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Safety Profile

Safety Profile Across Trials

ALK+ First-Line Adverse Reactions

 Selected Adverse Reactions Across Trials

Tab Number 4

Tab Number 5

XALKORI® (crizotinib) has an established safety profile based on 1719 patients with ALK+ (n=1669) and ROS1+ (n=50) metastatic NSCLCWarnings and Precautions
  • Hepatotoxicity: Fatal hepatotoxicity occurred in 0.1% of XALKORI patients (n=1719). Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI
  • Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2.9% of XALKORI patients (n=1719). Permanently discontinue in patients with ILD/pneumonitis
  • QT Interval Prolongation: Occurred in 2.1% of XALKORI patients (n=1616). 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
  • Bradycardia: Reported in 13% of XALKORI patients (n=1719). Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI
  • Severe Visual Loss: Reported in 0.2% of XALKORI patients (n=1719). Monthly assessment of visual symptoms is recommended. Report new visual symptoms to an eye specialist. Permanently discontinue for Grade 3 or 4 ocular disorders or severe visual loss (best corrected vision less than 20/200 in one or both eyes) unless another cause is identified.
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception
Adverse Reactions
  • The most common adverse reactions (≥25%) with XALKORI are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy
  • Dosing interruptions and/or dose reduction may be required based on adverse reactions
ROS1-positive metastatic NSCLC
  • Safety was evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study, and was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC
  • Vision disorders occurred in 92% of patients in the ROS1 study; 90% of patients had Grade 1 vision disorders and 2% had Grade 2
  • Median duration of treatment was 34.4 months
Reference:Dorland’s Illustrated Medical Dictionary. 32nd ed. Philadelphia, PA: Elsevier Saunders; 2011.
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Safety analysis in the first-line study
  • The most common adverse reactions (ARs) in the XALKORI arm (n=171) include vision disorders, elevated transaminases, diarrhea, and nausea
  • Median time to response (TTR)1
    • The most frequent serious AEs were dyspnea (4.1%) and pulmonary embolism (2.9%)
    • Fatal AEs occurred in 2.3% of patients: septic shock, acute respiratory failure, and diabetic ketoacidosis
  • The majority of ARs in the XALKORI arm were Grades 1 and 2
  • Patients remained on XALKORI treatment for more than twice as long as on chemotherapy (median 10.9 months for XALKORI vs 4.1 months for chemotherapy)
Adverse reactions reported at a higher incidence (≥5% higher for all grades or ≥2% higher for Grades 3-4) with XALKORI than with chemotherapy in Study 1*Adverse reactions were graded using NCI CTCAE version 4.0. Includes cases reported within the clustered terms:Bradycardia (bradycardia, sinus bradycardia).Vision disorder (diplopia, photophobia, photopsia, reduced visual acuity, blurred vision, vitreous floaters, visual impairment).Abdominal pain (abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness).Esophagitis (esophagitis, esophageal ulcer).Edema (edema, peripheral edema, face edema, generalized edema, local swelling, periorbital edema).Upper respiratory infection (nasopharyngitis, pharyngitis, rhinitis, upper respiratory tract infection).Dizziness (balance disorder, dizziness, postural dizziness, presyncope).Additional ARs occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included
  • Nausea (56%)
  • Decreased appetite (30%)
  • Fatigue (29%)
  • Neuropathy (21%)
  • Rash (11%)
  • Renal cyst (5%)
  • ILD/pneumonitis (1%)
  • Syncope (1%)
  • Decreased blood testosterone (1%)
Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.3%).

Most frequent ARs that led to dose reduction:

  • Nausea (1.8%)
  • Increased transaminases (1.8%)

Most frequent ARs that led to discontinuation:

  • Increased transaminases (1.2%)
  • Hepatotoxicity (1.2%)
  • ILD (1.2%)
Laboratory abnormalities with Grade 3/4 incidence of ≥4% in XALKORI-treated patients in the first-line ALK studyAdditional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any grade: 99%; Grade 3: 2%; Grade 4: 0%) compared to the chemotherapy arm (Any grade: 92%; Grade 3: 0%; Grade 4: 1%).Reference:Dorland’s Illustrated Medical Dictionary. 32nd ed. Philadelphia, PA: Elsevier Saunders; 2011.
Description of selected adverse drug reactions

Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 63% of 1719 patients across clinical trials.

  • The majority (95%) of these patients had Grade 1 visual ARs. There were 13 (0.8%) patients with Grade 3, and 4 (0.2%) patients with Grade 4 visual impairment
  • Based on the Visual Symptom Assessment Questionnaire (VSAQ)-ALK, patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration
  • The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances that occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities as captured in the VSAQ-ALK questionnaire
  • Vision disorders occurred in 92% of patients in the ROS1 study (Study 3); 90% of patients had Grade 1 vision disorders and 2% had Grade 2
Neuropathy: Neuropathy, most commonly sensory in nature, occurred in 25% of 1719 patients.
  • Most events (95%) were Grade 1 or Grade 2 in severity
Renal cysts: Renal cysts were experienced by 52 (3%) of 1719 patients. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.
Renal impairment: 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 (n=1499) in patients with ALK-positive advanced NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median eGFR from 12 to 104 weeks of treatment. Median eGFR slightly increased (83.02 mL/min/1.73 m2) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in eGFR to <90 mL/min/1.73 m2, 38% had a decrease in eGFR to <60 mL/min/1.73 m2, and 3.6% had a decrease in eGFR to <30 mL/min/1.73 m2.
ALK=anaplastic lymphoma kinase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCCN=National Comprehensive Cancer Network® (NCCN®); NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; NSCLC=non-small cell lung cancer.Reference:Dorland’s Illustrated Medical Dictionary. 32nd ed. Philadelphia, PA: Elsevier Saunders; 2011.
 XALKORI efficacy in ROS1+ metastatic NSCLCSee ROS1+ efficacy dataLoading
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INDICATIONS

XALKORI is indicated for the treatment of adult patients with metastatic non small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1719). Increased transaminases generally occurred within the first 2 months. Monitor liver function tests, including ALT, AST, 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 increased transaminases. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated. Interstitial Lung Disease/Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1719), 2.9% of XALKORI-treated patients had any grade ILD, 1.0% had Grade 3/4, and 0.5% had fatal ILD. ILD generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis. QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1616), 2.1% of patients had QTcF (corrected QT by the Fridericia method) ≥500 ms and 5% of 1582 patients had an increase from baseline QTcF ≥60 ms by automated machine-read evaluation of ECGs. Avoid use in patients with congenital long QT
syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias,  electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to baseline or a QTc <481 ms, then resume at next lower dosage. Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 13% of patients treated with XALKORI (n=1719). Avoid use in combination with other medications known to cause bradycardia. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. 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. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring. Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with visual loss was 0.2% of 1719 patients. Optic atrophy and optic nerve disorder have been reported as potential causes of visual loss. Monthly assessment of visual symptoms is recommended. Report new visual symptoms to an eye specialist. Permanently discontinue for Grade 3 or 4 ocular disorders or severe visual loss (best corrected vision less than 20/200 in one or both eyes) unless another cause is identified. There is insufficient information to characterize the risks of resumption of XALKORI in patients with visual loss; a decision to resume should consider the potential benefits to the patient. Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters occurred in 63% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities. Embryo-Fetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for 45 days following the last dose. Advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for 90 days after the last dose.  ROS1-positive Metastatic NSCLC: Safety was evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study, and was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC. Vision disorders occurred in 92% of patients in the ROS1 study; 90% of patients had Grade 1 vision disorders and 2% had Grade 2. Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%), esophagitis (2% vs 0%), and constipation (2% vs 0%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [10% vs 6%]). Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.3%). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%), and rash (11%) also occurred in patients taking XALKORI. Drug Interactions: Avoid concomitant use of XALKORI with strong CYP3A inhibitors as these increase XALKORI plasma concentrations. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of XALKORI. Use caution with concomitant use of moderate CYP3A inhibitors. Concomitant use of XALKORI with strong CYP3A inducers decreases XALKORI plasma concentrations which may decrease the efficacy of XALKORI. Avoid concomitant use of strong CYP3A inducers. Concomitant use of XALKORI increases plasma concentrations of CYP3A substrates. Avoid concomitant use of XALKORI with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use of XALKORI is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling. Lactation: Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with XALKORI and for 45 days after the last dose. Hepatic Impairment: Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin >1.5x ULN and ≤3x ULN) or severe (any AST and total bilirubin >3x ULN) hepatic impairment. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment. The recommended dose of XALKORI in patients with pre-existing moderate hepatic impairment is 200 mg orally twice daily or with pre-existing severe hepatic impairment is 250 mg orally once daily. Renal Impairment: Decreases in estimated glomerular filtration rate occurred in patients treated with XALKORI. Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis.
Photosensitivity: Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure and to use sunscreen or protective clothing during treatment with XALKORI.
INDICATIONS
XALKORI is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test.

Please see Full Prescribing Information 
for XALKORI.