药】
儿童用药的安全性和有效性尚未确定。
【老年患者用药】
在临床研究中，盐酸替罗非班对老年患者（≥65岁）的有效性与年轻患者（<65岁）的相似。老年患者接受盐酸替罗非班和肝素联合治疗或者肝素单独治疗比年轻患者有较高的出血发生率。不考虑年龄因素，接受盐酸替罗非班与肝素联用治疗的患者与单独应用肝素的患者相比其出血危险性的增加相似。非出血性不良事件的总发生率在老年患者要高一些（与年轻患者相比）；但在老年患者中，替罗非班与肝素联合治疗和肝素单独治疗相比，非出血性不良事件的发生率相似。不需要调整剂量（参见用法用量，其他患者）。
【药物相互作用】
对于替罗非班与阿司匹林和肝素的相互作用已进行了研究。
盐酸替罗非班与肝素和阿司匹林联用时，比单独使用肝素和阿司匹林出血的发生率增加（参见不良反应）。当盐酸替罗非班与其它影响止血的药物（如华法令）合用时应谨慎（参见注意事项，出血的预防）。
在临床研究中盐酸替罗非班与b-阻滞剂、钙拮抗剂、非甾体类抗炎药（NSAIDs）及硝酸酯类联用，未见有临床意义的不良相互作用。
在PRISM研究（血小板受体抑制剂对缺血综合征的治疗）一个亚组的患者（n=762）中，接受下列药物之一的患者的替罗非班血浆清除率与未接受这些药物的患者的血浆清除率相似。这些药物对替罗非班的血浆清除率没有具有临床意义的相互作用。这些药物是：醋丁洛尔、醋氨酚、阿普唑仑、氨氯地平、阿司匹林、阿替洛尔、溴西泮、卡托普利、地西泮、地高辛、地尔硫卓、多库酯钠、依那普利、呋塞米、优降糖、肝素、胰岛素、异山梨酯、左旋甲状腺素、劳拉西泮、洛伐他汀、甲氧氯普胺、美托洛尔、吗啡、硝苯地平、硝酸酯类、奥美拉唑、奥沙西泮、氯化钾、普萘洛尔、雷尼替丁、辛伐他汀、硫糖铝和替马西泮。
【药物过量】
临床试验中，曾由于疏忽导致替罗非班过量，分别发生在推注和负荷滴注时，为推荐剂量的5倍和2倍，及0.15μg/kg/min的维持滴注速率的9.8倍。
过量用药最常见的表现是出血，主要是轻度的粘膜皮肤出血和心导管部位的轻度出血（参见注意事项，出血的预防）。
过量使用替罗非班时，应根据患者的临床情况适当中断治疗或调整滴注剂量。
盐酸替罗非班可通过血液透析清除。
【药理毒理】
药理学
血小板激活、粘附和聚集是粥样斑块破裂表面动脉血栓形成的关键性起始步骤，血栓形成是急性冠脉缺血综合症即不稳定型心绞痛及心肌梗塞以及冠脉血管成形术后心脏缺血性并发症的主要病理生理学问题。
盐酸替罗非班是一种非肽类的血小板糖蛋白IIb/IIIa受体的可逆性拮抗剂，该受体是与血小板聚集过程有关的主要血小板表面受体。盐酸替罗非班阻止纤维蛋白原与糖蛋白IIb/IIIa结合，因而阻断血小板的交联及血小板的聚集。
体外试验显示，盐酸替罗非班可抑制二磷酸腺苷（ADP）诱导的血小板聚集及延长健康受试者和冠心病患者的出血时间（BT），这表明盐酸替罗非班可强效抑制血小板功能。抑制的时间与药物的血浆浓度相平行。停用盐酸替罗非班注射液后，血小板功能迅速恢复到基线水平。
盐酸替罗非班注射液以0.15μg/kg/min的速度输注4小时，与阿司匹林合用可近乎最大程度地抑制血小板聚集，对延长出血时间有轻度的相加作用。
在不稳定型心绞痛患者，盐酸替罗非班静脉两步输注方案（在肝素及阿司匹林应用条件下负荷输入0.4μg/kg/min 30分钟，而后0.1μg/kg/min至48小时），于输注期间可以抑制体外ADP诱导的血小板聚集约90%及延长出血时间2.9倍。在30分钟负荷输注时可迅速抑制并在输注期间保持这种抑制程度。
在冠脉血管成形术患者中应用盐酸替罗非班，两步静脉输注方案（负荷量10μg/kg静脉推注，在5分钟内推注完毕，而后以0.15μg/kg/min维持输注16-24小时），与肝素及阿司匹林联用，几乎对所有患者都可达到抑制体外ADP诱导的血小板聚集大于90%。5分钟推注并维持输注可快速达到近乎最大程度的抑制。停止输注替罗非班后，血小板功能迅速恢复到基线水平。
毒理学
盐酸替罗非班对小鼠或大鼠单次静脉用的半数致死量（LD50）大约是﹥5mg/kg。5mg/kg的最大剂量（为推荐每日人体用剂量的22倍）受化合物溶解度和最大可接受剂量容积的限制。盐酸替罗非班对小鼠的单次口服用LD50大约是﹥500mg/kg。在静脉或口服给药的研究中，未见死亡、异常体征或与药物相关的体重改变。
在大鼠及狗中经一系列连续静脉输注5周的毒性研究评估盐酸替罗非班的潜在毒性。使用治疗剂量达108小时都无需停药。
对盐酸替罗非班的潜在致癌危险性尚未作过评估。
盐酸替罗非班在微生物及V-79哺乳类细胞的致突变实验为阴性。此外，在实验室碱性洗出液及染色体畸变实验中未见直接遗传毒性。在这些检验中替罗非班的浓度高达3mM，相当于人推荐治疗剂量平均血浆浓度的20,000倍以上。文献资料显示，盐酸替罗非班注射液经静脉用量达5mg/kg（推荐用于人每日最大剂量的22倍）在雄性小鼠骨髓细胞中未诱发染色体畸变。
在雄性及雌性大鼠用盐酸替罗非班静脉剂量至5mg/kg/日的一项研究中，未见对生育及生殖能力有何影响。这些剂量大约是推荐用于人体每日最高剂量的22倍以上。大鼠及兔的发育毒性研究也未见对母体或幼胎有毒性证据。再有，通过宫内接触及哺乳对大鼠性成熟的一项潜在发育毒性研究表明关于死亡、生长、发育及F1代性成熟未见与药物相关的影响。在有关发育毒性研究中，静脉输注盐酸替罗非班最高剂量达5mg/kg/日（推荐用于人每日最大剂量的22倍）。
【药代动力学】
在0.01-25μg/ml的浓度范围内，替罗非班与血浆蛋白结合率不高，其结合率与药物浓度无关。人体血浆中不结合部分为35%。替罗非班的稳态分布容积范围为22-42升。替罗非班可以通过大鼠及兔的胎盘。
分析以14C标记替罗非班在尿液及粪便中的代谢产物情况，表明其放射性主要来自未改变的替罗非班，循环血浆放射性主要来自未改变的替罗非班（用药后达10小时）。这些资料提示替罗非班的代谢有限。
在健康人中以14C标记替罗非班单次静脉给药后，在尿液、粪便中探测到的放射性分布分别占给药量的66%、23%，探测到的总放射性约为91%。替罗非班主要从尿路及胆道排出。
在健康人中替罗非班血浆清除率范围从213到314ml/min。肾脏清除率占血浆清除率的39%至69%，半衰期范围从1.4至1.8小时。
在冠心病患者中替罗非班血浆清除率范围从152至267ml/min。肾脏清除率占血浆清除率的39%，半衰期范围从1.9至2.2小时。
在大鼠中，替罗非班可泌入乳汁。
患者的特点：
性别：冠心病患者中替罗非班的血浆清除率男女相似。
老年人：与较年轻患者（年龄≤65岁）相比，年龄>65岁的老年冠心病患者的替罗非班血浆清除率约降低19-26%。
种族：不同种族患者未见血浆清除率有差异。
肝功能不全：在轻中度肝功能不全患者中，替罗非班的血浆清除率与健康人没有明显差别。
肾功能不全：在血浆肌酐清除率<30ml/min的患者中（包括需要血液透析的患者），替罗非班的血浆清除率降低到有临床意义的程度（>50%）（参见用法用量，严重肾功能不全患者）。替罗非班可以通过血液透析清除。
【贮藏】遮光，密闭保存。
AGGRASTAT®
(tirofiban hydrochloride) Injection Premixed
AGGRASTAT®
(tirofiban hydrochloride) Injection
DRUG 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.
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.
INDICATIONS
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.
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:
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
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 lntraVia*** containers (PL 2408 plastic). To open the lntraVia 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.
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(see USP Controlled Room Temperature). Do not freeze. Protect from light during storage.
AGGRASTAT Injection Premixed
Store at 25°C(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
SIDE EFFECTS
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.
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).
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 postmarketing 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).
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.
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. 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° 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).
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).
OVERDOSE
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 condition and cessation or adjustment of the drug infusion as appropriate.
AGGRASTAT can be removed by hemodialysis.
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 AGGRASTAThistory 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 | 
