Crizotinib

XALKORI is a kinase inhibitor 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. • pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive. o Limitations of Use: The safety and efficacy of XALKORI have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. • adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive.

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 echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

• Metastatic NSCLC: The recommended dosage is 250 mg orally twice daily. • Systemic ALCL: The recommended dosage is 280 mg/m 2 orally twice daily based on body surface area. • Unresectable IMT: o Adult: The recommended dosage is 250 mg orally twice daily. o Pediatric: The recommended dosage is 280 mg/m 2 orally twice daily based on body surface area. • See full prescribing information for dosage adjustments by indication for patients with moderate or severe hepatic impairment or severe renal impairment.

None. None.

• Hepatotoxicity: Fatal hepatotoxicity has occurred. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. • Interstitial Lung Disease (ILD)/Pneumonitis: Permanently discontinue in patients with ILD/pneumonitis. • 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. • Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. • 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.

The following clinically significant adverse reactions are described elsewhere in the labeling: • Hepatotoxicity • Interstitial Lung Disease/Pneumonitis • QT Interval Prolongation • Bradycardia • Severe Visual Loss • Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT The most common adverse reactions (≥25%) in adult patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. The most common adverse reactions (≥35%) in patients with ALCL are diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus. Grade 3–4 laboratory abnormalities (≥15%) are neutropenia, lymphopenia, and thrombocytopenia.

• Strong CYP3A Inhibitors: Avoid concomitant use. • Strong CYP3A Inducers: Avoid concomitant use. • CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious adverse reactions.

Store at room temperature 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F). Oral Pellets: • 20 mg oral pellets Hard gelatin capsule, size 4, light blue opaque cap and white opaque body, printed with black ink “Pfizer” on the cap, “CRZ 20” on the body, available in: Bottles of 60 capsules: NDC 0069-0251-60 • 50 mg oral pellets Hard gelatin capsule, size 3, gray opaque cap and light gray opaque body, printed with black ink “Pfizer” on the cap, “CRZ 50” on the body, available in: Bottles of 60 capsules: NDC 0069-0507-60 • 150 mg oral pellets Hard gelatin capsule, size 0, light blue opaque cap and body, printed with black ink “Pfizer” on the cap, “CRZ 150” on…