Crizotinib

1 INDICATIONS AND USAGE XALKORI is a kinase inhibitor indicated for the treatment of • adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. ( 1.1 , 2.1 ) • pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive. ( 1.2 , 2.3 ) o Limitations of Use: The safety and efficacy of XALKORI have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. • adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. ( 1.3 , 2.3 ) 1.1 ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer XALKORI is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test [see Dosage and Administration (2.1) ] . 1.2 Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell Lymphoma XALKORI is indicated for the treatment of pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive . Limitations of Use : The safety and efficacy of XALKORI have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. 1.3 Unresectable, Recurrent, or Refractory ALK-Positive Inflammatory Myofibroblastic Tumor XALKORI is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive.

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity: Fatal hepatotoxicity has occurred. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 2.2 , 2.6 , 5.1 ) • Interstitial Lung Disease (ILD)/Pneumonitis: Permanently discontinue in patients with ILD/pneumonitis. ( 2.6 , 5.2 ) • QT Interval Prolongation: Monitor electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 2.6 , 5.3 ) • Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 2.6 , 5.4 ) • Severe Visual Loss: XALKORI can cause visual changes including severe visual loss. Monitor and evaluate for ocular toxicity throughout treatment. Discontinue XALKORI in patients with severe visual loss. ( 2.2 , 2.6 , 5.5 ) • Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT: XALKORI can cause severe nausea, vomiting, diarrhea, and stomatitis. Provide standard antiemetic and antidiarrheal agents. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 2.6 , 5.6 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Hepatotoxicity Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of the 1719 patients treated with XALKORI for NSCLC across clinical trials [see Adverse Reactions (6.1) ] . Concurrent elevations in ALT or AST ≥3 times the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in 5 times the ULN occurred in 11% and 6% of patients, respectively. One percent (1.0%) of patients required permanent discontinuation due to elevated transaminases. Increased transaminases generally occurred within the first 2 months of treatment. In Study ADVL0912, of 121 patients ages 1 to ≤21 years treated with XALKORI for relapsed or refractory tumors including ALCL and IMT, 71% and 79% had increases of AST and ALT, respectively, with increased ALT or AST >5 times the ULN in 6% each. Of the 26 patients with ALCL treated with XALKORI, 65% and 81% had increases of AST and ALT, respectively, with increases >5 times the ULN in 4% each. Of the 14 pediatric patients with IMT treated with XALKORI, 71% had increases of AST and 71% had increases of ALT. In Study A8081013, of the 7 adult patients with IMT treated with XALKORI, 57% and 43% had increases of AST and ALT, respectively. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop increased transaminases. Withhold, reduce dose, or permanently discontinue XALKORI for hepatotoxicity as recommended [see Dosage and Administration (2.6) ] . 5.2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials in patients with NSCLC (n=1719), 2.9% of XALKORI-treated patients had ILD of any grade, 1% had Grade 3 or 4 ILD, and 0.5% had fatal ILD [see Adverse Reactions (6.1) ] . Interstitial lung disease generally occurred within 3 months after the initiation of XALKORI. In Study ADVL0912, among 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including ALCL and IMT, ILD occurred in 0.8% of patients. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.6) ] . 5.3 QT Interval Prolongation QTc prolongation can occur in patients treated with XALKORI. Across clinical trials in patients with NSCLC, 2.1% of 1616 patients had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 500 ms and 5% of 1582 patients had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read evaluation of ECGs. In Study ADVL0912, QTc prolongation was reported as an adverse reaction in 4.1% of patients, including 8% of patients with ALCL and 7% of pediatric patients with IMT. Avoid use of XALKORI in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Withhold, reduce dose, or permanently discontinue XALKORI for QT/QTc interval prolongation as recommended [see Dosage and Administration (2.6) , Clinical Pharmacology (12.2) ] . 5.4 Bradycardia Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials in patients with NSCLC, bradycardia occurred in 13% of 1719 patients treated with XALKORI. Grade 3 syncope occurred in 2.4% of XALKORI-treated patients and in 0.6% of the chemotherapy-treated patients [see Adverse Reactions (6.1) ] . In Study ADVL0912, among 121 patients ages 1 to ≤21 years treated with XALKORI, bradycardia was reported in 14%, including Grade 3 bradycardia in 0.8% of patients. Of the 26 patients with ALCL treated with XALKORI, bradycardia (all Grade 1) was reported in 19%. Of the 14 pediatric patients with IMT treated with XALKORI, bradycardia was reported in 14% of patients, including Grade 3 bradycardia in 7% of patients. Avoid using XALKORI in combination with other medications known to cause bradycardia (e.g., beta-blockers, nondihydropyridine-calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. Withhold, reduce dose, or permanently discontinue XALKORI for bradycardia as recommended [see Dosage and Administration (2.6) ] . 5.5 Severe Visual Loss Across all clinical trials in patients with NSCLC, the incidence of Grade 4 visual field defect with visual loss was 0.2% of 1719 patients [see Adverse Reactions (6.1) ] . Optic atrophy and optic nerve disorder have been reported as potential causes of visual loss. In Study ADVL0912, visual disorders occurred in 46% of 121 patients with XALKORI, including 65% of 26 patients with ALCL and 50% of 14 patients with IMT. Of the 56 patients who experienced visual disorders, one pediatric patient with IMT experienced Grade 3 myopic optic nerve disorder. The most common visual symptoms were blurred vision and visual impairment. Assessment of visual symptoms for all patients is recommended monthly during treatment. Report new visual symptoms to an eye specialist. For pediatric and young adult patients with ALCL or pediatric patients with IMT, obtain baseline and follow-up ophthalmologic examinations including retinal examination within 1 month of starting XALKORI and every 3 months thereafter. The ophthalmological evaluation should consist of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate [see Dosage and Administration (2.6) , Adverse Reactions (6.1) ] . Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders or severe visual loss (best corrected vision less than 20/200 in one or both eyes) unless another cause is identified [see Dosage and Administration (2.6) ] . There is insufficient information to characterize the risks of resumption of XALKORI in patients who develop visual symptoms or visual loss. A decision to resume XALKORI should consider the potential benefits versus risks to the patient. 5.6 Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT XALKORI can cause severe gastrointestinal toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT [see Adverse Reactions (6.1) ] . In patients with ALCL (n=26), gastrointestinal toxicity occurred in 100% of patients; Grade 3 gastrointestinal toxicity occurred in 27% of patients and included diarrhea, nausea, vomiting, and stomatitis. In pediatric patients with IMT (n=14), vomiting occurred in 93%, nausea occurred in 86%, and diarrhea occurred in 64% of patients. Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT. Antiemetics are recommended prior to and during treatment with XALKORI to prevent nausea and vomiting. If patients develop Grade 3 nausea lasting 3 days or Grade 3 or 4 diarrhea or vomiting despite maximum medical therapy, withhold XALKORI until resolved, and then resume at the next lower dose level. Consider supportive care such as hydration, electrolyte supplementation, and nutritional support as clinically indicated [see Dosage and Administration (2.6) ] . 5.7 Embryo-Fetal Toxicity Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for 45 days following the last dose. Advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for 90 days after the last dose [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions (5.1) ] • Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2) ] • QT Interval Prolongation [see Warnings and Precautions (5.3) ] • Bradycardia [see Warnings and Precautions (5.4) ] • Severe Visual Loss [see Warnings and Precautions (5.5) ] • Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥25%) in adult patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. ( 6.1 ) The most common adverse reactions (≥35%) in patients with ALCL are diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus. Grade 3–4 laboratory abnormalities (≥15%) are neutropenia, lymphopenia, and thrombocytopenia. ( 6.1 ) The most common adverse reactions (≥35%) in adult patients with IMT are vision disorders, nausea, and edema. ( 6.1 ) The most common adverse reactions (≥35%) in pediatric patients with IMT are vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data in the Warnings and Precautions reflect exposure to XALKORI in 1719 patients with NSCLC who received XALKORI 250 mg twice daily enrolled on Studies 1 (including an additional 109 patients who crossed over from the control arm), 2, 3, a single-arm trial (n=1063) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154). The data also reflect exposure to XALKORI in 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including 26 patients with systemic ALCL and 14 pediatric patients with IMT, in a single-arm trial (Study ADVL0912). The data are also described for 7 adult patients with IMT treated with XALKORI in a single-arm trial (Study A8081013). ALK- or ROS1-Positive Metastatic NSCLC The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg orally twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3). The most common adverse reactions (≥25%) of XALKORI in patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. Previously Untreated ALK-Positive Metastatic NSCLC – Study 1 (PROFILE 1014) The data in Table 9 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 169 patients in the chemotherapy arm received pemetrexed 500 mg/m 2 with cisplatin 75 mg/m 2 (n=91) or carboplatin at a dose calculated to produce an AUC of 5 or 6 mg×min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression. The median duration of study treatment was 10.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian. Serious adverse events were reported in 34% of patients treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Dose reductions due to adverse reactions were required in 6% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (1.8%) and elevated transaminases (1.8%). Permanent discontinuation of XALKORI treatment for adverse reactions was 8%. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (1.2%), hepatotoxicity (1.2%), and ILD (1.2%). Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients. Table 9. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3–4) with XALKORI than Chemotherapy in Study 1 Adverse reactions were graded using NCI CTCAE version 4.0. Includes cases reported within the clustered terms: Adverse Reaction XALKORI (N=171) Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=169) All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Cardiac Bradycardia Bradycardia (Bradycardia, Sinus bradycardia). 14 1 1 0 Electrocardiogram QT prolonged 6 2 2 0 Eye Vision disorder Vision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual impairment). 71 1 10 0 Gastrointestinal Diarrhea 61 2 13 1 Vomiting 46 2 36 3 Constipation 43 2 30 0 Abdominal pain Abdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal tenderness). 26 0 12 0 Dyspepsia 14 0 2 0 Dysphagia 10 1 2 1 Esophagitis Esophagitis (Esophagitis, Esophageal ulcer). 6 2 1 0 General Edema Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema). 49 1 12 1 Pyrexia 19 0 11 1 Infections Upper respiratory infection Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection). 32 0 12 1 Investigations Increased weight 8 1 2 0 Musculoskeletal and Connective Tissue Pain in extremity 16 0 7 0 Muscle spasm 8 0 2 1 Nervous System Dysgeusia 26 0 5 0 Headache 22 1 15 0 Dizziness Dizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope). 18 0 10 1 Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), syncope (1%), and decreased blood testosterone (1%; hypogonadism). Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.3%). Table 10. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 1 XALKORI Chemotherapy Laboratory Abnormality Any Grade (%) Grade 3–4 (%) Any Grade (%) Grade 3–4 (%) Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 99%; Grade 3: 2%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 92%; Grade 3: 0%; Grade 4: 1%). Hematology Neutropenia 52 11 59 16 Lymphopenia 48 7 53 13 Chemistry Increased ALT 79 15 33 2 Increased AST 66 8 28 1 Hypophosphatemia 32 10 21 6 Previously Treated ALK-Positive Metastatic NSCLC – Study 2 (PROFILE 1007) The data in Table 11 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). Patients in the XALKORI arm (n=172) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m 2 (n=99) or docetaxel 75 mg/m 2 (n=72) by intravenous infusion every 3 weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment. The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least 1 dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian. Serious adverse reactions were reported in 37% of patients treated with XALKORI and 23% of patients in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 5% of patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure, and sepsis. Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were increased ALT (8%) including some patients with concurrent increased AST, QTc prolongation (2.9%), and neutropenia (2.3%). XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), increased ALT and AST (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%). Tables 11 and 12 summarize common adverse reactions and laboratory abnormalities, respectively, in XALKORI-treated patients. Table 11. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3–4) with XALKORI than Chemotherapy in Study 2 Adverse reactions were graded using NCI CTCAE version 4.0. Includes cases reported within the clustered terms: Adverse Reaction XALKORI (N=172) Chemotherapy (Pemetrexed or Docetaxel) (N=171) All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Nervous System Dysgeusia 26 0 9 0 Dizziness Dizziness (Balance disorder, Dizziness, Postural dizziness). 22 1 8 0 Syncope 3 3 0 0 Eye Vision disorder Vision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters). 60 0 9 0 Cardiac Electrocardiogram QT prolonged 5 3 0 0 Bradycardia Bradycardia (Bradycardia, Sinus bradycardia). 5 0 0 0 Investigations Decreased weight 10 1 4 0 Gastrointestinal Diarrhea 60 0 19 1 Nausea 55 1 37 1 Vomiting 47 1 18 0 Constipation 42 2 23 0 Dyspepsia 8 0 3 0 Infections Upper respiratory infection Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection). 26 0 13 1 Respiratory, Thoracic and Mediastinal Pulmonary embolism Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism). 6 5 2 2 General Edema Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema). 31 0 16 0 Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), esophagitis (2%), hepatic failure (1%), and decreased blood testosterone (1%; hypogonadism). Clinically relevant adverse reactions in 50%) reported visual disturbances which occurred at a frequency of 4–7 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 the VSAQ-ALK questionnaire. Neuropathy: Neuropathy, most commonly sensory in nature, occurred in 25% of 1719 patients. Most events (95%) were Grade 1 or Grade 2 in severity. Renal cysts: Renal cysts were experienced by 3.0% of 1719 patients. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests. Renal toxicity: The estimated glomerular filtration rate (eGFR) decreased from a baseline median of 96.42 mL/min/1.73 m 2 (n=1681) to a median of 80.23 mL/min/1.73 m 2 at 2 weeks (n=1499) in patients with ALK-positive advanced NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median eGFR from 12 to 104 weeks of treatment. Median eGFR slightly increased (83.02 mL/min/1.73 m 2 ) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in eGFR to <90 mL/min/1.73 m 2 , 38% had a decrease to eGFR to <60 mL/min/1.73 m 2 , and 3.6% had a decrease to eGFR to 2.5 times upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and central nervous system tumors. Patients with ALCL received XALKORI 165 mg/m 2 or 280 mg/m 2 orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure was 5.4 months (range 1.8, 82.3 months), with 46% of patients treated for at least 6 months and 35% of patients treated for at least 12 months. Serious adverse reactions occurred in 35% of patients with ALCL treated with XALKORI. The most frequent serious adverse reactions were neutropenia (12%) and hypotension (8%). Dose interruptions and dose reductions occurred in 77% and 19% of patients with ALCL, respectively. XALKORI was discontinued for an adverse reaction in 8% of patients. The most common adverse reactions (≥35%), excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritis. The most common Grade 3 or 4 laboratory abnormalities (≥15%) included neutropenia, lymphopenia, and thrombocytopenia. Grade 4 laboratory abnormalities (≥15%) included neutropenia (62%), lymphopenia (35%), and thrombocytopenia (19%). Selected adverse reactions are summarized in Table 13. Table 13. Adverse Reactions in ≥20% of Patients with Systemic ALCL in Study ADVL0912 Adverse reactions were graded using NCI CTCAE version 4.0. Adverse Reaction XALKORI N=26 All Grades (%) Grade 3–4 (%) Blood and Lymphatic System Disorders Derived from laboratory values collected in Cycle 1 and adverse reaction data. Neutropenia Includes neutrophil count decreased. 100 77 Lymphopenia Includes lymphocyte count decreased. 58 38 Anemia 54 3.8 Thrombocytopenia Includes platelet count decreased. 38 19 Gastrointestinal Disorders Diarrhea 92 12 Vomiting 92 3.8 Nausea 77 3.8 Abdominal Pain 50 0 Stomatitis Includes oral pain, oropharyngeal pain, stomatitis. 46 8 Constipation 31 0 Renal Disorders Blood creatinine increased 100 0 Investigations ALT increased 81 3.8 AST increased 65 3.8 Hypocalcemia 62 3.8 Hypoalbuminemia 54 0 Hyperglycemia 46 0 Hypomagnesemia 46 0 Hypoglycemia 35 0 Hypokalemia 31 3.8 Hypermagnesemia 27 0 Hyperkalemia 23 0 Nervous System Disorders Headache 58 3.8 Dysgeusia 23 0 Dizziness 23 0 Eye Disorders Vision disorders Includes blurred vision, visual impairment, photophobia, photopsia, reduced visual acuity, vitreous floaters, cyanopsia, heterophoria, visual field defect. 65 0 Musculoskeletal Disorders Musculoskeletal pain Includes arthralgia, back pain, myalgia, non-cardiac chest pain, pain in extremity. 58 12 General Disorders Fatigue 46 0 Pyrexia 38 0 Edema Includes peripheral edema, face edema, periorbital edema, localized edema. 27 0 Chills 23 0 Metabolism and Nutrition Disorders Decreased appetite 42 0 Skin and Subcutaneous Disorders Pruritus 35 0 Rash Includes rash maculopapular, rash pustular. 23 0 Infections Upper respiratory tract infection Includes upper respiratory tract infection, pharyngitis, rhinitis, sinusitis. 31 0 Respiratory Disorders Cough 35 0 Rhinitis allergic 23 0 Vascular Disorders Hypertension 31 0 Clinically relevant adverse reactions in 15%) was neutropenia. Table 14 and Table 15 summarize the adverse reactions and laboratory abnormalities, respectively, in Study ADVL0912. Table 14. Adverse Reactions in ≥20% of Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912 Adverse reactions were graded using NCI CTCAE version 4.0. Adverse Reaction XALKORI N=14 All Grades (%) Grade 3–4 (%) Gastrointestinal Disorders Vomiting 93 0 Nausea 86 0 Diarrhea 64 7 Abdominal pain Includes abdominal pain and abdominal pain upper. 57 0 Constipation 36 0 Stomatitis Includes oral pain and oropharyngeal pain. 29 0 Infections Upper respiratory tract infection Includes upper respiratory tract infection, pharyngitis, rhinitis. 64 0 Skin Infection 29 0 Respiratory Disorders Cough Includes cough and productive cough. 64 0 Rhinitis allergic 29 0 Skin and Subcutaneous Disorders Rash Includes rash maculopapular, rash pustular, dermatitis acneiform. 57 0 General Disorders Pyrexia 50 0 Fatigue 43 0 Edema Includes face edema, localized edema, periorbital edema, peripheral edema. 36 7 Pain Includes pain, bone pain, ear pain. 29 0 Eye Disorders Vision disorders Includes photophobia, photopsia, vision blurred, visual impairment, vitreous floaters. 50 0 Musculoskeletal Disorders Musculoskeletal pain Includes arthralgia, myalgia, non-cardiac chest pain, pain in extremity. 43 0 Nervous System Disorders Headache 36 0 Metabolism and Nutrition Disorders Decreased appetite 29 0 Vascular Disorders Hypotension 21 7 Clinically relevant adverse reactions in <20% of pediatric patients with IMT treated with XALKORI included: Cardiac disorders: Bradycardia (14%), electrocardiogram QT prolonged (7%) Gastrointestinal disorders: Dyspepsia (14%), esophagitis (7%) Vascular disorders: Hypertension (14%) Nervous system disorders: Peripheral neuropathy (7%) Blood and lymphatic disorders: Febrile neutropenia (7%) Musculoskeletal disorders: Muscular weakness (7%) Table 15. Laboratory Abnormalities (≥15%) That Worsened from Baseline in Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912 Laboratory Abnormality XALKORI The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement and varied from 13 to 14. , Laboratory abnormality data were only collected for the 1 st cycle (28 days) of treatment for the duration of the study. Any Grade (%) Grade 3–4 (%) Chemistry Increased creatinine 100 0 Decreased calcium 36 0 Increased magnesium 23 0 Decreased phosphate 15 0 Hematology Decreased neutrophils 64 36 Hepatic Increased ALT 36 0 Study A8081013 The safety of XALKORI for adult patients with ALK-positive IMT was evaluated in Study A8081013 [see Clinical Studies (14.3) ] that included 7 patients with IMT with a median age of 38 years (range 23 to 73). The safety profile of this patient group was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive or ROS1-positive NSCLC. The most frequent adverse reactions (≥20%) were vision disorders, nausea, and edema. 6.2 Postmarketing Experience The following additional adverse reaction has been identified during post-approval use of XALKORI. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Investigations : Increased blood creatine phosphokinase

7 DRUG INTERACTIONS • Strong CYP3A Inhibitors: Avoid concomitant use. ( 2.9 , 7.1 ) • Strong CYP3A Inducers: Avoid concomitant use. ( 7.1 ) • CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious adverse reactions. ( 7.2 ) 7.1 Effect of Other Drugs on XALKORI Strong or Moderate CYP3A Inhibitors Concomitant use of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions of XALKORI. Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the XALKORI dosage [see Dosage and Administration (2.9) ] . Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Use caution with concomitant use of moderate CYP3A inhibitors. Strong CYP3A Inducers Concomitant use of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may decrease the efficacy of XALKORI. Avoid concomitant use of strong CYP3A inducers. 7.2 Effect of XALKORI on Other Drugs CYP3A Substrates Concomitant use of crizotinib increases plasma concentrations of CYP3A substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions of these substrates. Avoid concomitant use of XALKORI with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use of XALKORI is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling. 7.3 Drugs That Prolong the QT Interval XALKORI can prolong the QT/QTc interval. Avoid concomitant use of XALKORI with drugs that prolong the QT interval [see Warnings and Precautions (5.3) , Clinical Pharmacology (12.2) ] . 7.4 Drugs That Cause Bradycardia XALKORI can cause bradycardia. Avoid concomitant use of XALKORI with drugs that cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) [see Warnings and Precautions (5.4) ] .

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of XALKORI in pregnant women. In animal reproduction studies, oral administration of crizotinib to pregnant rats during organogenesis at exposures similar to those expected with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at doses ≥50 mg/kg/day (approximately 0.6 times the recommended human dose based on AUC) in rats. No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day (approximately 2.7 times the recommended human dose based on AUC) or in rabbits at doses of up to 60 mg/kg/day (approximately 1.6 times the recommended human dose based on AUC), though fetal body weights were reduced at these doses. 8.2 Lactation Risk Summary There is no information regarding the presence of crizotinib or its metabolites in human milk, or the effects on the breastfed child or on milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with XALKORI and for 45 days after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating XALKORI [see Use in Specific Population (8.1) ]. Contraception XALKORI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Females Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for 45 days after the last dose. Males Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for 90 days after the last dose [see Nonclinical Toxicology (13.1) ]. Infertility Based on reproductive organ findings in animals, XALKORI may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use The safety and effectiveness of XALKORI have been established in pediatric patients 1 year of age and older with relapsed or refractory, systemic ALK-positive ALCL or with unresectable, recurrent, or refractory ALK-positive IMT [see Adverse Reactions (6.1) , Clinical Studies (14.2 , 14.3) ] . The safety and effectiveness have not been established in pediatric patients younger than 1 year of age with ALCL or with IMT, or in any pediatric patients with NSCLC. In a study that evaluated XALKORI in combination with chemotherapy in pediatric patients with newly diagnosed ALCL (Study ANHL12P1; NCT01979536), 13 of 66 (20%) patients had a Grade 2 or higher thromboembolic event, including pulmonary embolism in 6%. The safety and effectiveness of XALKORI in combination with chemotherapy have not been established in patients with newly diagnosed ALCL. Juvenile Animal Toxicity Data 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 5.4 times the recommended human dose based on AUC). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. 8.5 Geriatric Use Of the total number of patients with ALK-positive metastatic NSCLC in clinical studies of XALKORI (n=1669), 16% were 65 years or older and 3.8% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Clinical studies of XALKORI in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin greater than 1.5 times ULN and less than or equal to 3 times ULN) or severe (any AST and total bilirubin greater than 3 times ULN) hepatic impairment [see Clinical Pharmacology (12.3) ] . Reduce XALKORI dosage in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.7) ] . No dose adjustment is recommended in patients with pre-existing mild hepatic impairment (AST > ULN and total bilirubin less than or equal to 1 times ULN or any AST and total bilirubin greater than 1 times ULN but less than or equal to1.5 times ULN). 8.7 Renal Impairment Increased exposure to crizotinib occurred in patients with pre-existing severe renal impairment (CL cr less than 30 mL/min calculated using the modified Cockcroft-Gault equation for adult patients and the Schwartz equation for pediatric patients) not requiring dialysis, therefore reduce dosage of XALKORI in these patients [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ] . No dose adjustment is recommended in patients with mild to moderate renal impairment (CL cr 30 to 89 mL/min).