Xalkori Capsule, Coated Pellets
FDA Label NDC 0069-0507

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)].

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.

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 (CL_cr) <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.

Reduce dose as below, if 1 or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0:

• 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

Dose reduction guidelines are provided in Tables 1 and 2.

Table 1. XALKORI Dose Modification – Hematologic Toxicities

Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Grade	XALKORI Dosing
Grade 3	Withhold until recovery to Grade 2 or less, then resume at the same dose schedule
Grade 4	Withhold until recovery to Grade 2 or less, then resume at next lower dose

Table 2. XALKORI Dose Modification – Non-Hematologic Toxicities

Criteria	XALKORI Dosing
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	Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at reduced dose.
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)	Permanently discontinue.
Any grade drug-related interstitial lung disease/pneumonitis	Permanently discontinue.
QT corrected for heart rate (QTc) greater than 500 ms on at least 2 separate electrocardiograms (ECGs)	Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at reduced dose.
QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia	Permanently discontinue.
Bradycardia Heart rate less than 60 beats per minute (bpm). (symptomatic, may be severe and medically significant, medical intervention indicated)	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.
Bradycardia, Permanently discontinue for recurrence. (life-threatening consequences, urgent intervention indicated)	Permanently discontinue if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at 250 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring.
Visual Loss (Grade 4 Ocular Disorder)	Discontinue during evaluation of severe vision loss.

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.

• 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.

None.

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)].

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)].

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 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)].

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)].

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.

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)].

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)]

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.

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.

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).

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.

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.

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).

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.

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) decreased from a baseline median of 96.42 mL/min/1.73 m² (n=1681) to a median of 80.23 mL/min/1.73 m² at 2 weeks (n=1499) in patients with ALK-positive advanced NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median eGFR from 12 to 104 weeks of treatment. Median eGFR slightly increased (83.02 mL/min/1.73 m²) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in eGFR to <90 mL/min/1.73 m², 38% had a decrease to eGFR to <60 mL/min/1.73 m², and 3.6% had a decrease to eGFR to <30 mL/min/1.73 m².

Risk Summary

Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of XALKORI during pregnancy. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those expected with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at doses ≥50 mg/kg/day (approximately 0.6 times the recommended human dose based on AUC) in rats. No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day (approximately 2.7 times the recommended human dose based on AUC) or in rabbits at doses of up to 60 mg/kg/day (approximately 1.6 times the recommended human dose based on AUC), though fetal body weights were reduced at these doses.

Risk Summary

There is no information regarding the presence of crizotinib in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants, do not breastfeed during treatment with XALKORI and for 45 days after the final dose.

Contraception

Females

XALKORI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days after the final dose.

Males

Because of the potential for genotoxicity, 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 Nonclinical Toxicology (13.1)].

Infertility

Based on reproductive organ findings in animals, XALKORI may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

Animal Data

Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 5.4 times the recommended human dose based on AUC). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Cardiac electrophysiology

In an ECG substudy conducted in 52 patients with ALK-positive NSCLC who received crizotinib 250 mg twice daily, the maximum mean QTcF (corrected QT by the Fridericia method) change from baseline was 12.3 ms (2-sided 90% upper CI: 19.5 ms). An exposure-QT analysis suggested a crizotinib plasma concentration-dependent increase in QTcF [see Warnings and Precautions (5.3)].

Absorption

Following a single oral dose, 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 [observed minimum concentration (C_min) 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 a single 250 mg oral dose.

A high-fat meal reduced crizotinib AUC from time zero to infinity (AUC_inf) and maximum observed plasma concentration (C_max) by approximately 14%. XALKORI can be administered with or without food [see Dosage and Administration (2.2)].

Distribution

The geometric mean volume of distribution (V_ss) of crizotinib was 1772 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.

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/h) after 250 mg twice daily than after a single 250 mg oral dose (100 L/h), which was likely due to auto-inhibition of CYP3A by crizotinib after multiple dosing.

Metabolism

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.

Specific populations

Hepatic impairment: Crizotinib is extensively metabolized in the liver. Following crizotinib 250 mg twice daily dosing, patients with mild hepatic impairment (n=10) showed similar systemic crizotinib exposure at steady state compared to patients with normal hepatic function (n=8), with geometric mean ratios of 91.1% for AUC and 91.2%, for C_max.

Following crizotinib 200 mg twice daily dosing, patients with moderate hepatic impairment (n=8) showed higher systemic crizotinib exposure at steady state compared to patients with normal hepatic function (n=9) at the same dose level, with geometric mean ratios of 150% for AUC and 144% for C_max. The systemic crizotinib exposure in patients with moderate hepatic impairment at the dose of 200 mg twice daily was comparable to that observed from patients with normal hepatic function at a dose of 250 mg twice daily, with geometric mean ratios of 114% for AUC and 109% for C_max [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

The systemic crizotinib exposure in patients with severe hepatic impairment at the dose of 250 mg once daily was lower than that observed from patients with normal hepatic function at a dose of 250 mg twice daily, with geometric mean ratios of 64.7% for AUC and 72.6% for C_max [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Renal impairment: The pharmacokinetics of crizotinib were evaluated using the population pharmacokinetic analysis in patients with mild (CL_cr 60–89 mL/min, n=433) and moderate (CL_cr 30–59 mL/min, n=137) renal impairment. Mild or moderate renal impairment has no clinically relevant effect on the exposure of crizotinib.

A study was conducted in 7 patients with severe renal impairment (CL_cr <30 mL/min) who did not require dialysis and 8 patients with normal renal function (CL_cr ≥90 mL/min). All patients received a single 250 mg oral dose of XALKORI. The mean AUC_inf for crizotinib increased by 79% and the mean C_max increased by 34% in patients with severe renal impairment compared to those with normal renal function. Similar changes in AUC_inf and C_max were observed for the active metabolite of crizotinib [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)].

Ethnicity: No clinically relevant difference in the exposure of crizotinib between Asian patients (n=523) and non-Asian patients (n=691).

Age: Age has no effect on the exposure of crizotinib based on the population pharmacokinetic analysis.

Body weight and gender: No clinically relevant effect of body weight or gender on the exposure of crizotinib based on the population pharmacokinetic analysis.

Drug interactions

Effect of Other Drugs on Crizotinib

Strong CYP3A inhibitors: Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, increased crizotinib AUC_inf and C_max values by 216% and 44%, respectively, compared to crizotinib alone. Coadministration of crizotinib (250 mg once daily) with itraconazole (200 mg once daily), a strong CYP3A inhibitor, increased crizotinib steady-state AUC and C_max by 57% and 33%, respectively, compared to crizotinib alone [see Drug Interactions (7.1)].

Strong CYP3A inducers: Coadministration of crizotinib (250 mg twice daily) with rifampin (600 mg once daily), a strong CYP3A inducer, decreased crizotinib steady-state AUC and C_max by 84% and 79%, respectively, compared to crizotinib alone [see Drug Interactions (7.2)].

Gastric pH elevating medications: In healthy subjects, coadministration of a single 250 mg oral dose of crizotinib following administration of esomeprazole 40 mg daily for 5 days did not result in a clinically relevant change in crizotinib exposure (AUC_inf decreased by 10% and no change in C_max).

Effect of Crizotinib on Other Drugs

CYP3A substrates: Coadministration of crizotinib (250 mg twice daily for 28 days) in patients increased the AUC_inf of oral midazolam 3.7-fold compared to midazolam alone, suggesting that crizotinib is a moderate inhibitor of CYP3A [see Drug Interactions (7.3)].

Other CYP substrates: In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 are unlikely to occur.

Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may increase plasma concentrations of coadministered drugs that are predominantly metabolized by CYP2B6.

An in vitro study suggests that clinical drug-drug interactions as a result of crizotinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A are unlikely to occur.

UGT substrates: In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for uridine diphosphate glucuronosyltransferase (UGT)1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7 are unlikely to occur.

Substrates of transporters: Crizotinib inhibited P-gp in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of P-gp.

Crizotinib inhibited the hepatic uptake transporter, organic cation transporter (OCT) 1, and renal uptake transporter, OCT2, in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2.

Crizotinib did not inhibit the human hepatic uptake transport proteins, organic anion transporting polypeptides (OATP) B1 or OATP1B3, or the renal uptake transport proteins organic anion transporter (OAT) 1 or OAT3 in vitro at clinically relevant concentrations.

Other transporters: Crizotinib did not inhibit the hepatic efflux bile salt export pump transporter (BSEP) in vitro at clinically relevant concentrations.

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1

The efficacy and safety of XALKORI for the treatment of patients with ALK-positive metastatic NSCLC, who had not received previous systemic treatment for advanced disease, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 1). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit, prior to randomization. The major efficacy outcome measure was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by independent radiology review (IRR) committee. Additional efficacy outcome measures included objective response rate (ORR) as assessed by IRR, duration of response (DOR), and overall survival (OS). Patient-reported lung cancer symptoms were assessed at baseline and periodically during treatment.

Patients were randomized to receive XALKORI (n=172) or chemotherapy (n=171). Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0–1, 2), race (Asian, non-Asian), and brain metastases (present, absent). Patients in the XALKORI arm 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. Chemotherapy consisted of pemetrexed 500 mg/m² with cisplatin 75 mg/m² or carboplatin AUC of 5 or 6 mg∙min/mL by intravenous infusion every 3 weeks for up to 6 cycles. Patients in the chemotherapy arm were not permitted to receive maintenance chemotherapy. At the time of documented disease progression, as per independent radiology review, patients randomized to chemotherapy were offered XALKORI.

The demographic characteristics of the overall study population were 62% female, median age of 53 years, baseline ECOG performance status 0 or 1 (95%), 51% White and 46% Asian, 4% current smokers, 32% past smokers, and 64% never smokers. The disease characteristics of the overall study population were metastatic disease in 98% of patients, 92% of patients' tumors were classified as adenocarcinoma histology, 27% of patients had brain metastases, and 7% received systemic chemotherapy as adjuvant or neoadjuvant therapy. Of those randomized to chemotherapy, 70% received XALKORI after IRR documented progression.

Study 1 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. The OS analysis conducted at the time of the PFS analysis did not suggest a difference in survival between arms. Table 7 and Figure 1 summarize the efficacy results. Exploratory patient-reported symptom measures of baseline and post-treatment dyspnea, cough, and chest pain suggested a delay in time to development of or worsening of dyspnea, but not cough or chest pain, in patients treated with XALKORI as compared to chemotherapy. The patient-reported delay in onset or worsening of dyspnea may be an overestimation, because patients were not blinded to treatment assignment.

Figure 1. Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 1
Figure 1 (Xalkori 02)

Previously Treated ALK-Positive Metastatic NSCLC - Study 2

The efficacy and safety of XALKORI as monotherapy for the treatment of 347 patients with ALK-positive metastatic NSCLC, previously treated with 1 platinum-based chemotherapy regimen, were demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 2). The major efficacy outcome was PFS according to RECIST version 1.1 as assessed by IRR. Additional efficacy outcomes included ORR as assessed by IRR, DOR, and OS.

Patients were randomized to receive XALKORI 250 mg orally twice daily (n=173) or chemotherapy (n=174). Chemotherapy consisted of pemetrexed 500 mg/m² (if pemetrexed-naïve; n=99) or docetaxel 75 mg/m² (n=72) intravenously (IV) every 21 days. Patients in both treatment arms continued treatment until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Randomization was stratified by ECOG performance status (0–1, 2), brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor treatment (yes, no). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit, prior to randomization. At the time of the final analysis of overall survival, 154 (89%) patients randomized to the chemotherapy arm subsequently received XALKORI.

The demographic characteristics of the overall study population were 56% female, median age of 50 years, baseline ECOG performance status 0 or 1 (90%), 52% White and 45% Asian, 4% current smokers, 33% past smokers, and 63% never smokers. The disease characteristics of the overall study population were metastatic disease in at least 95% of patients and at least 93% of patients' tumors were classified as adenocarcinoma histology.

Study 2 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. Table 8 and Figure 2 summarize the efficacy results.

Figure 2. Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 2
Figure 2 (Xalkori 03)

Hepatotoxicity

Inform patients to immediately report symptoms of hepatotoxicity [see Warnings and Precautions (5.1)].

Interstitial Lung Disease (Pneumonitis)

Advise patients to immediately report any new or worsening pulmonary symptoms [see Warnings and Precautions (5.2)].

Bradycardia

Advise patients to report any symptoms of bradycardia and to inform their healthcare provider about the use of any heart or blood pressure medications [see Warnings and Precautions (5.4)].

Severe Visual Loss

Inform patients of the potential risk of severe visual loss and to immediately contact their healthcare provider if they develop severe visual loss. Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse events and may occur while driving or operating machinery. The onset of visual disorders most commonly occurs during the first week of treatment [see Warnings and Precautions (5.5) and Adverse Reactions (6)].

Drug Interactions

Inform patients to avoid grapefruit or grapefruit juice while taking XALKORI. Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].

Dosing and Administration

Advise patients to take XALKORI with or without food and swallow XALKORI capsules whole.

If a patient misses a dose, advise the patient to take it as soon as remembered unless it is less than 6 hours until the next dose, in which case, advise the patient not to take the missed dose. If a patient vomits after taking a dose of XALKORI, advise the patient not to take an extra dose, but to take the next dose at the regular time.

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days after the final dose [see Use in Specific Populations (8.3)].

Females and Males of Reproductive Potential

Advise females and males of reproductive potential of the potential for reduced fertility from XALKORI [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

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)].

Lactation

Advise females not to breastfeed during treatment with XALKORI and for 45 days after the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential of the potential for reduced fertility from XALKORI [see Use in Specific Populations (8.3)].

This product's labeling may have been updated. For full prescribing information, please visit www.XALKORI.com.

Logo (Xalkori 04)

LAB-0440-19.0

Coadministration of crizotinib with strong cytochrome P450 (CYP) 3A inhibitors increases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inhibitors, including but not limited to clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, troleandomycin, voriconazole, grapefruit, and grapefruit juice. If the use of strong CYP3A inhibitors cannot be avoided, reduce the dose of XALKORI to 250 mg orally once daily [see Clinical Pharmacology (12.3)]. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor. Exercise caution with concomitant use of moderate CYP3A inhibitors.

Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort.

Crizotinib inhibits CYP3A both in vitro and in vivo [see Clinical Pharmacology (12.3)]. Avoid concomitant use of CYP3A substrates with narrow therapeutic range, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking XALKORI. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.

The safety and efficacy of XALKORI in pediatric patients has not been established.

Of the total number of patients with ALK-positive metastatic NSCLC in clinical studies of XALKORI (n=1669), 16% were 65 years or older and 3.8% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Clinical studies of XALKORI in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients.

Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin >1.5 times ULN and ≤3 times ULN) or severe (any AST and total bilirubin >3 times ULN) hepatic impairment [see Clinical Pharmacology (12.3)]. Reduce XALKORI dose in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.2)]. No dose adjustment is recommended in patients with pre-existing mild hepatic impairment.

Increased exposure to crizotinib occurred in patients with pre-existing severe renal impairment (CL_cr <30 mL/min) not requiring dialysis. Administer XALKORI at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild to moderate renal impairment.

There have been no known cases of XALKORI overdose. There is no antidote for XALKORI.

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:

Chemical Structure (Xalkori 01)

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.

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.

Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), 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, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

Carcinogenicity studies with crizotinib have not been conducted.

Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.

No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given greater than or equal to 50 mg/kg/day for 28 days (greater than 1.7 times the recommended human dose based on AUC). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) for 3 days.

The efficacy and safety of XALKORI was investigated in a multicenter, single-arm study (Study 3), in which patients with ROS1-positive metastatic NSCLC received XALKORI 250 mg orally twice daily. Patients were required to have histologically-confirmed advanced NSCLC with a ROS1 rearrangement, age 18 years or older, ECOG performance status of 0, 1, or 2, adequate organ function, and measurable disease. The efficacy outcome measures were ORR and DOR according to RECIST version 1.0 as assessed by IRR and investigator, with imaging performed every 8 weeks for the first 60 weeks.

Baseline demographic and disease characteristics were female (56%), median age of 53 years, baseline ECOG performance status of 0 or 1 (98%), White (54%), Asian (42%), past smokers (22%), never smokers (78%), metastatic disease (92%), adenocarcinoma (96%), no prior systemic therapy for metastatic disease (14%), and prior platinum-based chemotherapy for metastatic disease (80%). The ROS1 status of NSCLC tissue samples was determined by laboratory-developed break-apart FISH (96%) or RT-PCR (4%) clinical trial assays. For assessment by FISH, ROS1 positivity required that ≥15% of a minimum of 50 evaluated nuclei contained a ROS1 gene rearrangement.

Efficacy results are summarized in Table 9.

• 250 mg capsules
  Hard gelatin capsule with pink opaque cap and body, printed with black ink "Pfizer" on the cap, "CRZ 250" on the body; available in:

  Bottles of 60 capsules:

  NDC 0069-8140-20

• 200 mg capsules
  Hard gelatin capsule with pink opaque cap and white opaque body, printed with black ink "Pfizer" on the cap, "CRZ 200" on the body; available in:

  Bottles of 60 capsules:

  NDC 0069-8141-20

Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pfizer

NDC 0069-8140-20

XALKORI^®
(crizotinib) capsules,
for oral use

250 mg

60 Capsules
Rx only

Principal Display Panel (250 mg Capsule Bottle Label)

Pfizer

NDC 0069-8141-20

XALKORI^®
(crizotinib) capsules,
for oral use

200 mg

60 Capsules
Rx only

Principal Display Panel (200 mg Capsule Bottle Label)