What are the precautions for taking Crizotinib?

During clinical studies of crizotinib (Crizotinib), warnings and precautions such as hepatotoxicity, interstitial lung disease/pneumonitis, QT interval prolongation, bradycardia, severe vision loss, gastrointestinal toxicity in children and young adults with ALCL or pediatric IMT patients, embryo-fetal toxicity have emerged. Discontinue and resume at reduced dose upon recovery, or permanently discontinue based on severity.

1. Hepatotoxicity: Among patients treated with crizotinib, <1% of patients simultaneously experienced an increase in ALT or AST ≥3 times ULN and total bilirubin ≥2 times ULN, and alkaline phosphatase was normal. Transaminase elevations usually occur within the first 2 months of treatment. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then monthly and more frequently as clinically indicated in patients with elevated transaminases, with repeat testing of hepatic transaminases, alkaline phosphatase, or total bilirubin.

2. Interstitial lung disease (ILD)/pneumonitis: Patients receiving crizotinib may develop severe, life-threatening or fatal interstitial lung disease (ILD)/pneumonitis, usually occurring within 3 months after the start of treatment. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis, such as dyspnea, cough, sputum production, etc., rule out other potential causes of ILD/pneumonitis, and permanently discontinue crizotinib in patients diagnosed with drug-related ILD/pneumonitis.

3. QT interval prolongation: In clinical trials of patients with non-small cell lung cancer, 2.1% of patients had QTcF (heart rate QT corrected by Fridericia method) ≥500ms. Patients with congenital long QT syndrome should avoid using crizotinib. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking drugs known to prolong the QT interval.

4. Bradycardia: Patients may also experience syncope including bradycardia. As much as possible, avoid combining crizotinib with other drugs known to cause bradycardia (such asβ-blockers, non-dihydropyridine calcium channel blockers, clonidine and digoxin). Monitor heart rate and blood pressure regularly. If bradycardia occurs, reassess the use of concomitant medications known to cause bradycardia.

5. Severe vision loss: Optic atrophy and optic nerve disorders have been reported as potential causes of vision loss. Monthly assessment of visual symptoms in all patients is recommended during treatment. Report new visual symptoms to your eye specialist. In pediatric and young adult patients with ALCL or pediatric patients with IMT, after initiating crizotinibBaseline and follow-up ophthalmic examinations, including retinal examinations, were performed within 1 month and every 3 months thereafter. The ophthalmic evaluation should include best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other appropriate assessments. Unless other causes are identified, crizotinib should be permanently discontinued for Grade 3 or 4 eye disease or severe vision loss (best corrected visual acuity less than 20/200 in one or both eyes), and the decision to resume the drug should consider the potential benefits and risks to the patient.

6. Gastrointestinal toxicity : including diarrhea, nausea, vomiting and stomatitis. Physicians provide standard antiemetic and antidiarrheal medications to treat gastrointestinal toxicity in children and young adults with ALCL or pediatric patients with IMT. Antiemetics are recommended before and during treatment with crizotinib to prevent nausea and vomiting. If a patient develops Grade 3 nausea or Grade 3 or 4 diarrhea or vomiting that persists for 3 days despite maximal medical therapy, crizotinib should be withheld until symptoms resolve and then continued at the next lower dose level. Consider supportive care such as hydration, electrolyte replacement, and nutritional support as clinically indicated.

7. Embryo-Fetal toxicity: According to the mechanism of action of crizotinib, pregnant women taking this drug will cause harm to the fetus. In animal reproduction studies, oral administration of crizotinib to pregnant rats during organogenesis resulted in embryotoxicity and fetal toxicity under exposure conditions similar to the maximum recommended human dose. Therefore, it is recommended that females of reproductive potential use effective contraception during treatment with the drug and within 45 days after the last dose; male patients with female partners of reproductive potential are recommended to use condoms during treatment with the drug and within 90 days after the last dose.

The original drug Crizotinib has been launched in China and is covered by medical insurance, but it is only reimbursed for patients who meet the indications. The price per box may be around RMB 15,000. The price of the original Turkish version of Crizotinib sold overseas may be more than RMB 10,000 per box (the price may fluctuate due to exchange rates), which is expensive. There are also cheaper generic crizotinib drugs available overseas. The ingredients are basically similar to those of the original drugs sold domestically and abroad. For example, the price of 250mg*60 tablets produced by a Bangladesh pharmaceutical factory may be more than 2,000 yuan per box (the price may fluctuate due to exchange rates).