`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`202570Orig1s000
`LABELING
`
`
`
`

`

`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, oral
`Initial U.S. Approval: August 2011
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`XALKORI is a kinase inhibitor indicated for the treatment of patients with
`locally advanced or metastatic non-small cell lung cancer (NSCLC) that is
`anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved
`test. (1) This indication is based on response rate. There are no data available
`demonstrating improvement in patient reported outcomes or survival with
`XALKORI.
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`•
`250 mg taken orally twice daily with or without food. (2.1)
`•
`Dosing interruption and/or dose reduction to 200 mg taken orally twice
`daily may be required based on individual safety and tolerability, then to
`250 mg taken orally once daily if further reduction is necessary. (2.2)
`
`•
`
`reduce, or permanently
`
`elevations. Temporarily suspend, dose
`discontinue XALKORI as indicated. (5.2)
`QT Interval Prolongation: In patients who have a history of or
`predisposition for QTc prolongation, or who are taking medications that
`are known to prolong the QT interval, periodic monitoring with
`electrocardiograms and electrolytes should be considered. (5.3)
`ALK Testing: Detection of ALK-positive NSCLC using an FDA-
`approved test, indicated for this use, is necessary for selection of patients
`for treatment with XALKORI. (5.4)
`Pregnancy: XALKORI can cause fetal harm when administered to a
`pregnant woman. (5.5, 8.1)
`
`•
`
`•
`
`•
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`The most common adverse reactions (≥25%) are vision disorder, nausea,
`diarrhea, vomiting, edema, and constipation. (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-------------------------------
`• CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong
`CYP3A inhibitors. (7.1)
`• CYP3A Inducers: Avoid concurrent use of XALKORI with strong
`CYP3A inducers. (7.2)
`• CYP3A Substrates: Dose reduction may be needed for coadministered
`drugs that are predominantly metabolized by CYP3A. Avoid concurrent
`use of XALKORI with CYP3A substrates with narrow therapeutic
`indices. (7.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`Revised: 08/2011
`
`
`
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`•
`XALKORI Capsules: 250 mg and 200 mg. (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`•
`None (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`•
`Pneumonitis: Severe, including fatal, treatment-related pneumonitis has
`been observed. Monitor patients for pulmonary symptoms indicative of
`pneumonitis. Permanently discontinue in patients diagnosed with
`treatment-related pneumonitis. (5.1)
`Hepatic Laboratory Abnormalities: Concurrent elevations in ALT and
`total bilirubin have occurred. Monitor monthly and as clinically
`indicated with more frequent testing in patients with Grade 2-4
`_______________________________________________________________________________________________________________________________________
`
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Dose Modification
`3
`DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pneumonitis
`5.2 Hepatic Laboratory Abnormalities
`5.3 QT Interval Prolongation
`5.4 ALK Testing
`5.5 Pregnancy
`ADVERSE REACTIONS
`DRUG INTERACTIONS
`7.1 Drugs That May Increase Crizotinib Plasma Concentration
`7.2 Drugs That May Decrease Crizotinib Plasma Concentration
`7.3 Drugs Whose Plasma Concentrations May Be Altered By
`Crizotinib
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
` Sections or subsections omitted from the full prescribing information are not
`8.3 Nursing Mothers
`listed.
`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
`12.3 Pharmacokinetics
`12.4 Cardiac Electrophysiology
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Gastrointestinal Effects
`17.2 Visual Effects
`17.3 Effects on Ability to Drive and Use Machines
`17.4 Concomitant Medications
`17.5 Instructions for Taking XALKORI
`17.6 Pregnancy and Nursing
`17.7 FDA-Approved Patient Labeling
`
` *
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
`
`2
`
`6
`7
`
`8
`
`Reference ID: 3007054
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1. INDICATIONS AND USAGE
`XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung
`cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
`
`This indication is based on response rate. There are no data available demonstrating improvement in patient
`reported outcomes or survival with XALKORI.
`
`2. DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`The recommended dose and schedule of XALKORI is 250 mg taken orally twice daily. Continue treatment as
`long as the patient is deriving clinical benefit from therapy. Capsules should be swallowed whole. XALKORI
`may be taken with or without food. If a dose of XALKORI is missed, then it should be taken as soon as the
`patient remembers unless it is less than 6 hours until the next dose, in which case the patient should not take the
`missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.
`
`2.2 Dose Modification
`Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose
`reduction is necessary, then the dose of XALKORI should be reduced to 200 mg taken orally twice daily. If
`further dose reduction is necessary, then reduce the dosage to 250 mg taken orally once daily based on
`individual safety and tolerability. Dose reduction guidelines for hematologic and non-hematologic toxicities are
`provided in Tables 1 and 2.
`
`CTCAEb Grade
`Grade 3
`
`Grade 4
`
`Table 1: XALKORI Dose Modification – Hematologic Toxicitiesa
`XALKORI Dosing
`Withhold until recovery to Grade ≤2, then resume at the same dose schedule
`
`Withhold until recovery to Grade ≤2, then resume at 200 mg twice dailyc
`
`a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
`b NCI Common Terminology Criteria for Adverse Events.
`c In case of recurrence, withhold until recovery to Grade ≤2, then resume at 250 mg once daily. Permanently
`discontinue in case of Grade 4 recurrence.
`
`
`
`Reference ID: 3007054
`
`2
`
`

`

`Table 2: XALKORI Dose Modification – Non-Hematologic Toxicities
`XALKORI Dosing
`Withhold until recovery to Grade ≤1 or baseline, then resume at
`200 mg twice dailya
`
`Permanently discontinue
`
`CTCAE Grade
`Grade 3 or 4 alanine aminotransferase (ALT)
`or aspartate aminotransferase (AST)
`elevation with Grade ≤1 total bilirubin
`Grade 2, 3 or 4 ALT or AST elevation with
`concurrent Grade 2, 3 or 4 total bilirubin
`elevation (in the absence of cholestasis or
`hemolysis)
`Any Grade pneumonitisb
`
`Permanently discontinue
`
`Withhold until recovery to Grade ≤1, then resume at 200 mg twice
`dailya
`
`Permanently discontinue
`
`a In case of recurrence, withhold until recovery to Grade ≤1, then resume at 250 mg once daily. Permanently
`discontinue in case of further Grade 3 or 4 recurrence.
`b Not attributable to NSCLC progression, other pulmonary disease, infection, or radiation effect.
`
`Grade 3 QTc prolongation
`
`
`Grade 4 QTc prolongation
`
`
`Complete blood counts including differential white blood cell counts should be monitored monthly and as
`clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or
`infection occurs. Liver function tests should be monitored monthly and as clinically indicated, with more
`frequent repeat testing if Grade 2, 3 or 4 abnormalities are observed.
`
`3. DOSAGE FORMS AND STRENGTHS
`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.
`
`4. CONTRAINDICATIONS
`None
`
`5. WARNINGS AND PRECAUTIONS
`
`5.1 Pneumonitis
`XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical
`trials with a frequency of 4 in 255 (1.6%) patients across Studies A and B. All of these cases occurred within 2
`months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of
`pneumonitis. Other causes of pneumonitis should be excluded. XALKORI should be permanently discontinued
`in patients diagnosed with treatment-related pneumonitis [see Dosage and Administration (2.2)].
`
`5.2 Hepatic Laboratory Abnormalities
`Grade 3 or 4 ALT elevation was observed in 7% of patients in Study A and in 4% of patients in Study B.
`Grade 3 and 4 elevations were generally asymptomatic and reversible upon dosing interruption. Patients usually
`resumed treatment at a lower dose without recurrence; however, 3 patients from Study A (2%) and 1 patient
`from Study B (less than 1%) required permanent discontinuation from treatment. Concurrent elevations in ALT
`greater than 3 x ULN and total bilirubin greater than 2 x ULN without elevated alkaline phosphatase were
`detected in 1/255 (less than 0.5%) of patients with available laboratory data across both studies. Liver function
`tests including ALT and total bilirubin should be monitored once a month and as clinically indicated, with more
`3
`
`Reference ID: 3007054
`
`

`

`frequent repeat testing for Grades 2, 3 or 4 elevation in patients who develop transaminase elevations [see
`Dosage and Administration (2.2) and Adverse Reactions (6)].
`
`5.3 QT Interval Prolongation
`QTc prolongation has been observed. XALKORI should be avoided in patients with congenital long QT
`syndrome. In patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are
`taking medications that are known to prolong the QT interval, periodic monitoring with electrocardiograms
`(ECGs) and electrolytes should be considered. Permanently discontinue XALKORI in patients who develop
`Grade 4 QTc prolongation. Withhold XALKORI in patients who develop Grade 3 QTc prolongation until
`recovery to less than or equal to Grade 1, then resume XALKORI at 200 mg twice daily. In case of recurrence
`of Grade 3 QTc prolongation, withhold XALKORI until recovery to less than or equal to Grade 1, then resume
`XALKORI at 250 mg once daily. Permanently discontinue XALKORI if Grade 3 QTc prolongation recurs [see
`Dosage and Administration (2.2) and Clinical Pharmacology (12.4)].
`
`5.4 ALK Testing
`Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for
`selection of patients for treatment with XALKORI [see Clinical Studies (14)].
`
`Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in
`the specific technology being utilized. Improper assay performance can lead to unreliable test results.
`
`Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for
`treatment with XALKORI.
`
`5.5 Pregnancy
`XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. In
`nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to and above those
`observed in humans at the recommended clinical dose of 250 mg twice daily. There are no adequate and well-
`controlled studies in pregnant women using XALKORI. If this drug is used during pregnancy, or if the patient
`becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see
`Use in Specific Populations (8.1)].
`
`6. ADVERSE REACTIONS
`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 practice.
`
`In Studies A and B, patients with locally advanced or metastatic ALK-positive NSCLC received crizotinib 250
`mg orally twice daily continuously. Among the 255 patients for whom data on Grade 1-4 adverse reactions are
`available, median exposure to study drug was 5.1 months in Study A and 7.8 months in Study B. Dosing
`interruptions occurred in 36% and 45% of patients in Studies A and B, and lasted greater than 2 weeks in 13%
`and 19% of patients in Studies A and B, respectively. Dose reductions occurred in 44% and 29% of patients in
`Studies A and B, respectively. The rates of treatment-related adverse events resulting in permanent
`discontinuation were 6% in Study A and 3% in Study B. The most common adverse reactions (≥25%) across
`both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse
`reactions in at least 4% of patients in both studies included ALT increased and neutropenia.
`
`Among the 397 patients for whom information on deaths and serious adverse reactions are available, deaths
`within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of
`their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9),
`and other (4). Respiratory causes of death included pneumonia (2), hypoxia (2), ARDS (1), dyspnea (1),
`pneumonitis (1), empyema (1), and pulmonary hemorrhage (1). Other causes of deaths included septic shock,
`4
`
`Reference ID: 3007054
`
`

`

`DIC, cardiovascular event, and death due to unknown cause (1 each). Serious adverse events in greater than or
`equal to 2% of patients included pneumonia, dyspnea, and pulmonary embolism.
`
`Table 3 lists the common adverse reactions on Studies A and B in patients receiving XALKORI.
`
`Treatment Related
`N=255
`Grade 3/4
`n (%)
`
`
`
` 0
`
` 0
`
`
`0
`0
`1 (<1%)
`0
`0
`1 (<1%)
`
` 0
`
`
`4 (2%)
`0
`0
`
`Table 3: Adverse Reactions in ≥10% of Patients with Locally Advanced or
`Metastatic ALK-Positive NSCLC on Studies A and B1
`Treatment Emergent
`N=255
`All Grades
`Grade 3/4
`n (%)
`n (%)
`Eye Disorders
`
` Vision Disorder2
`163 (64%)
`Gastrointestinal Disorders
`
` Nausea
`145 (57%)
` Diarrhea
`124 (49%)
` Vomiting
`116 (45%)
` Constipation
`98 (38%)
` Esophageal Disorder3
`51 (20%)
` Abdominal Pain4
`40 (16%)
` Stomatitis5
`27 (11%)
`General Disorders
`
` Edema6
`97 (38%)
` Fatigue
`80 (31%)
` Chest Pain/Discomfort7
`30 (12%)
`30 (12%)
` Fever
`Infections and Infestations
`
` Upper Respiratory Infection8
`50 (20%)
`Investigations
`
`38 (15%)
` Alanine Aminotransferase Increased
`29 (11%)
` Aspartate Aminotransferase Increased
`Metabolism and Nutrition
`
`69 (27%)
` Decreased Appetite
`Musculoskeletal
`
`29 (11%)
` Arthralgia
` Back Pain
`28 (11%)
`Nervous System Disorders
`
` Dizziness9
`60 (24%)
`58 (23%)
` Neuropathy10
`34 (13%)
` Headache
`33 (13%)
` Dysgeusia
`Psychiatric Disorders
`
` Insomnia
`30 (12%)
`Respiratory Disorders
`
`57 (22%)
` Dyspnea
`54 (21%)
` Cough
`Skin Disorders
`
`41 (16%)
` Rash
`1Study A used CTCAE v4.0, and Study B used CTCAE v3.0.
`2Includes diplopia, photopsia, photophobia, vision blurred, visual field defect, visual impairment, vitreous floaters, visual
`brightness, and visual acuity reduced.
`3Includes dyspepsia, dysphagia, epigastric discomfort/pain/burning, esophagitis, esophageal obstruction/pain/spasm/ulcer,
`gastroesophageal reflux, odynophagia, and reflux esophagitis.
`4Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal tenderness.
`5Includes mouth ulceration, glossodynia, glossitis, cheilitis, mucosal inflammation, oropharyngeal pain/discomfort, oral pain,
`and stomatitis.
`
`All Grades
`n (%)
`
`159 (62%)
`
`136 (53%)
`109 (43%)
`101 (40%)
`69 (27%)
`29 (11%)
`20 (8%)
`15 (6%)
`
`72 (28%)
`51 (20%)
`3 (1%)
`2 (<1%)
`
`4 (2%)
`
`34 (13%)
`24 (9%)
`
`49 (19%)
`
`4 (2%)
`2 (<1%)
`
`42 (16%)
`34 (13%)
`10 (4%)
`30 (12%)
`
`8 (3%)
`
`5 (2%)
`9 (4%)
`
`25 (10%)
`
`
`
` 0
`
`
`2 (<1%)
`1 (<1%)
`3 (1%)
`2 (<1%)
`3 (1%)
`1 (<1%)
`1 (<1%)
`
`2 (<1%)
`6 (2%)
`1 (<1%)
`1 (<1%)
`
`1 (<1%)
`
`17 (7%)
`7 (3%)
`
`3 (1%)
`
`3 (1%)
`0
`
` 0
`
`
`1 (<1%)
`1 (<1%)
`0
`
`
`
` 0
`
`
`16 (6%)
`3 (1%)
`
`
`
` 0
`
`Adverse Event
`
`
`
`
`
`
`
`
`
`Reference ID: 3007054
`
`5
`
` 0
`
`
`
`
`
`
`14 (5%)
`5 (2%)
`
` 0
`
` 0
`
`
`0
`
` 0
`
`
`1 (<1%)
`0
`0
`
`
`
` 0
`
`
`
` 0
`
`
`3 (1%)
`0
`
`

`

`
`
`6Includes edema, edema localized, and peripheral edema.
`7Includes chest pain, chest discomfort, and musculoskeletal chest pain.
`8Includes nasopharyngitis, rhinitis, pharyngitis, and upper respiratory tract infection.
`9Includes balance disorder, dizziness, and presyncope.
`10Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, peripheral neuropathy,
`peripheral motor neuropathy, and peripheral sensory neuropathy.
`
`
`
`
`
`Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and
`diplopia were reported in 159 (62%) patients in clinical trials. These events generally started within two weeks
`of drug administration. Ophthalmological evaluation should be considered, particularly if patients experience
`photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or
`photopsia could also be signs of a retinal hole or pending retinal detachment. Caution should be exercised when
`driving or operating machinery by patients who experience vision disorder [see Patient Counseling Information
`(17)].
`
`Neuropathy as defined in Table 3 and attributed to study drug by the investigator was reported in 34 (13%)
`patients. While most events were Grade 1, Grade 2 motor neuropathy and Grade 3 peripheral neuropathy were
`reported in 1 patient each. Dizziness and dysgeusia were also very commonly reported in these studies, but were
`all Grade 1 or 2 in severity.
`
`Bradycardia has been reported in 12 (5%) patients treated with XALKORI. All of these cases were Grade 1 or 2
`in severity.
`
`Complex renal cysts have been reported in 2 (1%) patients treated with XALKORI. There were no reports of
`abnormal urinalyses or renal impairment in these cases.
`Laboratory Abnormalities
`Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia were seen in 5.2%, 0.4%, and 11.4% of patients,
`respectively.
`
`7. DRUG INTERACTIONS
`7.1 Drugs That May Increase Crizotinib Plasma Concentrations
`Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see
`Clinical Pharmacology (12.3)]. The concomitant use of strong CYP3A inhibitors, including but not limited to
`atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
`telithromycin, troleandomycin, and voriconazole, should be avoided. Grapefruit or grapefruit juice may also
`increase plasma concentrations of crizotinib and should be avoided. Caution should be exercised with
`concomitant use of moderate CYP3A inhibitors.
`
`7.2 Drugs That May Decrease Crizotinib Plasma Concentrations
`Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see
`Clinical Pharmacology (12.3)]. The concurrent use of strong CYP3A inducers, including but not limited to
`carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort, should be avoided.
`
`7.3 Drugs Whose Plasma Concentrations May Be Altered By Crizotinib
`Crizotinib inhibits CYP3A both in vitro and in vivo [see Clinical Pharmacology (12.3)]. Dose reduction may be
`needed for coadministered drugs that are predominantly metabolized by CYP3A. Coadministration of crizotinib
`with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil, cyclosporine,
`dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided.
`
`Reference ID: 3007054
`
`6
`
`

`

`8. USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category D [see “Warnings and Precautions” (5.5)]
`XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
`There are no adequate and well-controlled studies of XALKORI in pregnant women. In nonclinical studies in
`rats, crizotinib was embryotoxic and fetotoxic at exposures similar to and above those observed in humans at
`the recommended clinical dose of 250 mg twice daily. Crizotinib was administered to pregnant rats and rabbits
`during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at
`doses ≥ 50 mg/kg/day (approximately 1.2 times the AUC at the recommended human dose) in rats. No
`teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day
`(approximately 5 times the AUC at the recommended human dose) or in rabbits at doses of up to 60 mg/kg/day
`(approximately 3 times the AUC at the recommended human dose), though fetal body weights were reduced at
`these doses.
`
`Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI.
`Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential
`receiving this drug, should use adequate contraceptive methods during therapy and for at least 90 days after
`completing therapy. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant
`while taking this drug, the patient should be apprised of the potential hazard to a fetus.
`
`8.3 Nursing Mothers
`It is not known whether XALKORI is excreted in human milk. Because many drugs are excreted in human milk
`and because of the potential for serious adverse reactions in nursing infants from XALKORI, a decision should
`be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
`drug to the mother.
`
`8.4 Pediatric Use
`The safety and efficacy of XALKORI in pediatric patients has not been established. Decreased bone formation
`in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days
`(approximately 10 times the AUC in adult patients at the recommended human dose). Other toxicities of
`potential concern to pediatric patients have not been evaluated in juvenile animals.
`
`8.5 Geriatric Use
`Of the 119 patients in Study A, 16 (13%) were 65 years or older. Of the 136 patients in Study B, 19 (14%) were
`65 years or older. No overall differences in safety or efficacy were observed in comparison with younger
`patients.
`
`8.6 Hepatic Impairment
`XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in
`the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Clinical studies excluded
`patients with AST or ALT greater than 2.5 x ULN, or greater than 5 x ULN, if due to liver metastases. Patients
`with total bilirubin greater than 1.5 x ULN were also excluded. Treatment with XALKORI should be used with
`caution in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
`
`8.7 Renal Impairment
`No starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) and
`moderate renal impairment (CLcr 30 to 60 mL/min), as steady-state trough concentrations in these two groups
`were similar to those in patients with normal renal function (CLcr greater than 90 mL/min) in Study B. The
`potential need for starting dose adjustment in patients with severe renal impairment cannot be determined, as
`clinical and pharmacokinetic data were available for only one patient. In addition, no data are available for
`patients with end-stage renal disease. Therefore, caution should be used in patients with severe renal
`7
`
`Reference ID: 3007054
`
`

`

`impairment (CLcr less than 30 mL/min) or patients with end-stage renal disease [see Clinical Pharmacology
`(12.3)].
`
`10. OVERDOSAGE
`There have been no known cases of XALKORI overdose. Treatment of overdose with XALKORI should
`consist of general supportive measures. There is no antidote for XALKORI.
`
`11. DESCRIPTION
`XALKORI (crizotinib) is an oral receptor tyrosine kinase inhibitor. The molecular formula for crizotinib is
`C21H22Cl2FN5O. The molecular weight is 450.34 Daltons. Crizotinib is described chemically as (R)-3-[1-(2,6-
`Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.
`
`The chemical structure of crizotinib is shown below:
`
`NH
`
`NN
`
`Cl
`
`CH3
`
`(R)
`
`O
`
`Cl
`
`N
`
`NH2
`
`
`Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation).
`The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10
`mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.
`
`F
`
`XALKORI capsules are supplied as printed hard-shell capsules containing 250 mg or 200 mg of crizotinib
`together with colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium
`starch glycolate, magnesium stearate, and hard gelatin capsule shells as inactive ingredients.
`
`The pink opaque capsule shell components contain gelatin, titanium dioxide, and red iron oxide. The white
`opaque capsule shell components contain gelatin, and titanium dioxide. The printing ink contains shellac,
`propylene glycol, strong ammonia solution, potassium hydroxide, and black iron oxide.
`
`12. CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor
`(HGFR, c-Met), and Recepteur d’Origine Nantais (RON). Translocations can affect the ALK gene resulting in
`the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and
`dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and
`survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of
`ALK and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity
`in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.
`
`Reference ID: 3007054
`
`8
`
`

`

`12.3 Pharmacokinetics
`
`Absorption
`Following oral single-dose administration, crizotinib was absorbed with median time to achieve peak
`concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days
`and remained stable, with a median accumulation ratio of 4.8. Steady state systemic exposure (Cmin and AUC)
`appeared to increase in a greater than dose proportional manner over the dose range of 200-300 mg twice daily.
`
`The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following the administration of a
`single 250 mg oral dose.
`
`A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%. XALKORI can be administered
`with or without food [see Dosage and Administration (2.1)].
`
`Distribution
`The geometric mean volume of distribution (Vss) of crizotinib was 1,772 L following intravenous
`administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma.
`
`Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In
`vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma
`concentration ratio is approximately 1.
`
`Metabolism
`In vitro studies demonstrated that crizotinib is predominantly metabolized by CYP3A4/5. The primary
`metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation,
`with subsequent Phase 2 conjugation of O-dealkylated metabolites.
`
`In vitro studies in human liver microsomes demonstrated that crizotinib is a time-dependent inhibitor of
`CYP3A.
`
`Elimination
`Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in
`patients.
`
`Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22%
`of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented
`approximately 53% and 2.3% of the administered dose in feces and urine, respectively.
`
`The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/hr) after 250 mg twice daily
`than that after a single 250 mg oral dose (100 L/hr), which was likely due to autoinhibition of CYP3A by
`crizotinib after multiple dosing.
`
`Drug Interactions
`Coadministration of Crizotinib and CYP3A Substrates
`Crizotinib inhibits CYP3A both in vitro and in vivo. Coadministration of crizotinib (250 mg twice daily for 28
`days) in patients resulted in a geometric mean oral midazolam AUC that was 3.7-fold that observed when
`midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3A [see Drug
`Interactions (7.3)].
`
`Coadministration of Crizotinib and CYP3A Inhibitors
`Coadministration of a single 150 mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice
`daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib AUCinf
`9
`
`Reference ID: 3007054
`
`

`

`and Cmax values that were approximately 3.2-fold and 1.4-fold, respectively, those seen when crizotinib was
`administered alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure
`has not been evaluated [see Drug Interactions (7.1)].
`
`Coadministration of Crizotinib and CYP3A Inducers
`Coadministration of a single 250 mg crizotinib dose with rifampin (600 mg QD), a strong CYP3A inducer,
`decreased crizotinib AUCinf and Cmax by 82% and 69%, respectively, compared to crizotinib alone. However,
`the effect of CYP3A inducers on steady-state crizotinib exposure has not been evaluated [see Drug Interactions
`(7.2)].
`
`Coadministration of Crizotinib and Antacids
`The aqueous solubility of crizotinib is pH dependent, with higher pH resulting in lower solubility. Drugs that
`elevate the gastric pH (such as proton pump inhibitors, H2 blockers, or antacids) may decrease the solubility of
`crizotinib and subsequently reduce its bioavailability. However, no formal studies have been conducted.
`
`Coadministration With Other CYP Substrates
`In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-
`mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or
`CYP2D6.
`
`An in vitro study in human hepatocytes indicated that clinical drug-drug interactions are unlikely to occur as a
`result of crizotinib-mediated induction of the metabolism of substrates for CYP1A2 or CYP3A.
`
`Coadministration With Substrates of Transporters
`Crizotinib is an inhibitor of P-glycoprotein (P-gp) in vitro. Therefore, crizotinib may have the potential to
`increase plasma concentrations of coadministered substrates of P-gp.
`
`In vitro, crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3 at
`therapeutic concentrations. Therefore, clinical drug-drug interactions are unlikely to occur as a result of
`crizotinib-mediated inhibition of the hepatic uptake of substrates for these transporters.
`
`Pharmacokinetics in Special Populations
`Hepatic Impairment: As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to
`increase plasma crizotinib concentrations. However, XALKORI has not been studied in