Crizotinib

Crizotinib is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive or ROS1-positive. Crizotinib is the first FDA-approved biomarker-driven therapy for both ALK-positive and ROS1-positive metastatic NSCLC. It is the only FDA-approved drug for ROS1-positive NSCLC. Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1, and RON. It works by blocking the action of the abnormal protein that signals cancer cells to multiply, helping to stop or slow the spread of cancer cells.

• ALK-positive metastatic non-small cell lung cancer (NSCLC)
• ROS1-positive metastatic non-small cell lung cancer (NSCLC)

Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed ALK fusion proteins or c-Met.

Inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and RON. The gene's expression and signaling that contribute to increased cell proliferation and survival of the tumors become activated following the expression of ALK oncogenic fusion proteins. Inhibits the signaling that promotes the expression of these oncogenic fusion proteins, thereby inhibiting tumor cell proliferation.

Recommended Dose (Oral): 250 mg twice daily.

Dose Modifications: Dosing interruption and/or dose reduction to 200 mg twice daily may be required; decrease to 250 mg once daily if further reduction is needed.

Renal Dose: Severe renal impairment (CrCl <30 mL/min): 250 mg once daily. Mild (CrCl 60-89) or moderate (CrCl 30-59) renal impairment: No starting dose adjustment needed.

Hepatic Dose: Caution advised in hepatic impairment.

Take this medicine in the dose and duration as advised by your doctor. Do not chew, crush or break it. Crizotinib may be taken with or without food, but it is better to take it at a fixed time.

If you miss a dose of Crizotinib, skip it and continue with your normal schedule. Do not double the dose.

Common Side Effects (≥25%):

• Vision disorders
• Nausea
• Diarrhea
• Vomiting
• Edema
• Constipation
• Elevated transaminases
• Fatigue
• Decreased appetite
• Upper respiratory infection
• Dizziness
• Neuropathy

Serious Side Effects: Hepatotoxicity, ILD/Pneumonitis, QT prolongation, Bradycardia, Severe visual loss, Embryo-fetal toxicity.

• [UNSAFE] Crizotinib may decrease alertness, affect your vision or make you feel sleepy and dizzy. Do not drive if these symptoms occur.
• Hepatotoxicity: Periodic liver testing required.
• ILD/Pneumonitis: Permanently discontinue in patients with ILD/Pneumonitis.
• QT prolongation: Monitor ECGs and electrolytes.
• Bradycardia: Regularly monitor heart rate and blood pressure.
• Severe visual loss: Perform ophthalmological evaluation; discontinue in severe visual loss.
• Contraindicated during pregnancy; effective contraception required.

• Hypersensitivity.

CYP3A Inhibitors: Avoid concurrent use with strong CYP3A inhibitors (atazanavir, clarithromycin, itraconazole, ketoconazole, ritonavir, voriconazole, etc.).

CYP3A Inducers: Avoid concurrent use with strong CYP3A inducers (carbamazepine, phenytoin, rifampin, St. John's Wort, etc.).

CYP3A Substrates: Avoid concurrent use with CYP3A substrates with narrow therapeutic indices (cyclosporine, fentanyl, quinidine, sirolimus, tacrolimus, etc.).

[CONSULT YOUR DOCTOR] It is not known whether it is safe to consume alcohol with Crizotinib. Please consult your doctor.

[CONSULT YOUR DOCTOR] Crizotinib is unsafe to use during pregnancy as there is definite evidence of risk to the developing baby. Pregnancy Category D.

[CONSULT YOUR DOCTOR] Crizotinib is probably unsafe to use during breastfeeding. Limited human data suggests that the drug may pass into the breastmilk and harm the baby. Patients should not breastfeed during treatment and for 45 days after the final dose.

The safety and effectiveness of Crizotinib in pediatric patients have not been established.

No differences in safety or efficacy were observed between older and younger patients. Clinical studies in ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 and older to determine whether they respond differently.

[CAUTION] Crizotinib should be used with caution in patients with severe kidney disease. Dose adjustment may be needed. Severe renal impairment (CrCl <30 mL/min): 250 mg once daily.

[CAUTION] Crizotinib should be used with caution in patients with liver disease. Dose adjustment may be needed. Use may not be advised in patients with severe liver disease.

Information on Crizotinib overdosage is not available. In case of overdose, symptomatic and supportive treatment should be given.

Keep below 30°C temperature, away from light & moisture. Keep out of reach of children.

Crizotinib