英文药名: Gleevec(Imatinib Mesylate) 中文药名: 格列卫（甲磺酸伊马替尼胶囊） 生产厂家: Novartis 给药说明 甲磺酸伊马替尼（Imatinib Mesylate）由瑞士诺华公司（Novartis）发明研制的新型抗癌药物，是一种选择性酪氨酸激酶抑制剂（A tyrosine kinase inhibitor），属苯胺喹唑啉类化合物。该药物通过抑制酪氨酸激酶来有效治疗胃肠基质肿瘤（Gastrointestinal Stromal Tumor，GIST）和血癌，即慢性骨髓性白血病（Chronic Myelogenous Leukemia，CML)。 药品英文名 Imatinib 药品别名 ST1571、依曼替尼布、格利威克、格列卫、甲磺酸伊马替尼、Imatinib Mesylate、Gleevec、Glivec 药物剂型 甲磺酸伊马替尼胶囊：100mg/粒。30℃以下贮存。 药理作用 本品为苯氨嘧啶的衍生物，属新型酪氨酸激酶抑制剂。约95%的慢性粒细胞白血病(chronic myelocytic leukemia，CML)患者均有ph1染色体阳性，即9号染色体的原癌基因ABL异位到22号染色体的一段称为断裂点成簇区(breakpoint clustering region，BCR)的癌基因上，两种基因重组在一起，产生融合蛋白p-210，与正常的C-ABL蛋白p-150相比，p-210具有较高的酪氨酸激酶活性，可刺激白细胞增殖，导致白血病。本品在体内外均可强烈抑制ABL酪氨酸激酶的活性，特异性地抑制ABL的表达和BCR-ABL细胞的增殖，从而可用于治疗CML。此外，本品尚可抑制血小板衍化生长因子(platelet-derived growth factor，PDGF)和干细胞因子(stemcellfactor，SCF)受体的酪氨酸激酶，并可抑制PDGF和SCF介导的生化反应，但不影响其他刺激因子(如表皮生长因子等)的信号传导。 药动学 本品口服易于吸收，2～4h后血药浓度达峰值，口服生物利用度为98%，蛋白结合率为95%。临床前研究表明，本品不易透过血-脑脊液屏障。药物主要在肝脏被代谢为具有药理活性的代谢物(N-去甲基哌嗪衍生物)，原形药和代谢物的半衰期分别为18h、40h。口服本品后7天内，约81%排出体外(68%经粪便排泄，13%经尿液排出)，其中约25%为药物原形(尿中占5%，粪便中占20%)。 适应证 用于治疗各期慢性髓细胞白血病(CML)。也用于治疗CD117阳性的胃肠道间质细胞瘤(GIST)。 禁忌证 对本品过敏者禁用。 1.肝功能不全者慎用。 2.严重心力衰竭者慎用。 3.动物实验表明本品有致畸性，尚缺乏孕妇的用药资料，孕妇慎用。 4.可大量分泌人动物乳汁中，在人乳汁中的分布情况尚不清楚，哺乳期妇女慎用。 5.骨髓抑制者慎用。 6.病毒或细菌感染患者慎用。 7.胃肠功能紊乱者慎用。 注意事项 1.治疗前应检查肝功能(包括氨基转移酶、血胆红素和碱性磷酸酶)，以后可每月复查1次。 2.治疗的第1个月宜每周检查血常规，第2个月每2周检查1次。 3.建议定期监测体重。 不良反应 1.血液系统：可见中性粒细胞减少(14%)、血小板减少(14%)和贫血(11%)。中性粒细胞减少性发热、全血细胞减少也常见。 2.代谢内分泌系统：常见食欲缺乏，少见食欲增加、脱水、血尿酸及血钾升高或血钾及血钠降低。 3.神经精神系统：常见头痛(11%)、头晕、味觉障碍、失眠，少见出血性卒中、晕厥、周围神经病变、感觉减退、嗜睡、偏头痛及抑郁。 4.眼、耳：常见结膜炎、泪多，少见眼刺激症状、视力模糊、结膜出血、眼干、眶周浮肿及耳和迷路异常。 5.心血管系统：少见心力衰竭、肺水肿、心动过速、高血压、低血压、皮肤潮红、四肢发冷及血肿。6.呼吸系统：常见胸水、鼻衄，少见呼吸困难、咳嗽。 7.消化系统：常见恶心(56%)、呕吐(33%)、腹泻(24%)、消化不良(12%)、腹痛、腹胀、便秘、口干，少见胃肠出血、腹水、胃溃疡、胃炎、胃食管反流、口腔溃疡、氨基转移酶及血胆红素升高等肝功能异常。 8.皮肤：常见全身浮肿(30%)、各类皮炎及皮疹(约25%)、皮肤瘙痒、红皮症、皮肤干燥、脱发、盗汗。少见淤斑、多汗、荨麻疹、指甲断裂、光过敏反应、紫癜。 9.肌肉骨骼系统：可有肌肉痉挛(33%)、关节肿胀及疼痛(25%)，少见坐骨神经痛。 10.泌尿生殖系统：少见血肌酐升高、肾衰竭、男性乳房女性化、乳房肿大、阴囊水肿。 11.其他：常见水潴留(10%)、发热、疲劳乏力、畏寒和体重增加。少见全身不适、出血、体重减轻、败血症、肺炎、疱疹病毒感染等。   用法用量 CML急变期和加速期：口服，推荐开始剂量为每次600mg，1次/d，用药后如病情继续发展(治疗至少3个月后尚没有获得满意的疗效)，且患者没有出现严重不良反应时，可增加至每次400mg，2次/d。出现血液学不良反应，当中性粒细胞计数(ANC)少于0.5×109/L或血小板计数少于10×109/L时，建议减量至每天400mg。如血细胞减少持续2周，则应进一步减量至每天300mg；如血细胞减少持续4周，应停止治疗，直到ANC高于1.0×109/L、血小板计数高于20×109/L后，再恢复用药。干扰素治疗失败的CML慢性期：口服，开始剂量为每次400mg，1次/d，用药后如病情继续发展且患者没有出现严重不良反应时，可增加至每天600mg。当ANC少于1.0×109/L、血小板计数少于50×109/L时应停药；只有当ANC高于1.5×109/L、血小板计数高于75×109/L后，才能恢复用药，剂量为每天400mg，当ANC或血小板计数再次降低时，以后恢复用药，剂量应减至每天300mg。 药物相应作用 1.肝细胞色素P450 3A4抑制剂克拉霉素、红霉素、伊曲康唑、酮康唑、苯妥英钠可使本品血药浓度升高。 2.CYP3A4诱导剂(如苯妥英钠)可降低本品血浆药物浓度，其他诱导剂如地塞米松、卡他咪嗪、利福平、苯巴比妥等可能有类似问题，尚未进行研究，同时服用应谨慎。 3.本品可抑制肝细胞色素P450 3A4，使环孢素、匹莫齐特、辛伐他汀的血药浓度增加。 4.本品增加苯二卓类、双氢吡啶、钙离子拮抗剂和β-羟基-β-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂的血浆浓度，同服时应谨慎。 5.本品可与华法林竞争性抑制肝细胞色素P450 2C9和细胞色素P450 3A4，导致出血危险增加。 Higher initial dose of Gleevec achieved better early responses than standard dose for patients with chronic myeloid leukemia •Efficacy and safety profile in large randomized Phase III study consistent with landmark IRIS trial, which established Gleevec as standard of care •Study did not meet primary endpoint at 1 year, yet shows faster time to molecular responses with 800 vs. 400 mg dose •Findings reinforce that monitoring blood levels of Gleevec may help optimize treatment benefit for individual patients •Novartis committed to improving first-line treatment through additional study follow-up and completing enrollment to Tasigna vs. Gleevec trial East Hanover, NJ · June 13, 2008 /PRNewswire/ – New data from a large, international clinical trial find that patients with newly diagnosed chronic myeloid leukemia who received Gleevec® (imatinib meslyate) tablets at 800 mg/day as their initial treatment achieved clinical milestones significantly faster than those receiving the standard 400 mg/day dose. The Tyrosine Kinase Inhibitor Optimization and Selectivity Study (TOPS) is the first Phase III, randomized, controlled clinical trial designed to evaluate the potential benefits of an 800 mg starting dose across all risk categories of newly diagnosed, previously untreated patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). Numerically, more patients achieved a major molecular response (MMR) with the 800 mg dose than the 400 mg dose (46.4% vs. 40.1%); however, the difference between the two arms -- the primary endpoint of the study -- was not statistically significant. This trend of improved MMR rate at 12 months in the 800 mg vs. 400 mg arms was most pronounced in the subset of patients with the highest risk for disease progression (41.1% vs. 26.2%). Further, patients in the 800 mg arm achieved MMR significantly faster than those who started treatment with Gleevec at 400 mg1. Achievement of a MMR is an important goal of therapy for CML. "TOPS reaffirms Gleevec as the standard of care for newly diagnosed CML patients," said Jorge Cortes, MD, Professor of Medicine and Deputy Chair of Leukemia at the University of Texas MD Anderson Cancer Center in Houston. "We see a strong trend for rapid response with the 800 mg dose. As with trials like IRIS, further follow up will be needed to assess what this rapid early response will mean in terms of long-term benefit." TOPS also showed that patients with lower blood levels of Gleevec at one month had a lower molecular response at a year, an observation made in previous studies2. Cumulatively, these data suggest that maintaining adequate blood levels may help attain better clinical responses2. These findings, from the first analysis of the TOPS data set, will be presented on Saturday, June 14, at the 2008 Congress of the European Hematology Association (EHA) in Copenhagen. "Our robust clinical program with Gleevec continues to provide meaningful insights into the treatment of Ph+ CML and other types of cancer," said Diane Young, MD, Head of Global Medical Affairs at Novartis Oncology. "Novartis continues to invest in trials like ENESTnd, which is comparing Tasigna to Gleevec in the first-line setting, to build on this knowledge and further enhance treatment outcomes for patients." ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of newly diagnosed Ph+ CML patients) is designed to study the efficacy and safety of Tasigna® (nilotinib) capsules vs. Gleevec in newly diagnosed patients in the chronic phase. ENESTnd is currently underway and will enroll approximately 771 patients at 220 centers worldwide. Tasigna is currently approved for the treatment of Ph+ CML in the chronic or accelerated phase in patients resistant to, or intolerant of, Gleevec. Chronic myeloid leukemia (CML) is a cancer of the blood and bone marrow in which the body produces cancerous white blood cells. Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which produces a protein called Bcr-Abl that causes malignant white blood cells to proliferate. Gleevec, the first therapy to inhibit the activity of Bcr-Abl, revolutionized the treatment of Ph+ CML and is now the standard of care for this disease. Study details TOPS is a Phase III, international, open label, randomized, multi-center clinical trial that included 103 study sites from 19 countries. The 476 patients with newly diagnosed, previously untreated Ph+ CML in chronic phase were randomized to receive Gleevec at either 800 mg/day or the standard 400 mg/day dose in a 2:1 ratio. Patients were stratified by Sokal score for evaluation. Sokal score is a clinical measure that is used to identify those at highest risk for disease progression1. A secondary endpoint of the study was the rate of complete cytogenetic response (the elimination of Ph+ cells) at 12 months. Patients in the 800 mg arm achieved complete cytogenetic response (CCyR) faster than patients in the 400 mg arm. The response rates for the 800 mg and 400 mg arms were 56.7% vs. 44.6% by six months (p=0.0146) and 69.9% vs. 65.6% by 12 months (p=0.3470), respectively. More than 95% of patients on either dose achieved some cytogenetic response by six months. The safety profile in the TOPS trial was similar to that previously reported for both doses of Gleevec. At twelve months, discontinuation rates due to adverse events were 5.6% and 1.3% in the 800 mg arm and 400 mg arm, respectively. The 800 mg/day dose was associated with a higher frequency of adverse events, including grade 3/4 hematologic laboratory abnormalities. There was no difference between the two doses in the rate of grade 3/4 biochemical laboratory abnormalities. About IRIS The IRIS study (International Randomized Interferon versus STI571) is the largest ongoing clinical trial in newly diagnosed CML patients. IRIS is an open-label, Phase III clinical trial involving 1,106 newly diagnosed patients with Ph+ CML in chronic phase in 177 centers across 16 countries. The results showed that after six years of Gleevec therapy, 93% of patients remained free of progression to advanced disease and an estimated 88% were still alive. When deaths from causes unrelated to CML or following transplantation were excluded, the estimated overall six-year survival rate reported in IRIS was 95%1. Further, among those who remained on Gleevec after five years, no patients progressed to advanced disease between years five and six. At the six-year follow-up, the type and frequency of adverse events reported in IRIS were similar to previously reported profiles. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent. About Gleevec Gleevec® (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase. Follow-up is limited to 5 years. Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in the chronic phase (CP) after failure of interferon-alpha therapy. Important safety information3 Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking Gleevec tablets and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking Gleevec should use adequate contraception. If the patient does become pregnant while taking Gleevec, the patient should be advised of the potential hazard to the fetus. Severe (NCI Grades 3/4) lab abnormalities-including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (approx 5%)-and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) and superficial edema (1.3%-11%), hemorrhage (1.8%-19%), and musculoskeletal pain (2%-9%) were reported among patients receiving Gleevec*. Severe fluid retention appears to be dose-related, was more common in the advanced phase studies (where the dosage was 600 mg/day), and is more common in the elderly. Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated. Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse reactions, or hematologic adverse reactions. Therapy with Gleevec was discontinued for drug-related adverse reactions in 2.4% to 5% of patients. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, papilledema, and gastrointestinal (GI) perforation. Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction. Consider potential toxicities-specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use. Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving Gleevec with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions). For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron. Common side effects of Gleevec tablets The majority of adult Ph+ CML patients who received Gleevec in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), muscle cramps (28%-62%), vomiting (23%-58%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), and rash and related terms (36%-47%).* † Supportive care may help management of some mild-to-moderate adverse reactions so that the prescribed dose can be maintained whenever possible. However, in some cases, either a dose reduction or interruption of treatment with Gleevec may be necessary. Gleevec tablets should be taken with food and a large glass of water to minimize GI irritation. Gleevec tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4. Patients should be informed to take Gleevec exactly as prescribed, not to change their dose or stop taking Gleevec unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. * Numbers indicate the range of percentages in 4 studies among adult patients with Ph+ CML in blast crisis, accelerated phase, and chronic phase. For more detailed study information please see full Prescribing Information. About Tasigna Tasigna (nilotinib) capsules is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. Please see Important Safety Information, including BOXED WARNING, below. Tasigna important safety information Myelosuppresion Treatment with Tasigna is associated with Grade 3/4 neutropenia, thrombocytopenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months, then monthly thereafter as clinically indicated. Myelosuppression with Tasigna was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. QT prolongation Tasigna prolongs the QT interval. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Use caution in patients with hepatic impairment. Obtain ECGs at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. Sudden deaths There were sudden deaths reported in the safety population and the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence. Elevated serum lipase Caution is recommended in patients with history of pancreatitis. Check serum lipase periodically. Liver function abnormality Serum bilirubin and hepatic transaminases The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Check hepatic function tests periodically. Electrolyte abnormalities Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy. Hepatic impairment Metabolism of Tasigna is mainly hepatic. Tasigna has not been investigated in patients with hepatic impairment. Caution is recommended in these patients and QT interval should be monitored closely. Drug interactions The concomitant use of QT prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of Tasigna. Concomitant strong CYP3A4 inhibitors The concomitant use of strong CYP3A4 inhibitors should be avoided (including, but not limited to, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval, and a dose reduction to ½ the daily dose is recommended (400 mg once daily). If the strong inhibitor is discontinued, a washout period should be allowed before Tasigna is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided. Concomitant strong CYP3A4 inducers The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St John's Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the Tasigna dose should be reduced to the indicated dose. Tasigna is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. Since warfarin is metabolized by CYP2C9 and CYP3A4, it should be avoided if possible. Tasigna inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised. Tasigna may also induce CYP2B6, CYP2C8, and CYP2C9. Therefore, Tasigna may alter serum concentration of other drugs. Food effects Food increases blood levels of Tasigna. Patients should avoid food 2 hours before and 1 hour after taking dose. Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or of glucose-galactose malabsorption. Pregnancy Fetal harm can occur when Tasigna is administered to a pregnant woman. Women should be advised not to become pregnant when taking Tasigna. Adverse reacions In chronic phase patients, the most commonly reported adverse reactions (>10%) were rash (33%), pruritus (29%), nausea (31%), fatigue (28%), headache (31%), constipation (21%), diarrhea (22%), and vomiting (21%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (28%), neutropenia (28%), elevated lipase (15%), and hyperglycemia (11%). In accelerated phase patients, the most commonly reported adverse reactions (>10%) were rash (28%), pruritus (20%), and constipation (18%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (37%), neutropenia (37%), anemia (23%), and elevated lipase (17%). Other serious adverse reactions included pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, and pyrexia (Grade 3/4: 2%). Dose adjustments or modifications Tasigna may need to be temporarily withheld and/or dose reduced for QT prolongation, hematological toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors. With concomitant use of strong CYP3A4 inducers, the dose of Tasigna may need to be increased, depending on patient tolerability. Other patients in whom Tasigna should be used with caution Tasigna should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast feed while taking Tasigna. There are no data to support the use of Tasigna in pediatric patients. Use with caution in patients with hepatic impairment. ------------------------------------------------------------ 产地国家: 瑞士 原产地英文商品名: GLIVEC 100mg/cap 120caps/box 原产地英文药品名: IMATINIB MESYLATE 中文参考商品译名: 格列卫 100毫克/胶囊 120胶囊/盒 中文参考药品译名: 甲磺酸伊马替尼 生产厂家中文参考译名: 诺华制药 生产厂家英文名: Novartis