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.

2 DOSAGE AND ADMINISTRATION • Metastatic NSCLC: The recommended dosage is 250 mg orally twice daily. ( 2.3 ) • Systemic ALCL: The recommended dosage is 280 mg/m 2 orally twice daily based on body surface area. ( 2.3 ) • Unresectable IMT: o Adult: The recommended dosage is 250 mg orally twice daily. ( 2.3 ) o Pediatric: The recommended dosage is 280 mg/m 2 orally twice daily based on body surface area. ( 2.3 ) • See full prescribing information for dosage adjustments by indication for patients with moderate or severe hepatic impairment or severe renal impairment. ( 2.7 , 2.8 ) 2.1 Patient Selection Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK or ROS1 positivity in tumor specimens [see Clinical Studies (14.1 , 14.2 , 14.3) ] . Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available at http://www.fda.gov/companiondiagnostics . 2.2 Recommended Testing During Treatment with XALKORI • Monitor liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (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 [see Warnings and Precautions (5.1) ] . • Monitor complete blood counts including differential weekly for the first month of therapy and then at least monthly, with more frequent monitoring if Grade 3 or 4 abnormalities, fever, or infection occur [see Adverse Reactions (6.1) ] . • 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 [see Warnings and Precautions (5.5) ] . 2.3 Recommended Dosage The recommended dosage of XALKORI is provided in Table 1. Table 1. Recommended Dosage of XALKORI Indication Recommended Dosage of XALKORI ALK- or ROS1-Positive Metastatic NSCLC Adults : 250 mg orally twice daily Relapsed or Refractory, Systemic ALK-Positive ALCL Pediatric Patients and Young Adults : 280 mg/m 2 orally twice daily See Table 2 for Recommended Dosage based on body surface area for pediatric patients and young adults with ALCL for the capsules and oral pellets. Unresectable, Recurrent, or Refractory ALK-Positive IMT Adults : 250 mg orally twice daily Pediatric Patients : 280 mg/m 2 orally twice daily See Table 3 for Recommended Dosage based on body surface area for pediatric patients with IMT for the capsules and oral pellets. Recommended Dosage for Adult Patients with ALK- or ROS1-Positive Metastatic NSCLC • The recommended dosage for adult patients with ALK- or ROS1-positive metastatic NSCLC is XALKORI capsules 250 mg orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs. • For adults who cannot swallow capsules, the recommended dosage of XALKORI pellets is 250 mg (2 x 50 mg + 1 x 150 mg) orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs. Recommended Dosage for Pediatric and Young Adult Patients with ALK-Positive ALCL • The recommended dosage for pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic ALK-positive ALCL is based on body surface area (BSA) and is provided in Table 2. • Administer XALKORI capsules or pellets orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs. Table 2 provides the dosage based on body surface area (BSA) for XALKORI capsules or pellets. Table 2. Recommended XALKORI Dosage for Pediatric Patients 1 Year of Age and Older and Young Adults With ALK-Positive ALCL Using Either XALKORI Capsules or Pellets Body Surface Area (BSA) Recommended XALKORI Dosage to Achieve 280 mg/m 2 Twice Daily Dose Strength Combinations of XALKORI Pellets to Administer No more than 4 oral pellet shells are to be used for a single dose. Dose Strength Combinations of XALKORI Capsules to Administer 0.38 to 0.46 m 2 120 mg twice daily 1 x 20 mg + 2 x 50 mg --- 0.47 to 0.51 m 2 140 mg twice daily 2 x 20 mg + 2 x 50 mg --- 0.52 to 0.61 m 2 150 mg twice daily 1 x 150 mg --- 0.62 to 0.80 m 2 200 mg twice daily 1 x 50 mg + 1 x 150 mg --- 0.81 to 0.97 m 2 250 mg twice daily 2 x 50 mg + 1 x 150 mg --- 0.98 to 1.16 m 2 300 mg twice daily 2 x 150 mg --- 1.17 to 1.33 m 2 350 mg twice daily 1 x 50 mg + 2 x 150 mg --- 1.34 to 1.51 m 2 400 mg twice daily 2 x 50 mg + 2 x 150 mg 2 x 200 mg 1.52 to 1.69 m 2 450 mg twice daily 3 x 150 mg 1 x 200 mg + 1 x 250 mg 1.7 m 2 or greater 500 mg twice daily 1 x 50 mg + 3 x 150 mg 2 x 250 mg Recommended Dosage for Pediatric and Adult Patients with ALK-Positive IMT • The recommended dosage for adult patients with unresectable, recurrent, or refractory ALK-positive IMT is provided in Table 1. • The recommended dosage for pediatric patients 1 year of age and older with unresectable, recurrent, or refractory ALK-positive IMT is based on BSA and is provided in Table 3. • Administer XALKORI capsules or pellets orally twice daily, with or without food, until disease progression or unacceptable toxicity occurs. Table 3 provides the dosage based on BSA for XALKORI capsules or pellets. Table 3. Recommended XALKORI Dosage for Pediatric Patients 1 Year of Age and Older with ALK-positive IMT Using Either XALKORI Capsules or Pellets Body Surface Area (BSA) Recommended XALKORI Dosage to Achieve 280 mg/m 2 Twice Daily Dose Strength Combinations of XALKORI Pellets to Administer No more than 4 oral pellet shells are to be used for a single dose. Dose Strength Combinations of XALKORI Capsules to Administer 0.38 to 0.46 m 2 120 mg twice daily 1 x 20 mg + 2 x 50 mg --- 0.47 to 0.51 m 2 140 mg twice daily 2 x 20 mg + 2 x 50 mg --- 0.52 to 0.61 m 2 150 mg twice daily 1 x 150 mg --- 0.62 to 0.80 m 2 200 mg twice daily 1 x 50 mg + 1 x 150 mg --- 0.81 to 0.97 m 2 250 mg twice daily 2 x 50 mg + 1 x 150 mg --- 0.98 to 1.16 m 2 300 mg twice daily 2 x 150 mg --- 1.17 to 1.33 m 2 350 mg twice daily 1 x 50 mg + 2 x 150 mg --- 1.34 to 1.51 m 2 400 mg twice daily 2 x 50 mg + 2 x 150 mg 2 x 200 mg 1.52 to 1.69 m 2 450 mg twice daily 3 x 150 mg 1 x 200 mg + 1 x 250 mg 1.7 m 2 or greater 500 mg twice daily 1 x 50 mg + 3 x 150 mg 2 x 250 mg 2.4 Administration • Administer XALKORI capsules or pellets orally, twice daily, with or without food. • If a dose of XALKORI capsules or pellets is missed, make up that dose unless the next dose is due within 6 hours. • If vomiting occurs after taking a dose of XALKORI capsules or pellets, do not take an additional dose. Take the next dose at the regular scheduled time. XALKORI Capsules • Swallow XALKORI capsules whole, with or without food twice daily. • Do not chew, crush or split XALKORI capsules. XALKORI Pellets • XALKORI pellets are supplied encapsulated in shells. • Do not chew or crush XALKORI pellets. • Do not swallow XALKORI pellets encapsulated in the shell. • XALKORI pellets can be administered by 2 options: 1. Open shell(s) containing XALKORI pellets and empty the contents directly into the patient’s mouth. 2. Open shell(s) containing XALKORI pellets and empty the contents into a consumer-supplied oral dosing aid (e.g., spoon, medicine cup). Administer XALKORI pellets via the dosing aid directly into the patient’s mouth. • Immediately after administration, give a sufficient amount of water to ensure that all medication is swallowed. 2.5 Concomitant Treatments for 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. Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities. Consider intravenous or oral hydration for patients at risk of dehydration, and replace electrolytes as clinically indicated [see Warnings and Precautions (5.6) ] . 2.6 Dosage Modifications for Adverse Reactions The recommended dosage modifications for adverse reactions for adult patients with NSCLC or IMT are provided in Table 4. Table 4. Recommended Dosage Reductions for Adverse Reactions for Adult Patients with NSCLC or IMT Using XALKORI Capsules or Pellets Dose Reduction Dose and Schedule First Dose Reduction 200 mg twice daily Second Dose Reduction 250 mg once daily Permanently discontinue XALKORI capsules or pellets if unable to tolerate 250 mg taken once daily. The recommended dosage modifications for adverse reactions for pediatric patients with ALCL or IMT and young adults with ALCL are based on body surface area and are provided in Table 5. Table 5. Recommended Dosage Reductions for Adverse Reactions for Pediatric Patients with ALCL or IMT and Young Adults with ALCL Using XALKORI Capsules or Pellets Body Surface Area (BSA) First Dose Reduction Second Dose Reduction Permanently discontinue in patients who are unable to tolerate XALKORI capsules or pellets after 2 dose reductions. Dosage Dosage Form and Strength to Achieve Recommended Dose Reduction Dosage Dosage Form and Strength to Achieve Recommended Dose Reduction 0.38 to 0.46 m 2 90 mg twice daily Pellets: 2 x 20 mg + 1 x 50 mg 70 mg twice daily Pellets: 1 x 20 mg + 1 x 50 mg 0.47 to 0.51 m 2 100 mg twice daily Pellets: 2 x 50 mg 80 mg twice daily Pellets: 4 x 20 mg 0.52 to 0.61 m 2 120 mg twice daily Pellets: 1 x 20 mg + 2 x 50 mg 90 mg twice daily Pellets: 2 x 20 mg + 1 x 50 mg 0.62 to 0.80 m 2 150 mg twice daily Pellets: 1 x 150 mg 120 mg twice daily Pellets: 1 x 20 mg + 2 x 50 mg 0.81 to 0.97 m 2 200 mg twice daily Pellets: 1 x 50 mg + 1 x 150 mg 150 mg twice daily Pellets: 1 x 150 mg 0.98 to 1.16 m 2 220 mg twice daily Pellets: 1 x 20 mg + 1 x 50 mg + 1 x 150 mg 170 mg twice daily Pellets: 1 x 20 mg + 1 x 150 mg 1.17 to 1.33 m 2 250 mg twice daily Pellets: 2 x 50 mg + 1 x 150 mg 200 mg twice daily Pellets: 1 x 50 mg + 1 x 150 mg 1.34 to 1.69 m 2 250 mg twice daily Pellets: 2 x 50 mg + 1 x 150 mg Or Capsule: 1 x 250 mg 200 mg twice daily Pellets: 1 x 50 mg + 1 x 150 mg Or Capsule: 1 x 200 mg 1.7 m 2 or greater 400 mg twice daily Pellets: 2 x 50 mg + 2 x 150 mg Or Capsule: 2 x 200 mg 250 mg twice daily Pellets: 2 x 50 mg + 1 x 150 mg Or Capsule: 1 x 250 mg Recommended Dosage Modifications for Hematologic Adverse Reactions for Adult Patients with NSCLC or IMT The recommended dosage modifications for hematologic adverse reactions for adult patients with NSCLC or IMT are provided in Table 6. Table 6. Adult Patients with NSCLC or IMT: XALKORI Dosage Modification – Hematologic Toxicities Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). Severity of Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. XALKORI Dosage Modification Grade 3 Withhold until recovery to Grade 2 or less, then resume at the same dosage. Grade 4 Withhold until recovery to Grade 2 or less, then resume at next lower dosage. Monitor complete blood counts including differential weekly for the first month of therapy and then at least monthly, with more frequent monitoring if Grade 3 or 4 abnormalities, fever, or infection occur. Recommended Dosage Modifications for Hematologic Adverse Reactions in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT The recommended dosage modifications for hematologic adverse reactions in pediatric and young adult patients with ALCL or pediatric patients with IMT are provided in Table 7. Table 7. Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT: XALKORI Dosage Modification for Hematologic Adverse Reactions Severity of Adverse Reaction XALKORI Dosage Modification Absolute Neutrophil Count (ANC) Less than 0.5 x 10 9 /L First occurrence: Withhold until recovery to ANC greater than 1.0 x 10 9 /L, then resume at the next lower dosage. Second occurrence: • Permanently discontinue for recurrence complicated by febrile neutropenia or infection. • For uncomplicated Grade 4 neutropenia, either permanently discontinue, or withhold until recovery to ANC greater than 1.0 x 10 9 /L, then resume at the next lower dosage. Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions. Platelet Count 25 to 50 x 10 9 /L with concurrent bleeding Withhold until recovery to platelet count greater than 50 x 10 9 /L and bleeding resolves, then resume at the same dosage. Less than 25 x 10 9 /L Withhold until recovery to platelet count greater than 50 x 10 9 /L, then resume at the next lower dosage. Permanently discontinue for recurrence. Anemia Hemoglobin less than 8 g/dL Withhold until recovery to hemoglobin 8 g/dL or more, then resume at the same dosage. Life-threatening anemia; urgent intervention indicated. Withhold until recovery to hemoglobin 8 g/dL or more, then resume at the next lower dosage. Permanently discontinue for recurrence. Recommended Dosage Modifications for Non-Hematologic Adverse Reactions The recommended dosage modifications for non-hematologic adverse reactions are provided in Table 8. Table 8. All Patients: XALKORI Dosage Modification for Non-Hematologic Adverse Reactions Severity of Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. XALKORI Dosage Modification Hepatotoxicity [see Warnings and Precautions (5.1) ] Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at next lower dosage. ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis) Permanently discontinue. Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2) ] Any grade drug-related interstitial lung disease/pneumonitis Permanently discontinue. QT Interval Prolongation [see Warnings and Precautions (5.3) ] QT corrected for heart rate (QTc) greater than 500 ms on at least 2 separate electrocardiograms (ECGs) Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage. QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Permanently discontinue. Bradycardia [see Warnings and Precautions (5.4) ] Bradycardia Adult patients: Heart rate less than 60 beats per minute (bpm); Pediatric patients: Resting heart rate less than the 2.5 th percentile per age-specific norms. (symptomatic, may be severe and medically significant, medical intervention indicated) Withhold until recovery to a resting heart rate according to the patient’s age (based on the 2.5 th percentile per age-specific norms) as follows: • 1 to less than 2 years: 91 bpm or above • 2 to 3 years: 82 bpm or above • 4 to 5 years: 72 bpm or above • 6 to 8 years: 64 bpm or above • Older than 8 years: 60 bpm or above Evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to the age-specific heart rate provided above. If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose adjusted, resume at reduced dose upon recovery to asymptomatic bradycardia or to the age-specific heart rate provided above. Bradycardia (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 the second dose reduction level in Table 4 or 5 upon recovery to asymptomatic bradycardia or to the heart rate criteria listed for management of symptomatic or severe, medically significant bradycardia, with frequent monitoring. Permanently discontinue for recurrence. Ocular Toxicity, including Visual Loss [see Warnings and Precautions (5.5) ] Visual Symptoms, Grade 1 (mild symptoms) or Grade 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living) Monitor symptoms and report any symptoms to an eye specialist. Consider dose reduction for Grade 2 visual disorders. Visual Loss (Grade 3 or 4 Ocular Disorder, marked decrease in vision) Discontinue during evaluation of severe visual loss. Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders or severe visual loss if no other cause found on evaluation. Gastrointestinal Toxicity Dosage modifications for gastrointestinal toxicity for pediatric patients with ALCL or IMT and young adults with ALCL only. [see Warnings and Precautions (5.6) ] Nausea (Grade 3: inadequate oral intake for more than 3 days, medical intervention required) Grade 3 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level. Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions. Vomiting (Grade 3: more than 6 episodes in 24 hours for more than 3 days, medical intervention required, i.e., tube feeding or hospitalization; Grade 4: life-threatening consequences, urgent intervention indicated) Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level. Diarrhea (Grade 3: increase of 7 or more stools per day over baseline; incontinence; hospitalization indicated; Grade 4: life-threatening consequences, urgent intervention indicated) Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level. 2.7 Dosage Modifications for Moderate and Severe Hepatic Impairment The recommended dose of XALKORI in patients with moderate hepatic impairment [any aspartate aminotransferase (AST) and total bilirubin greater than 1.5 times the upper limit of normal (ULN) and less than or equal to 3 times ULN] is the first dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . The recommended dose of XALKORI in patients with severe hepatic impairment (any AST and total bilirubin greater than 3 times ULN) is the second dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Dosage and Administration (2.6) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 2.8 Dosage Modification for Severe Renal Impairment The recommended dosage of XALKORI in patients with severe renal impairment [creatinine clearance (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 is the second dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 2.9 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors [see Drug Interactions (7.1) ] . If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to the second dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.

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 <1% of patients who received XALKORI included photosensitivity (0.4%). Table 12. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 2 Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 96%; Grade 3: 1%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 72%; Grade 3: 0%; Grade 4: 0%). XALKORI Chemotherapy Laboratory Abnormality Any Grade (%) Grade 3–4 (%) Any Grade (%) Grade 3–4 (%) Hematology Lymphopenia 51 9 60 25 Neutropenia 49 12 28 12 Chemistry Increased ALT 76 17 38 4 Increased AST 61 9 33 0 Hypophosphatemia 28 5 25 6 Hypokalemia 18 4 10 1 ROS1-Positive Metastatic NSCLC - Study 3 (PROFILE 1001) The safety profile of XALKORI from Study 3, which was evaluated in 50 patients with ROS1-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=1669). Vision disorders occurred in 92% of patients in Study 3; 90% were Grade 1 and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months. Description of Selected Adverse Reactions in Patients with Metastatic NSCLC Vision disorders: Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 63% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 0.8% of patients with Grade 3 and 0.2% of patients with Grade 4 visual impairment. Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies 1 and 2 (>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 <30 mL/min/1.73 m 2 . Relapsed or Refractory, Systemic ALK-Positive ALCL - Study ADVL0912 The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies 14.2 ] , which included 26 patients with relapsed or refractory, systemic ALCL after at least one systemic therapy. Eligible patients were 1 to ≤21 years of age and were required to have an absolute neutrophil count ≥1000/mm 3 (750/mm 3 if bone marrow was involved), platelet count ≥75,000/mm 3 (25,000/mm 3 if bone marrow was involved), creatinine clearance ≥70ml/min/1.73m 2 , and QTc ≤480 msec. The study excluded patients with ALT >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 <20% of patients treated with XALKORI included: • Cardiac disorders: Bradycardia (19%), electrocardiogram QT prolonged (8%) • Vascular disorders: Hypotension (19%) • Investigations: Alkaline phosphatase increase (19%), hypernatremia (19%), GGT increase (8%), hyponatremia (12%), hyperuricemia (12%), hypophosphatemia (12%) • Nervous system disorders: Peripheral neuropathy (12%) • Gastrointestinal disorders: Esophagitis (8%) • Blood and lymphatic disorders: Febrile neutropenia (3.8%) • Musculoskeletal disorders: Muscular weakness (8%) • Renal disorders: Acute renal injury (8%) Unresectable, Recurrent, or Refractory ALK-Positive IMT Study ADVL0912 The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies (14.3) ] that included 14 pediatric patients with unresectable, recurrent, or refractory IMT. Pediatric patients with IMT received XALKORI 280 mg/m 2 orally twice daily until disease progression or unacceptable toxicity. Two patients received a lower dose. The median duration of treatment with XALKORI was 20.5 months. Serious adverse reactions occurred in 7% of pediatric patients with IMT treated with XALKORI. The most frequent serious adverse reaction was neutropenia and hypotension (7% for each). Dose interruptions due to an adverse reaction occurred in 71% of patients. Dose reductions due to an adverse reaction occurred in 29% of patients. Permanent discontinuation occurred in 29% of patients. The most common adverse reactions (≥35%) were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache. The most common Grade 3 or 4 laboratory abnormality (>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

12.3 Pharmacokinetics Following XALKORI 250 mg capsules twice daily, steady-state was reached within 15 days with a median accumulation ratio of 4.8. Steady-state minimum concentration (C min.ss ) and AUC increased in a greater than dose-proportional manner over the dose range of 200 mg to 300 mg twice daily (0.8 to 1.2 times the approved recommended dosage). Absorption A single crizotinib capsule dose was absorbed with median time to achieve peak concentration (T max ) of 4 to 6 hours, and the mean absolute bioavailability of 43% (range: 32% to 66%). The oral pellets had a comparable crizotinib bioavailability compared with the capsules. Effect of Food A high-fat meal, reduced AUC 0-INF and maximum plasma concentration (C max ) of crizotinib each by 14% for the capsule formulation; reduced AUC 0-INF and C max of crizotinib by 15% and 23%, respectively, for the pellet formulation as compared to those under fasted conditions. Distribution The geometric mean volume of distribution (V ss ) of crizotinib was 1772 L following a single intravenous dose. Protein binding of crizotinib is 91% and is independent of drug concentration in vitro. Crizotinib is a substrate for P-glycoprotein (P-gp) in vitro. The blood-to-plasma concentration ratio is approximately 1. Elimination The mean apparent plasma terminal half-life of crizotinib was 42 hours following single doses of crizotinib in patients. The mean apparent clearance (CL/F) of crizotinib was lower at steady-state (60 L/h) after 250 mg twice daily than after a single 250 mg oral dose (100 L/h). Metabolism Crizotinib is predominantly metabolized by CYP3A. Excretion Following administration of a single oral 250 mg dose of radiolabeled crizotinib dose to healthy subjects, 63% (53% as unchanged) of the administered dose was recovered in feces and 22% (2.3% as unchanged) in urine. Specific Populations No clinically significant difference in crizotinib pharmacokinetics were observed based on age, sex, or ethnicity (Asian, non-Asian). For patients <18 years of age, body weight has a significant effect on the pharmacokinetics of crizotinib, with lower crizotinib exposures observed in patients with higher body weight. Pediatric Patients In pediatric patients, crizotinib steady-state exposure increased proportionally with dose over the dose range of 165 mg/m 2 to 280 mg/m 2 orally twice daily. At a dosing regimen of 280 mg/m 2 (approximately 2 times the recommended adult dose), geometric mean (CV%) steady-state maximum plasma concentrations (C max ) of crizotinib was 621 (73%) ng/mL and AUC 0–tau was 6530 (34%) ng∙hr/mL. Patients with Hepatic Impairment Steady-state mean crizotinib AUC and C max decreased by 9% in patients with mild hepatic impairment (AST >ULN and total bilirubin ≤1 times ULN or any AST and total bilirubin >1 times ULN but ≤1.5 times ULN) compared to patients with normal hepatic function following XALKORI 250 mg orally twice daily. Steady-state mean crizotinib AUC increased by 14% and C max increased by 9% in patients with moderate hepatic impairment (any AST and total bilirubin >1.5 times ULN and ≤3 times ULN) following XALKORI 200 mg orally twice daily compared with patients with normal hepatic function following XALKORI 250 mg orally twice daily. Mean crizotinib AUC decreased by 35% and C max decreased by 27% in patients with severe hepatic impairment (any AST and total bilirubin >3 times ULN) following XALKORI 250 mg orally once daily compared with patients with normal hepatic function following XALKORI 250 mg orally twice daily [see Dosage and Administration (2.7) , Use in Specific Populations (8.6) ] . Patients with Renal Impairment Mild or moderate renal impairment (CL cr of 60–89 ml/min or 30–59 ml/min, respectively, calculated using the modified Cockcroft-Gault equation) has no clinically significant effect on the exposure of crizotinib. Following a single 250 mg dose, the mean AUC 0–INF of crizotinib increased by 79% and the mean C max increased by 34% in patients with severe renal impairment (CL cr <30 mL/min) who did not require dialysis compared to those with normal renal function (CL cr ≥90 mL/min). Similar changes in AUC 0–INF and C max were observed for the active metabolite of crizotinib [see Dosage and Administration (2.8) , Use in Specific Populations (8.7) ] . Drug Interaction Studies Clinical Studies Gastric Acid Reducing Agents: No clinically significant differences in crizotinib pharmacokinetics were observed when used concomitantly with esomeprazole, a proton pump inhibitor. Strong CYP3A Inhibitors: Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole, a strong CYP3A inhibitor, increased crizotinib AUC 0–INF by 216% and C max by 44% compared to crizotinib alone. Coadministration of XALKORI 250 mg orally once daily with itraconazole, a strong CYP3A inhibitor, increased crizotinib steady-state AUC by 57% and C max by 33% compared to crizotinib alone [see Drug Interactions (7.1) ] . Strong CYP3A Inducers: Coadministration of XALKORI 250 mg orally twice daily with rifampin, a strong CYP3A inducer, decreased crizotinib steady-state AUC 0–Tau by 84% and C max by 79%, compared to crizotinib alone [see Drug Interactions (7.1) ] . CYP3A Substrates: Coadministration of XALKORI 250 mg orally twice daily for 28 days increased AUC 0–INF of oral midazolam (CYP3A substrate) 3.7-fold compared to midazolam alone [see Drug Interactions (7.2) ] . In Vitro Studies CYP Enzymes: Crizotinib inhibits CYP2B6 in vitro. Crizotinib does not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Crizotinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A. UDP-glucuronosyltransferase (UGT): Crizotinib does not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7. Transporters: Crizotinib inhibits P-gp, organic cation transporter (OCT) 1, and OCT2. Crizotinib does not inhibit organic anion transporting polypeptides (OATP) B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, or bile salt export pump transporter (BSEP).