Drug-induced hepatotoxicity with fatal outcome has occurred. These cases have occurred during XALKORI treatment in less than 1% of patients in clinical trials. Concurrent elevations in ALT greater than 3 times the upper limit of normal and total bilirubin greater than 2 times the upper limit of normal, with normal alkaline phosphatase, occurred in less than 1% of patients in clinical trials. Elevation in ALT greater than 5 times the upper limit of normal occurred in 7% of patients in Study A and in 4% of patients in Study B. These laboratory findings 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. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin 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 [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].
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. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes of pneumonitis, and permanently discontinue XALKORI in patients diagnosed with treatment-related pneumonitis [see DOSAGE AND ADMINISTRATION].
QT Interval Prolongation
QTc prolongation has been observed. 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 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 and CLINICAL PHARMACOLOGY].
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].
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.
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, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations].
Patient Counseling Information
See for FDA-Approved Patient Labeling.
Inform patients that symptoms of weakness, fatigue, anorexia, nausea, vomiting, abdominal pain (especially RUQ abdominal pain), jaundice, dark urine, generalized pruritus, and bleeding diathesis, especially in combination with fever and rash, should be reported immediately [see WARNINGS AND PRECAUTIONS].
Inform patients that nausea, diarrhea, vomiting, and constipation are the most commonly reported gastrointestinal adverse events occurring in patients who received XALKORI. Supportive care for gastrointestinal adverse events requiring treatment may include standard anti-emetic and/or anti-diarrheal or laxative medications [see ADVERSE REACTIONS].
Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse events. These events began most commonly during the first two weeks of treatment. Advise patients to report flashes or floaters to their physicians [see ADVERSE REACTIONS].
Effects on Ability to Drive and Use Machines
No studies on the effect of XALKORI on the ability to drive and use machines have been performed. However, advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder, dizziness, or fatigue while taking XALKORI [see ADVERSE REACTIONS].
Instructions for Taking XALKORI
Advise patients to take XALKORI exactly as prescribed, not to change their dose or to stop taking XALKORI unless they are told to do so by their doctor. Take XALKORI with or without food. Swallow XALKORI capsules whole.
Advise patients to keep XALKORI in the original container. Do not crush, dissolve, or open capsules. Inform patients to avoid grapefruit or grapefruit juice while taking XALKORI.
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. Advise patients not to take two doses at the same time to make up for a missed dose.
Pregnancy and Nursing
Inform patients of childbearing potential to use adequate contraceptive methods during therapy and for at least 90 days after completing therapy. Advise patients to inform their doctor if they or their partners are pregnant or think they may be pregnant. Also advise patients not to breastfeed while taking XALKORI.
Carcinogcncsis, Mutagenesis, Impairment of Fertility
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 3 times the AUC at the recommended human dose). 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 daily dose on a mg/m2 basis) for 3 days.
Use In Specific Populations
Pregnancy Category D [see "WARNINGS AND PRECAUTIONS"]
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.
Advise women of childbearing potential 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, apprise the patient of the potential hazard to a fetus.
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, consider whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
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.
Clinical studies of XALKORI did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Of the 136 patients in Study A, 19 (14%) were 65 years or older. Of the 119 patients in Study B, 16 (13%) were 65 years or older.
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. Therefore, use caution in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].
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, use caution in patients with severe renal impairment (CLcr less than 30 mL/min) or patients with end-stage renal disease [see CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 3/15/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Xalkori Information
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