英文药名: Tasigna (Nilotinib capsule)

中文药名: 尼洛替尼胶囊

原研厂家: 诺华公司
药品介绍
作用机制
尼罗替尼是一种Bcr-Abl激酶的抑制剂。尼罗替尼结合至和稳定化Abl蛋白的激酶结构区的无活性构象。在体外，尼罗替尼抑制Bcr-Abl介导的鼠类白血病细胞株和衍化从Ph+ CML患者人细胞株的增殖。在分析的条件下，在32/33株受试的突变中，尼罗替尼能克服Bcr-Abl激酶突变造成的伊马替尼耐药。在体内中，尼罗替尼减小鼠类Bcr-Abl异种移植模型中肿瘤大小。尼罗替尼抑制以下激酶的自身磷酸化如IC50值所示：Bcr-Abl(20-60 nM)，PDGFR(69 nM)，c-Kit(210nM)，CSR-1R(125-250 nM)和DDR(3.7nM)。
适应证和用途
（1）有费城染色体阳性慢性粒性白血病(Ph+ CML)慢性期新诊断的成年患者的治疗。正在进行研究为确定长期结果所需和进一步资料。
（2）在成年患者对既往治疗包括伊马替尼[imatinib]耐药或不能耐受慢性期(CP)和加速期(AP)Ph+ CML的治疗。尚未证实临床效应，例如疾病相关症状的改善和增加生存。
剂量和给药方法
（1）推荐剂量：新诊断的Ph+ CML-CP：300mg口服每天2次。耐药或不能耐受Ph+ CML-CP和CML-AP：400mg口服每天2次。
（2）给Tasigna约12小时间隔和必须不与食物服用。
（3）与水吞服整个胶囊。给药前至少2小时和至少1小时后不要进食。
（4）可能需要为血液学和非血液学毒性，和药物相互作用调整剂量。
（5）在患者有肝受损(在基线时)建议较低开始剂量。
剂型和规格
150mg和200mg硬胶囊
禁忌
有低钾血症，低镁血症，或长QT综合征患者中不要使用。
警告和注意事项
（1）骨髓抑制：伴随中性粒细胞减少，血小板减少和贫血。对头2个月应每2周检查CBC，然后每月。用预扣剂量[withholding dose]可逆。可能需要减低剂量。
（2）QT延长：Tasigna延长T间期。给药前纠正低钾血症或低镁血症和定期监测。避免已知延长QT间期和强CYP3A4抑制剂药物。有肝受损患者谨慎使用。在基线时，开始后7天，和其后定期，以及任何调整剂量后获得ECGs。
（3）猝死：在Ph+ CML接受尼罗替尼有耐药或不能耐受患者中曾报道猝死。室性复极化异常对其发生可能有贡献。
（4）血清脂肪酶升高：定期核查血清脂肪酶。脂肪酶升高情况是伴随腹部症状，中断给药和考虑适当诊断除外胰腺炎。在有胰腺炎史患者中建议谨慎。
（5）肝功能异常：Tasigna可能导致胆红素，AST/ALT，和碱性磷酸酶升高。定期核对肝功能试验。
（6）电解质异常：Tasigna可引起低磷血症，低钾血症，高钾血症，低钙血症，和低钠血症。开始Tasigna前纠正电解质异常和治疗期间定期监测。
（7）肝受损：有受损肝功能患者中尼罗替尼暴露增加。在这些患者中建议减低剂量和应严密监查QT间期。
（8）药物相互作用：避免同时使用CYP3A4的强抑制剂或诱导剂。如患者必须与强CYP3A4抑制剂共同给药，应考虑减低剂量而应密切监视QT间期。
（9）食物效应：食物增加Tasigna的血水平。
（10）避免给药前2小时和1小时后进食。
（11）胃全切除术：应考虑更频随访这些患者，如必要时，考虑增加剂量。
（12）妊娠：可能危害胎儿当给予妊娠妇女。当用Tasigna时应建议不要成为妊娠。
不良反应
在新诊断的Ph+CML-CP，耐药或不能耐受Ph+CML-CP，或耐药或不能耐受Ph+CML-AP患者中最常报道非血液学不良药物反应(≥10%)是皮疹，瘙痒，头痛，恶心，疲乏，肌肉痛，鼻咽炎，便秘，腹泻，腹痛，呕吐，关节痛，发热，上泌尿道感染，背痛，咳嗽，和虚弱。血液学不良药物反应包括骨髓抑制：血小板减少，中性粒细胞减少和贫血。
药物相互作用
Tasigna是一种CYP3A4，CYP2C8，CYP2C9，和CYP2D6的抑制剂。它可能也诱导CYP2B6，CYP2C8和CYP2C9。所以，Tasigna可能改变其它药物的血清浓度。
CYP3A4抑制剂可能改影响血清浓度。
CYP3A4诱导剂可能改影响血清浓度。
在特殊人群中使用
（1）性行为活跃的女性患者治疗期间应使用有效避孕。
（2）不应避孕喂养。
（3）在儿童中无资料支持使用。
（4）有肝受损患者中建议较低起始剂量。
Tasigna® demonstrates rapid response as initial therapy in life-threatening form of leukemia
•Tasigna now shows potential to become the treatment of choice for certain newly diagnosed patients with chronic myeloid leukemia
•Two separate studies show rapid elimination of cancer cells in 96% of Tasigna patients and reduction of abnormal CML protein by six months
•Larger front-line Phase III trial eva luating Tasigna vs. Gleevec® now fully accrued
East Hanover, December 8, 2008/PRNewswire/—New results from two separate trials demonstrate that Tasigna® (nilotinib) 200 mg capsules helps achieve rapid responses when used as initial therapy in newly diagnosed patients with a life threatening form of leukemia.
The study results were presented today at the 50th Annual Meeting of the American Society of Hematology.
In both Phase II studies, 96% of patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in early chronic phase achieved a complete cytogenetic response (CCyR) after six months of Tasigna treatment1,2. CCyR is defined as undetectable Philadelphia chromosome cells in a patient's bone marrow.
Although CCyR remains the primary goal of therapy, achieving major molecular response (MMR) may be a more sensitive predictor of long-term progression-free survival. In the two studies, 74%2 and 45%1 of patients treated with Tasigna exhibited MMR after six months. Tasigna was well tolerated in both studies.
"Newly diagnosed patients taking Tasigna experienced remarkable responses with minimal toxicity," said Jorge Cortes, MD, Professor of Medicine and Deputy Chair of Leukemia at the University of Texas MD Anderson Cancer Center in Houston. "These results indicate there is potential for patients to reach important clinical milestones faster."
Gleevec® (imatinib mesylate) tablets* is the standard treatment for Ph+ CML and rapidly transformed the treatment of CML when it was introduced in 2001. An ongoing Phase III trial called ENESTnd (eva luating Nilotinib Efficacy in Clinical Trials of Newly Diagnosed Ph+ CML Patients) is eva luating Tasigna vs. Gleevec in newly diagnosed patients and is now fully accrued. Data from ENESTnd will be reported once available.
"Building on the wealth of scientific and clinical knowledge we have gained with Gleevec, Novartis strives to continually uncover novel approaches to help Ph+ CML patients achieve the best long-term outcomes," said David Epstein, President and CEO, Novartis Oncology.
Tasigna is a tyrosine kinase inhibitor approved for the treatment of adult Ph+ CML patients in the chronic or accelerated phases who are resistant or intolerant to prior treatment including Gleevec. Tasigna was specifically designed to inhibit Bcr-Abl, the key cause and driver of Ph+ CML and its mutations. The Philadelphia chromosome is found in nearly all patients with CML.
Study results
The first study, conducted by the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA), is an ongoing, open-label, single-stage, multicenter Phase II clinical trial, designed to eva luate the therapeutic efficacy and safety of Tasigna 800 mg/day as a first-line treatment. Seventy-three patients with newly diagnosed Ph+ CML in early chronic phase are enrolled in the trial. After six months of treatment, 96% of patients had achieved CCyR2.
In addition, 74% of patients achieved MMR, defined as Bcr-Abl/Abl ratio < 0.1%. The percentage of patients achieving this level of response rapidly increased after one month of treatment. Adverse reactions were manageable with dose adaptations. The incidence of any Grade 2 and 3 non-hematologic adverse events decreased considerably between months one to three and months four to six2.
The second study, conducted by researchers at MD Anderson Cancer Center, is an ongoing Phase II clinical trial investigating the efficacy and safety of Tasigna as initial therapy for patients with CML-CP (chronic phase). The current analysis, which includes data from 48 patients, shows that nearly all eva luable patients (96%) achieved CCyR. By six and 12 months, 45% and 52% of patients achieved MMR, respectively. Adverse reactions were manageable with temporary treatment interruptions or dose reductions1. Notably, there was no marked incidence of severe fluid retention or effusions, side effects commonly observed with other drugs of this class.
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. Tasigna has been approved in more than 50 countries. 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
WARNING: QT PROLONGATION AND SUDDEN DEATHS
TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. Use caution in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.
Myelosuppression
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, hyponatremia and hypocalcemia. 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 reactions
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.
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 patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in the chronic phase (CP) after failure of interferon-alpha therapy.
Gleevec 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 (e.g., 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 co-morbidities 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 eva luated 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 with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Gleevec should be used with caution in patients with severe renal 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, acute respiratory failure, and GI perforation.
Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon re-challenge. Several post marketing 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 newly diagnosed Ph+ CML, patients in blast crisis, accelerated phase, and in the chronic phase after failure of interferon-alpha therapy.
†For more detailed study information please see full Prescribing Information.  
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