部份中文阿替普酶处方资料（仅供参考）
【中文品名】阿替普酶
【药效类别】抗凝药>纤维蛋白溶酶原激活药
【通用药名】ALTEPLASE
【别　　名】Actase, Actilyse, Actiplas, Activacin, Activase, Plasminogen activator, tPA
【化学名称】 Plasminogen activator (human tissue-type protein moiety)
【CA登记号】[105857-23-6]
【结 构 式】
【分 子 式】CHNOPS·
【分 子 量】
【收录药典】
【开发单位】Genentech
【首次上市】1987年，美国
【性　　状】
【用　　途】阿替普酶是一种重组单链血纤维蛋白溶酶原活化剂（tPA），用于急性心肌梗塞和肺栓塞。
【药物剂型】
注射剂(粉)：20mg，50mg。
【药理作用】
本药是一种血栓溶解药，主要成分是糖蛋白，含526个氨基酸。本药可通过其赖氨酸残基与纤维蛋白结合，并激活与纤维蛋白结合的纤溶酶原转变为纤溶酶，这一作用比本药激活循环中的纤溶酶原显著增强。由于本药选择性地激活纤溶酶原，因而不产生应用链激酶时常见的出血并发症。对于急性心肌梗死，静脉使用本药可使阻塞的冠状动脉再通。
【药动学】
本药经静脉注射后迅速自血中消除，用药5min后，总药量的50%自血中消除；用药10min后，体内剩余药量仅占总给药量的20%；用药20min后，则剩余10%。本药主要在肝脏代谢。
【适应证】
1.用于急性心肌梗死和肺栓塞。
2.用于急性缺血性脑卒中、深静脉血栓及其他血管疾病。用于动静脉瘘血栓形成
【禁忌证】
1.出血性疾病(如近期内有严重内出血、脑出血或2个月内曾进行过颅脑手术者、10天内发生严重创伤或做过大手术者、严重的未能控制的原发性高血压、妊娠期和产后14天内妇女、细菌性心内膜炎和急性胰腺炎)患者。
2.颅内肿瘤、动静脉畸形或动脉瘤患者。
3.已知为出血体质(包括正在使用华法林、脑卒中前48h内使用过肝素、血小板计数小于100000/mm3)患者。
4.急性缺血性脑卒中可能伴有蛛网膜下腔出血或癫痫发作者。
【注意事项】
1.慎用：
(1)脑血管疾病者；
(2)高血压患者；
(3)急性心包炎患者；
(4)严重肝功能障碍者；
(5)感染性血栓性静脉炎患者；
(6)高龄(年龄大于75岁)患者；
(7)正在口服抗凝药的患者；
(8)活动性经期出血者。
2.用药期间应监测心电图。
3.本药一般不能与其他药物配伍静脉滴注，也不能与其他药物共用一条静脉血管来滴注。
4.国外资料报道，可与本药配伍的溶液有：
(1)葡萄糖溶液或氯化钠：500μg/ml的本药可加入5%的葡萄糖溶液或0.9%氯化钠溶液中，室温下盛于玻璃或聚氯乙烯容器中可保持稳定8h；
(2)注射用无菌水：注射用无菌水无抑菌作用，可用来配制浓度为1mg/ml的阿替普酶，但不作更进一步的稀释。
5.国外资料报道，与本药有配伍禁忌的溶液有：
(1)注射用抑菌水：注射用苯甲醇抑菌水及注射用对羟苯甲酸类抑菌水不用来配制阿替普酶溶液；
(2)平衡盐溶液：平衡盐溶液与本药相混，室温下24h内会发生沉淀，如在－20℃时放置24h，融化以后的光散射增加，则提示药物已发生变化。
6.患者的凝血酶原时间超过15秒时，禁止本药和口服抗凝药同时使用。
7.使用本药时可见注射部位出血，但不影响继续用药，发现出血迹象则应停药。
8.本药每天最大剂量不能超过150mg，否则会增加颅内出血的危险性。
【不良反应】
1.血液系统：出血最常见。与溶栓治疗相关的出血类型有胃肠道、泌尿生殖道、腹膜后或颅内的出血，浅层的或表面的出血主要出现在侵入性操作的部位(例如静脉切口，动脉穿刺，近期做了外科手术的部位)。另外，有出现硬膜外血肿和筋膜下血肿的报道。全身性纤维蛋白溶解比用链激酶时要少见，但出血的发生率相似。
2.心血管系统：
(1)心律失常：使用本药治疗急性心肌梗死时，血管再通期间可出现再灌注心律失常，如加速性室性自主心律、心动过缓或室性早搏等。这些反应通常为良性，通过标准的抗心律失常治疗可以控制，但有可能引起再次心肌梗死和梗死面积扩大。心律失常的发生率和静脉滴注链激酶时相似。
(2)血管再闭塞：血管开通后，需继续用肝素抗凝，否则可能再次形成血栓，造成血管再闭塞。有报道用本药进行溶栓治疗后发生了胆固醇结晶栓塞。
3.中枢神经系统：可出现颅内出血、癫痫发作。
4.泌尿生殖系统：有报道用药后立即出现肾血管肌脂瘤引起的腹膜后出血
5.骨骼/肌系统：可出现膝部出血性滑膜囊炎。
6.其他：过敏反应。
【用法用量】
1.静脉注射：
将50mg的本药溶解为1mg/ml的浓度，注射给药。
2.静脉滴注：将本药100mg溶于注射用生理盐水500ml中，在3h内按以下方式滴完，即前2min先注入本药10mg，以后60min内滴入50mg，最后120min内滴完余下的40mg。
1.负荷给药法(front loading)：总剂量为100mg，先弹丸(bolus)注射15mg，然后30min内再静脉滴注50mg，接着1h内静脉滴注剩余35mg。
2.按体重法：先静脉弹丸注射15mg，接着30min静脉滴注0.75mg/kg，然后1h内静脉滴注0.5mg/kg。
3.二次弹丸法(two bolus)：总量100mg，分2次静脉弹丸注射，间隔30min，此方法可有88%的再通率。
【药物相应作用】
1.与其他影响凝血功能的药物(包括醋硝香豆素、茴茚二酮、双香豆素、苯茚二酮，华法林、肝素)同用时，会显著增加出血的危险性。
2.与依替贝肽合用时，由于附加的抗凝作用，使出血的危险性增加。
3.硝酸甘油可增加肝脏的血流量，从而增加本药的清除率，使本药的血浆浓度降低及冠状动脉的再灌注减少、再灌注时间延长、再闭塞增多。
【专家点评】
本品具有促进体内纤维蛋白溶解系统活性的作用，但与链激酶和尿激酶不同，本品能特异性地使血栓内的纤溶酶原转变成纤溶酶，从而发挥溶解血栓的作用。临床多用于治疗各种新鲜形成的血栓。本品存在血管内皮细胞及组织中的丝氨酸蛋白酶，能选择性地与血栓表面的纤维蛋白结合，并激活与纤维蛋白结合的纤溶酶原转变为纤溶酶。本品由于其两个环状结构对纤维蛋白具有强大亲和力，故用药后可选择性激活血栓中的纤溶酶原，进而发挥溶栓作用。由于本品选择性地激活与纤维蛋白结合的纤溶酶原，因而不产生应用链激酶时常见的出血并发症。主要用于治疗急性心肌梗死和肺栓塞

Alteplase, recombinant
Description
Cathflo Activase (Alteplase) is a tissue plasminogen activator (t-PA) produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue-type plasminogen activator (t-PA) obtained from an established human cell line. The manufacturing process involves secretion of the enzyme Alteplase into the culture medium by an established mammalian cell line (Chinese hamster ovary cells) into which the cDNA for Alteplase has been genetically inserted. Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin sulfate, 100 mg/L. The presence of the antibiotic is not detectable in the final product.
Cathflo Activase is a sterile, white to pale yellow, lyophilized powder for intracatheter instillation for restoration of function to central venous access devices following reconstitution with Sterile Water for Injection, USP.
Each vial of Cathflo Activase contains 2.2 mg of Alteplase (which includes a 10% overfill), 77 mg of L-arginine, 0.2 mg of polysorbate 80, and phosphoric acid for pH adjustment. Each reconstituted vial will deliver 2 mg of Cathflo Activase, at a pH of approximately 7.3.
Clinical Pharmacology
Alteplase is an enzyme (serine protease) that has the property of fibrin-enhanced conversion of plasminogen to plasmin. It produces limited conversion of plasminogen in the absence of fibrin. Alteplase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin, thereby initiating local fibrinolysis. 1
In patients with acute myocardial infarction administered 100 mg of Activase as an accelerated intravenous infusion over 90 minutes, plasma clearance occurred with an initial half-life of less than 5 minutes and a terminal half-life of 72 minutes. Clearance is mediated primarily by the liver. 2
When Cathflo Activase is administered for restoration of function to central venous access devices according to the instructions in DOSAGE AND ADMINISTRATION , circulating plasma levels of Alteplase are not expected to reach pharmacologic concentrations. If a 2 mg dose of Alteplase were administered by bolus injection directly into the systemic circulation (rather than instilled into the catheter), the concentration of circulating Alteplase would be expected to return to endogenous circulating levels of 5-10 ng/mL within 30 minutes. 1
Clinical Studies
Two clinical studies were performed in patients with improperly functioning central venous access devices (CVADs). A placebo-controlled, double-blind, randomized trial (Trial 1) and a larger open-label trial (Trial 2) investigated the use of Alteplase in patients who had an indwelling CVAD for administration of chemotherapy, total parenteral nutrition, or long-term administration of antibiotics or other medications. Both studies enrolled patients whose catheters were not functioning (defined as the inability to withdraw at least 3 cc of blood from the device) but had the ability to instill the necessary volume of study drug. Patients with hemodialysis catheters or a known mechanical occlusion were excluded from both studies. Also excluded were patients considered at high risk for bleeding or embolization (see PRECAUTIONS , Bleeding ), as well as patients who were younger than 2 years old or weighed less than 10 kg. Restoration of function was assessed by successful withdrawal of 3 cc of blood and infusion of 5 cc of saline through the catheter.
Trial 1 tested the efficacy of a 2 mg/2 mL Alteplase dose in restoring function to occluded catheters in 150 patients with catheter occlusion up to 24 hours in duration. Patients were randomized to receive either Alteplase or placebo instilled into the lumen of the catheter, and catheter function was assessed at 120 minutes. Restoration of function was assessed by successful withdrawal of 3 cc of blood and infusion of 5 cc of saline through the catheter. All patients whose catheters did not meet these criteria were then administered Alteplase, until function was restored or each patient had received up to two active doses. After the initial dose of study agent, 51 (67%) of 76 patients randomized to Alteplase and 12 (16%) of 74 patients randomized to placebo had catheter function restored. This resulted in a treatment-associated difference of 51% (95% Cl is 37% to 64%). A total of 112 (88%) of 127 Alteplase-treated patients had restored function after up to two doses.
Trial 2 was an open-label, single arm trial in 995 patients with catheter dysfunction and included patients with occlusions present for any duration. Patients were treated with Alteplase with up to two doses of 2 mg/2 mL (less for children who weighed less than 30 kg, see DOSAGE AND ADMINISTRATION ) instilled into the lumen of the catheter. Assessment for restoration of function was made at 30 minutes after each instillation. If function was not restored, catheter function was re-assessed at 120 minutes. Thirty minutes after instillation of the first dose, 516 (52%) of 995 patients had restored catheter function. One hundred twenty minutes after the instillation of the first dose, 747 (75%) of 995 patients had restored catheter function. If function was not restored after the first dose, a second dose was administered. Two hundred nine patients received a second dose. Thirty minutes after instillation of the second dose, 70 (33%) of 209 patients had restored catheter function. One hundred twenty minutes after the instillation of the second dose, 97 (46%) of 209 patients had restored catheter function. A total of 844 (85%) of 995 patients had function restored after up to 2 doses.
Similar rates of catheter function restoration were seen among all catheter types studied (single-, double-, and triple-lumen, and implanted ports).
There were no gender differences observed in the rate of catheter function restoration. Results were similar across age subgroups, but there was insufficient enrollment of pediatric patients to draw any conclusions regarding relative efficacy in pediatric patients (see PRECAUTIONS , Pediatric Use ).
Across both trials, 796 (68%) of 1043 patients with occlusions present for less than 14 days had restored function after one dose, and 902 (88%) had function restored after up to two doses. Of 53 patients with occlusions present for longer than 14 days, 30 (57%) patients had function restored after a single dose, and a total of 38 patients (72%) had restored function after up to two doses.
Three hundred forty-six patients who had successful treatment outcome were evaluated at 30 days after treatment. The incidence of recurrent catheter dysfunction within this period was 26%.
Indications and Usage
Cathflo Activase (Alteplase) is indicated for the restoration of function to central venous access devices as assessed by the ability to withdraw blood.
Contraindications
Cathflo Activase should not be administered to patients with known hypersensitivity to Alteplase or any component of the formulation (see DESCRIPTION ).
Warnings
None.
Precautions
General
Catheter dysfunction may be caused by a variety of conditions other than thrombus formation, such as catheter malposition, mechanical failure, constriction by a suture, and lipid deposits or drug precipitates within the catheter lumen. These types of conditions should be considered before treatment with Cathflo Activase.
Because of the risk of damage to the vascular wall or collapse of soft-walled catheters, vigorous suction should not be applied during attempts to determine catheter occlusion.
Excessive pressure should be avoided when Cathflo Activase is instilled into the catheter. Such force could cause rupture of the catheter or expulsion of the clot into the circulation.
Bleeding
The most frequent adverse reaction associated with all thrombolytics in all approved indications is bleeding. 3,4 Cathflo Activase has not been studied in patients known to be at risk for bleeding events that may be associated with the use of thrombolytics. Caution should be exercised with patients who have active internal bleeding or who have had any of the following within 48 hours: surgery, obstetrical delivery, percutaneous biopsy of viscera or deep tissues, or puncture of non-compressible vessels. In addition, caution should be exercised with patients who have thrombocytopenia, other hemostatic defects (including those secondary to severe hepatic or renal disease), or any condition for which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location, or who are at high risk for embolic complications (e.g., venous thrombosis in the region of the catheter). Death and permanent disability have been reported in patients who have experienced stroke and other serious bleeding episodes when receiving pharmacologic doses of a thrombolytic.
Should serious bleeding in a critical location (e.g., intracranial, gastrointestinal, retroperitoneal, pericardial) occur, treatment with Cathflo Activase should be stopped and the drug should be withdrawn from the catheter.
Infections
Cathflo Activase should be used with caution in the presence of known or suspected infection in the catheter. Using Cathflo Activase in patients with infected catheters may release a localized infection into the systemic circulation (see ADVERSE REACTIONS ). As with all catheterization procedures, care should be used to maintain aseptic technique.
Re-Administration
In clinical trials, patients received up to two 2 mg/2 mL doses (4 mg total) of Alteplase. Additional re-administration of Cathflo Activase has not been studied. Antibody formation in patients receiving one or more doses of Cathflo Activase for restoration of function to CVADs has not been studied.
Drug Interactions
The interaction of Cathflo Activase with other drugs has not been formally studied. Concomitant use of drugs affecting coagulation and/or platelet function has not been studied.
Drug/Laboratory Test Interactions
Potential interactions between Cathflo Activase and laboratory tests have not been studied.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility. Short-term studies that evaluated tumorigenicity of Alteplase and effect on tumor metastases were negative in rodents. Studies to determine mutagenicity (Ames test) and chromosomal aberration assays in human lymphocytes were negative at all concentrations tested. Cytotoxicity, as reflected by a decrease in mitotic index, was evidenced only after prolonged exposure at high concentrations exceeding those expected to be achieved with Cathflo Activase (Alteplase).
Pregnancy (Category C)
Alteplase has been shown to have an embryocidal effect due to an increased postimplantation loss rate in rabbits when administered intravenously at doses approximately 100 times (3 mg/kg) the human dose for restoration of function to occluded CVADs. No maternal or fetal toxicity was evident at 33 times (1 mg/kg) the human dose for restoration of function to occluded CVADs in pregnant rats and rabbits dosed during the period of organogenesis.
There are no adequate and well-controlled studies in pregnant women. Cathflo Activase should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether Cathflo Activase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cathflo Activase is administered to a nursing woman.
Pediatric Use
Cathflo Activase has not been studied in patients who are younger than 2 years of age or who weigh less than 10 kg. In Trials 1 and 2, 126 (11%) of 1135 patients treated were from 2 to 16 years of age. No study drug-related adverse events were observed in these patients. A total of 65 patients (6% of all patients treated in the studies) weighed >/=10 kg and <30 kg. These low body weight patients received up to two doses of Alteplase, with each dose equal to 110% of the internal lumen volume of the catheter (to a maximum dose of 2 mg). The rates of catheter function restoration in these subsets of patients were similar to those observed in adult patients. However, there was insufficient enrollment of pediatric patients to draw any conclusions regarding relative efficacy in the pediatric or low weight subgroups, relative efficacy related to catheter types used in these patients, or relative rates of adverse events.
Geriatric Use
In 312 patients enrolled who were age 65 years and over, no incidents of intracranial hemorrhage (ICH), embolic events, or major bleeding events were observed. One hundred three of these patients were age 75 years and over, and 12 were age 85 years and over. The effect of Alteplase on common age-related comorbidities has not been studied. In general, caution should be used in geriatric patients with conditions known to increase the risk of bleeding (see PRECAUTIONS , Bleeding ).
Adverse Reactions
In the clinical trials, the most serious adverse events reported after treatment were sepsis (see PRECAUTIONS , Infections ), gastrointestinal bleeding, and venous thrombosis.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to Cathflo Activase in 1122 patients, of whom 880 received a single dose and 242 received two sequential doses of Cathflo Activase.
In the Cathflo Activase clinical trials, only limited, focused types of serious adverse events were recorded, including death, major hemorrhage, intracranial hemorrhage, pulmonary or arterial emboli, and other serious adverse events not thought to be attributed to underlying disease or concurrent illness. Major hemorrhage was defined as severe blood loss (>5 mL/kg), blood loss requiring transfusion, or blood loss causing hypotension. Non-serious adverse events and serious events thought to be due to underlying disease or concurrent illness were not recorded. Patients were observed for serious adverse events until catheter function was deemed to be restored or for a maximum of 4 or 6 hours depending on study. For most patients the observation period was 30 minutes to 2 hours. Spontaneously reported deaths and serious adverse events that were not thought to be related to the patient's underlying disease were also recorded during the 30 days following treatment.
Four catheter-related sepsis events occurred from 15 minutes to 1 day after treatment with Alteplase, and a fifth sepsis event occurred on Day 3 after Alteplase treatment. All 5 patients had positive catheter or peripheral blood cultures within 24 hours after symptom onset.
Three patients had a major hemorrhage from a gastrointestinal source from 2 to 3 days after Alteplase treatment. One case of injection site hemorrhage was observed at 4 hours after treatment in a patient with pre-existing thrombocytopenia. These events may have been related to underlying disease and treatments for malignancy, but a contribution to occurrence of the events from Alteplase cannot be ruled out. There were no reports of intracranial hemorrhage.
Three cases of subclavian and upper extremity deep venous thrombosis were reported 3 to 7 days after treatment. These events may have been related to underlying disease or to the long-term presence of an indwelling catheter, but a contribution to occurrence of the events from Alteplase treatment cannot be ruled out. There were no reports of pulmonary emboli.
There were no gender-related differences observed in the rates of adverse reactions. Adverse reactions profiles were similar across age subgroups, but there was insufficient enrollment of pediatric patients to draw any conclusions regarding relative adverse event rates (see PRECAUTIONS , Pediatric Use ).
Allergic Reactions
No allergic-type reactions were observed in the trials in patients treated with Alteplase. If an anaphylactic reaction occurs, appropriate therapy should be administered.
Dosage and Administration
Cathflo Activase (Alteplase) is for instillation into the dysfunctional catheter at a concentration of 1 mg/mL.
· Patients weighing >/=30 kg: 2 mg in 2 mL
· Patients weighing >/=10 to <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL
If catheter function is not restored at 120 minutes after 1 dose of Cathflo Activase, a second dose may be instilled (see Instructions for Administration). There is no efficacy or safety information on dosing in excess of 2 mg per dose for this indication. Studies have not been performed with administration of total doses greater than 4 mg (two 2 mg doses).
Instructions for Administration
Preparation of Solution
Reconstitute Cathflo Activase to a final concentration of 1 mg/mL:
1.Aseptically withdraw 2.2 mL of Sterile Water for Injection, USP (diluent is not provided). Do not use Bacteriostatic Water for Injection.
2.Inject the 2.2 mL of Sterile Water for Injection, USP, into the Cathflo Activase vial, directing the diluent stream into the powder. Slight foaming is not unusual; let the vial stand undisturbed to allow large bubbles to dissipate.
3.Mix by gently swirling until the contents are completely dissolved. Complete dissolution should occur within 3 minutes. DO NOT SHAKE . The reconstituted preparation results in a colorless to pale yellow transparent solution containing 1 mg/mL Cathflo Activase at a pH of approximately 7.3.
4.Cathflo Activase contains no antibacterial preservatives and should be reconstituted immediately before use. The solution may be used for intracatheter instillation within 8 hours following reconstitution when stored at 2-30°C (36-86°F).
No other medication should be added to solutions containing Cathflo Activase.
Instillation of Solution into the Catheter
1.Inspect the product prior to administration for foreign matter and discoloration.
2.Withdraw 2.0 mL (2.0 mg) of solution from the reconstituted vial.
3.Instill the appropriate dose of Cathflo Activase (see DOSAGE AND ADMINISTRATION ) into the occluded catheter.
4.After 30 minutes of dwell time, assess catheter function by attempting to aspirate blood. If the catheter is functional, go to Step 7. If the catheter is not functional, go to Step 5.
5.After 120 minutes of dwell time, assess catheter function by attempting to aspirate blood and catheter contents. If the catheter is functional, go to Step 7. If the catheter is not functional, go to Step 6.
6.If catheter function is not restored after one dose of Cathflo Activase, a second dose may be instilled. Repeat the procedure beginning with Step 1 under Preparation of Solution.
7.If catheter function has been restored, aspirate 4-5 mL of blood to remove Cathflo Activase and residual clot, and gently irrigate the catheter with 0.9% Sodium Chloride, USP.
Any unused solution should be discarded.
Stability and Storage
Store lyophilized Cathflo Activase at refrigerated temperature (2-8°C/36-46°F). Do not use beyond the expiration date on the vial. Protect the lyophilized material during extended storage from excessive exposure to light.
How Supplied
Cathflo Activase is supplied as a sterile, lyophilized powder in 2 mg vials.
Each Cathflo Activase carton contains one 2 mg vial of Cathflo Activase (Alteplase): NDC 50242-041-64.
Each Novaplus™ Cathflo Activase carton contains one 2 mg vial of Novaplus™ Cathflo Activase (Alteplase): NDC 50242-041-65.