Xalkori Adverse Reactions

Summary of Safety Profile: The data described as follows reflect exposure to crizotinib in 1669 patients with ALK-positive advanced NSCLC who participated in randomized Phase 3 Studies 1007 or 1014 or in single-arm Studies 1001 or 1005, and in 53 patients with ROS1-positive advanced NSCLC who participated in single-arm Study 1001, for a total of 1722 patients (see Pharmacology: Pharmacodynamics under Actions). These patients received a starting oral dose of 250 mg twice daily continuously. In Study 1014, the median duration of study treatment was 47 weeks for patients in the crizotinib arm (N=171); the median duration of treatment was 23 weeks for patients who crossed over from the chemotherapy arm to receive crizotinib treatment (N=109). In Study 1007, the median duration of study treatment was 48 weeks for patients in the crizotinib arm (N=172). For ALK-positive NSCLC patients in Studies 1001 (N=154) and 1005 (N=1063), the median duration of treatment was 57 and 45 weeks, respectively. For ROS1-positive NSCLC patients in Study 1001 (N=53), the median duration of treatment was 101 weeks.
The most serious adverse reactions in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC were hepatotoxicity, ILD/pneumonitis, and QT interval prolongation (see Precautions). The most common adverse reactions (≥25%) in patients with either ALK-positive or ROS1-positive NSCLC were vision disorder, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, dizziness, and neuropathy.
In 1722 patients with either ALK-positive or ROS1-positive NSCLC treated with crizotinib, all causality adverse events associated with dosing interruptions or dose reductions occurred in 763 (44%) and 259 (15%) patients, respectively. All-causality adverse events associated with permanent treatment discontinuation occurred in 302 (18%) patients.
The adverse drug reactions listed in the table as follows are presented by System Organ Class (SOC) and frequency categories, defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness or clinical importance. (See Table 7.)

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Description of Selected Adverse Reactions: Visual Effects: In clinical trials of patients with either ALK-positive or ROS1-positive advanced NSCLC, all-causality vision disorder, most commonly visual impairment, photopsia, vision blurred, and vitreous floaters, was experienced by 1084 (63%) of 1722 patients treated with crizotinib. Of the 1084 patients who experienced vision disorder, 95% had events that were mild in severity. Ophthalmological evaluation should be considered if vision disorder persists or worsens in severity. Seven (0.4%) patients had temporary treatment discontinuation and 2 (0.1%) patients had a dose reduction associated with vision disorder. There were no permanent discontinuations associated with vision disorder for any of the 1722 patients treated with crizotinib.
Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with crizotinib in Study 1007 and Study 1014 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally occurred during the first week of drug administration. The majority of patients in the crizotinib arms in Study 1007 and Study 1014 (>50%) reported visual disturbances, which occurred at a frequency of 4 to 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 by the VSAQ-ALK questionnaire.
Gastrointestinal Effects: Nausea (57%), diarrhea (54%), vomiting (51%), and constipation (43%) were the most commonly reported all-causality gastrointestinal events. Most events were mild to moderate in severity. Median times to onset for nausea and vomiting were 3 days, and these events declined in frequency after 3 weeks of treatment. Supportive care should include the use of antiemetic medications. In clinical trials, the most commonly used antiemetic medications were ondansetron and prochlorperazine. Median times to onset for diarrhea and constipation were 13 and 17 days, respectively. Supportive care for diarrhea and constipation should include the use of standard antidiarrheal and laxative medications, respectively.
Nervous System Effects: All-causality neuropathy, as defined in Table 7, was experienced by 435 (25%) of 1722 patients treated with crizotinib, and was primarily Grade 1 or 2 in severity. Dizziness and dysgeusia were also very commonly reported and were primarily Grade 1 in severity.
Bradycardia: In clinical trials of patients with either ALK-positive or ROS1-positive advanced NSCLC, all-causality bradycardia was experienced by 219 (13%) of 1722 patients treated with crizotinib. Most events were mild in severity. A total of 259 (16%) of 1666 patients with at least 1 post-baseline vital sign assessment had a pulse rate <50 bpm. The use of concomitant medications associated with bradycardia should be carefully evaluated. Patients who develop symptomatic bradycardia should be managed as recommended in Dose Modification under Dosage & Administration and Precautions.
Renal Cyst: All-causality complex renal cysts were experienced by 52 (3%) of 1722 patients treated with crizotinib. There were no reports of clinically relevant abnormal urinalyses or renal impairment in these cases, although local cystic invasion beyond the kidney was observed in some patients. Periodic monitoring with imaging and urinalysis should be considered in patients who develop renal cysts.
Laboratory Abnormalities/Testing: Hematologic Laboratory Abnormalities: In clinical studies of crizotinib in patients with either ALK-positive or ROS1-positive advanced NSCLC, shifts to Grade 3 or 4 decreases in leukocytes and neutrophils were observed in 64 (4%) and 226 (13%) patients, respectively. Complete blood counts including differential white blood cell counts should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs. In patients who develop hematologic laboratory abnormalities, see Recommended Dose: Dose Modification under Dosage & Administration.
Hepatic Laboratory Abnormalities: In clinical studies of crizotinib in patients with either ALK-positive or ROS1-positive advanced NSCLC, shifts to Grade 3 or 4 ALT, AST, and alkaline phosphatase were observed in 187 (11%), 95 (6%), and 33 (2%) patients, respectively. Patients should be monitored for hepatotoxicity and managed as recommended in Precautions.
Renal Laboratory Abnormalities: In clinical studies of crizotinib in patients with ALK-positive advanced NSCLC, 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 of treatment (n=1499). Median eGFR appeared to be relatively stable from 12 weeks of treatment (78.06 mL/min/1.73 m², n=1338) through 104 weeks of treatment (75.45 mL/min/1.73 m², n=315) and increased to 83.02 mL/min/1.73 m² at 28 days after the last dose of crizotinib (n=123).
Shifts to eGFR Grade 4 (15 to <30 mL/min/1.73 m²) or to eGFR Grade 5 (<15 mL/min/1.73 m²) were observed in 3% and <1% of patients, respectively.