Alkixen

Approved Indications:

• ALK-positive metastatic non-small cell lung cancer (NSCLC) in adults.
• ROS1-positive metastatic NSCLC in adults.
• ALK-positive anaplastic large cell lymphoma (ALCL) in pediatric patients aged 1 year and older with relapsed or refractory disease.
• ALK-positive inflammatory myofibroblastic tumor (IMT) in adults and pediatric patients aged 1 year and older with unresectable, recurrent, or refractory disease.

Clinically Accepted Off-Label Uses:

• ALK-positive histiocytic neoplasms.
• ROS1-positive malignancies in other tumor types (e.g., melanoma, uterine sarcoma).
• Potential use in MET-amplified tumors in certain clinical protocols.

Adults:

• Recommended dose: 250 mg orally twice daily.
• Administer with or without food.
• Dose adjustments required in case of adverse reactions: first to 200 mg twice daily, then to 250 mg once daily if necessary.

Pediatric Patients (1 year and older):

• Dose based on body surface area (BSA), typically 280 mg/m²/day in divided doses.
• Microsphere formulation available for patients unable to swallow capsules.

Renal Impairment:

• Moderate: No dose adjustment.
• Severe (CrCl <30 mL/min): 250 mg once daily.

Hepatic Impairment:

• Mild: No adjustment needed.
• Moderate: 200 mg twice daily.
• Severe: 250 mg once daily.

Elderly:

• No dose adjustment required based on age alone.

Crizotinib is a selective, orally bioavailable inhibitor of receptor tyrosine kinases including ALK (anaplastic lymphoma kinase), ROS1, and MET (mesenchymal epithelial transition factor). It inhibits phosphorylation of these kinases and blocks downstream signaling pathways responsible for tumor cell proliferation and survival. In ALK- or ROS1-positive tumors, chromosomal rearrangements lead to constitutive kinase activation, and crizotinib suppresses this oncogenic signaling, leading to apoptosis and reduced tumor growth.

• Absorption: Peak plasma concentration occurs in 4–6 hours post-dose; oral bioavailability ~43%.
• Distribution: High volume of distribution (~1772 L); ~91% plasma protein bound.
• Metabolism: Primarily metabolized by CYP3A4/5.
• Active Metabolite: Less potent than the parent compound.
• Elimination: Excreted ~63% in feces, ~22% in urine; elimination half-life ~42 hours.
• Steady State: Achieved within 15 days with twice-daily dosing.

Pregnancy:

• Based on animal studies, crizotinib may cause fetal harm. It is advised to avoid use during pregnancy unless clearly necessary.
• Women of childbearing potential should use effective contraception during treatment and for 45 days after the final dose.

Lactation:

• Not known if excreted in human milk.
• Breastfeeding should be avoided during treatment and for 45 days after the last dose due to potential serious adverse effects in infants.

• Primary Class: Antineoplastic agent
• Subclass: ALK/ROS1/MET tyrosine kinase inhibitor (TKI)

• Known hypersensitivity to crizotinib or any excipients.
• Use in patients with congenital long QT syndrome or severe baseline QT prolongation is discouraged.

• QT Prolongation: Risk of arrhythmias; ECG monitoring recommended in patients with predisposing factors.
• Hepatotoxicity: Monitor liver enzymes regularly; may require dose reduction or discontinuation.
• Bradycardia: Monitor heart rate; avoid concomitant use with other heart rate–lowering drugs.
• Visual Disorders: Commonly reported; typically transient, but ophthalmologic evaluation is advised in pediatrics.
• Interstitial Lung Disease (ILD)/Pneumonitis: Discontinue if suspected.
• Myelosuppression: Regular blood count monitoring is advised, especially during initial months.
• Embryofetal Toxicity: Can cause fetal harm; contraception necessary for both sexes.

Common (≥10%):

• Gastrointestinal: Nausea, vomiting, diarrhea, constipation
• Hematologic: Neutropenia, anemia
• General: Fatigue, edema, decreased appetite
• Neurologic/Ocular: Visual disturbances, dizziness
• Hepatic: Elevated ALT/AST

Serious/Rare:

• QT prolongation
• Severe hepatotoxicity
• Pneumonitis
• Bradycardia
• Hypersensitivity reactions

Onset varies from days to weeks, with hematologic and hepatic effects typically emerging early. Dose dependence is seen in liver enzyme elevations and QT prolongation.

• CYP3A4 Inhibitors (e.g., ketoconazole): Increase crizotinib plasma levels; monitor for toxicity.
• CYP3A4 Inducers (e.g., rifampin): Reduce crizotinib levels; avoid concomitant use.
• CYP3A Substrates: Crizotinib may increase exposure to drugs metabolized by CYP3A (e.g., fentanyl, midazolam).
• QT-Prolonging Drugs: Additive effects; concurrent use should be avoided.
• Bradycardia-inducing Drugs (e.g., beta-blockers, clonidine): Use cautiously due to additive risk.

• Expanded indication to include ALK-positive IMT and ALCL in pediatric patients aged ≥1 year.
• Pediatric-specific microsphere (pellet) formulation approved for children with swallowing difficulties.
• Updated labeling includes recommendations for more frequent ECG and liver function monitoring, particularly in pediatric populations.

• Capsules:
• Store at 20°C to 25°C (68°F to 77°F).
• Excursions permitted between 15°C to 30°C.
• Keep container tightly closed and protected from moisture.
• Do not refrigerate or freeze.
• Microsphere Formulation (if applicable):
• Store under similar conditions.
• Keep away from light and out of reach of children.