February 9, 2016
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Xalkori

"Another targeted agent for non-small-cell lung cancer (NSCLC) that is positive for the ALK rearrangement (found in about 5% of NSCLC patients) has just been approved by the US Food and Drug Administration (FDA). The new drug, alectinib ("...

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Xalkori




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 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=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 and ADVERSE REACTIONS].

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 evaluation 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 and CLINICAL PHARMACOLOGY].

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-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].

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 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.

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].

Patient Counseling Information

Advise the patient to read the 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 of the potential risk of severe visual loss and to immediately contact their physician 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 and ADVERSE REACTIONS].
  • 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 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-thecounter 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.
  • 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, Use In Specific Populations]. 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].
  • Advise females not to breastfeed during treatment with XALKORI and for 45 days after the final dose [see Use in Specific Populations].
  • Advise females and males of reproductive potential of the potential for reduced fertility from XALKORI [see Use in Specific Populations and Nonclinical Toxicology].
  • 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 and Nonclinical Toxicology].

Nonclinical Toxicology

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 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.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. 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 2-4% and 15-20%, 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.

Lactation

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 breast feed during treatment with XALKORI and for 45 days after the final dose.

Females And Males Of Reproductive Potential

Contraception

Females

XALKORI can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. 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 genotoxicty, advise males with females partners of reproductive potential to use condoms during treatment with XALKORI and for at least 90 days after the final dose [see Nonclinical Toxicology].

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].

Pediatric Use

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

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.

Geriatric Use

Of the total number of patients in clinical studies of XALKORI (n=1669), 16% were 65 years or older and 3.7% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

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. Therefore, use caution in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].

Renal Impairment

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].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 10/3/2015

Warnings
Precautions

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