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
`
`
`
`
`--------------------------- 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 (1, 2.1).
`
`
`----------------------- DOSAGE AND ADMINISTRATION -----------------------
`
`
`
`Recommended Dosage: 250 mg orally twice daily. (2.2)
`
`
`
`
` Moderate Hepatic Impairment: 200 mg orally twice daily. (2.4)
`
`
`
`
`Severe Hepatic Impairment: 250 mg orally once daily. (2.4)
`
`
`
`
`
`
`Severe Renal Impairment: 250 mg orally once daily. (2.5)
`
`
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS----------------------
`
`
`
`Capsules: 250 mg, 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. (2.3, 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. (2.3, 5.3)
`
`Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and
`
`blood pressure regularly. Temporarily suspend, dose reduce, or
`
`
`
`
`
`permanently discontinue XALKORI. (2.3, 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 concomitant use. (2.6, 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)
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
`
`
`Lactation: Advise not to breastfeed. (8.2)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA‐approved patient labeling.
`
`
`
`
`Revised: 06/2019
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`2
`
`
`8
`
`
`7.2 Effect of XALKORI on Other Drugs
`
`
`7.3 Drugs That Prolong the QT Interval
`
`7.4 Drugs That Cause Bradycardia
`INDICATIONS AND USAGE
`
`USE IN SPECIFIC POPULATIONS
`DOSAGE AND ADMINISTRATION
`
`8.1 Pregnancy
`
`2.1 Patient Selection
`
`
`8.2 Lactation
`
`2.2 Recommended Dosage
`8.3 Females and Males of Reproductive Potential
`
`
`
`2.3 Dosage Modifications for Adverse Reactions
`
`8.4 Pediatric Use
`
`2.4 Dosage Modifications for Moderate and Severe Hepatic
`
`
`8.5 Geriatric Use
`Impairment
`8.6 Hepatic Impairment
`
`2.5 Dosage Modification for Severe Renal Impairment
`
`
`8.7 Renal Impairment
`
`2.6 Dosage Modification for Concomitant Use of Strong CYP3A
`
`11 DESCRIPTION
`
`Inhibitors
`
`12 CLINICAL PHARMACOLOGY
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`12.1 Mechanism of Action
`
`
`CONTRAINDICATIONS
`4
`
`12.2 Pharmacodynamics
`
`
`5 WARNINGS AND PRECAUTIONS
`
`12.3 Pharmacokinetics
`
`
`5.1 Hepatotoxicity
`
`
`13 NONCLINICAL TOXICOLOGY
`
`Interstitial Lung Disease/Pneumonitis
`5.2
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`5.3 QT Interval Prolongation
`
`
`14 CLINICAL STUDIES
`
`5.4 Bradycardia
`14.1 ALK-Positive Metastatic NSCLC
`
`
`5.5 Severe Visual Loss
`
`
`14.2 ROS1-Positive Metastatic NSCLC
`
`
`5.6 Embryo-Fetal Toxicity
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`ADVERSE REACTIONS
`
`17 PATIENT COUNSELING INFORMATION
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`* Sections or subsections omitted from the full prescribing information are not
`
`
`DRUG INTERACTIONS
`
`
`listed.
`
`7.1 Effect of Other Drugs on XALKORI
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`6
`
`
`
`7
`
`
`
`Reference ID: 4454072
`
`1
`
`
`

`

`DOSAGE AND ADMINISTRATION
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`INDICATIONS AND USAGE
`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
`Dosage and Administration (2.1)].
`
`
`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 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/companiondiagnostics.
`
`
`2.2 Recommended Dosage
`
`The recommended dosage of XALKORI is 250 mg orally twice daily, with or without food, until disease
`progression or no longer tolerated by the patient.
`
`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 Dosage Modifications for Adverse Reactions
`
`
`The recommended dose reductions are:
`
`
`
`
`
`
`
`
`Dosage modifications for adverse reactions for XALKORI are provided in Tables 1 and 2.
`
`
`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.
`
`
`Table 1. XALKORI Dosage Modification – Hematologic Toxicitiesa
`
` Severity of Adverse Reactionb
`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
` 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.
`
`Reference ID: 4454072
`
`2
`
`
`

`

`
`
`
`
`Permanently discontinue.
`
`Permanently discontinue.
`
`
`
`
` Table 2. XALKORI Dosage Modification – Non-Hematologic Toxicities
`
`XALKORI Dosage Modification
` Severity of Adverse Reactiona
`
`
`Hepatotoxicity [see Warnings and Precautions (5.1)]
`
`Alanine aminotransferase (ALT) or aspartate
`Withhold until recovery to baseline or less than or equal to
`
`aminotransferase (AST) greater than 5 times
`
`3 times ULN, then resume at next lower dosage.
`upper limit of normal (ULN) with total
`bilirubin less than or equal to 1.5 times ULN
`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)
`Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)]
`
`
`Any grade drug-related interstitial lung
`Permanently discontinue.
`
`disease/pneumonitis
`QT Interval Prolongation [see Warnings and Precautions (5.3)]
`
`
`Withhold until recovery to baseline or to a QTc less than 481 ms,
`QT corrected for heart rate (QTc) greater than
`then resume at next lower dosage.
`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
`Bradycardia [see Warnings and Precautions (5.4)]
`
`Bradycardiab (symptomatic, may be severe and
` Withhold until recovery to asymptomatic bradycardia or to a
`medically significant, medical intervention
`heart rate of 60 bpm or above.
`indicated)
`
`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.
`
`
` Severe Vision Loss [see Warnings and Precautions (5.5)]
`
`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.
`
`
`
`
`
`
`Bradycardiab,c (life-threatening consequences,
`
`urgent intervention indicated)
`
`Reference ID: 4454072
`
`3
`
`

`

`
`2.4 Dosage Modifications for Moderate and Severe Hepatic Impairment
`
`
`The recommended dose of XALKORI in patients with pre-existing 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 200 mg orally twice daily.
`
`The recommended dose of XALKORI in patients with pre-existing severe hepatic impairment (any AST and
`total bilirubin greater than 3 times ULN) is 250 mg orally once daily [see Use in Specific Populations (8.6),
`
`Clinical Pharmacology (12.3)].
`
`2.5 Dosage Modification for Severe Renal Impairment
`
` The recommended dosage of XALKORI in patients with severe renal impairment [creatinine clearance (CLcr)
`
`less than 30 mL/min, calculated using the modified Cockcroft-Gault equation] not requiring dialysis is 250 mg
`orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
`
`2.6 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors
`
`Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is
`unavoidable, reduce the dose of XALKORI to 250 mg orally once daily [see Drug Interactions (7.1)]. After
`
`discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong
`
`CYP3A inhibitor.
`
`3
`
`Capsules:
`
`
` 250 mg: hard gelatin capsule, size 0, pink opaque cap and body, with “Pfizer” on the cap and “CRZ 250” on
`
`the body.
`
` 200 mg: hard gelatin capsule, size 1, white opaque body and pink opaque cap, with “Pfizer” on the cap and
`“CRZ 200” on the body.
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`4
`
`
` None.
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Hepatotoxicity
`
`Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of the 1719 patients treated with XALKORI
`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 <1% treated with
`
`XALKORI. Increased ALT or AST >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.
`
`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 (2.3)].
`
`Reference ID: 4454072
`
`4
`
`

`

`
`
`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), 2.9% of XALKORI-treated patients had ILD of any grade, 1.0%
`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.
`
`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)].
`
`5.3 QT Interval Prolongation
`
`QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 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.
`
`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 (2.3), Clinical
`Pharmacology (12.2)].
`
`5.4 Bradycardia
`
`Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, 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)].
`
`Avoid using XALKORI in combination with other medications 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. 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 (2.3)].
`
`5.5 Severe Visual Loss
`
`Across all clinical trials, the incidence of Grade 4 visual field defect with vision 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
`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
`
`
`Reference ID: 4454072
`
`

`

`
`
` ADVERSE REACTIONS
`
`
`
`
`
`
`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.
`Advise males 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 (8.1, 8.3), Nonclinical Toxicology
`
`(13.1)].
`
`6
`
`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)]
`
`
`
`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 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 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 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 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 with cisplatin 75 mg/m2 (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,
`6
`
`
`Reference ID: 4454072
`
`

`

`
`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 3 and 4 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated
`patients.
`
`
`
`Reference ID: 4454072
`
`7
`
`
`

`

`
`
`Adverse Reaction
`
`
`
`
`
`c
`
`
`
`All Grades
`(%)
`Cardiac
`
`Bradycardiaa
`14
`
`
`6
`Electrocardiogram QT prolonged
`
`Eye
`
` Vision disorderb
`
`71
`Gastrointestinal
`
`Diarrhea
`61
`
`Vomiting
`46
`
`Constipation
`43
`
`Abdominal painc
`26
`
`14
`
`Dyspepsia
`10
`
`Dysphagia
`
`Esophagitisd
`6
`General
`
`Edemae
`
`49
`19
`
` Pyrexia
`
`Infections
`
`Upper respiratory infectionf
`32
`
`Investigations
`
` Increased weight
`
`8
`Musculoskeletal and Connective
`
`Tissue
`
`
`16
`Pain in extremity
`
`8
`Muscle spasm
`Nervous System
`
`Dysgeusia
`
`26
`Headache
`
`
`22
`
`Dizzinessg
`18
`†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).
`
`
`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).
`
`
`
`
` 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†
`Chemotherapy
`(Pemetrexed/Cisplatin or
`Pemetrexed/Carboplatin)
`(N=169)
`All Grades
`(%)
`
`1
`2
`
`
` 10
`
`13
`
`36
`
`30
`
`12
`
`2
`2
`1
`
`
`12
`
`11
`
`12
`
`
`2
`
`
`7
`2
`
`5
`
`15
`
`10
`
`XALKORI
`(N=171)
`
`Grade 3-4
`(%)
`
`1
`2
`
`1
`
`2
`2
`2
`0
`0
`1
`2
`
`1
`0
`
`0
`
`1
`
`
`0
`0
`
`0
`1
`0
`
`Grade 3-4
`(%)
`
`0
`0
`
`0
`
`1
`3
`0
`0
`0
`1
`0
`
`1
`1
`
`1
`
`0
`
`
`0
`1
`
`0
`0
`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).
`
`
`
`Reference ID: 4454072
`
`8
`
`
`

`

`
`
`Laboratory Abnormality
`
`Chemotherapy
`Any Grade
`Grade 3-4
`(%)
`(%)
`
`Table 4. Laboratory Abnormalities with Grade 3 or 4 Occurring in ≥4% of XALKORI-Treated Patients
`
`in Study 1
`
`XALKORI
`
`Grade 3-4
`Any Grade
`(%)
`(%)
`Hematology
`
`
`52
`Neutropenia
`
`48
`Lymphopenia
`
`
`Chemistry
`
`
`2
`33
`15
`79
`Increased ALT
`1
`28
`8
`Increased AST
`66
`6
`21
`10
`Hypophosphatemia
`32
`
`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 (PROFILE 1007)
`
`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.
`
`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 5 and 6 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated
`
`patients.
`
`
`11
`7
`
`59
`53
`
`16
`13
`
`Reference ID: 4454072
`
`9
`
`
`

`

`
`
`Adverse Reaction
`
`
`
`
` 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†
`Chemotherapy
`XALKORI
`(Pemetrexed or Docetaxel)
`(N=172)
`(N=171)
`All Grades
`Grade 3-4
`All Grades
`Grade 3-4
`(%)
`(%)
`(%)
`(%)
`Nervous System
`
`
`
`
`Dysgeusia
`
`26
`0
`9
`0
`Dizzinessa
`
`
`22
`1
`8
`0
`
`3
`3
`0
`0
`Syncope
`Eye
`
`
`
`
` Vision disorderb
`60
`0
`9
`0
`Cardiac
`
`
`
`
`Electrocardiogram QT prolonged
`
`5
`3
`0
`0
`
`Bradycardiac
`5
`0
`0
`0
`Investigations
`
`
`
`
` Decreased weight
`
`10
`1
`4
`0
`Gastrointestinal
`
`
`
`
`1
`19
`0
`
`60
`
`Diarrhea
`1
`37
`1
`
`55
`
`Nausea
`0
`18
`1
`
`47
`
`Vomiting
`0
`23
`2
`
`42
`
`Constipation
`0
`3
`0
`8
`Dyspepsia
`Infections
`
`
`
`
`
`Upper respiratory infectiond
`13
`26
`0
`1
`
`
`Respiratory, Thoracic and
`
`
`
`
`Mediastinal
`
`
`
`
`Pulmonary embolisme
`2
`6
`5
`2
`General
`
`
`
`
`Edemaf
`16
`31
`0
`0
`
`†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).
`
`
`
`
`Reference ID: 4454072
`
`10
`
`
`
`

`

`25
`12
`
`4
`0
`6
`1
`
`Laboratory Abnormality
`
`Table 6. Laboratory Abnormalities with Grade 3 or 4 Occurring in ≥4% of XALKORI-Treated Patients
`
`in Study 2
`
`Chemotherapy
`XALKORI
`
`Any Grade
`Grade 3-4
`Grade 3-4
`Any Grade
`(%)
`(%)
`(%)
`(%)
`Hematology
`
`
`
`60
`51
`Lymphopenia
`
`
`
`28
`49
`Neutropenia
`
`
`Chemistry
`
`
`
`38
`17
`76
`Increased ALT
`33
`9
`61
`Increased AST
`25
`5
`28
`Hypophosphatemia
`
`
`10
`4
`18
`Hypokalemia
`
`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 (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
`
`
`
`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 case