Usage
Crizotinib is prescribed for the treatment of:
- Non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive. This is the most common use case.
- ROS1-positive metastatic NSCLC.
- Systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive in pediatric patients and young adults (ages 1 and older). Crizotinib is used when the ALCL has not responded to other treatment or has returned.
- Inflammatory myofibroblastic tumor (IMT) that cannot be removed by surgery (unresectable) in adults and children aged 1 year and older.
Pharmacological Classification: Crizotinib is a kinase inhibitor, specifically an ALK and ROS1 inhibitor. It is also classified as a targeted therapy or antineoplastic agent.
Mechanism of Action: Crizotinib works by blocking the activity of ALK and ROS1 tyrosine kinases. These enzymes are involved in cell growth and division. In certain types of cancer, ALK and ROS1 genes are abnormal and produce too much of these tyrosine kinase enzymes, driving uncontrolled cell growth and tumor development. Crizotinib binds to and inhibits the activity of these enzymes to slow or stop cancer cell growth.
Alternate Names
International Nonproprietary Name (INN): Crizotinib
Brand Name: XALKORI®
How It Works
Pharmacodynamics: Crizotinib exerts its antineoplastic effect by inhibiting ALK and ROS1, thereby decreasing tumor cell proliferation and promoting tumor regression. Crizotinib also inhibits c-Met, another tyrosine kinase receptor.
Pharmacokinetics:
- Absorption: Crizotinib is absorbed orally, reaching peak plasma concentrations in approximately 4-6 hours. Food does not significantly affect absorption.
- Metabolism: Primarily metabolized in the liver, mainly by CYP3A4.
- Elimination: Crizotinib is primarily eliminated via the hepatic route (feces), with a small portion excreted in the urine. The elimination half-life is approximately 42 hours.
Mode of Action: Crizotinib acts as a competitive ATP-binding site inhibitor of ALK and ROS1 tyrosine kinases. It binds to the ATP-binding pocket of these kinases, preventing ATP from binding and thereby inhibiting their phosphorylation activity. This disruption of downstream signaling pathways leads to reduced cell growth and proliferation in ALK-positive and ROS1-positive cancer cells.
Dosage
Standard Dosage
Adults:
- NSCLC (ALK-positive, ROS1-positive) and IMT: 250 mg orally twice daily.
Children (1 year and older):
- ALCL (ALK-positive): 280 mg/m² orally twice daily (based on body surface area).
- IMT: 280 mg/m² orally twice daily (based on body surface area).
Special Cases:
- Elderly Patients: No specific dose adjustments are required based solely on age.
- Patients with Renal Impairment:
- Severe renal impairment (CrCl <30 mL/min not requiring dialysis): Initially 250 mg once daily; if tolerated, may increase to 200 mg twice daily after at least 4 weeks.
- Patients with Hepatic Dysfunction:
- Moderate hepatic impairment: 200 mg orally twice daily.
- Severe hepatic impairment: 250 mg orally once daily. XALKORI doses greater than 250 mg once daily have not been studied in patients with severe hepatic impairment and may result in increased exposure to potentially harmful levels.
- Patients with Comorbid Conditions: Dose modifications may be necessary depending on the specific comorbidity and its impact on drug metabolism or clearance.
Clinical Use Cases
Crizotinib is not typically used in the clinical scenarios you described (intubation, surgical procedures, mechanical ventilation, ICU use, emergency situations). It is an oral medication for chronic cancer treatment.
Dosage Adjustments
Dose reductions or interruptions may be required based on individual patient tolerance and adverse events.
Side Effects
Common Side Effects:
Nausea, vomiting, diarrhea, constipation, decreased appetite, vision changes (blurred vision, double vision, visual disturbances), fatigue, edema, numbness or tingling in the hands and feet, headache, dizziness, upper respiratory tract infection, rash.
Rare but Serious Side Effects:
Hepatotoxicity (liver damage), pneumonitis (lung inflammation), QT prolongation (heart rhythm abnormality), severe bradycardia (slow heart rate), heart failure, gastrointestinal perforation, visual loss.
Long-Term Effects:
Potential long-term effects of crizotinib can include cardiac dysfunction, pulmonary fibrosis, and secondary malignancies.
Adverse Drug Reactions (ADR):
The ADRs listed above under “Rare but Serious Side Effects” require immediate intervention.
Contraindications
- Hypersensitivity to crizotinib.
- Severe hepatic impairment.
- Congenital long QT syndrome.
- Coadministration with certain drugs that prolong the QT interval.
- Coadministration with strong CYP3A inhibitors, unless dosage adjustments are made.
Drug Interactions
- Strong CYP3A Inhibitors: Increase crizotinib levels.
- Strong CYP3A Inducers: Decrease crizotinib levels.
- Drugs that Prolong the QT Interval: Increase the risk of arrhythmias.
- Drugs that Cause Bradycardia: Increase the risk of severe bradycardia.
- Grapefruit and grapefruit juice: May increase crizotinib plasma concentrations.
- Many other drug interactions exist. Consult a drug interaction database for comprehensive information.
Pregnancy and Breastfeeding
- Pregnancy: Crizotinib can cause fetal harm. Effective contraception is required for both male and female patients during treatment and for a period after the last dose (90 days for males, 45 days for females).
- Breastfeeding: Crizotinib may pass into breast milk. Breastfeeding is not recommended during treatment and for 45 days after the last dose.
Drug Profile Summary
- Mechanism of Action: ALK and ROS1 tyrosine kinase inhibitor.
- Side Effects: Nausea, vomiting, diarrhea, vision changes, fatigue, edema, hepatotoxicity, pneumonitis, QT prolongation.
- Contraindications: Hypersensitivity, severe hepatic impairment.
- Drug Interactions: Strong CYP3A inhibitors/inducers, drugs that prolong QT interval.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy, not recommended during breastfeeding.
- Dosage: Adults: 250 mg twice daily; Children (ALCL, IMT): 280 mg/m² twice daily.
- Monitoring Parameters: Liver function tests (LFTs), electrocardiogram (ECG), complete blood count (CBC), vision assessments, pulmonary function tests (PFTs) as clinically indicated.
Popular Combinations
Crizotinib is typically used as a single agent.
Precautions
Standard precautions such as pre-screening for organ dysfunction should be undertaken. Closely monitor for hepatotoxicity, cardiotoxicity, and pneumonitis.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Crizotinib?
A: Adults (NSCLC, IMT): 250 mg orally twice daily. Children (ALCL, IMT): 280 mg/m² orally twice daily. Dosage adjustments are needed for hepatic and renal impairment.
Q2: What are the most common side effects?
A: Nausea, vomiting, diarrhea, vision changes, fatigue, and edema.
Q3: What are the serious side effects to watch for?
A: Hepatotoxicity, pneumonitis, QT prolongation, and bradycardia.
Q4: Can Crizotinib be used during pregnancy?
A: No, crizotinib is contraindicated during pregnancy due to the risk of fetal harm.
Q5: Is it safe to breastfeed while taking Crizotinib?
A: Breastfeeding is not recommended as crizotinib may pass into breast milk.
Q6: What are the important drug interactions to be aware of?
A: Strong CYP3A inhibitors/inducers and drugs that prolong the QT interval can interact significantly with crizotinib.
Q7: How should Crizotinib be administered?
A: Crizotinib capsules should be swallowed whole with or without food. The pellets can be emptied into the mouth or administered through an oral dosing aid.
Q8: What if a dose of Crizotinib is missed?
A: If a dose is missed, take it as soon as remembered unless it is close to the next scheduled dose (within 6 hours). Do not double the dose. If vomiting occurs after taking crizotinib, do not take another dose.
Q9: What should patients be counseled about regarding crizotinib?
A: Inform patients about potential side effects, the importance of reporting any symptoms, and the need for regular monitoring, including eye exams and laboratory tests. Emphasize adherence to contraceptive methods.
Please note that this information is current as of February 16, 2025, and may be subject to change.
