Crizotinib

Symptomatic bradycardia may occur; heart rate • GI toxicity: Crizotinib is associated with a moderate emetic potential (Hesketh 2017); antiemetics may be needed to prevent nausea and vomiting.

Fatalities due to crizotinib-induced hepatotoxicity have occurred. Grade 3 or 4 ALT increases (usually asymptomatic and reversible) have been observed in clinical trials. May require dosage interruption and/or reduction; permanent discontinuation was necessary in some cases. Elevations in ALT or AST >5 × ULN were observed; concurrent ALT or AST elevations ≥3 × ULN and total bilirubin elevations ≥2 × ULN (without alkaline phosphatase elevations) occurred rarely. Transaminase elevation onset generally was within 2 months of treatment initiation. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of therapy, then monthly and as clinically necessary.

Ocular toxicities (eg, blurred vision, diplopia, photophobia, photopsia, visual acuity decreased, visual brightness, visual field defect, visual impairment, and/or vitreous floaters) commonly occur. Onset is generally within 1 week of treatment initiation. Grade 4 visual field defect with vision loss had been reported (rare); optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. Discontinue with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Obtain ophthalmic evaluation (including best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography, and other evaluations as appropriate). The risks of restarting crizotinib after severe vision loss have not been evaluated; the decision to resume therapy should consider the potential benefits of treatment.

Severe, life-threatening, and potentially fatal interstitial lung disease (ILD)/pneumonitis has been associated with crizotinib. Onset was generally within 3 months of treatment initiation. Monitor for pulmonary symptoms which may indicate ILD/pneumonitis; exclude other potential causes (eg, disease progression, infection, other pulmonary disease, or radiation therapy). Permanently discontinue if treatment-related ILD/pneumonitis is confirmed.

QTc prolongation has been observed. Monitor ECG and electrolytes in patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QT interval. May require treatment interruption, dosage reduction, or discontinuation. Avoid use in patients with congenital long QT syndrome. Disease-related concerns:

Use with caution in patients with hepatic impairment; has not been studied; patients with ALT or AST >2.5 times ULN (>5 times ULN if due to liver metastases) and total bilirubin >1.5 times ULN were excluded from studies. Crizotinib is extensively metabolized in the liver and liver impairment is likely to increase crizotinib levels.

Reduce initial dose in patients with severe renal impairment not requiring dialysis. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Avoid concomitant use with strong CYP3A4 inhibitors and inducers and with CYP3A4 substrates. Other warnings/precautions:

Approved for use only in patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene or ROS1 rearrangements. The Vysis ALK break-apart FISH probe kit is approved to test for the ALK gene abnormality. An approved test is not currently available for detection of ROS1 rearrangements; in clinical trials, ROS1 positivity was determined by laboratory-developed break-apart FISH or RT-PCR.