近日,美国食品和药物管理局FDA新推的替罗非班AGGRASTAT（tirofiban hydrochloride）给予抗血小板药物它含有盐酸替罗非班，一个的非肽拮抗剂血小板糖蛋白IIb/IIIa受体，其抑制血小板聚集，为减少血栓形成的心血管事件的患者与非ST段抬高的急性冠状动脉综合征（NSTE-ACS）的速率。
批准日期：2016年10月28日 公司：Medicure
AGGRASTAT（盐酸替罗非班[tirofiban hydrochloride]）注射，静脉内使用
最初美国批准：1998
作用机理
是替罗非班的纤维蛋白原的可逆拮抗剂结合到糖蛋白IIb/IIIa受体，参与血小板聚集的血小板主要表面受体，当静脉内给药，以剂量和浓度依赖的方式抑制替罗非班离体血小板聚集。
当根据0.4微克/kg/min，历经30分钟，接着0.1微克/kg/min的维持输注的PRISM-PLUS方案给出的血小板聚集的>90％的抑制是通过在30分钟输注结束实现。当根据25微克/公斤，接着0.15微克/kg/min的维持输注推荐的方案给出的，>90％的血小板聚集的抑制达到10分钟内。血小板聚集抑制作用是可逆的以下替罗非班的停止输注。
适应症和用法
AGGRASTAT®是表示，以减少血栓形成的心血管事件的发生率血小板聚集抑制剂的患者非ST段抬高急性冠脉综合征（NSTE-ACS）（死亡，心肌梗死，难治性缺血的复合终点/重复心脏手术）。
用法用量
静脉内施用25微克/5分钟之内，然后0.15微克/kg/分钟达18小时。在患有肌酐清除率≤60毫升/分钟，得到25微克/5分钟内公斤然后0.075微克/kg/分钟公斤。
剂型和规格
注射剂：100mL袋  5毫克/100毫升（50mcg/mL）
注射剂：250mL袋  12.5mg/250mL（50mcg/mL）
注射剂：5mL/100毫升（50mcg/mL）100毫升/小瓶
注射剂：3.75mg/15毫升（250mcg/mL）15mL/小瓶丸
禁忌症
已知过敏的替罗非班的任何组件。
与之前曝光血小板替罗非班的历史。
活动性内出血，或前一个月内，出血倾向，主要的外科手术或严重身体创伤史。
警告和注意事项
替罗非班可导致严重出血。如果出血无法控制中止替罗非班。
血小板减少症：替罗非班请停止和肝素。
不良反应
出血是最常见的不良反应。
药物相互作用
纤溶，抗凝血剂和抗血小板药物合用，增加出血的风险。
特殊人群中使用
肾功能不全：减少患者严重肾功能不全的剂量。
包装规格/储存与处理
50微克/毫升   5毫克/100毫升/袋        NDC:25208-002-01
50微克/毫升   12.5毫克/250毫升/袋     NDC:25208-002-02
50微克/毫升   5毫克/100毫升/瓶        NDC:25208-002-03
250微克/毫升  3.75毫克/15毫升/小瓶    NDC:25208-001-04
仅供静脉使用
替罗非班商店在受控的室温下，25℃（77°F）15-30℃（59-86°F）[见USP]之间允许偏移。不要冻结。贮存过程中避光。
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.
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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.
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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 50mL from the bag and replace this volume with 50mL of AGGRASTAT Injection from one 50mL vial.
Mix well prior to administration.
AGGRASTAT Injection Premixed is supplied as 100 mL or 250mL 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.
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HOW SUPPLIED
FOR INTRAVENOUS USE ONLY
AGGRASTAT Injection 12.5mg per 50mL(250mcg 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, 50mL vials.
AGGRASTAT Injection Premixed 5mg tirofiban per 100mL(50mcg per mL) and 12.5mg tirofiban per 250mL(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, 100mL single-dose IntraVia containers (PL 2408 Plastic).
NDC 25208-002-02, 250mL 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
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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).
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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.
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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.
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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 eva luated.
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).
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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.
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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
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=FE0CED75-CCBF-4D2E-BD0D-B57E60AB913F