HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use XALKORI ® safely and effectively. See full prescribing information for XALKORI.
XALKORI ® (crizotinib) capsules, for oral use
Initial U.S. Approval: 2011
RECENT MAJOR CHANGES
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)-positive as detected by an FDA-approved test. (1)
DOSAGE AND ADMINISTRATION
-
Recommended dose: 250 mg orally, twice daily (2.2)
-
Renal Impairment: 250 mg orally, once daily in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis. (2.2)
DOSAGE FORMS AND STRENGTHS
-
Capsules: 250 mg and 200 mg (3)
CONTRAINDICATIONS
-
Hepatotoxicity: Fatal hepatotoxicity occurred in 0.1% of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.1)
-
Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2.9% of patients. Permanently discontinue in patients with ILD/pneumonitis. (5.2)
-
QT Interval Prolongation: Occurred in 2.1% of patients. Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.3)
-
Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.4)
-
Severe Visual Loss: Reported in 0.2% of patients. Discontinue XALKORI in patients with severe visual loss. Perform an ophthalmological eva luation. (5.5)
-
Embryofetal 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, diarrhea, nausea, vomiting, constipation, edema, elevated transaminases, upper respiratory infection, decreased appetite, and dysgeusia. (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.
-
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: Avoid concurrent use of XALKORI with CYP3A substrates with narrow therapeutic indices. (7.3)
USE IN SPECIFIC POPULATIONS
-
Lactation: Do not breastfeed while taking XALKORI (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
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)-positive as detected by an FDA-approved test.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.
2.2 Recommended Dosing
The recommended dose of XALKORI is 250 mg orally, twice daily until disease progression or no longer tolerated by the patient. The recommended dose of XALKORI in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis is 250 mg orally, once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of XALKORI, take the next dose at the regular time.
2.3 Dose Modification
Reduce dose as below, if one or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by NCI Common Terminology Criteria for Adverse Events (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 once daily
Dose reduction guidelines are provided in Tables 1 and 2.
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.
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
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.1%) of the 1669 patients treated with XALKORI across clinical trials in patients with NSCLC. Concurrent elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to three times the upper limit of normal (ULN) and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in 10 patients (0.6%) treated with XALKORI. Additionally, elevations in ALT or AST greater than five times the ULN occurred in 184 (11%) and 93 (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 with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as described in Table 2 [see Dosage and Administration (2.3) and Adverse Reactions (6)].
5.2 Interstitial Lung Disease (Pneumonitis)
Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1669), 49 XALKORI-treated patients (2.9%) had ILD of any grade, 18 patients (1.1%) had Grade 3 or 4 ILD, and 8 patients (0.5%) had fatal ILD. These cases generally occurred within 3 months after the initiation of XALKORI.
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6)].
5.3 QT Interval Prolongation
QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 32 of 1560 patients (2.1%) had QTcF (corrected QT by the Fridericia method) greater than or equal to 500 ms and 76 of 1520 patients (5.0%) had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read eva luation of ECG.
Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume XALKORI at a reduced dose as described in Table 2 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)].
5.4 Bradycardia
Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia occurred in 205 (12.3%) of 1669 patients treated with XALKORI. A total of 242 (14.9%) patients had a heart rate less than 50 beats per minute. In Studies 1 and 2, Grade 3 syncope occurred in 2.0% 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-eva luate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse Reactions (6)].
5.5 Severe Visual Loss
Across all clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (4/1669). 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 eva luation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other eva luations as appropriate for new onset of severe visual loss. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume XALKORI should consider the potential benefits to the patient.
5.6 Embryofetal Toxicity
Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days following the final dose [see Use in Specific Populations (8.1, 8.3)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
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 safety of XALKORI is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg twice daily in two open-label, randomized, active-controlled trials (Studies 1 and 2). This is supplemented with information on adverse drug reactions in 1326 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg twice daily across clinical trials, for a total of 1669 patients across all clinical studies.
The most common adverse reactions (≥25%) of XALKORI in Studies 1 and 2 are vision disorders, diarrhea, nausea, vomiting, constipation, edema, elevated transaminases, upper respiratory infection, decreased appetite, and dysgeusia.
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.
|
