Crizocent250 mg

Crizocent is a tyrosine kinase inhibitor with established, FDA-approved indications in oncology. It is used based on confirmed biomarker status.

• Metastatic non-small cell lung cancer (NSCLC), ALK-positive: First-line and subsequent treatment of adults with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive, as detected by an approved test.
• Metastatic NSCLC, ROS1-positive: Treatment of adults with metastatic NSCLC whose tumors are ROS1-positive.
• Anaplastic large cell lymphoma (ALCL), ALK-positive: Treatment of relapsed or refractory systemic ALK-positive ALCL in pediatric patients 1 year of age and older and young adults.
• Inflammatory myofibroblastic tumor (IMT), ALK-positive: Treatment of unresectable, recurrent, or refractory ALK-positive IMT in adults and pediatric patients 1 year of age and older.

Important: ALK or ROS1 biomarker status must be confirmed by a validated test before starting Crizocent, as efficacy depends entirely on this status. Crizocent is not indicated in ALK-negative or ROS1-negative tumors.

Each capsule of Crizotinib contains Crizotinib as the active ingredient, available in strengths of 200 mg and 250 mg. Inactive ingredients typically include microcrystalline cellulose, calcium hydrogen phosphate anhydrous, sodium starch glycolate, and magnesium stearate, with a gelatin capsule shell.

Crizocent is an orally administered small-molecule tyrosine kinase inhibitor (TKI) that selectively targets the anaplastic lymphoma kinase (ALK), ROS1, and MET/hepatocyte growth factor receptor (HGFR) signalling pathways. It represented one of the first targeted therapies approved for genomically-defined subsets of non-small cell lung cancer.

Crizocent is supplied as an oral capsule (200 mg and 250 mg) and, for pediatric weight-based dosing, as oral pellets in some markets. It is used only after laboratory confirmation of the relevant genetic alteration (ALK or ROS1 rearrangement) in tumor tissue.

Crizocent belongs to the class of antineoplastic agents known as tyrosine kinase inhibitors (TKIs), specifically an ALK/ROS1/MET inhibitor used in targeted cancer therapy.

Crizotinib is a potent, selective, small-molecule inhibitor of the ALK, ROS1, and MET receptor tyrosine kinases. In tumors harboring an ALK or ROS1 gene rearrangement, the resulting fusion protein drives constitutive kinase activity that promotes cell proliferation and survival.

Crizotinib competitively binds to the ATP-binding site of these kinases, inhibiting phosphorylation and downstream signalling in a concentration-dependent manner. This leads to inhibition of tumor cell growth, induction of apoptosis, and tumor regression in ALK- or ROS1-positive tumors.

Pharmacokinetics: Crizotinib is absorbed orally with a median time to peak concentration of 4-6 hours at steady state; absolute bioavailability is approximately 43%. It is extensively metabolized in the liver mainly via CYP3A4/5, and eliminated primarily via the hepatobiliary route, with a terminal half-life of approximately 42 hours.

Crizocent capsules may be taken with or without food. Capsules should be swallowed whole and must not be opened, crushed, dissolved, or chewed. Avoid grapefruit or grapefruit juice, which may increase Crizocent plasma concentrations.

Strong CYP3A4 Inhibitors

Concurrent use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, ritonavir, certain protease inhibitors, grapefruit products) increases Crizocent plasma concentrations and the risk of toxicity. Avoid concomitant use where possible; if unavoidable, monitor closely and reduce the Crizocent dose per prescribing guidance.

Strong CYP3A4 Inducers

Concurrent use of strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) can substantially decrease Crizocent plasma concentrations, reducing efficacy. Avoid concomitant use.

CYP3A4 Substrates

Crizocent can increase plasma concentrations of co-administered CYP3A4 substrates. Avoid combining with CYP3A4 substrates that have a narrow therapeutic index (e.g., certain ergot alkaloids, pimozide, quinidine, certain statins); dose adjustment of the concomitant drug may be needed.

QT-Prolonging Drugs

Combining Crizocent with other drugs known to prolong the QT interval increases the risk of clinically significant arrhythmia. Avoid concurrent use where possible and monitor ECG/electrolytes when co-administration is necessary. See Precautions and Warnings.

Bradycardia-Causing Agents

Concomitant use with beta-blockers, non-dihydropyridine calcium channel blockers, or other heart-rate-lowering drugs may compound the bradycardia risk associated with Crizocent; use with caution and monitor heart rate.

The most common adverse reactions (occurring in ≥25% of patients) associated with Crizocent in NSCLC trials include:

• Vision disorders (visual impairment, photopsia, blurred vision, vitreous floaters)
• Nausea, vomiting, diarrhea, constipation
• Edema
• Elevated liver transaminases
• Fatigue and decreased appetite
• Upper respiratory tract infection
• Dizziness and peripheral neuropathy

Serious but less common reactions include hepatotoxicity, interstitial lung disease/pneumonitis, QT prolongation, bradycardia, and severe visual loss - see Precautions and Warnings for detail. In pediatric ALCL/IMT patients, gastrointestinal toxicity (nausea, vomiting, diarrhea) is very common, and myelosuppression (neutropenia, lymphopenia, thrombocytopenia) can occur.

Pregnancy: Crizocent can cause fetal harm based on its mechanism of action and animal reproduction data. Crizocent should be used during pregnancy only if clearly needed and the potential benefit justifies the potential risk to the fetus; consult a physician. Females of reproductive potential should use effective contraception during treatment and for at least 45 days after the final dose. Males with female partners of reproductive potential should use effective contraception during treatment and for at least 90 days after the final dose.

Lactation: It is not known whether Crizocent is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women are advised not to breastfeed during treatment with Crizocent and for at least 45 days after the final dose; consult a physician.

Hepatotoxicity

Drug-induced hepatotoxicity, including cases with fatal outcome, has occurred with Crizocent. Monitor liver function tests (ALT, AST, total bilirubin) every 2 weeks during the first 2 months of treatment, then periodically, with more frequent testing in patients who develop elevations. Interrupt, reduce dose, or permanently discontinue Crizocent based on severity.

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, or fatal ILD/pneumonitis can occur. Monitor for new or worsening pulmonary symptoms (dyspnea, cough, fever) indicative of ILD/pneumonitis, and evaluate promptly. Permanently discontinue Crizocent in patients diagnosed with treatment-related ILD/pneumonitis.

QT Interval Prolongation

Crizocent can prolong the QT interval, increasing risk of ventricular arrhythmia. Avoid use in patients with congenital long QT syndrome. Monitor ECG and electrolytes at baseline and periodically, especially in patients with cardiac disease or those taking other QT-prolonging medications, or with electrolyte abnormalities.

Bradycardia

Symptomatic bradycardia can occur. Monitor heart rate and blood pressure regularly; avoid concomitant use with other bradycardia-causing agents where possible, and adjust dose if symptomatic bradycardia develops.

Severe Visual Loss

Cases of severe visual loss (loss of vision) have been reported with Crizocent. Any patient reporting grade 4 visual changes should have Crizocent withheld and undergo prompt ophthalmologic evaluation. Periodic ophthalmologic monitoring is recommended for pediatric and young adult patients.

Biomarker Testing

Confirmation of ALK or ROS1 positivity by a validated test is required before initiating Crizocent, as safety and efficacy have not been established in biomarker-negative tumors.

Embryo-Fetal Toxicity

Crizocent can cause fetal harm; see Pregnancy and Lactation for contraception guidance.

Renal Cysts and Renal Function

Complex renal cysts have been reported; periodic monitoring of renal function is advised, particularly in patients with baseline renal impairment.

There is limited clinical experience with overdose of Crizocent. In case of suspected overdose, discontinue Crizocent, institute general supportive measures, and seek immediate medical attention or contact emergency services/poison control. There is no specific antidote for Crizocent overdose; management should be symptomatic, with monitoring of cardiac and hepatic function as clinically indicated.

Store at room temperature (below 30°C), away from light and moisture. Keep out of reach of children.

Hepatic Impairment

Dose adjustment of Crizocent is recommended in patients with moderate to severe hepatic impairment; consult detailed prescribing information for the specific reduced dosing schedule. No adjustment is needed for mild hepatic impairment.

Renal Impairment

No dose adjustment is needed for mild to moderate renal impairment. In severe renal impairment not requiring dialysis, the adult NSCLC dose should be reduced to 250 mg once daily. See Dosage and Administration.

Elderly Patients

Limited data are available in patients over 65 years; no overall differences in safety have been reported, but individual monitoring for adverse reactions is advised.

Pediatric Patients

Safety and effectiveness of Crizocent for NSCLC have not been established in pediatric patients. For ALCL and IMT, Crizocent is approved for use in pediatric patients 1 year of age and older using body-surface-area-based dosing; safety and efficacy in children younger than 1 year have not been established.

Crizocent is continued until disease progression, unacceptable toxicity, or as otherwise directed by the treating oncologist. There is no fixed maximum duration; long-term therapy is typical for responding patients, with periodic monitoring for safety and disease response.

Antineoplastic agent; tyrosine kinase inhibitor (ALK/ROS1/MET inhibitor).

Crizotinib works by selectively inhibiting the tyrosine kinase activity of ALK, ROS1, and MET receptors. In tumors driven by ALK or ROS1 gene fusions, this inhibition blocks the abnormal signalling that drives uncontrolled cancer cell growth and survival, leading to tumor cell apoptosis and inhibition of tumor growth.

Crizocent is not established as safe and effective for NSCLC in pediatric patients. For relapsed/refractory ALK-positive ALCL and ALK-positive IMT, Crizocent is approved in pediatric patients 1 year of age and older, dosed by body surface area (280 mg/m² twice daily). Gastrointestinal toxicity is very common in this population; supportive antiemetic/antidiarrheal therapy and periodic ophthalmologic and growth monitoring are recommended. Safety in children under 1 year has not been established.