Crizotinib - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity: Fatal hepatotoxicity has occurred.

Monitor with periodic liver testing.

Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 2.2 , 2.6 , 5.1 ) • Interstitial Lung Disease (ILD)/Pneumonitis: Permanently discontinue in patients with ILD/pneumonitis. ( 2.6 , 5.2 ) • QT Interval Prolongation: Monitor 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. ( 2.6 , 5.3 ) • Bradycardia: XALKORI can cause bradycardia.

Monitor heart rate and blood pressure regularly.

Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 2.6 , 5.4 ) • Severe Visual Loss: XALKORI can cause visual changes including severe visual loss.

Monitor and evaluate for ocular toxicity throughout treatment.

Discontinue XALKORI in patients with severe visual loss. ( 2.2 , 2.6 , 5.5 ) • Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT: XALKORI can cause severe nausea, vomiting, diarrhea, and stomatitis.

Provide standard antiemetic and antidiarrheal agents.

Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 2.6 , 5.6 ) • Embryo-Fetal Toxicity: Can cause fetal harm.

Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Hepatotoxicity Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of the 1719 patients treated with XALKORI for NSCLC across clinical trials [see Adverse Reactions ] .

Concurrent elevations in ALT or AST ≥3 times the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in <1% of patients treated with XALKORI.

Increased ALT or AST >5 times the ULN occurred in 11% and 6% of patients, respectively.

One percent (1.0%) of patients required permanent discontinuation due to elevated transaminases.

Increased transaminases generally occurred within the first 2 months of treatment.

In Study ADVL0912, of 121 patients ages 1 to ≤21 years treated with XALKORI for relapsed or refractory tumors including ALCL and IMT, 71% and 79% had increases of AST and ALT, respectively, with increased ALT or AST >5 times the ULN in 6% each.

Of the 26 patients with ALCL treated with XALKORI, 65% and 81% had increases of AST and ALT, respectively, with increases >5 times the ULN in 4% each.

Of the 14 pediatric patients with IMT treated with XALKORI, 71% had increases of AST and 71% had increases of ALT.

In Study A8081013, of the 7 adult patients with IMT treated with XALKORI, 57% and 43% had increases of AST and ALT, respectively.

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.

Withhold, reduce dose, or permanently discontinue XALKORI for hepatotoxicity as recommended [see Dosage and Administration ] .

5.2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI.

Across clinical trials in patients with NSCLC (n=1719), 2.9% of XALKORI-treated patients had ILD of any grade, 1% had Grade 3 or 4 ILD, and 0.5% had fatal ILD [see Adverse Reactions ] .

Interstitial lung disease generally occurred within 3 months after the initiation of XALKORI.

In Study ADVL0912, among 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including ALCL and IMT, ILD occurred in 0.8% of patients.