英文药名：XALKORI(Crizotinib）caps 中文药名：克唑替尼胶囊 生产厂家：Pfizer 药品介绍： 2012年10月31日，辉瑞(Pfizer)肺癌药物Xalkori（crizotinib）已获欧盟委员会有条件上市许可（conditional marketing approval），用于既往治疗过的间变性淋巴瘤激酶（ALK）阳性晚期非小细胞肺癌（NSCLC）成人患者的治疗。 Xalkori已于去年8月获FDA批准在美国上市。今年7月，EMA已建议有条件批准Xalkori。 Xalkori 200mg and 250mg hard capsule 1. Name of the medicinal product XALKORI 200mg hard capsules XALKORI 250mg hard capsules 2. Qualitative and quantitative composition Each hard capsule contains 200 mg of crizotinib. Each hard capsule contains 250 mg of crizotinib. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Hard capsule. White opaque and pink opaque hard capsule, with “Pfizer” imprinted on the cap and “CRZ 200” on the body. Pink opaque hard capsule, with “Pfizer” imprinted on the cap and “CRZ 250” on the body. 4. Clinical particulars 4.1 Therapeutic indications XALKORI is indicated for the treatment of adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). 4.2 Posology and method of administration Treatment with XALKORI should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. ALK testing An accurate and validated ALK assay is necessary for the selection of patients for treatment with XALKORI (see section 5.1 for information on assays used in the trials). ALK-positive NSCLC status should be established prior to initiation of XALKORI therapy. Assessment should be performed by laboratories with demonstrated proficiency in the specific technology being utilised (see section 4.4). Posology The recommended dose schedule of XALKORI is 250 mg twice daily (500 mg daily) taken continuously. If a dose is missed, then it should be taken as soon as the patient remembers unless it is less than 6 hours until the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose. Dose adjustments Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. In randomised Phase 3 Study 1, the most frequent adverse reactions that led to dosing interruptions were neutropenia, elevated transaminases, nausea and vomiting. The most frequent adverse reactions that led to dose reductions were elevated transaminases, electrocardiogram QT prolonged, and neutropenia. If dose reduction is necessary, then the dose of XALKORI should be reduced to 200 mg taken twice daily. If further dose reduction is necessary, then the dose should be modified to 250 mg taken once daily based on individual safety and tolerability. Dose reduction guidelines for hematologic and non-hematologic toxicities are provided in Tables 1 and 2. Table 1. XALKORI dose modification – Hematologic toxicitiesa,b CTCAEc Grade XALKORI treatment Grade 3 Withhold until recovery to Grade ≤2, then resume at the same dose schedule Grade 4 Withhold until recovery to Grade ≤2, then resume at 200 mg twice dailyd a. Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). b. For patients who develop neutropenia and leukopenia, see also sections 4.4 and 4.8. c. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events d. In case of recurrence, dosing should be withheld until recovery to Grade ≤2, then dosing should be resumed at 250 mg once daily. XALKORI must be permanently discontinued in case of further Grade 4 recurrence. Table 2. XALKORI dose modification – Non-hematologic toxicities CTCAEa Grade XALKORI treatment Grade 3 or 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation with Grade ≤ 1 total bilirubin Withhold until recovery to Grade ≤ 1 or baseline, then resume at 250 mg once daily and escalate to 200 mg twice daily if clinically toleratedb Grade 2, 3 or 4 ALT or AST elevation with concurrent Grade 2, 3 or 4 total bilirubin elevation (in the absence of cholestasis or haemolysis) Permanently discontinue Any Grade interstitial lung disease (ILD)/pneumonitis Withhold if ILD/pneumonitis is suspected, and permanently discontinue if treatment-related ILD/pneumonitis is diagnosed c Grade 3 QTc prolongation Withhold until recovery to Grade ≤ 1, check and if necessary correct electrolytes, then resume at 200 mg twice dailyb Grade 4 QTc prolongation Permanently discontinue Grade 2, 3 Bradycardiac, d Symptomatic, may be severe and medically significant, medical intervention indicated Withhold until recovery to Grade ≤ 1 or to heart rate 60 or above Evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to Grade ≤ 1 or to heart rate 60 or above If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume at reduced dose upon recovery to Grade ≤ 1 or to heart rate 60 or above Grade 4 Bradycardiac,d,e Life-threatening consequences, urgent intervention indicated Permanently discontinue if no contributing concomitant medication is identified If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at 250 mg once daily upon recovery to Grade ≤ 1 or to heart rate 60 or above, with frequent monitoring a. NCI Common Terminology Criteria for Adverse Events b. XALKORI must be permanently discontinued in case of further Grade ≥ 3 recurrence. See sections 4.4 and 4.8. c. See sections 4.4 and 4.8. d. Heart rate less than 60 beats per minute (bpm). e. Permanently discontinue for recurrence. Hepatic impairment XALKORI has not been studied in patients with hepatic impairment. Clinical studies that were conducted excluded patients with AST or ALT >2.5×upper limit of normal (ULN), or if due to underlying malignancy, >5.0×ULN or with total bilirubin >1.5×ULN. Treatment with XALKORI should be used with caution in patients with mild and moderate hepatic impairment. XALKORI should not be used in patients with severe hepatic impairment (see sections 4.3, 4.4 and 4.8). Renal impairment No starting dose adjustment is recommended for patients with mild (60 ≤ creatinine clearance [CLcr] < 90 mL/min) or moderate (30 ≤ CLcr < 60 mL/min) renal impairment, since the population pharmacokinetic analysis indicated no clinically meaningful changes in steady-state crizotinib exposure in these patients. Crizotinib plasma concentrations may be increased in patients with severe renal impairment (CLcr <30 mL/min). The crizotinib dose should be adjusted to 250 mg taken orally once daily in patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis. The dose may be increased to 200 mg twice daily based on individual safety and tolerability after at least 4 weeks of treatment (see sections 4.4 and 5.2). Elderly Of the 172 crizotinib-treated patients in randomised Phase 3 Study 1, 27 (16%) were 65 years or older. Of the 149 patients in Study A, 20 (13%) were 65 years or older. Of the 934 patients in Study B, 152 (16%) were 65 years or older (see section 5.2). No overall differences in safety or efficacy were observed in comparison with younger patients. Paediatric population The safety and efficacy of XALKORI in paediatric patients has not been established. No data are available. Method of administration The capsules should be swallowed whole preferably with water, and should not be crushed, dissolved, or opened. They may be taken with or without food. Grapefruit or grapefruit juice should be avoided since it may increase crizotinib plasma concentration; St. John's wort should be avoided since it may decrease crizotinib plasma concentration (see section 4.5). 4.3 Contraindications Hypersensitivity to crizotinib or to any of the excipients listed in section 6.1. Severe hepatic impairment (see sections 4.2, 4.4 and 4.8). 4.4 Special warnings and precautions for use Assessment of ALK status When assessing the ALK status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations. Hepatotoxicity Drug-induced hepatotoxicity with fatal outcome has occurred. These cases have occurred during XALKORI treatment in less than 1% of patients in clinical trials. Concurrent elevations in ALT greater than 3×ULN and total bilirubin greater than 2×ULN without elevated alkaline phosphatase have been observed in less than 1% patients in clinical trials. Increases to Grade 3 or 4 ALT elevations were observed in 17% of patients receiving crizotinib versus 4% of patients receiving chemotherapy in randomised Phase 3 Study 1. Increases to Grade 3 or 4 ALT elevations were observed in 7% of patients in Study A and 8% of patients in Study B. Grade 3 and 4 elevations were generally reversible upon dosing interruption. Two patients from randomised Phase 3 Study 1 (1%), 1 patient from Study A (< 1%) and 6 patients from Study B (< 1%) required permanent discontinuation from treatment. Transaminase elevations generally occurred within the first 2 months of treatment. XALKORI should not be used in patients with severe hepatic impairment (including patients with total bilirubin > 3 × ULN regardless of ALT/AST) (see sections 4.2, 4.3 and 4.8). Liver function tests including ALT, AST, and total bilirubin should be monitored once a week during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevations. For patients who develop transaminase elevations, see section 4.2. Interstitial lung disease/Pneumonitis Severe, life-threatening, and/or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across randomized Phase 3 Study 1 and Studies A and B (n=1255), 33 (2.6%) patients treated with crizotinib had any grade ILD, including 13 (1%) patients with Grade 3 or 4, and 6 (0.5%) patients with fatal cases. These cases generally occurred within 2 months after the initiation of treatment. Patients with pulmonary symptoms indicative of ILD/pneumonitis should be monitored. XALKORI treatment should be withheld if ILD/pneumonitis is suspected. Drug-induced ILD/pneumonitis should be considered in the differential diagnosis of patients with ILD-like conditions such as: pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), alveolitis, lung infiltration, pneumonia, pulmonary edema, chronic obstructive pulmonary disease, pleural effusion, aspiration pneumonia, bronchitis, obliterative bronchiolitis, and bronchiectasis. Other potential causes of ILD/pneumonitis should be excluded, and XALKORI should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis (see sections 4.2 and 4.8). QT interval prolongation QTc prolongation has been observed in clinical studies in patients treated with XALKORI (see sections 4.8 and 5.2) which may lead to an increased risk for ventricular tachyarrhythmias (e.g., Torsade de Pointes) or sudden death. The benefits and potential risks of crizotinib should be considered before beginning therapy in patients with pre-existing bradycardia, who have a history of or predisposition for QTc prolongation, who are taking antiarrhythmics or other medicinal products that are known to prolong QT interval and in patients with relevant pre-existing cardiac disease and/or electrolyte disturbances. XALKORI should be administered with caution in these patients and periodic monitoring of electrocardiograms (ECG), electrolytes and renal function is required. When using XALKORI, ECG and electrolytes (e.g., calcium, magnesium, potassium) should be obtained as close as possible prior to the first dose and periodic monitoring with ECGs and electrolytes is recommended, especially at the beginning of treatment in case of vomiting, diarrhoea, dehydration or impaired renal function. Correct electrolytes as necessary. If QTc increases by greater than or equal to 60 msec from baseline but QTc is < 500 msec, crizotinib should be withheld and cardiologist advice should be sought. If QTc increases to greater than or equal to 500 msec, cardiologist advice must be immediately sought. For patients who develop QTc prolongation, see sections 4.2, 4.8 and 5.2. Bradycardia Treatment-emergent all-causality bradycardia was reported in clinical studies in 5 to 10% of patients treated with crizotinib. Symptomatic bradycardia (e.g., syncope, dizziness, hypotension) can occur in patients receiving XALKORI. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after start of treatment. Avoid using crizotinib in combination with other bradycardic agents (e.g., beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia. Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. For management of patients who develop symptomatic bradycardia, see Dose Modification and Undesirable Effects sections (see sections 4.2 and 4.8). Neutropenia and Leukopenia In clinical trials with crizotinib (randomised Phase 3 Study 1 and Studies A and B) Grade 3 or 4 neutropenia has been very commonly (6%-13%) reported. Grade 3 or 4 leukopenia has been commonly (2%) reported (see section 4.8). Less than 1% of patients experienced febrile neutropenia in clinical trials with crizotinib. Complete blood counts including differential white blood cell counts should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs (see section 4.2). Gastrointestinal perforation In clinical studies with crizotinib, events of gastrointestinal perforations were reported. There were reports of fatal cases of gastrointestinal perforation during post-marketing use of XALKORI (see section 4.8). Crizotinib should be used with caution in patients at risk for gastrointestinal perforation (e.g., history of diverticulitis, metastases to the gastrointestinal tract, concomitant use of medications with a recognized risk of gastrointestinal perforation). Crizotinib should be discontinued in patients who develop gastrointestinal perforation. Patients should be informed of the first signs of gastrointestinal perforations and be advised to consult rapidly in case of occurrence. Renal impairment If patients have severe renal impairment not requiring peritoneal dialysis or hemodialysis, the dose of crizotinib should be adjusted (see sections 4.2 and 5.2). Visual effects Vision disorder occurred in patients in randomised Phase 3 Study 1, Study A and Study B. Ophthalmological evaluation (e.g., visual acuity, fundoscopy, and slit lamp examinations) should be considered if vision disorder persists or worsens in severity (see section 4.8). Drug-drug interactions The concomitant use of crizotinib with strong CYP3A4 inhibitors/inducers and CYP3A4 substrates with narrow therapeutic indices should be avoided (see section 4.5). Avoid using crizotinib in combination with other bradycardic agents, medicinal products that are known to prolong QT interval and/or antiarrhythmics (see section 4.4 QT interval prolongation, Bradycardia, and section 4.5). Non-adenocarcinoma histology Limited information is available in patients with ALK-positive NSCLC with non-adenocarcinoma histology. (see section 5.1). 4.5 Interaction with other medicinal products and other forms of interaction Pharmacokinetic interactions Agents that may increase crizotinib plasma concentrations Coadministration of crizotinib with strong CYP3A inhibitors may increase crizotinib plasma concentrations. Coadministration of a single 150 mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib AUCinf and Cmax values that were approximately 3.2-fold and 1.4-fold, respectively, those seen when crizotinib was administered alone. Therefore, the concomitant use of strong CYP3A inhibitors (certain protease inhibitors like atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, and, certain azole antifungals like itraconazole, ketoconazole, and voriconazole, certain macrolides like clarithromycin, telithromycin, and troleandomycin) should be avoided. Grapefruit or grapefruit juice may also increase plasma concentrations of crizotinib and should be avoided (see sections 4.2 and 4.4). Furthermore, the effect of CYP3A inhibitors on steady-state crizotinib exposure has not been established. Agents that may decrease crizotinib plasma concentrations Coadministration of a single 250 mg crizotinib dose with rifampicin (600 mg QD), a strong CYP3A4 inducer, resulted in 82% and 69% decreases in crizotinib AUCinf and Cmax, respectively, compared to when crizotinib was given alone. Coadministration of crizotinib with strong CYP3A inducers may decrease crizotinib plasma concentrations. The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John's wort, should be avoided (see section 4.4). Furthermore, the effect of CYP3A inducers on steady-state crizotinib exposure has not been established. Coadministration with medicinal products that increase gastric pH The aqueous solubility of crizotinib is pH dependent, with low (acidic) pH resulting in higher solubility. Administration of a single 250 mg crizotinib dose following treatment with esomeprazole 40 mg QD for 5 days resulted in an approximately 10% decrease in crizotinib total exposure (AUCinf) and no change in peak exposure (Cmax); the extent of the change in total exposure was not clinically meaningful. Therefore, starting dose adjustment is not required when crizotinib is coadministered with agents that increase gastric pH (such as proton-pump inhibitors, H2 blockers, or antacids). Agents whose plasma concentrations may be altered by crizotinib Following 28 days of crizotinib dosing at 250 mg taken twice daily in cancer patients, the oral midazolam AUC was 3.7-fold of those seen when midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3A. Therefore, coadministration of crizotinib with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil, cisapride, cyclosporine, ergot derivatives, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus should be avoided (see section 4.4). If the combination is needed, then close clinical monitoring should be exercised. In vitro studies indicated that crizotinib is an inhibitor of CYP2B6. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are metabolized by CYP2B6 (e.g., bupropion, efavirenz). In vitro studies in human hepatocytes indicated that crizotinib may induce pregnane X receptor (PXR)- and constitutive androstane receptor (CAR)-regulated enzymes (e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1). However, there was no observed induction in vivo when crizotinib was coadministered with the CYP3A probe substrate midazolam. Caution should be exercised in administering crizotinib in combination with medicinal products that are predominantly metabolised by these enzymes. Of note, the effectiveness of concomitant administration of oral contraceptives may be reduced. In vitro studies indicated that crizotinib is a weak inhibitor of UGT1A1 and UGT2B7. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are metabolized predominantly by UGT1A1 (e.g., raltegravir, irinotecan) or UGT2B7 (e.g., morphine, naloxone). Based on an in vitro study, crizotinib is predicted to inhibit intestinal P-gp. Therefore, administration of crizotinib with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) may increase their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when crizotinib is administered with these medicinal products. Crizotinib is an inhibitor of OCT1 and OCT2 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2 (e.g., metformin, procainamide). Pharmacodynamic interactions In clinical studies, prolonged QT interval was observed with crizotinib. Therefore, the concomitant use of crizotinib with medicinal products known to prolong QT interval or medicinal products able to induce Torsades de pointes (e.g., class IA [quinidine, disopyramide] or class III [e.g., amiodarone, sotalol, dofetilide, ibutilide], methadone, cisapride, moxifloxacine, antipsychotics, etc.) should be carefully considered. A monitoring of the QT interval should be made in case of combinations of such medicinal products (see sections 4.2 and 4.4). Bradycardia has been reported during clinical studies; therefore, use crizotinib with caution due to the risk of excessive bradycardia when used in combination with other bradycardic agents (e.g., non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, beta-blockers, clonidine, guanfacine, digoxin, mefloquine, anticholinesterases, pilocarpine) (see sections 4.2 and 4.4). 4.6 Fertility, pregnancy and lactation Contraception in males and females Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. Adequate contraceptive methods should be used during therapy, and for at least 90 days after completing therapy (see section 4.5). Pregnancy XALKORI may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3). There are no data in pregnant women using crizotinib. This medicinal product should not be used during pregnancy unless the clinical condition of the mother requires treatment. Pregnant women, or patients becoming pregnant while receiving crizotinib, or treated male patients as partners of pregnant women, should be apprised of the potential hazard to the foetus. Breast-feeding It is not known whether crizotinib and its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should be advised to avoid breast-feeding while receiving XALKORI (see section 5.3). Fertility Based on nonclinical safety findings, male and female fertility may be compromised by treatment with XALKORI (see section 5.3). Both men and women should seek advice on fertility preservation before treatment. 4.7 Effects on ability to drive and use machines Caution should be exercised when driving or operating machines as patients may experience symptomatic bradycardia (e.g., syncope, dizziness, hypotension), vision disorder, or fatigue while taking XALKORI (see sections 4.2, 4.4 and 4.8). 4.8 Undesirable effects Summary of the safety profile Data described below reflect exposure to XALKORI in 172 patients with ALK-positive advanced NSCLC who participated in randomised Phase 3 Study 1 and in 1083 patients with ALK-positive advanced NSCLC who participated in 2 single-arm clinical trials (Studies A and B). These patients received a starting oral dose of 250 mg taken twice daily continuously. The most serious adverse reactions in patients with ALK-positive advanced NSCLC are hepatotoxicity, ILD/pneumonitis, neutropenia and QT interval prolongation (see section 4.4). The most common adverse reactions (≥25%) in patients with ALK-positive NSCLC are vision disorder, nausea, diarrhoea, vomiting, constipation, oedema, elevated transaminases, and fatigue. Tabulated list of adverse reactions Table 3 presents adverse reactions reported in patients with ALK-positive advanced NSCLC who received crizotinib in randomised Phase 3 Study 1 with median duration of study treatment 31 weeks. The most frequent adverse reactions that led to dosing interruptions were neutropenia (8 %), elevated transaminases (8%), nausea (5%) and vomiting (3%). The most frequent adverse reactions that led to dose reductions were elevated transaminases (8%), electrocardiogram QT prolonged (3%), and neutropenia (2%). Investigator-assessed treatment-related adverse events resulting in permanent discontinuation occurred in 11 (6%) patients on crizotinib. The most frequent adverse reactions that led to permanent discontinuation were interstitial lung disease (2%) and elevated transaminases (1%). The adverse reactions listed in Table 3 are presented by system organ class and frequency categories are defined using the following convention: very common (greater than or equal to 1/10); common (greater than or equal to 1/100 to less than 1/10), uncommon (greater than or equal to 1/1,000 to less than 1/100) or rare (greater than or equal to 1/10,000 to less than 1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 3. Adverse reactions reported in crizotinib randomised Phase 3 Study 1 System organ class Very common ≥ 1/10 Common ≥ 1/100 to < 1/10 Uncommon ≥ 1/1,000 to < 1/100 Blood and lymphatic system disorders Neutropeniaa (27%) Anaemiab (17%) Leukopenia (9%)   Metabolism and nutrition disorders Decreased appetite (27%) Hypophosphataemia (3%)   Nervous system disorders Neuropathyc (19%) Dysgeusia (26%)     Eye disorders Vision disordere (60%)     Cardiac disorders Dizzinessd (22%) Electrocardiogram QT prolonged (5%) Bradycardiaf (5%)   Respiratory, thoracic and mediastinal disorders   Interstitial Lung Diseaseg (4%)   Gastrointestinal disorders Diarrhoea (60%) Vomiting (47%) Nausea (55%) Constipation (42%) Dyspepsia (8%) Gastrointestinal Perforation (1%) Hepatobiliary disorders Elevated transaminasesh (38%) Blood alkaline phosphatase increased (8%) Hepatic failure (1%) Skin and subcutaneous tissue disorders   Rash (9%)   Renal and urinary disorders   Renal cysti (4%)   General disorders and administration site conditions Oedemaj (31%) Fatigue (27%)   Includes cases reported within the clustered terms: a. Neutropenia (Febrile neutropenia, Neutropenia, Neutrophil count decreased) b. Anaemia (Anaemia, Haemoglobin decreased) c. Neuropathy (Dysaesthesia, Gait disturbance, Hypoaesthesia, Muscular weakness, Neuralgia, Neuropathy peripheral, Paraesthesia, Peripheral sensory neuropathy, Polyneuropathy, Skin burning sensation) d. Dizziness (Balance disorder, Dizziness, Dizziness postural) e. Vision disorder (Diplopia, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual impairment, Vitreous floaters) f. Bradycardia (Bradycardia, Sinus bradycardia) g. Interstitial Lung Disease (Acute respiratory distress syndrome, Interstitial lung disease, Pneumonitis) h. Elevated Transaminases (Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Hepatic function abnormal, Transaminases increased) i. Renal Cyst (Renal cyst) j. Oedema (Face oedema, Generalised oedema, Local swelling, Localised oedema, Oedema, Oedema peripheral, Periorbital oedema) The safety analysis population in Study B included 934 patients who received crizotinib. The median duration of treatment was 23 weeks. The most common adverse reactions (≥25%) included vision disorder, nausea, vomiting, diarrhoea, oedema, constipation, and fatigue. The most common Grade 3 or 4 adverse reactions (>3%) in Study B were neutropenia, elevated transaminases, and constipation. The safety analysis population in Study A included 149 patients who received crizotinib. The median duration of treatment was 43 weeks. The most common adverse reactions (≥25%) in Study A included nausea, vision disorder, diarrhoea, vomiting, oedema, constipation, dizziness, fatigue and decreased appetite. Description of selected adverse reactions Hepatotoxicity Drug-induced hepatotoxicity with fatal outcome has occurred. These cases have occurred during XALKORI treatment in less than 1% of patients in clinical trials. Concurrent elevations in ALT greater than 3×ULN and total bilirubin greater than 2×ULN without elevated alkaline phosphatase have been observed in less than 1% patients in clinical trials. Increases to Grade 3 or 4 ALT elevation were observed in 17% of patients receiving crizotinib versus 4% of patients receiving chemotherapy in randomised Phase 3 Study 1. Increases to Grade 3 or 4 ALT elevations were observed in 7% of patients in Study A and 8% of patients in Study B. Transaminase (ALT, AST) elevations generally occurred within the first 2 months of treatment. Across Study A, Study B and randomised Phase 3 Study 1, median times to onset of increased Grade 1 or 2 transaminases ranged from 22 to 26 days. Median times to onset of increased Grade 3 or 4 transaminases ranged from 30 to 43 days. Grade 3 and 4 elevations were generally reversible upon dosing interruption. Dose reductions associated with transaminase elevations occurred in 8% of patients from randomised Phase 3 Study 1 and 3% of patients from Study A and Study B. Two patients from randomised Phase 3 Study 1 (1%), 1 patient from Study A (<1%) and 6 patients from Study B (< 1%) required permanent discontinuation from treatment. XALKORI should not be used in patients with severe hepatic impairment (see sections 4.2, 4.3 and 4.4). Liver function tests including ALT, AST, and total bilirubin should be monitored once a week during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevation. Patients should be monitored for hepatotoxicity and managed as recommended in sections 4.2 and 4.4. Gastrointestinal effects Nausea, diarrhoea, vomiting, and constipation were the most commonly reported gastrointestinal events. Median times to onset for nausea and vomiting were 2 to 3 days. Most events of these were mild to moderate in severity, and declined in frequency after 3 to 4 weeks. Supportive care should include the use of antiemetic medicinal products. Diarrhoea and constipation were primarily mild to moderate in severity. Supportive care for diarrhoea and constipation should include the use of standard antidiarrheal and laxative medicinal products, respectively. In clinical studies with crizotinib, events of gastrointestinal perforations were reported. There were reports of fatal cases of gastrointestinal perforation during post-marketing use of XALKORI (see section 4.4). QT interval prolongation The mean changes from baseline for QTcF (corrected QT by the Fridericia method) on Cycle 1 Day 1 and Cycle 2 Day 1 were 8.3 msec and 8.7 msec in randomised Phase 3 Study 1 and study B, respectively (highest upper bound of 2-sided 90% CI for QTcF were 13.1 msec and 10.2 msec respectively and was <15 msec, which is unlikely to constitute a clinically relevant QTc effect). A QTcF ≥500 msec was recorded in 5 (3.4%) and 10 (1.1%) patients in randomised Phase 3 Study 1 and B, respectively and a maximum increase from baseline in QTcF ≥60 msec was observed in 9 (6.3%) and 38 (4.3%) patients in randomised Phase 3 Study 1 and B, respectively. In randomised Phase 3 Study 1, all-causality Grade 3 or 4 Electrocardiogram QT prolonged was reported in 6 (3.5%) patients (see sections 4.2, 4.4, 4.5 and 5.2). QT prolongation can result in arrhythmias and is a risk factor for sudden death. QT prolongation may clinically manifest as bradycardia, dizziness, and syncope. Electrolyte disturbances, dehydration and bradycardia may further increase the risk of QTc prolongation and thus, periodic monitoring of ECG and electrolyte levels is recommended in patients with GI toxicity (see section 4.4). Bradycardia Treatment-emergent all-causality bradycardia was reported by 8 (5%) patients in randomised Phase 3 Study 1 and 13 (9%) and 108 (10%) patients in Studies A and B, respectively. In Studies 1, A, and B, 19 of 170 (11%) patients, 26 of 144 (18%) patients, and 90 of 890 (10%) patients, respectively, had a heart rate <50 bpm. The use of concomitant medications associated with bradycardia should be carefully evaluated. Patients who develop symptomatic bradycardia should be managed as recommended in the Dose Modification and Warnings and Precautions sections (see sections 4.2, 4.4 and 4.5). Interstitial lung disease/Pneumonitis Severe, life-threatening, and/or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across randomized Phase 3 Study 1 and Studies A and B (n=1255), 33 (2.6%) patients treated with crizotinib had any grade ILD, 13 (1%) patients had Grade 3 or 4, and 6 (0.5%) patients had fatal outcome. These cases generally occurred within 2 months after the initiation of treatment. Patients with pulmonary symptoms indicative of ILD/pneumonitis should be monitored. Other potential causes of ILD/pneumonitis should be excluded, (see sections 4.2 and 4.4). Visual effects Treatment-emergent all-causality vision disorder, most commonly visual impairment, photopsia, vision blurred, and vitreous floaters was experienced by 103 (60%) patients in randomised Phase 3 Study 1 and in 99 (66%) and 513 (55%) patients in Study A and Study B, respectively. This event was reported as mild (96%), moderate (3%), and severe (< 1%) with median times to onset of 5 days, 15 days and 7 days in Studies 1, A, and B, respectively. No patients from randomised Phase 3 Study 1, 1 patient from Study A and 4 patients from Study B had temporary treatment discontinuation. One patient from randomised Phase 3 Study 1 and 1 patient from Study B had a dose reduction for vision disorder. Permanent discontinuation from crizotinib treatment due to vision disorder was not required for any patients in Studies 1, A, or B. Ophthalmological evaluation should be considered if vision disorder persists or worsens in severity (see section 4.4). Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in randomised Phase 3 Study 1 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorders generally started within the first week of drug administration. The majority (of patients on the XALKORI arm in randomised Phase 3 Study 1 (> 50%) reported visual disturbances; which occurred at a frequency of 4 to 7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in a patient questionnaire. Nervous system effects Treatment-emergent all-causality neuropathy as defined in Table 3, was experienced by 33 (19%) patients in randomised Phase 3 Study 1 and 36 (24%) and 178 (19%) patients in Studies A and B, respectively. Dysgeusia was also very commonly reported in these studies, and was primarily Grade 1 in severity. Renal cyst Treatment-emergent all-causality complex renal cysts were experienced by 7 (4%) patients in randomised Phase 3 Study 1 and 1 (< 1%) and 12 (1%) patients in Studies A and B, respectively. Local cystic invasion beyond the kidney was observed in some patients. Periodic monitoring with imaging and urinalysis should be considered in patients who develop renal cysts. Neutropenia and Leukopenia Grade 3 or 4 neutropenia was observed in 13%, 6% and 11% of patients treated with crizotinib in randomised Phase 3 Study 1, Study A and Study B, respectively. Median times to onset of any Grade neutropenia was 43, 197 and 47 days, respectively; median times to onset of Grade 3 or 4 neutropenia was 165, 197 and 64 days, respectively. Neutropenia was associated with dose reduction for 2%, 1% and 3% of crizotinib-treated patients in randomised Phase 3 Study 1, Study A and Study B, respectively. Neutropenia was associated with permanent treatment discontinuation for <1% of patients in Study B. There were no permanent treatment discontinuation due to neutropenia in Study A and randomised Phase 3 Study 1. Less than 1% of patients experienced febrile neutropenia in clinical trials with crizotinib. Grade 3 or Grade 4 leukopenia was observed in 2% of patients in both the randomised Phase 3 Study 1 and Study B and in <1% of patients in Study A. In randomised Phase 3 Study 1, Study A and Study B, median times to onset of any Grade leukopenia was 64, 75 and 43 days, respectively; median times to onset of Grade 3 or 4 leukopenia was 373, 299 and 75 days, respectively. Leukopenia was associated with a dose reduction for <1% of patients in randomised Phase 3 Study 1 and Study B. There were no dose reductions associated with leukopenia in Study A. Leukopenia was not associated with permanent treatment discontinuation for any patients in randomised Phase 3 Study 1, Study A or Study B. In randomised Phase 3 Study 1, shifts to Grade 3 or 4 decreases in leukocytes and neutrophils were observed at frequencies of 5% and 13%, respectively. In Study A, shifts to Grade 3 or 4 decreases in leukocytes and neutrophils were observed at frequencies of <3% and 8%, respectively. In Study B, shifts to Grade 3 or 4 decreases in leukocytes and neutrophils were observed at a frequency of <3% and 8%, respectively. Complete blood counts including differential white blood cell counts should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs. For patients who develop hematologic laboratory abnormalities, see section 4.2. 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 internet at www.mhra.gov.uk/yellowcard. 4.9 Overdose Treatment of overdose with the medicinal product consists of general supportive measures. There is no antidote for XALKORI. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Anti-neoplastic agents, protein kinase inhibitor; ATC code: L01XE16. Mechanism of action Crizotinib is a selective small-molecule inhibitor of the ALK receptor tyrosine kinase (RTK) and its oncogenic variants (i.e. ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the Hepatocyte Growth Factor Receptor (HGFR, c-Met) RTK, and Recepteur d'Origine Nantais (RON) RTK. Crizotinib demonstrated concentration-dependent inhibition of the kinase activity of ALK and c-Met in biochemical assays and inhibited phosphorylation and modulated kinase-dependent phenotypes in cell-based assays. Crizotinib demonstrated potent and selective growth inhibitory activity and induced apoptosis in tumour cell lines exhibiting ALK fusion events (including EML4-ALK and NPM-ALK), or exhibiting amplification of the ALK or MET gene locus. Crizotinib demonstrated anti-tumour efficacy, including marked cytoreductive anti-tumour activity, in mice bearing tumour xenografts that expressed ALK fusion proteins. The anti-tumour efficacy of crizotinib was dose-dependent and correlated to pharmacodynamic inhibition of phosphorylation of ALK fusion proteins (including EML4-ALK and NPM-ALK) in tumours in vivo. Clinical studies Randomised Phase 3 Study 1 The use of single-agent crizotinib in the treatment of ALK-positive advanced NSCLC with or without brain metastases was investigated in 2 a multicenter, multinational, randomised, open-label Phase 3 study (Study 1). The primary objective of this study was to demonstrate that crizotinib 250 mg orally twice daily was superior to second-line standard-of-care chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2) intravenously (IV) every 21 days in prolonging Progression-Free Survival (PFS) in patients with ALK-positive advanced NSCLC who were to receive only 1 prior platinum-based chemotherapy regimen for advanced NSCLC. Patients were required to have ALK-positive NSCLC identified by the Vysis ALK Break Apart FISH Probe Kit from the central laboratory prior to randomization. For patients randomized to the chemotherapy arm, the first choice was to be pemetrexed unless patients received pemetrexed as part of their prior therapy or had squamous histology. The primary efficacy endpoint was PFS with disease progression events determined by IRR. Secondary endpoints included Objective Response Rate (ORR) as determined by independent radiology review (IRR), Duration of Response (DR), Overall Survival (OS), 6-month and 1-year OS probabilities, and Patient-Reported Outcomes (PRO). Patients could continue treatment as assigned beyond the time of RECIST-defined disease progression, as assessed by IRR, at the discretion of the investigator if the patient was perceived to be experiencing clinical benefit. Patients randomised to chemotherapy could cross over to receive crizotinib upon RECIST-defined disease progression confirmed by IRR. The full analysis population for Study 1 included 347 patients with ALK-positive advanced NSCLC. One hundred seventy-three (173) patients were randomised to the crizotinib arm (172 patients received crizotinib) and 174 patients were randomised to the chemotherapy arm (99 [58%] patients received pemetrexed and 72 [42%] patients received docetaxel). Randomization was stratified by ECOG performance status (0-1, 2), brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor treatment (yes, no). The median duration of study treatment was 31 weeks in the crizotinib arm as compared to 12 weeks in the chemotherapy arm. Fifty eight of 84 (69%) crizotinib-treated patients and 17 of 119 (14%) chemotherapy-treated patients continued treatment for at least 3 weeks after objective disease progression. Key demographic and baseline characteristics for patients in this study were comparable between the crizotinib and chemotherapy arms. The demographic characteristics of the overall study population were 56% female, median age of 50 years, baseline ECOG performance status 0 (39%) or 1 (52%), 52% White and 45% Asian, 4% current smokers, 33% past-smokers, and 63% never smokers. The disease characteristics were metastatic disease in 93% of patients and in 93% of patients' tumors were classified as adenocarcinoma histology. Crizotinib significantly prolonged PFS compared to chemotherapy as assessed by IRR (see Table 4 and Figure 1). The PFS benefit of crizotinib was consistent across subgroups of baseline patient characteristics such as age, gender, race, smoking class, time since diagnosis, ECOG performance status score, presence of brain metastases and prior EGFR TKI therapy. Crizotinib also significantly improved IRR-assessed ORR as compared to chemotherapy. Median DR was 32.1 weeks (95% CI: 26.4, 42.3) in the crizotinib arm and 24.4 weeks (95% CI: 15.0, 36.0) in the chemotherapy arm. Overall survival (OS) data were not mature at the time of the PFS analysis. There was no statistically significant difference between crizotinib and chemotherapy in the preliminary OS analysis that was not adjusted for the potentially confounding effects of crossover. Of the 174 patients in the chemotherapy arm, 112 (64.4%) patients subsequently received crizotinib treatment. Efficacy data from randomised Phase 3 Study 1 are summarized in Table 4, and the Kaplan-Meier curve for PFS is shown in Figure 1. The Kaplan-Meier curve for OS is shown in Figure 2. Table 4. ALK-positive advanced NSCLC efficacy results from randomised phase 3 Study 1 (full analysis population) Response Parameter Crizotinib (N=173) Chemotherapy (N=174) Progression-Free Survival (Based on IRR) Number with event, n (%) 100 (58%) 127 (73%) Type of event, n (%)     Progressive Disease 84 (49%) 119 (68%) Death without objective progression 16 (9%) 8 (5%) Median PFS in months (95% CI) 7.7 (6.0, 8.8) 3.0a (2.6, 4.3) HR (95% CI)b 0.49 (0.37, 0.64) p-valuec <0.0001 Overall Survivald Number of deaths, n (%) 49 (28%) 47 (27%) Median OS in months (95% CI) 20.3 (18.1, NR) 22.8 (18.6, NR) HR (95% CI)b 1.02 (0.68, 1.54) p-value c 0.54 6-Month Survival Probability,e % (95% CI) 86.8 (80.4, 91.2) 83.8 (77.0, 88.7) 1-Year Survival Probability,e % (95% CI) 69.5 (60.6, 76.8) 71.8 (63.3, 78.7) Tumor Responses (Based on IRR) Objective Response Rate % (95% CI) 65% (58, 72) 20%f (14, 26) p-valueg <0.0001 Duration of Response Mediane, Months (95% CI) 7.4 (6.1, 9.7) 5.6 (3.4, 8.3) HR = Hazard Ratio; CI = confidence interval; NR= not reached a. The median PFS was 4.2 months (95% CI: 2.8, 5.7) with pemetrexed (HR=0.59; p=0.0004 for XALKORI compared with pemetrexed) and 2.6 months (95% CI: 1.6, 4.0) with docetaxel (HR=0.30; p<0.0001 for XALKORI compared with docetaxel). b. Based on the Cox proportional hazards stratified analysis. c. Based on the stratified Log-rank test. d. Interim OS analysis conducted at 40% of total events required for final analysis. e. Estimated using the Kaplan-Meier method. f. The ORR was 29% (95% CI: 21%, 39%) with pemetrexed (p<0.0001 compared with XALKORI) and 7% (95% CI: 2%, 16%) with docetaxel (p<0.0001 compared with XALKORI). g. Based on the stratified Cochran-Mantel-Haenszel test. Figure 1. Kaplan-Meier curves for progression-free survival (based on IRR) by treatment arm in randomised phase 3 Study 1 (full analysis population) Figure 2. Kaplan-Meier curves for overall survival by treatment arm in randomized phase 3 Study 1 (full analysis population) A total of 162 patients in the Crizotinib arm and 151 patients in the chemotherapy arm had completed the EORTC QLQ-C30 and LC-13 questionnaires at baseline and at least one post baseline visit. Crizotinib resulted in symptom benefits by significantly prolonging time to deterioration (median 5.6 months versus 1.4 months) in patient reported symptoms of pain in chest, dyspnoea, or cough, compared to chemotherapy (hazard ratio 0.54; 95% CI: 0.40, 0.71; Hochberg adjusted log-rank p< 0.0001). Figure 3. Kaplan-Meier plot of time to deterioration in pain (in chest), dyspnea, or cough (composite endpoint) by arm (patient-reported outcome evaluable population) Crizotinib showed a significantly greater improvement from baseline compared to chemotherapy in alopecia (cycle 2 to 15; p<0.05), cough (Cycle 2 to 20; p<0.0001), dyspnea (cycles 2 to 20; p<0.0001), hemoptysis (cycle 2 to 20; p<0.05), pain in arm or shoulder (cycles 2 to 20; p<0.0001), pain in chest (cycles 2 to 20; p<0.0001), and pain in other parts (cycles 2 to 20; p<0.05). Crizotinib resulted in a significantly lower deterioration from baseline in peripheral neuropathy (cycle 6 to 20; p<0.05), dysphagia (cycles 5 to 11; p<0.05) and sore mouth (cycle 2 to 20; p<0.05) compared to chemotherapy. Crizotinib resulted in overall global quality of life benefits with a significantly greater improvement from baseline observed in the crizotinib arm compared to the chemotherapy arm (cycles 2 to 20; p<0.05). Single-Arm Studies in ALK-Positive Advanced NSCLC The use of single-agent XALKORI in the treatment of ALK-positive advanced NSCLC was investigated in 2 multicenter, multinational, single-arm studies (Studies A and B). Of the patients enrolled in these studies, the patients described below had received prior systemic therapy for locally advanced or metastatic disease. The primary efficacy endpoint in both studies was ORR according to Response Evaluation Criteria in Solid Tumours (RECIST). Secondary endpoints included Time to Tumour Response (TTR) DR, PFS, and OS. Patients received crizotinib 250 mg orally twice daily. In Study A, patients with advanced NSCLC were required to have ALK-positive tumours prior to entering the clinical trial. ALK-positive NSCLC was identified using a number of local clinical trial assays. One hundred forty-nine ALK-positive advanced NSCLC patients, including 125 patients with previously treated ALK-positive advanced NSCLC were enrolled into Study A at the time of data cutoff. The demographic characteristics were 50% female, median age of 51 years, baseline ECOG performance status of 0 (32%) or 1 (55%), 61% White and 30% Asian, less than 1% were current smokers, 27% past-smokers, and 72% never smokers. The disease characteristics were 94% metastatic, 98% of the cancers were classified as adenocarcinoma histology.The median duration of treatment was 42 weeks. In Study B, patients with advanced NSCLC were required to have ALK-positive tumours prior to entering the clinical trial. For most patients,ALK-positive NSCLC was identified using the Vysis ALK Break-Apart FISH Probe Kit assay. Nine hundred thirty-four patients with ALK-positive advanced NSCLC were treated with crizotinib in Study B at the time of data cutoff. The demographic characteristics were 57% female, median age of 52 years, baseline ECOG performance status of 0/1 (82%) or 2/3 (18%), 52% White and 44% Asian, 4% current smokers, 30% past-smokers, and 66% never smokers. The disease characteristics were 92% metastatic; 94% of the cancers were classified as adenocarcinoma histology. The median duration of treatment for these patients was 23 weeks. Patients could continue treatment as assigned beyond the time of RECIST-defined disease progression at the discretion of the investigator if the benefit/risk assessment justified continuation of treatment. Seventy seven of 106 patients (73%) continued crizotinib treatment for at least 3 weeks after objective disease progression. Seven hundred sixty-five patients (82%) with previously treated ALK-positive advanced NSCLC from Study B were both evaluable for response and identified by the same FISH assay used in randomised Phase 3 study 1. There were 8 complete responses and 357 partial responses for an ORR of 48%. The median DR was 47.3 weeks. Eighty-three percent of objective tumour responses were achieved within the first 12 weeks of treatment. Main efficacy data from Studies A and B are provided in Table 5. Table 5: ALK-positive advanced NSCLC efficacy results from Studies A and B Efficacy Parameter Study A (N=125) Study B (N=765) Objective Response Ratea [% (95% CI)] 60 (51, 69) 48 (44, 51) Time to Tumour Response [median (range)] weeks 7.9 (2.1, 39.6) 6.1 (3, 49) Duration of Responseb [median (95% CI)] weeks 48.1 (35.7, 64.1) 47.3 (36, 54) Progression-Free Survivalb [median (95% CI)] months 9.2 (7.3, 12.7) 7.8 (6.9, 9.5)c Median OS Not reached Not reached OS probability at 12 monthsb [% (95% CI)] 72 (63, 80) 66.5 (62, 70.6)c CI = confidence interval a. Four patients were not evaluable for response in Study A and 42 patients were not evaluable for response in Study B. b. Estimated using the Kaplan-Meier method. c. PFS and OS data from Study B included 807 patients in the safety analysis population who were identified by the FISH assay. Non-adenocarcinoma histology Twelve patients with previously treated advanced ALK-positive non-adenocarcinoma histology NSCLC were enrolled in randomised Phase 3 Study 1. This subgroup was small to draw reliable conclusions. Information is available from only 48 response-evaluable patients with previously treated non-adenocarcinoma NSCLC in Studies A and B. Partial responses were observed in 20 of these patients for an ORR of 42%, which was less than the ORRs reported in Study A (60%) and Study B (48%). Elderly Of the 172 crizotinib-treated patients in randomised Phase 3 Study 1, 27 (16%) were 65 years or older. Of the 149 patients in Study A, 20 (13%) were 65 years or older. Of the 934 patients in Study B, 152 (16%) were 65 years or older. No patients in the crizotinib arm of randomised Phase 3 Study 1, or Studies A or B were 85 years or older. Patients with brain metastases Fifty-two (52) crizotinib-treated patients and 57 chemotherapy-treated patients with previously treated or untreated asymptomatic brain metastases (BM) were enrolled in randomised Phase 3 Study 1. Disease Control Rate (DCR) at 12 weeks was defined as best overall response of confirmed CR, confirmed PR or SD at 12 weeks. Intracranial (IC) DCR at 12 weeks was 65% and 46% for crizotinib and chemotherapy-treated patients respectively. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with XALKORI in all subsets of the paediatric population in NSCLC. Lung carcinoma is included under the list of conditions waived for paediatric development since this condition does not normally occur in the paediatric population(see section 4.2 for information on paediatric use). Conditional approval This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited, including the final OS results of a Randomised Phase 3 Study 1. The European Medicines Agency will review new information on this medicinal product at least every year, and this SmPC will be updated as necessary. 5.2 Pharmacokinetic properties Absorption Following oral single dose administration in the fasted state, crizotinib is absorbed with median time to achieve peak concentrations of 4 to 6 hours. With twice daily dosing, steady-state was achieved within 15 days. The absolute bioavailability of crizotinib was determined to be 43% following the administration of a single 250 mg oral dose. A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14% when a 250 mg single dose was given to healthy volunteers. Crizotinib can be administered with or without food (see section 2.1). Distribution The geometric mean volume of distribution (Vss) of crizotinib was 1772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma. Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of medicinal product concentration. In vitro studies suggest that crizotinib is a substrate for P-glycoprotein (P-gp). Biotransformation In vitro studies demonstrated that CYP3A4/5 were the major enzymes involved in the metabolic clearance of crizotinib. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites. In vitro studies in human liver microsomes demonstrated that crizotinib is a time-dependent inhibitor of CYP2B6 and CYP3A (see section 4.5). In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of medicinal products that are substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. In vitro studies showed that crizotinib is a weak inhibitor of UGT1A1 and UGT2B7 (see section 4.5). However, in vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for UGT1A4, UGT1A6, or UGT1A9. In vitro studies in human hepatocytes indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated induction of the metabolism of medicinal products that are substrates for CYP1A2. Elimination Following single doses of crizotinib, the apparent plasma terminal half life of crizotinib was 42 hours in patients. Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. Coadministration with medicinal products that are substrates of transporters Crizotinib is an inhibitor of P-glycoprotein (P-gp) in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered medicinal products that are substrates of P-gp (see section 4.5). Crizotinib is an inhibitor of OCT1 and OCT2 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2 (see section 4.5). In vitro, crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3 or the renal uptake transport proteins OAT1 or OAT3 at clinically relevant concentrations. Therefore, clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the hepatic or renal uptake of medicinal products that are substrates for these transporters. Effect on other transport proteins In vitro, crizotinib is not an inhibitor of BSEP at clinically relevant concentrations. Pharmacokinetics in special patient groups Hepatic insufficiency As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, crizotinib has not been studied in patients with hepatic impairment. Clinical studies that were conducted excluded patients with ALT or AST >2.5 x ULN or, if due to underlying malignancy, >5.0 x ULN or with total bilirubin >1.5 x ULN (see section 4.2). The population pharmacokinetic analysis using the data from these studies indicated that baseline total bilirubin or AST levels, did not have a clinically meaningful effect on the pharmacokinetics of crizotinib. Renal insufficiency Patients with mild (60 ≤ CLcr <90 mL/min) and moderate (30 ≤ CLcr < 60 mL/min) renal impairment were enrolled in single-arm Studies A and B. The effect of renal function as measured by baseline CLcr on observed crizotinib steady state trough concentrations (Ctrough, ss) was evaluated. In Study A, the adjusted geometric mean of plasma Ctrough, ss in mild (N=35) and moderate (N=8) renal impairment patients were 5.1% and 11% higher, respectively, than those in patients with normal renal function. In Study 1005, the adjusted geometric mean Ctrough, ss of crizotinib in mild (N=191) and moderate (N=65) renal impairment groups were 9.1% and 15% higher, respectively, than those in patients with normal renal function. In addition, the population pharmacokinetic analysis using data from Studies A and B indicated CLcr did not have a clinically meaningful effect on the pharmacokinetics of crizotinib. Due to the small size of the increases in crizotinib exposure (5-15%), no starting dose adjustment is recommended for patients with mild or moderate renal impairment. After a single 250-mg dose in subjects with severe renal impairment (CLcr <30 mL/min) not requiring peritoneal dialysis or hemodialysis, crizotinib AUC and Cmax increased by 79% and 34%, respectively, compared to those with normal renal function. An adjustment of the dose of crizotinib is recommended when administering crizotinib to patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis (see sections 4.2 and 4.4). Age Based on the population pharmacokinetic analysis of data from Studies A and B, age has no effect on crizotinib pharmacokinetics. Body weight and gender Based on the population pharmacokinetic analysis of data from Studies A and B, there was no clinically meaningful effect of body weight or gender on crizotinib pharmacokinetics. Ethnicity Based on the population pharmacokinetic analysis of data from Studies A and B, the predicted steady state AUC (95% CI) was 23-37% higher in Asian patients (n=523) than in non-Asian patients (n=691). Adverse effects were generally reported with a slightly higher incidence in Asian patients than in non-Asian patients, including renal cysts and Grade 3/4 neutropenia. Geriatric Limited data are available in this subgroup of patients (see sections 4.2, 4.4 and 5.1). Based on the population pharmacokinetic analysis of data in Studies A and B, age has no effect on crizotinib pharmacokinetics. Cardiac electrophysiology The QT interval prolongation potential of crizotinib was assessed in all patients who received crizotinib 250 mg twice daily. Serial ECGs in triplicate were collected following a single dose and at steady-state to evaluate the effect of crizotinib on QT intervals. Sixteen of 1196 patients (1.3%) were found to have QTcF ≥500 msec, and 51 of 1165 patients (4.4%) had an increase from baseline QTcF ≥60 msec by automated machine-read evaluation of ECG. A central tendency analysis of the QTcF data demonstrated that the highest upper bound of the two-sided 90% CI for QTcF was <15 msec at the protocol pre-specified time points. A pharmacokinetic/pharmacodynamic analysis suggested a relationship between crizotinib plasma concentration and QTc. A decrease in heart rate was found to be associated with increasing crizotinib plasma concentration (see section 4.4). 5.3 Preclinical safety data In rat and dog repeat-dose toxicity studies up to 3 months duration, the primary target organ effects were related to the gastrointestinal (emesis, fecal changes, congestion), hematopoietic (bone marrow hypocellularity), cardiovascular (mixed ion channel blocker, decreased heart rate and blood pressure, increased LVEDP, QRS and PR intervals, and decreased myocardial contractility), or reproductive (testicular pachytene spermatocyte degeneration, single-cell necrosis of ovarian follicles) systems. The No Observed Adverse Effect Levels (NOAEL) for these findings were either subtherapeutic or up to 2.6-fold human clinical exposure based on AUC. Other findings included an effect on the liver (elevation of liver transaminases) and retinal function, and potential for phospholipidosis in multiple organs without correlative toxicities. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. Crizotinib was aneugenic in an in vitro micronucleus assay in Chinese Hamster Ovary cells and in an in vitro human lymphocyte chromosome aberration assay. Small increases of structural chromosomal aberrations at cytotoxic concentrations were seen in human lymphocytes. The NOAEL for aneugenicity was approximately 1.8-fold human clinical exposure based on AUC. Carcinogenicity studies with crizotinib have not been performed. No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given ≥50 mg/kg/day for 28 days (approximately 1.1-fold human clinical exposure based on AUC). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day for 3 days. Crizotinib was not shown to be teratogenic in pregnant rats or rabbits. Post-implantation loss was increased at doses ≥50 mg/kg/day (approximately 0.4 times the AUC at the recommended human dose) in rats, and reduced fetal body weights were considered adverse effects in the rat and rabbit at 200 and 60 mg/kg/day, respectively (approximately 1.2-fold human clinical exposure based on AUC). Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 3.3 times human clinical exposure based on AUC). Other toxicities of potential concern to paediatric patients have not been evaluated in juvenile animals. The results of an in vitro phototoxicity study demonstrated that crizotinib may have phototoxic potential. 6. Pharmaceutical particulars 6.1 List of excipients  Capsule content Silica, colloidal anhydrous Cellulose, microcrystalline Calcium hydrogen phosphate, anhydrous Sodium starch glycolate (Type A) Magnesium stearate Capsule shell Gelatin Titanium dioxide (E171) Red iron oxide (E172) Printing ink Shellac Propylene glycol Potassium hydroxide Black iron oxide (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 HDPE bottles with a polypropylene closure containing 60 hard capsules. PVC-foil blisters containing 10 hard capsules. Each carton contains 60 hard capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling  Any unused 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/1/12/793/001 EU/1/12/793/002 EU/1/12/793/003 EU/1/12/793/004 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 23 October 2012 10. Date of revision of the text 05/2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. FDA批准Xalkori和伴随诊断试验用于晚期肺癌 2011年8月26日，辉瑞和美国食品药品管理局(FDA)宣布，Xalkori(crizotinib)已获准用于治疗特定的晚期(局部进展性或转移性)、表达间变性淋巴瘤激酶(ALK)基因的非小细胞肺癌(NSCLC)患者。罹患这种肺癌的患者通常不吸烟。Xalkori被批准与雅培的一种伴随诊断基因检测——Vysis ALK Break Apart FISH Probe Kit——共同使用。该检测用于确定患者的癌症是否表达异常的ALK基因。 Xalkori是一种激酶抑制剂，其治疗肺癌的适应证是以应答率为基础的。尚无数据证实该药可改善患者报告的预后或生存率。Xalkori被认为通过阻断多种细胞通路的信号传导而发挥疗效，据称这些细胞通路对于肿瘤细胞的生长和生存至关重要，该药可使肿瘤趋于稳定和退化。ALK基因的改变被认为是NSCLC之类肿瘤进展的关键驱动因素。 Xalkori的安全性和有效性已在2项多中心、单组研究中获得证实，这2项研究共纳入了255例晚期ALK阳性NSCLC患者。研究者在招募患者前采集其肺癌组织样本，进行ALK基因检测。多数入组患者曾接受过化疗。在其中一项研究中，客观应答率为50%、中位应答时间为42周，而在另一项研究中分别为61%和48周。 两项研究中最常报告的不良反应均为视力障碍、恶心、腹泻、呕吐、浮肿和便秘。两项研究中均有至少4%的患者发生3或4级不良反应，包括谷丙转氨酶水平升高和中性粒细胞减少。 使用Xalkori还与肺炎相关，甚至可危及生命。发生治疗相关性肺炎的患者必须永久停用Xalkori。 Xalkori为胶囊制剂，每日服药2次，单药治疗。 关于 XALKORI(®) (Crizotinib) XALKORI®是一种用于治疗通过FDA批准的检测确认为间变性淋巴瘤激酶 (ALK)阳性的晚期或转移的非小细胞肺癌 (NSCLC)患者的激酶抑制剂。获批适应症基于客观缓解率。目前尚无数据表明XALKORI®可以改善患者报告结果（patient reported outcome）或生存。XALKORI® 通过阻断对肿瘤细胞生长与存活起关键作用的多种细胞通路，导致肿瘤的稳定或消退。ALK基因变异被认为是非小细胞肺癌（NSCLC）等癌症发生的关键驱动因素。尽管ALK 在非鳞状细胞癌、无吸烟史或轻度吸烟史患者中较为常见，但也在吸烟和鳞状细胞癌组织患者中也有发现。ALK 基因变异的出现与年龄、性别、种族 和是否吸烟等无关。 试验同时证明，XALKORI®可以抑制 c-MET 受体酪氨酸激酶，目前正在进行试验之中。 重要的XALKORI(®) (Crizotinib) 安全性信息 在临床研究中与XALKORI®治疗相关的严重的、危及生命或致死的局限性肺炎发生率为 4/255 (1.6%)。应该排除其他因素引起的局限性肺炎。如果患者出现治疗相关的局限性肺炎，应永久停止XALKORI® 治疗。 患者在试验 A和试验B 中，分别有7% 和4%的患者出现3级或 4级 ALT升高。在试验 A和试验B 中，分别有3名(2%)患者和1名(<1%)患者需要永久停止治疗。应该每月和出现临床症状时监测包括ALT与总胆红素指标在内的肝功能变化，如果出现2-4级转氨酶升高时，应增加肝功能监测频度，并根据情况采取临时中断、减少剂量或永久性停用 XALKORI®等措施。 试验曾发现QT 延长。XALKORI®应避免用于先天性长QT 综合症的患者。充血性心力衰竭、缓慢性心律失常、电解质异常或服用可延长QT间期药品的患者，应对心电图与电解质进行定期监测。如出现4级QTc 延长，则应永久停止XALKORI® 。如果出现3级 QTc延长，则应暂停XALKORI®，直至恢复到≤1级。如果再次出现3级 QTc，则应永久停用XALKORI®。 在选择使用XALKORI®治疗的患者时，必须使用经过FDA批准的检测方法来诊断ALK阳性非小细胞肺癌（NSCLC）。 根据其作用机制，孕妇服用XALKORI®可导致胎儿受损。可能怀孕的妇女应避免在服用XALKORI®期间受孕，如果患者或其伙伴在服药时怀孕，则患者应对胎儿的危险进行评估。 在两项单臂临床试验 (试验 A与试验B)中，对255 名局部晚期或转移的 ALK-阳性 非小细胞肺癌（NSCLC）患者进行了XALKORI®安全性的分析。在两项临床试验中，最常见的副作用 (≥25%)为视力障碍、恶心、腹泻、呕吐、水肿与便秘。在两项临床试验中，≥4% 的患者出现的3/4级副作用包括ALT升高与嗜中性白血球减少症。 视力障碍包括视力受损、闪光感 (感受到光线闪耀)、视力模糊、 玻璃体漂浮物、畏光 (对亮光敏感)以及复视 (重影)，在临床试验中，有159 (62%) 名患者出现过上述问题。 如果患者出现闪光感或出现新的玻璃体漂浮物（vitreous floaters）或玻璃体漂浮物增多，应予以眼科检查评估。玻璃体漂浮物及/或闪光感（photopsia）的加重或恶化，也可能是提示有视网膜裂孔（retinal hole） 或即将发生视网膜脱离（retinal detachment）的信号。对于出现视力障碍的患者，在驾车或者操作机器时应谨慎对待。 ---------------------------------------------------------- 提示：本品已全球上市销售，各个国家的价格有所不同，购买以咨询为准！ ---------------------------------------------------------- 原产地英文商品名: XALKORI 250MG/CAP 60CAPS/BOX 原产地英文药品名: CRIZOTINIB 中文参考商品译名: XALKORI 250毫克/胶囊 60胶囊/盒 中文参考药品译名: 克里唑蒂尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: PFIZER --------------------------------------------------------------- 原产地英文商品名: XALKORI 200MG/CAP 60CAPS/BOX 原产地英文药品名: CRIZOTINIB 中文参考商品译名: XALKORI 200毫克/胶囊 60胶囊/盒 中文参考药品译名: 克里唑蒂尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: PFIZER 该药品相关信息网址1: http://www.xalkori.com/ 该药品相关信息网址2: http://www.drugs.com/xalkori.html