英文药名：INLYTA（Axitinib filmcoated tabs） 中文药名：阿西替尼片 生产厂家：辉瑞 Pfizer Inc. 药品介绍 2012年5月25日，欧盟顾问委员会建议批准辉瑞（Pfizer）公司肾癌药物Inlyta，用于经SUTENT或细胞因子治疗无效的晚期肾细胞癌患者。SUTENT也是辉瑞公司的肾癌药物，目前在欧美已不再广泛使用。该委员会建议仅批准Inlyta用于成人。 肾细胞癌是肾癌中最常见的形式。Inlyta，或称阿西替尼（axitinib），是日服2次的抗癌药丸，FDA在1月份批准该药作为肾细胞癌的辅助治疗药物。 INLYTA® (axitinib)片为口服给药 作用机制 Axitinib曾显示在治疗血浆浓度时抑制酪氨酸激酶受体包括血管内皮生长因子受体(VEGFR)-1，VEGFR-2，和VEGFR-3。这些受体与病理性血管生成，肿瘤生长，和癌进展中有牵连。在体外和小鼠模型中axitinib抑制VEGF-介导内皮细胞增殖和生存。肿瘤异种移植小鼠模型中Axitinib显示抑制肿瘤生长和VEGFR-2的磷酸化。 适应证和用途 INLYTA 是一种激酶抑制剂适用于一种既往全身治疗失败后晚期肾细胞癌的治疗。 剂量和给药方法 （1）开始剂量为5 mg口服每天2次。可根据个体安全性和耐受性调整剂量。 （2）约间隔12小时给予INLYTA剂量有或无食物。 （3）INLYTA应与一杯水整片吞服。 （4）如需要强CYP3A4/5抑制剂，减低INLYTA 剂量约半量. （5）对中度肝受损患者，减低开始剂量约半量。 剂型和规格 1 mg和5mg片。 禁忌证 无。 警告和注意事项 （1）曾观察到高血压包括高血压危象。开始INLYTA前应充分控制血压。需要监视和治疗高血压。尽管使用抗高血压药物，对持续高血压减低INLYTA剂量。 （2）曾观察到动脉和静脉血栓事件和可能致死。对这些事件风险增加患者慎用。 （3）曾报道出血事件, 包括致命性事件。尚未在未治疗脑转移或最近活动性胃肠道出血证据患者中研究过INLYTA和在这些患者中不应使用。 （4）曾发生胃肠道穿孔和瘘管，包括死亡。对胃肠道穿孔或瘘管风险患者慎用。 （5）曾报道甲状腺低下症需要甲状腺激素替代。用NLYTA治疗开始前监视甲状腺功能，和自始至终定期。 （6）计划手术前至少24小时停止INLYTA。 （7）曾观察到可逆性后部白质脑病综合征(RPLS)。如发生RPLS体征或症状永久终止INLYTA。 （8）用INLYTA治疗开始前，和自始至终定期监视蛋白尿。对中度至严重蛋白尿，减低剂量或暂时中断用INLYTA治疗。 （9）用INLYTA治疗时曾观察到肝酶升高。用INLYTA治疗开始前和自始至终定期监视ALT，AST和胆红素。 （10）中度肝受损患者如使用INLYTA开始剂量应减低。严重肝受损患者中未曾研究过INLYTA。 （11）当给予妊娠妇女根据其作用机制INLYTA可能致胎儿危害。应忠告生育能力妇女对胎儿潜在危害和当接受INLYTA避免成为妊娠。 不良反应 最常见(≥20%)不良反应是腹泻，高血压，疲乏，食欲减低，恶心，发音障碍，手掌-足底erythrodysesthesia (手-足)综合征，体重减轻，呕吐，乏力，和便秘。 药物相互作用 （1）避免强CYP3A4/5抑制剂。如不可避免，减低INLYTA 剂量。 （2）避免强CYP3A4/5诱导剂。 英文说明书http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202324lbl.pdf Inlyta 1 mg 3mg, 5 mg & 7mg film-coated tablets 1. Name of the medicinal product Inlyta 1 mg film-coated tablets Inlyta 3 mg film-coated tablets Inlyta 5 mg film-coated tablets Inlyta 7 mg film-coated tablets 2. Qualitative and quantitative composition 1 mg film-coated tablets Each film-coated tablet contains 1 mg of axitinib. 3 mg film-coated tablets Each film-coated tablet contains 3 mg of axitinib. 5 mg film-coated tablets Each film-coated tablet contains 5 mg of axitinib. 7 mg film-coated tablets Each film-coated tablet contains 7 mg of axitinib. Excipients with known effect: 1 mg film-coated tablets Each film-coated tablet contains 33.6 mg of lactose monohydrate. 3 mg film-coated tablets Each film-coated tablet contains 35.3 mg of lactose monohydrate. 5 mg film-coated tablets Each film-coated tablet contains 58.8 mg of lactose monohydrate 7mg film-coated tablets Each film-coated tablet contains 82.3 mg of lactose monohydrate. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet (tablet) 1 mg: Red oval film-coated tablet debossed with “Pfizer” on one side and “1 XNB” on the other 3 mg: Red round film-coated tablet debossed with “Pfizer” on one side and “3 XNB” on the other 5 mg: Red triangular film-coated tablet debossed with “Pfizer” on one side and “5 XNB” on the other 7 mg: Red diamond shaped film-coated tablet debossed with “Pfizer” on one side and “7 XNB” on the other 4. Clinical particulars 4.1 Therapeutic indications Inlyta is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. 4.2 Posology and method of administration Treatment with Inlyta should be conducted by a physician experienced in the use of anticancer therapies. Posology The recommended dose of axitinib is 5 mg twice daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs that cannot be managed by concomitant medicinal products or dose adjustments. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose adjustments Dose increase or reduction is recommended based on individual safety and tolerability. Patients who tolerate the axitinib starting dose of 5 mg twice daily with no adverse reactions > Grade 2 (i.e. without severe adverse reactions according to the Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) for two consecutive weeks may have their dose increased to 7 mg twice daily unless the patient's blood pressure is > 150/90 mmHg or the patient is receiving antihypertensive treatment. Subsequently, using the same criteria, patients who tolerate an axitinib dose of 7 mg twice daily may have their dose increased to a maximum of 10 mg twice daily. Management of some adverse reactions may require temporary or permanent discontinuation and/or dose reduction of axitinib therapy (see section 4.4). When dose reduction is necessary, the axitinib dose may be reduced to 3 mg twice daily and further to 2 mg twice daily. Dose adjustment is not required on the basis of patient age, race, gender, or body weight. Concomitant strong CYP3A4/5 inhibitors Co-administration of axitinib with strong CYP3A4/5 inhibitors may increase axitinib plasma concentrations (see section 4.5). Selection of an alternate concomitant medicinal product with no or minimal CYP3A4/5 inhibition potential is recommended. Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of axitinib to approximately half the dose (e.g. the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily) is recommended. Management of some adverse reactions may require temporary or permanent discontinuation of axitinib therapy (see section 4.4). If co-administration of the strong inhibitor is discontinued, a return to the axitinib dose used prior to initiation of the strong CYP3A4/5 inhibitor should be considered (see section 4.5). Concomitant strong CYP3A4/5 inducers Co-administration of axitinib with strong CYP3A4/5 inducers may decrease axitinib plasma concentrations (see section 4.5). Selection of an alternate concomitant medicinal product with no or minimal CYP3A4/5 induction potential is recommended. Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inducers, if a strong CYP3A4/5 inducer must be co-administered, a gradual dose increase of axitinib is recommended. Maximal induction with high-dose strong CYP3A4/5 inducers has been reported to occur within one week of treatment with the inducer. If the dose of axitinib is increased, the patient should be monitored carefully for toxicity. Management of some adverse reactions may require temporary or permanent discontinuation and/or dose reduction of axitinib therapy (see section 4.4). If co-administration of the strong inducer is discontinued, the axitinib dose should be immediately returned to the dose used prior to initiation of the strong CYP3A4/5 inducer (see section 4.5). Special populations Older people (≥ 65 years): No dose adjustment is required (see sections 4.4 and 5.2). Renal impairment: No dose adjustment is required (see section 5.2). Virtually no data are available regarding axitinib treatment in patients with a creatinine clearance of < 15 mL/min. Hepatic impairment: No dose adjustment is required when administering axitinib to patients with mild hepatic impairment (Child-Pugh class A). A dose decrease is recommended when administering axitinib to patients with moderate hepatic impairment (Child-Pugh class B) (e.g. the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily). Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population (see sections 4.4 and 5.2). Paediatric population The safety and efficacy of axitinib in children and adolescents < 18 years have not been established. No data are available. Method of administration Axitinib should be taken orally twice daily approximately 12 hours apart with or without food (see section 5.2). Axitinib tablets should be swallowed whole with a glass of water. 4.3 Contraindications Hypersensitivity to axitinib or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Specific safety events should be monitored before initiation of, and periodically throughout, treatment with axitinib as described below. Cardiac failure events In a controlled clinical study with axitinib for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported (see section 4.8). Signs or symptoms of cardiac failure should periodically be monitored throughout treatment with axitinib. Management of cardiac failure events may require temporary interruption or permanent discontinuation and/or dose reduction of axitinib therapy. Hypertension In a controlled clinical study with axitinib for the treatment of patients with RCC, hypertension was very commonly reported (see section 4.8). The median onset time for hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg) was within the first month of the start of axitinib treatment and blood pressure increases have been observed as early as 4 days after starting axitinib. Blood pressure should be well-controlled prior to initiating axitinib. Patients should be monitored for hypertension and treated as needed with standard antihypertensive therapy. In the case of persistent hypertension, despite use of antihypertensive medicinal products, the axitinib dose should be reduced. For patients who develop severe hypertension, temporarily interrupt axitinib and restart at a lower dose once the patient is normotensive. If axitinib is interrupted, patients receiving antihypertensive medicinal products should be monitored for hypotension (see section 4.2). In case of severe or persistent arterial hypertension and symptoms suggestive of posterior reversible encephalopathy syndrome (PRES) (see below), a diagnostic brain magnetic resonance image (MRI) should be considered. Thyroid dysfunction In a controlled clinical study with axitinib for the treatment of patients with RCC, events of hypothyroidism and, to a lesser extent, hyperthyroidism, were reported (see section 4.8). Thyroid function should be monitored before initiation of, and periodically throughout, treatment with axitinib. Hypothyroidism or hyperthyroidism should be treated according to standard medical practice to maintain euthyroid state. Arterial embolic and thrombotic events In clinical studies with axitinib, arterial embolic and thrombotic events (including transient ischemic attack, myocardial infarction, cerebrovascular accident and retinal artery occlusion) were reported (see section 4.8). Axitinib should be used with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had an arterial embolic or thrombotic event within the previous 12 months. Venous embolic and thrombotic events In clinical studies with axitinib, venous embolic and thrombotic events (including pulmonary embolism, deep vein thrombosis, and retinal vein occlusion/thrombosis) were reported (see section 4.8). Axitinib should be used with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had a venous embolic or thrombotic event within the previous 6 months. Elevation of haemoglobin or haematocrit Increases in haemoglobin or haematocrit, reflective of increases in red blood cell mass, may occur during treatment with axitinib (see section 4.8, polycythaemia). An increase in red blood cell mass may increase the risk of embolic and thrombotic events. Haemoglobin or haematocrit should be monitored before initiation of, and periodically throughout, treatment with axitinib. If haemoglobin or haematocrit becomes elevated above the normal level, patients should be treated according to standard medical practice to decrease haemoglobin or haematocrit to an acceptable level. Haemorrhage In clinical studies with axitinib, haemorrhagic events were reported (see section 4.8). Axitinib has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding, and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the axitinib dose. Gastrointestinal perforation and fistula formation In clinical studies with axitinib, events of gastrointestinal perforation and fistulas were reported (see section 4.8). Symptoms of gastrointestinal perforation or fistula should be periodically monitored for throughout treatment with axitinib. Wound healing complications No formal studies of the effect of axitinib on wound healing have been conducted. Treatment with axitinib should be stopped at least 24 hours prior to scheduled surgery. The decision to resume axitinib therapy after surgery should be based on clinical judgment of adequate wound healing. Posterior reversible encephalopathy syndrome (PRES) In clinical studies with axitinib, events of PRES were reported (see section 4.8). PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. In patients with signs or symptoms of PRES, temporarily interrupt or permanently discontinue axitinib treatment. The safety of reinitiating axitinib therapy in patients previously experiencing PRES is not known. Proteinuria In clinical studies with axitinib, proteinuria, including that of Grade 3 severity, was reported (see section 4.8). Monitoring for proteinuria before initiation of, and periodically throughout, treatment with axitinib is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt axitinib treatment (see section 4.2). Liver-related adverse reactions In a controlled clinical study with axitinib for the treatment of patients with RCC, liver-related adverse reactions were reported. The most commonly reported liver-related adverse reactions included increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood bilirubin (see section 4.8). No concurrent elevations of ALT (> 3 times the upper limit of normal [ULN]) and bilirubin (> 2 times the ULN) were observed. In a clinical dose-finding study, concurrent elevations of ALT (12 times the ULN) and bilirubin (2.3 times the ULN), considered to be drug-related hepatotoxicity, were observed in 1 patient who received axitinib at a starting dose of 20 mg twice daily (4 times the recommended starting dose). Liver function tests should be monitored before initiation of, and periodically throughout, treatment with axitinib. Hepatic impairment In clinical studies with axitinib, the systemic exposure to axitinib was approximately two-fold higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering axitinib to patients with moderate hepatic impairment (Child-Pugh class B) (see section 4.2). Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population. Older people (≥ 65 years) and race In a controlled clinical study with axitinib for the treatment of patients with RCC, 34% of patients treated with axitinib were ≥ 65 years of age. The majority of patients were White (77%) or Asian (21%). Although greater sensitivity to develop adverse reactions in some older patients and Asian patients cannot be ruled out, overall, no major differences were observed in the safety and effectiveness of axitinib between patients who were ≥ 65 years of age and non-elderly, and between White patients and patients of other races. No dosage adjustment is required on the basis of patient age or race (see sections 4.2 and 5.2). Lactose This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction In vitro data indicate that axitinib is metabolised primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 inhibitors Ketoconazole, a strong inhibitor of CYP3A4/5, administered at a dose of 400 mg once daily for 7 days, increased the mean area under the curve (AUC) 2-fold and Cmax 1.5-fold of a single 5-mg oral dose of axitinib in healthy volunteers. Co-administration of axitinib with strong CYP3A4/5 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, erythromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) may increase axitinib plasma concentrations. Grapefruit may also increase axitinib plasma concentrations. Selection of concomitant medicinal products with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-administered, a dose adjustment of axitinib is recommended (see section 4.2). CYP1A2 and CYP2C19 inhibitors CYP1A2 and CYP2C19 constitute minor (< 10%) pathways in axitinib metabolism. The effect of strong inhibitors of these isozymes on axitinib pharmacokinetics has not been studied. Caution should be exercised due to the risk of increased axitinib plasma concentrations in patients taking strong inhibitors of these isozymes. CYP3A4/5 inducers Rifampicin, a strong inducer of CYP3A4/5, administered at a dose of 600 mg once daily for 9 days, reduced the mean AUC by 79% and Cmax by 71% of a single 5 mg dose of axitnib in healthy volunteers. Co-administration of axitinib with strong CYP3A4/5 inducers (e.g. rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and Hypericum perforatum [St. John's wort]) may decrease axitinib plasma concentrations. Selection of concomitant medicinal products with no or minimal CYP3A4/5 induction potential is recommended. If a strong CYP3A4/5 inducer must be co-administered, a dose adjustment of axitinib is recommended (see section 4.2). In vitro studies of CYP and UGT inhibition and induction In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations. In vitro studies indicated that axitinib has a potential to inhibit CYP1A2. Therefore, co-administration of axitinib with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2 substrates (e.g. theophylline). In vitro studies also indicated that axitinib has the potential to inhibit CYP2C8. However, co-administration of axitinib with paclitaxel, a known CYP2C8 substrate, did not result in increased plasma concentrations of paclitaxel in patients with advanced cancer, indicating lack of clinical CYP2C8 inhibition. In vitro studies in human hepatocytes also indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5. Therefore co-administration of axitinib is not expected to reduce the plasma concentration of co-administered CYP1A1, CYP1A2, or CYP3A4/5 substrates in vivo. In vitro studies with P-glycoprotein In vitro studies indicated that axitinib inhibits P-glycoprotein. However, axitinib is not expected to inhibit P-glycoprotein at therapeutic plasma concentrations. Therefore, co-administration of axitinib is not expected to increase the plasma concentration of digoxin, or other P-glycoprotein substrates, in vivo. 4.6 Fertility, pregnancy and lactation Pregnancy There are no data regarding the use of axitinib in pregnant women. Based on the pharmacological properties of axitinib, it may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). Axitinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with this medicinal product. Women of childbearing potential must use effective contraception during and up to 1 week after treatment. Breast-feeding It is unknown whether axitinib is excreted in human milk. A risk to the suckling child cannot be excluded. Axitinib should not be used during breast-feeding. Fertility Based on non-clinical findings, axitinib has the potential to impair reproductive function and fertility in humans (see section 5.3). 4.7 Effects on ability to drive and use machines Axitinib has a minor influence on the ability to drive and use machines. Patients should be advised that they may experience events such as dizziness and/or fatigue during treatment with axitinib. 4.8 Undesirable effects Summary of the safety profile The most important serious adverse reactions reported in patients receiving axitinib were cardiac failure events, arterial embolic and thrombotic events, venous embolic and thrombotic events, haemorrhage (including gastrointestinal haemorrhage, cerebral haemorrhage and haemoptysis), gastrointestinal perforation and fistula formation, hypertensive crisis, and posterior reversible encephalopathy syndrome. These risks, including appropriate action to be taken, are discussed in section 4.4. The most common (≥ 20%) adverse reactions observed following treatment with axitinib were diarrhoea, hypertension, fatigue, dysphonia, nausea, decreased appetite, and palmar-plantar erythrodysaesthesia (hand-foot) syndrome. Tabulated list of adverse reactions Table 1 presents adverse reactions reported in patients who received axitinib in a pivotal clinical study for the treatment of patients with RCC (see section 5.1). The adverse reactions are listed by system organ class, frequency category and grade of severity. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). The current safety database for axitinib is too small to detect rare and very rare adverse reactions. Categories have been assigned based on absolute frequencies in the clinical study data. Within each system organ class, adverse reactions with the same frequency are presented in order of decreasing seriousness. Table 1. Adverse reactions reported in the RCC study in patients who received axitinib (N = 359) System Organ Class Frequency Category Adverse Reactionsa All Gradesb % Grade 3b % Grade 4b % Blood and lymphatic system disorders Common Anaemia 4.5 0.8 0 Thrombocytopenia 1.7 0.3 0 Polycythaemiac 1.4 0.3 0 Uncommon Neutropenia 0.6 0.3 0 Leukopenia 0.6 0 0 Endocrine disorders Very Common Hypothyroidismc 20.9 0.3 0 Common Hyperthyroidismc 1.1 0 0 Metabolism and nutrition disorders Very Common Decreased appetite 38.7 4.7 0.6 Common Dehydration 7.0 3.6 0.3 Hyperkalaemia 3.3 1.1 0.3 Hypercalcaemia 2.8 0 0.3 Nervous system disorders Very Common Headache 15.3 0.8 0 Dizziness 10.0 0.6 0 Dysgeusia 11.7 0 0 Uncommon Posterior reversible encephalopathy syndrome 0.3 0.3 0 Ear and labyrinth disorders Common Tinnitus 3.6 0 0 Cardiac disorders Common Cardiac failure eventsc,d 1.7 0 0.6 Vascular disorders Very Common Hypertension 43.2 17.0 0.3 Haemorrhagec, d 21.4 2.8 0.6 Common Venous embolic and thrombotic eventsc, d 3.9 1.1 2.3 Arterial embolic and thrombotic eventsc, d 4.7 1.9 1.4 Uncommon Hypertensive crisis 0.6 0.3 0.3 Respiratory, thoracic and mediastinal disorders Very Common Dyspnoead 18.7 2.8 0.6 Cough 18.7 0.8 0 Dysphonia 31.8 0 0 Common Oropharyngeal pain 6.4 0 0 Gastrointestinal disorders Very Common Diarrhoea 57.9 11.7 0.3 Vomiting 26.5 3.3 0.3 Nausea 35.4 3.1 0.3 Abdominal pain 15.6 1.9 0.3 Constipation 22.0 1.4 0 Stomatitis 16.2 1.4 0 Upper abdominal pain 10.3 0.8 0 Dyspepsia 10.9 0 0 Common Flatulence 5.6 0 0 Haemorrhoids 4.2 0 0 Glossodynia 3.1 0 0 Gastrointestinal Perforation and fistulac 1.7 0.6 0.3 Hepatobiliary disorders Common Hyperbilirubinaemia 1.4 0.3 0 Skin and subcutaneous tissue disorders Very Common Palmar-plantar erythrodysaesthesia (hand-foot syndrome) 27.9 5.6 0 Rash 13.9 0.3 0 Dry skin 10.0 0 0 Common Pruritus 7.0 0 0 Erythema 2.8 0 0 Alopecia 5.0 0 0 Musculoskeletal and connective tissue disorders Very Common Arthralgia 17.3 1.9 0.6 Pain in extremity 13.9 0.3 0.6 Common Myalgia 7.5 0.6 0.3 Renal and urinary disorders Very Common Proteinuria 13.4 3.1 0 Common Renal failuree 2.5 1.4 0.3 General disorders and administration site conditions Very Common Fatigue 42.3 12.0 0.6 Asthaeniad 22.0 4.7 0.6 Mucosal inflammation 16.7 1.4 0 Investigations Very Common Weight decreased 29.0 4.5 0 Common Lipase increased 3.6 0.6 0.3 Alanine aminotransferase increased 3.1 0.6 0 Amylase increased 2.5 0 0.6 Aspartate aminotransferase increased 1.9 0.6 0 Alkaline phosphatase increased 1.9 0.3 0 Creatinine increased 3.6 0.3 0 Thyroid stimulating hormone increased 5.3 0 0 a Adverse reactions are according to treatment-emergent, all causality frequency. bNational Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 c See Description of selected adverse reactions section. d Fatal (Grade 5) cases were reported. e Including acute renal failure Description of selected adverse reactions Cardiac failure events (see section 4.4) In a controlled clinical study with axitinib (N = 359) for the treatment of patients with RCC, cardiac failure events were reported in 1.7 % patients receiving axitinib, including cardiac failure (0.6%), cardiopulmonary failure (0.6%), left ventricular dysfunction (0.3%), and right ventricular failure (0.3%). Grade 4 cardiac failure adverse reactions were reported in 0.6 % of patients receiving axitinib. Fatal cardiac failure was reported in 0.6 % of patients receiving axitinib. In monotherapy studies with axitinib (N = 672) for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported in 1.8% patients receiving axitinib. Grade 3/4 cardiac failure events were reported in 1.0% patients and fatal cardiac failure events were reported in 0.3% patients receiving axitinib. Thyroid dysfunction (see section 4.4) In a controlled clinical study with axitinib for the treatment of patients with RCC, hypothyroidism was reported in 20.9% of patients and hyperthyroidism was reported in 1.1% of patients. Thyroid stimulating hormone (TSH) increased was reported as an adverse reaction in 5.3% of patients receiving axitinib. During routine laboratory assessments, in patients who had TSH < 5 μU/mL before treatment, elevations of TSH to ≥ 10 μU/mL occurred in 32.2% of patients receiving axitinib. Venous embolic and thrombotic events (see section 4.4) In a controlled clinical study with axitinib for the treatment of patients with RCC, venous embolic and thrombotic adverse reactions were reported in 3.9% of patients receiving axitinib, including pulmonary embolism (2.2%), retinal vein occlusion/thrombosis (0.6%) and deep vein thrombosis (0.6%). Grade 3/4 venous embolic and thrombotic adverse reactions were reported in 3.1% of patients receiving axitinib. Fatal pulmonary embolism was reported in one patient (0.3%) receiving axitinib. Arterial embolic and thrombotic events (see section 4.4) In a controlled clinical study with axitinib for the treatment of patients with RCC, arterial embolic and thrombotic adverse reactions were reported in 4.7% of patients receiving axitinib, including myocardial infarction (1.4%), transient ischemic attack (0.8%) and cerebrovascular accident (0.6%). Grade 3/4 arterial embolic and thrombotic adverse reactions were reported in 3.3% of patients receiving axitinib. A fatal acute myocardial infarction and cerebrovascular accident was reported in one patient each (0.3%). In monotherapy studies with axitinib (N = 850), arterial embolic and thrombotic adverse reactions (including transient ischemic attack, myocardial infarction, and cerebrovascular accident) were reported in 5.3% of patients receiving axitinib. Polycythaemia (see Elevation of haemoglobin or haematocrit in section 4.4) In a controlled clinical study with axitinib for the treatment of patients with RCC, polycythaemia was reported in 1.4% of patients receiving axitinib. Routine laboratory assessments detected elevated haemoglobin above ULN in 9.7% of patients receiving axitinib. In four clinical studies with axitinib for the treatment of patients with RCC (N = 537), elevated haemoglobin above ULN was observed in 13.6% receiving axitinib. Haemorrhage (see section 4.4) In a controlled clinical study with axitinib for the treatment of patients with RCC that excluded patients with untreated brain metastasis, haemorrhagic adverse reactions were reported in 21.4% of patients receiving axitinib. The haemorrhagic adverse reactions in patients treated with axitinib included epistaxis (7.8%), haematuria (3.6%), haemoptysis (2.5%), rectal haemorrhage (2.2%), gingival bleeding (1.1%), gastric haemorrhage (0.6%), cerebral haemorrhage (0.3%) and lower gastrointestinal haemorrhage (0.3%). Grade ≥ 3 haemorrhagic adverse reactions were reported in 3.1% of patients receiving axitinib (including cerebral haemorrhage, gastric haemorrhage, lower gastrointestinal haemorrhage and haemoptysis). Fatal haemorrhage was reported in one patient (0.3%) receiving axitinib (gastric haemorrhage). In monotherapy studies with axitinib (N = 850), haemoptysis was reported in 3.9% of patients; Grade ≥ 3 haemoptysis was reported in 0.5% of patients. Gastrointestinal perforation and fistula formation (see section 4.4) In a controlled clinical study with axitinib for the treatment of patients with RCC, gastrointestinal perforation-type events were reported in 1.7% of patients receiving axitinib, including anal fistula (0.6%), fistula (0.3%) and gastrointestinal perforation (0.3%). In monotherapy studies with axitinib (N = 850), gastrointestinal perforation-type events were reported in 1.9% of patients and fatal gastrointestinal perforation was reported in one patient (0.1%). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard. 4.9 Overdose There is no specific treatment for axitinib overdose. In a controlled clinical study with axitinib for the treatment of patients with RCC, one patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). n a clinical dose finding study with axitinib, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal haemoptysis. In cases of suspected overdose, axitinib should be withheld and supportive care instituted. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group:Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE17 Mechanism of action Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2 and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumour vasculature that expressed the target in vivo and produced tumour growth delay, regression, and inhibition of metastases in many experimental models of cancer. Effect on QTc interval In a randomised, 2-way crossover study, 35 healthy subjects were administered a single oral dose of axitinib (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days. Results of this study indicated that axitinib plasma exposures up to two-fold greater than therapeutic levels expected following a 5 mg dose, did not produce clinically-significant QT interval prolongation. Clinical efficacy The safety and efficacy of axitinib were evaluated in a randomised, open-label, multicenter Phase 3 study. Patients (N = 723) with advanced RCC whose disease had progressed on or after treatment with one prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, or cytokine-containing regimens were randomised (1:1) to receive axitinib (N = 361) or sorafenib (N = 362). The primary endpoint, progression-free survival (PFS), was assessed using a blinded independent central review. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Of the patients enrolled in this study, 389 patients (53.8%) had received one prior sunitinib-based therapy, 251 patients (34.7%) had received one prior cytokine-based therapy (interleukin-2 or interferon-alpha), 59 patients (8.2%) had received one prior bevacizumab-based therapy, and 24 patients (3.3%) had received one prior temsirolimus-based therapy. The baseline demographic and disease characteristics were similar between the axitinib and sorafenib groups with regard to age, gender, race, Eastern Cooperative Oncology Group (ECOG) performance status, geographic region, and prior treatment. In the overall patient population and the two main subgroups (prior sunitinib treatment and prior cytokine treatment), there was a statistically significant advantage for axitinib over sorafenib for the primary endpoint of PFS (see Table 2 and Figures 1, 2 and 3). The magnitude of median PFS effect was different in the subgroups by prior therapy. Two of the subgroups were too small to give reliable results (prior temsirolimus treatment or prior bevacizumab treatment). There were no statistically significant differences between the arms in OS in the overall population or in the subgroups by prior therapy. Table 2. Efficacy results Endpoint / Study Population Axitinib Sorafenib HR(95% CI) p-value Overall ITT N = 361 N = 362     Median PFS a,b in months (95% CI) 6.8 (6.4, 8.3) 4.7 (4.6, 6.3) 0.67 (0.56, 0.81) < 0.0001c Median OS d in months (95% CI) 20.1 (16.7, 23.4) 19.2 (17.5, 22.3) 0.97 (0.80, 1.17) NS ORR b,e % (95% CI) 19.4 (15.4, 23.9) 9.4 (6.6, 12.9) 2.06f (1.41, 3.00) 0.0001g Prior sunitinib treatment N = 194 N = 195     Median PFS a,b in months (95% CI) 4.8 (4.5, 6.5) 3.4 (2.8, 4.7) 0.74 (0.58, 0.94) 0.0063h Median OS d in months (95% CI) 15.2 (12.8, 18.3) 16.5 (13.7, 19.2) 1.00 (0.78, 1.27) NS ORR b,e % (95% CI) 11.3 (7.2, 16.7) 7.7 (4.4, 12.4) 1.48f (0.79, 2.75) NS Prior cytokine treatment N = 126 N = 125     Median PFS a,b in months (95% CI) 12.0 (10.1, 13.9) 6.6 (6.4, 8.3) 0.52 (0.38, 0.72) < 0.0001h Median OS d in months (95% CI) 29.4 (24.5, NE) 27.8 (23.1, 34.5) 0.81 (0.56, 1.19) NS ORR b,e % (95% CI) 32.5 (24.5, 41.5) 13.6 (8.1, 20.9) 2.39f (1.43-3.99) 0.0002i CI = Confidence interval, HR=Hazard ratio (axitinib/sorafenib); ITT: Intent-to-treat; NE: not estimable; NS: not statistically significant; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival. a Time from randomisation to progression or death due to any cause, whichever occurs first. Cutoff date: 03 June 2011. b Assessed by independent radiology review according to Response Evaluation Criteria in Solid Tumours (RECIST). c One-sided p-value from a log-rank test of treatment stratified by ECOG performance status and prior therapy. d Cutoff date: 01 November 2011. e Cutoff date: 31 August 2010. f Risk ratio is used for ORR. A risk ratio > 1 indicated a higher likelihood of responding in the axitinib arm; a risk ratio < 1 indicated a higher likelihood of responding in the sorafenib arm. g One-sided p-value from Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status and prior therapy. h One-sided p-value from a log-rank test of treatment stratified by ECOG performance status. i One-sided p-value from Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status. Figure 1. Kaplan-Meier curve of progression-free survival by independent assessment for the overall population Figure 2. Kaplan-Meier curve of progression-free survival by independent assessment for the prior sunitinib subgroup Figure 3. Kaplan-Meier curve of progression-free survival by independent assessment for the prior cytokine subgroup Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with axitinib in all subsets of the paediatric population for treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties After oral administration of axitinib tablets, the mean absolute bioavailability is 58% compared to intravenous administration. The plasma half life of axitinib ranges from 2.5 to 6.1 hours. Dosing of axitinib at 5 mg twice daily resulted in less than two-fold accumulation compared to administration of a single dose. Based on the short half-life of axitinib, steady state is expected within 2 to 3 days of the initial dose. Absorption and distribution Peak axitinib concentrations in plasma are generally reached within 4 hours following oral administration of axitinib with median Tmax ranging from 2.5 to 4.1 hours. Administration of axitinib with a moderate fat meal resulted in 10% lower exposure compared to overnight fasting. A high fat, high-calorie meal resulted in 19% higher exposure compared to overnight fasting. Axitinib may be administered with or without food (see section 4.2). The average Cmax and AUC increased proportionally over an axitinib dosing range of 5 to 10 mg. In vitro binding of axitinib to human plasma proteins is > 99% with preferential binding to albumin and moderate binding to α1-acid glycoprotein. At the 5 mg twice daily dose in the fed state, the geometric mean peak plasma concentration and 24-hour AUC were 27.8 ng/mL and 265 ng.h/mL, respectively, in patients with advanced RCC. The geometric mean oral clearance and apparent volume of distribution were 38 L/h and 160 L, respectively. Biotransformation and elimination Axitinib is metabolised primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral administration of a 5 mg radioactive dose of axitinib, 30-60% of the radioactivity was recovered in faeces and 23% of the radioactivity was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in faeces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity. The sulfoxide and N-glucuronide metabolites show approximately 400-fold and 8000-fold less in vitro potency, respectively, against VEGFR-2 compared to axitinib. Special populations Older people, gender, and race Population pharmacokinetic analyses in patients with advanced cancer (including advanced RCC) and healthy volunteers indicate that there are no clinically relevant effects of age, gender, body weight, race, renal function, UGT1A1 genotype, or CYP2C19 genotype. Paediatric population Axitinib has not been studied in patients < 18 years of age. Hepatic impairment In vitro and in vivo data indicate that axitinib is primarily metabolised by the liver. Compared to subjects with normal hepatic function, systemic exposure following a single dose of axitinib was similar in subjects with mild hepatic impairment (Child-Pugh class A) and higher (approximately two-fold) in subjects with moderate hepatic impairment (Child-Pugh class B). Axitinib has not been studied in subjects with severe hepatic impairment (Child-Pugh class C) and should not be used in this population (see section 4.2 for dose adjustment recommendations). Renal impairment Unchanged axitinib is not detected in the urine. Axitinib has not been studied in subjects with renal impairment. In clinical studies with axitinib for the treatment of patients with RCC, patients with serum creatinine > 1.5 times the ULN or calculated creatinine clearance < 60 mL/min were excluded. Population pharmacokinetic analyses have shown that axitinib clearance was not altered in subjects with renal impairment and no dose adjustment of axitinib is required. 5.3 Preclinical safety data Repeat dose toxicity Major toxicity findings in mice and dogs following repeated dosing for up to 9 months were the gastrointestinal, haematopoietic, reproductive, skeletal and dental systems, with No Observed Adverse Effect Levels (NOAEL) approximately equivalent to or below expected human exposure at the recommended clinical starting dose (based on AUC levels). Carcinogenicity Carcinogenicity studies have not been performed with axitinib. Genotoxicity Axitinib was not mutagenic or clastogenic in conventional genotoxicity assays in vitro. A significant increase in polyploidy was observed in vitro at concentrations > 0.22 µg/mL, and an elevation in micronucleated polychromatic erythrocytes was observed in vivo with No Observed Effect Level (NOEL) 69-fold the expected human exposure. Genotoxicity findings are not considered clinically relevant at exposure levels observed in humans. Reproduction toxicity Axitinib-related findings in the testes and epididymis included decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, and reduced sperm density and count. These findings were observed in mice at exposure levels approximately 12-fold the expected human exposure, and in dogs at exposure levels below the expected human exposure. There was no effect on mating or fertility in male mice at exposure levels approximately 57-fold the expected human exposure. Findings in females included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at exposures approximately equivalent to the expected human exposure. Reduced fertility and embryonic viability were observed in female mice at all doses tested, with exposure levels at the lowest dose approximately 10-fold the expected human exposure. Pregnant mice exposed to axitinib showed an increased occurrence of cleft palate malformations and skeletal variations, including delayed ossification, at exposure levels below the expected human exposure. Perinatal and postnatal developmental toxicity studies have not been conducted. Toxicity findings in immature animals Reversible physeal dysplasia was observed in mice and dogs given axitinib for at least 1 month at exposure levels approximately six-fold higher than the expected human exposure. Partially reversible dental caries were observed in mice treated for more than 1 month at exposure levels similar to the expected human exposure. Other toxicities of potential concern to paediatric patients have not been evaluated in juvenile animals. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core: Microcrystalline cellulose Lactose monohydrate Croscarmellose sodium Magnesium stearate Tablet film-coating: Hypromellose Titanium dioxide (E171) Lactose monohydrate Triacetin (E1518) Iron oxide red (E172) 6.2 Incompatibilities Not applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions.6.5 Nature and contents of container 1 mg, 3mg, 5mg, 7mg film-coated tablets Aluminium/aluminium blister containing 14 film-coated tablets. Each pack contains 28 or 56 film-coated tablets. 1 mg film-coated tablets HDPE bottle with a silica gel desiccant and a polypropylene closure containing 180 film-coated tablets. 3 mg, 5 mg, 7 mg film-coated tablets HDPE bottle with a silica gel desiccant and a polypropylene closure containing 60 film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Pfizer Limited Ramsgate Road Sandwich, Kent CT13 9NJ United Kingdom 8. Marketing authorisation number(s) EU/1/12/777/001 EU/1/12/777/002 EU/1/12/777/003 EU/1/12/777/004 EU/1/12/777/005 EU/1/12/777/006 EU/1/12/777/007 EU/1/12/777/008 EU/1/12/777/009 EU/1/12/777/010 EU/1/12/777/011 EU/1/12/777/012 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 3 September 2012 10. Date of revision of the text 05/2014 11. Legal category POM Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 2012年1月27日美国FDA批准Inlyta(axitinib)治疗一类晚期肾患者 批准日期：2012年1月27日；公司：辉瑞 Pfizer Inc. 美国食品药品监督管理局批Inlyta(axitinib)治疗晚期肾癌(肾细胞癌)对这类型癌对另外药物不反应的患者。 肾细胞癌是一种类型肾癌开始是在肾中非常小管衬里中。Inlyta通过阻断肿瘤生长和癌进展起作用的某些蛋白被称为激酶发挥作用。 Inlyta是一种药物患者每天用2次。 FDA药物评价和研究中心的血液学和肿瘤产品室主任Richard Pazdur, M.D. 说“这是自2005来对转移或晚期肾细胞癌的治疗曾被批准的第7个药物。”“总的来说，在前所未有的水平，在这段时间内的药物开发已显著改变转移肾癌治疗的范式，和提供患者多种治疗选择。” 最近治疗肾癌被批准药物包括索拉非尼[sorafenib](2005)，舒尼替尼[sunitinib](2006)，驮瑞塞尔[temsirolimus](2007)，依维莫司[everolimus](2009)，贝伐单抗[bevacizumab](2009)和帕唑帕尼[pazopanib] (2009)。 在一项723例用一种既往全身治疗或治疗后疾病有进展患者中进行的单个随机化，开放，多中心临床研究评价Inlyta的安全性和有效性。研究被设计成测量无进展生存，患者生存无癌症进展的时间。结果显示中位无进展生存时间6.7 个月与之比较用标准治疗(索拉非尼)为4.7个月。 在临床研究中在大于20%患者观察到的最常见副作用是腹泻，高血压，疲乏，食欲减低，恶心，失声(发音障碍)，手足综合征(手指-足底erythrodysesthesia)，体重减轻，呕吐, 虚弱(乏力)和便秘。 有高血压患者服用Inlyta前应很好控制。有些患者用Inlyta经受出血问题，在有些病例中是致命性的。有未治疗脑肿瘤或胃肠道出血患者不应用Inlyta。 ---------------------------------------------------------------------- 注：以下产品有多种包装规格，购买以咨询为准！（其中有14、28、56、180包装） ---------------------------------------------------------------------- 产地国家: 德国 原产地英文商品名: INLYTA 5MG/TAB 56TABS/box(Controlled; can only sell to oncology centers and hospitals) 原产地英文药品名: AXITINIB 中文参考商品译名: INLYTA 5毫克/片 56片/盒 (Controlled; can only sell to oncology centers and hospitals) 中文参考药品译名: 阿西替尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: PFIZER -------------------------------------------------------------- 产地国家: 德国 原产地英文商品名: INLYTA 3MG/TAB 56TABS/box(Controlled; can only sell to oncology centers and hospitals) 原产地英文药品名: AXITINIB 中文参考商品译名: INLYTA 3毫克/片 56片/盒 (Controlled; can only sell to oncology centers and hospitals) 中文参考药品译名: 阿西替尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: PFIZER -------------------------------------------------------------- 产地国家: 德国 原产地英文商品名: INLYTA 5MG/TAB 56TABS/box(Controlled; can only sell to oncology centers and hospitals) 原产地英文药品名: AXITINIB 中文参考商品译名: INLYTA 5毫克/片 56片/盒 (Controlled; can only sell to oncology centers and hospitals) 中文参考药品译名: 阿西替尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: PFIZER -------------------------------------------------------------- 产地国家: 德国 原产地英文商品名: INLYTA 7MG/TAB 56TABS/box(Controlled; can only sell to oncology centers and hospitals) 原产地英文药品名: AXITINIB 中文参考商品译名: INLYTA 7毫克/片 56片/盒 (Controlled; can only sell to oncology centers and hospitals) 中文参考药品译名: 阿西替尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: PFIZER