"Jan. 13, 2015 -- Drug-maker Bristol-Myers Squibb says a trial of nivolumab (Opdivo) has been stopped early because the drug improves how long people with a type of advanced lung cancer live compared to chemotherapy.
This is the first time a"...
Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.2%) of the 1225 patients treated with XALKORI across three main clinical trials. Concurrent elevations in alanine aminotransferase (ALT) greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, occurred in 7 patients (0.6%). Additionally, elevations in ALT greater than five times the upper limit of normal occurred in 109 patients (9.2%). Eight patients (0.7%) required permanent discontinuation due to elevated transaminases. These laboratory findings were generally reversible upon dosing interruption. 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 and ADVERSE REACTIONS].
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=1225), 31 XALKORI-treated patients (2.5%) had any grade ILD, 11 patients (0.9%) had Grade 3 or 4, and 6 patients (0.5%) had fatal cases. These cases generally occurred within 2 months after the initiation of treatment.
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 and ADVERSE REACTIONS].
QT Interval Prolongation
QTc prolongation can occur in patients treated with XALKORI. Across clinical trials (n=1225), QTc prolongation (all grades) was observed in 34 (2.7%) patients and QTc greater than 500 ms on at least 2 separate ECGs occurred in 17 (1.4%) patients.
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 and CLINICAL PHARMACOLOGY].
Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia with a heart rate less than 50 beats per minute occurred in 11% of 1174 patients treated with XALKORI. In Study 1, Grade 3 syncope occurred in 2.9% of XALKORI-treated patients and in none 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 and ADVERSE REACTIONS].
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 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 FDA-approved patient labeling (PATIENT INFORMATION).
- Inform patients of the symptoms of hepatotoxicity, and that they should be reported immediately [see WARNINGS AND PRECAUTIONS].
- Advise patients to immediately report any new or worsening pulmonary symptoms [see WARNINGS AND PRECAUTIONS].
- Inform patients that symptoms of bradycardia including dizziness, lightheadedness, and syncope can occur while taking XALKORI. Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications [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. Nausea and vomiting began most commonly during the first few days of treatment [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 and may occur while driving or operating machinery. The onset of visual disorders most commonly occurs during the first week of treatment [see ADVERSE REACTIONS].
- Inform patients to avoid grapefruit or grapefruit juice while taking XALKORI. Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see DRUG INTERACTIONS].
- 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.
- 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 [see Use In Specific Populations].
This product's label may have been updated. For full prescribing information, please visit www.XALKORI.com.
Carcinogenesis, 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 1.7 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 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 0.6 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 2.7 times the AUC at the recommended human dose) or in rabbits at doses of up to 60 mg/kg/day (approximately 1.6 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 5.4 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.
Of XALKORI treated patients in Study 1, 27 (16%) were 65 years or older, in Study 2, 152 (16%) were 65 years or older, and in Study 3, 16 (13%) were 65 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.
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] 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis.
Increased exposure to crizotinib occurred in patients with severe renal impairment (CLcr < 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 and CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 4/6/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Xalkori Information
Report Problems to the Food and Drug Administration
Get the latest treatment options.