`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`XALKORI® safely and effectively. See full prescribing information for
`XALKORI.
`
`XALKORI® (crizotinib) capsules, for oral use
`Initial U.S. Approval: 2011
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Dosage and Administration, Recommended Dosing (2.2)
`2/2018
`
` --------------------------- INDICATIONS AND USAGE ----------------------------
`XALKORI is a kinase inhibitor indicated for the treatment of 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.
`
` ----------------------- DOSAGE AND ADMINISTRATION -----------------------
`
`Recommended Dose: 250 mg orally twice daily. (2.2)
` Moderate Hepatic Impairment: 200 mg orally twice daily. (2.2)
`
`Severe Hepatic Impairment: 250 mg orally once daily. (2.2)
`
`Severe Renal Impairment: 250 mg orally once daily. (2.2)
`
` --------------------- DOSAGE FORMS AND STRENGTHS ----------------------
`Capsules: 250 mg and 200 mg. (3)
`
` ------------------------------ CONTRAINDICATIONS ------------------------------
`None. (4)
`
` ----------------------- WARNINGS AND PRECAUTIONS ------------------------
`Hepatotoxicity: Fatal hepatotoxicity occurred in 0.1% of patients.
`
`Monitor with periodic liver testing. Temporarily suspend, dose reduce,
`or permanently discontinue XALKORI. (5.1)
`Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2.9% of
`patients. Permanently discontinue in patients with ILD/pneumonitis.
`(5.2)
`
`
`
`QT Interval Prolongation: Occurred in 2.1% of patients. 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. (5.3)
`Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and
`blood pressure regularly. Temporarily suspend, dose reduce, or
`permanently discontinue XALKORI. (5.4)
`Severe Visual Loss: Reported in 0.2% of patients. Discontinue
`XALKORI in patients with severe visual loss. Perform an
`ophthalmological evaluation. (5.5)
`Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`reproductive potential of the potential risk to a fetus and use of effective
`contraception. (5.6, 8.1, 8.3)
`
`
`
`
`
`
`
`
`
`
`
`
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`The most common adverse reactions (≥25%) are vision disorders, nausea,
`diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue,
`decreased appetite, upper respiratory infection, dizziness, and neuropathy. (6)
`
`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.
`
` ------------------------------ DRUG INTERACTIONS-------------------------------
`
`Strong CYP3A Inhibitors: Avoid coadministration with XALKORI.
`(7.1)
`Strong CYP3A Inducers: Avoid coadministration with XALKORI. (7.2)
`CYP3A Substrates: Avoid coadministration of CYP3A substrates with
`narrow therapeutic indices with XALKORI. (7.3)
`
`
` ----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`Lactation: Do not breastfeed while taking XALKORI. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA‐approved patient labeling.
`
`
`Revised: 12/2018
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`8
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
`
`2
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 ALK-Positive Metastatic NSCLC
`14.2 ROS1-Positive Metastatic NSCLC
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 Patient Selection
`2.2 Recommended Dosing
`2.3 Dose Modification
`3
`DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hepatotoxicity
`5.2
`Interstitial Lung Disease (Pneumonitis)
`5.3 QT Interval Prolongation
`5.4 Bradycardia
`5.5 Severe Visual Loss
`5.6 Embryo-Fetal Toxicity
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`7.1 Drugs That May Increase Crizotinib Plasma Concentrations
`7.2 Drugs That May Decrease Crizotinib Plasma Concentrations
`7.3 Drugs Whose Plasma Concentrations May Be Altered By
` Sections or subsections omitted from the full prescribing information are not
`Crizotinib
`listed.
`_______________________________________________________________________________________________________________________________________
`
`
` *
`
`6
`
`7
`
`Reference ID: 4358948
`
`1
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`
` 1
`
`
`
`
`XALKORI is indicated for the treatment of 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
`Clinical Studies (14.1 and 14.2)].
`
`DOSAGE AND ADMINISTRATION
`
` 2
`
`
`
`
`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 Indications and Usage (1) and Clinical Studies (14.1, 14.2)].
`
`Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available
`at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.
`
`2.2 Recommended Dosing
`
`The recommended dose of XALKORI is 250 mg orally twice daily until disease progression or no longer
`tolerated by the patient.
`
`The recommended dose of XALKORI in patients with pre-existing moderate hepatic impairment [any aspartate
`aminotransferase (AST) and total bilirubin >1.5 times the upper limit of normal (ULN) and 3 times ULN] is
`200 mg orally twice daily. The recommended dose of XALKORI in patients with pre-existing severe hepatic
`impairment [any AST and total bilirubin >3 times ULN] is 250 mg orally once daily [see Use in Specific
`Populations (8.6) and Clinical Pharmacology (12.3)].
`
`The recommended dose of XALKORI in patients with severe renal impairment [creatinine clearance
`(CLcr) <30 mL/min] not requiring dialysis is 250 mg orally once daily [see Use in Specific Populations (8.7)
`and Clinical Pharmacology (12.3)].
`
`XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed,
`make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of
`XALKORI, take the next dose at the regular time.
`
`2.3 Dose Modification
`
`The recommended dose reductions are:
`
` 
`
`
`
`
`
`First dose reduction: XALKORI 200 mg taken orally twice daily
`Second dose reduction: XALKORI 250 mg taken orally once daily
`Permanently discontinue if unable to tolerate XALKORI 250 mg taken orally once daily
`
`Dosage modifications for adverse reactions for XALKORI are provided in Tables 1 and 2.
`
`
`Reference ID: 4358948
`
`2
`
`

`

`
`
`Table 1. XALKORI Dose Modification – Hematologic Toxicitiesa
`XALKORI Dosing
`Gradeb
`Withhold until recovery to Grade 2 or less, then resume at the same dose schedule.
`Grade 3
`Withhold until recovery to Grade 2 or less, then resume at next lower dose.
`Grade 4
`a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
`b Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
`Monitor complete blood counts including differential white blood cell counts monthly and as clinically
`indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection
`occurs.
`
`Table 2. XALKORI Dose Modification – Non-Hematologic Toxicities
`XALKORI Dosing
`Withhold until recovery to baseline or less than or equal to 3 times
`ULN, then resume at next lower dosage.
`
`Permanently discontinue.
`
`Permanently discontinue.
`
`Withhold until recovery to baseline or to a QTc less than 481 ms,
`then resume at next lower dosage.
`
`Permanently discontinue.
`
`
`Withhold until recovery to asymptomatic bradycardia or to a heart
`rate of 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 a heart rate of 60 bpm
`or above.
`
`If no contributing concomitant medication is identified, or if
`contributing concomitant medications are not discontinued or dose
`modified, resume at reduced dose, upon recovery to asymptomatic
`bradycardia or to a heart rate of 60 bpm or above.
`Permanently discontinue if no contributing concomitant medication
`is identified.
`
`If contributing concomitant medication is identified and
`discontinued, or its dose is adjusted, resume at 250 mg once daily
`upon recovery to asymptomatic bradycardia or to a heart rate of
`60 bpm or above, with frequent monitoring.
`
`3
`
`Criteriaa
`Alanine aminotransferase (ALT) or aspartate
`aminotransferase (AST) elevation greater
`than 5 times upper limit of normal (ULN)
`with total bilirubin less than or equal to
`1.5 times ULN
`ALT or AST elevation greater than 3 times
`ULN with concurrent total bilirubin elevation
`greater than 1.5 times ULN (in the absence
`of cholestasis or hemolysis)
`Any grade drug-related interstitial lung
`disease/pneumonitis
`QT corrected for heart rate (QTc) greater
`than 500 ms on at least 2 separate
`electrocardiograms (ECGs)
`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
`Bradycardiab (symptomatic, may be severe
`and medically significant, medical
`intervention indicated)
`
`Bradycardiab,c (life-threatening
`consequences, urgent intervention indicated)
`
`Reference ID: 4358948
`
`

`

`XALKORI Dosing
`Criteriaa
`Discontinue during evaluation of severe vision loss.
`Visual Loss (Grade 4 Ocular Disorder)
`a Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
`b Heart rate less than 60 beats per minute (bpm).
`c Permanently discontinue for recurrence.
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
` 3
`
`
`
` 
`
` 250 mg capsules: hard gelatin capsule, size 0, pink opaque cap and body, with “Pfizer” on the cap and
`“CRZ 250” on the body.
` 200 mg capsules: hard gelatin capsule, size 1, white opaque body and pink opaque cap, with “Pfizer” on the
`cap and “CRZ 200” on the body.
`
`CONTRAINDICATIONS
`
` 4
`
`
`
`
`None.
`
` 5
`
` WARNINGS AND PRECAUTIONS
`
`
`5.1 Hepatotoxicity
`
`Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.1%) of the 1719 patients treated with
`XALKORI across clinical trials. Concurrent elevations in alanine aminotransferase (ALT) or AST greater than
`or equal to 3 times the ULN and total bilirubin greater than or equal to 2 times the ULN, with normal alkaline
`phosphatase, occurred in 10 patients (<1%) treated with XALKORI. Elevations in ALT or AST greater than
`5 times the ULN occurred in 187 (11.2%) and 95 (5.7%) patients, respectively. Seventeen patients (1.0%)
`required permanent discontinuation due to elevated transaminases. Transaminase elevations generally occurred
`within the first 2 months of treatment.
`
`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 transaminase elevations.
`Temporarily suspend, dose reduce, or permanently discontinue XALKORI as described in Table 2 [see Dosage
`and Administration (2.3) and Adverse Reactions (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 (n=1719), 50 XALKORI-treated patients (2.9%) had ILD of any grade,
`18 patients (1.0%) had Grade 3 or 4 ILD, and 8 patients (0.5%) had fatal ILD. Interstitial lung disease generally
`occurred within 3 months after the initiation of XALKORI.
`
`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 (2.3) and Adverse Reactions (6)].
`
`5.3 QT Interval Prolongation
`
`QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 34 of 1616 patients
`(2.1%) had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 500 ms and
`
`Reference ID: 4358948
`
`4
`
`

`

`
`79 of 1582 patients (5.0%) had an increase from baseline QTcF greater than or equal to 60 ms by automated
`machine-read evaluation of ECGs.
`
`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. Permanently discontinue XALKORI in patients who
`develop 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. Withhold
`XALKORI in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a
`QTc less than or equal to 480 ms, then resume XALKORI at a reduced dose as described in Table 2 [see
`Dosage and Administration (2.3) and Clinical Pharmacology (12.2)].
`
`5.4 Bradycardia
`
`Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia
`occurred in 219 (12.7%) 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.
`
`Avoid using XALKORI in combination with other agents known to cause bradycardia (e.g., beta-blockers,
`non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate
`and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI
`until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of
`concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening
`bradycardia due to XALKORI; however, if associated with concomitant medications known to cause
`bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of
`60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg
`once daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse Reactions (6)].
`
`5.5 Severe Visual Loss
`
`Across all clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (4/1719). Optic
`atrophy and optic nerve disorder have been reported as potential causes of vision loss.
`
`Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than
`20/200 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity,
`retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for
`new onset of severe visual loss. There is insufficient information to characterize the risks of resumption of
`XALKORI in patients with a severe visual loss; a decision to resume XALKORI should consider the potential
`benefits to the patient.
`
`5.6 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 of the potential risk to a fetus. Advise females of reproductive potential to
`use effective contraception during treatment with XALKORI and for at least 45 days following the final dose
`[see Use in Specific Populations (8.1, 8.3)]. Advise male patients with female partners of reproductive potential
`to use condoms during treatment with XALKORI and for at least 90 days after the final dose [see Use in
`Specific Populations (8.3) and Nonclinical Toxicology (13.1)].
`5
`
`Reference ID: 4358948
`
`

`

`
`
` 6
`
`
`The following adverse reactions are discussed in greater detail in other sections of 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)]
`
`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 section reflect exposure to XALKORI in 1719 patients 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) [see Warnings and Precautions (5)].
`
`The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who
`received XALKORI 250 mg 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 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
`
`The data in Table 3 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/m2 in combination with cisplatin 75 mg/m2 (n=91) or
`carboplatin at a dose calculated to produce an area under the concentration-time curve (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.
`
`
`
`
`ADVERSE REACTIONS
`
`Reference ID: 4358948
`
`6
`
`

`

`
`Serious adverse events were reported in 58 patients (34%) 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 6.4% 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 8.2%. 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 3 and 4 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated
`patients.
`
`
`
`
` 0
`
`0
`
` 0
`
` 3
`
`
`1
`0
`0
`1
`0
`0
`
`
`
`
`
`
` 1
`
`1
`
` 1
`
` 0
`
`
`
` 0
`
`1
`
`Grade 3-4
`(%)
`
` 2
`
`
`
`1
`
` 1
`
` 2
`
`
`2
`2
`0
`1
`0
`2
`
`
`
`
`
`
` 1
`
`0
`
` 0
`
` 1
`
`
`
` 0
`
`0
`
`All Grades
`(%)
`
` 6
`
`
`14
`
`71
`
`46
`61
`43
`14
`10
`26
`6
`
`
`49
`19
`
`32
`
` 8
`
`
`
`16
`8
`
`Adverse Reaction
`
`
`Cardiac Disorders
`Electrocardiogram QT prolonged
`Bradycardiaa
`Eye Disorders
`Vision disorderb
`Gastrointestinal Disorders
`Vomiting
`Diarrhea
`Constipation
`Dyspepsia
`Dysphagia
`Abdominal painc
`Esophagitisd
`General Disorders and
`Administration Site Conditions
`Edemae
`Pyrexia
`Infections and Infestations
`Upper respiratory infectionf
`Investigations
`Increased weight
`Musculoskeletal and Connective
`Tissue Disorders
`Pain in extremity
`Muscle spasm
`
`Reference ID: 4358948
`
`7
`
`Table 3. 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†
`XALKORI
`Chemotherapy (Pemetrexed/Cisplatin
`(N=171)
`or Pemetrexed/Carboplatin)
`(N=169)
`All Grades
`Grade 3-4
`(%)
`(%)
`
`
`
` 2
`
`1
`
`10
`
`36
`13
`30
`2
`2
`12
`1
`
`
`12
`11
`
`12
`
` 2
`
`
`
` 7
`
`2
`
`
`
`

`

`Chemotherapy (Pemetrexed/Cisplatin
`or Pemetrexed/Carboplatin)
`(N=169)
`All Grades
`Grade 3-4
`(%)
`(%)
`
`10
`5
`15
`
`
`0
`0
`
` 1
`
`
`
`Adverse Reaction
`
`
`XALKORI
`(N=171)
`
`Grade 3-4
`(%)
`
` 0
`
`
`0
`1
`
`All Grades
`(%)
`Nervous System Disorders
`
`Dizzinessg
`18
`26
`Dysgeusia
`Headache
`22
`†Adverse reactions were graded using NCI CTCAE version 4.0.
`Includes cases reported within the clustered terms:
`a Bradycardia (Bradycardia, Sinus bradycardia).
`b Vision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual
`impairment).
`c Abdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal
`tenderness).
`d Esophagitis (Esophagitis, Esophageal ulcer).
`e Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema).
`f Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
`g Dizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope).
`
`
`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).
`
`
`Laboratory Abnormality
`
`
`Chemotherapy
`Any Grade
`Grade 3-4
`(%)
`(%)
`
`11
`7
`
`59
`53
`
`16
`13
`
`Table 4. Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients
`in Study 1
`XALKORI
`Any Grade
`Grade 3-4
`(%)
`(%)
`Hematology
`
`52
`Neutropenia
`48
`Lymphopenia
`Chemistry
`
`2
`33
`15
`79
`ALT elevation
`1
`28
`8
`66
`AST elevation
`6
`21
`10
`32
`Hypophosphatemia
`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%).
`
`Previously Treated ALK-Positive Metastatic NSCLC - Study 2
`
`The data in Table 5 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/m2 (n=99) or docetaxel 75 mg/m2 (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.
`
`
`Reference ID: 4358948
`
`8
`
`

`

`
`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 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%)
`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 9 (5%) 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 ALT
`elevation (7.6%) including some patients with concurrent AST elevation, 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%), ALT and AST elevation (1.2%), dyspnea (1.2%), and
`pulmonary embolism (1.2%).
`
`Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated
`patients.
`
`
` 0
`
`
`0
`0
`
` 0
`
` 0
`
`
`
`
`
`
`0
`
` 0
`
` 0
`
`
`1
`1
`0
`0
`
`
`
` 1
`
` 9
`
` 0
`
`0
`
`
`
` 4
`
`
`18
`37
`19
`23
`3
`
`13
`
`Table 5. 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†
`XALKORI
`Chemotherapy
`(N=172)
`(Pemetrexed or Docetaxel)
`(N=171)
`All Grades
`Grade 3-4
`(%)
`(%)
`
` 8
`
`
`9
`0
`
`Grade 3-4
`(%)
`
` 1
`
`
`0
`3
`
` 0
`
` 3
`
`0
`
`
`
` 1
`
` 1
`
`
`1
`0
`2
`0
`
` 0
`
`All Grades
`(%)
`
`22
`26
`3
`
`60
`
` 5
`
`
`
`5
`
`10
`
`47
`55
`60
`42
`8
`
`26
`
`Adverse Reaction
`
`
`Nervous System Disorders
`Dizzinessa
`Dysgeusia
`Syncope
`Eye Disorders
`Vision disorderb
`Cardiac Disorders
`Electrocardiogram QT prolonged
`Bradycardiac
`Investigations
`Decreased weight
`Gastrointestinal Disorders
`Vomiting
`Nausea
`Diarrhea
`Constipation
`Dyspepsia
`Infections and Infestations
`Upper respiratory infectiond
`
`Reference ID: 4358948
`
`9
`
`

`

`Chemotherapy
`(Pemetrexed or Docetaxel)
`(N=171)
`All Grades
`Grade 3-4
`(%)
`(%)
`
`
`
`
`
`
`
` 2
`
`
`
` 0
`
` 2
`
`
`
`16
`
`
`
`Adverse Reaction
`
`
`XALKORI
`(N=172)
`
`Grade 3-4
`(%)
`
`
` 5
`
`
`
` 0
`
`All Grades
`(%)
`
`
` 6
`
`Respiratory, Thoracic and
`Mediastinal Disorders
`Pulmonary embolisme
`General Disorders and
`
`Administration Site Conditions
`
`Edemaf
`31
`†Adverse reactions were graded using NCI CTCAE version 4.0.
`Includes cases reported within the clustered terms:
`a Dizziness (Balance disorder, Dizziness, Postural dizziness).
`b Vision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters).
`c Bradycardia (Bradycardia, Sinus bradycardia).
`d Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
`e Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism).
`f Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema).
`
`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).
`
`
`Table 6. Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients
`in Study 2
`XALKORI
`Any Grade
`Grade 3-4
`(%)
`(%)
`
`Laboratory Abnormality
`
`
`Chemotherapy
`Any Grade
`Grade 3-4
`(%)
`(%)
`
`Hematology
`Neutropenia
`Lymphopenia
`Chemistry
`4
`38
`17
`76
`ALT elevation
`0
`33
`9
`61
`AST elevation
`1
`10
`4
`18
`Hypokalemia
`6
`25
`5
`28
`Hypophosphatemia
`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%).
`
`ROS1-Positive Metastatic NSCLC - Study 3
`
`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.
`
`28
`60
`
`12
`25
`
`49
`51
`
`12
`9
`
`Reference ID: 4358948
`
`10
`
`

`

`
`
`Description of Selected Adverse Drug Reactions
`
`Vision disorders
`Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in
`1084 (63.1%) of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions.
`There were 13 (0.8%) patients with Grade 3 and 4 (0.2%) 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 435 (25%) of 1719 patients. Most events (95%)
`were Grade 1 or Grade 2 in severity.
`
`Renal cysts
`Renal cysts were experienced by 52 (3%) 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 impairment
`The estimated glomerular filtration rate (eGFR)