Index of drugs

Treatment of adult patients with previously treated ALK-positive (with the current rearrangement in the anaplastic lymphoma kinase gene) of non-small cell lung cancer (ALK-positive NSCLC).

1 hard capsules contain 200 mg crizotinib.

A selective small molecule inhibitor of the ALK tyrosine kinase (RTK) receptor and its oncogenic variants (i.e. ALK fusion and selected ALK mutations) and the RTK receptor of the hepatocyte growth factor receptor. Crizotinib exhibits concentration-dependent inhibition of ALK and c-Met kinase activity in biochemical assays and inhibits phosphorylation and modulated kinase-dependent phenotypes in cellular assays. Crizotinib exhibited strong and selective growth inhibitory activity, and induced apoptosis in tumor cell lines in which events of the ALK fusion type (including EML4-ALK and NPM-ALK) occurred, or ALK or MET locus gene amplification. Crizotinib demonstrated antitumor efficacy, including significant cytoreductive antitumor activity, in mice after xenogenic (xenogenic) transplants of tumors expressing ALK fusion proteins. The anti-tumor efficacy of crizotinib was dose-dependent and correlated with pharmacodynamic inhibition of phosphorylation of ALK fusion proteins (including EML4-ALK and NPM-ALK) in tumors.in vivo. After a single oral dose, crizotinib is absorbed with maximum concentrations in 4-6 h. When administered twice daily, steady-state was reached within 15 days. The absolute bioavailability of crizotinib was assessed at 43% after a single oral dose of 250 mg. Plasma proteins are 91% bound. researchin vitro showed that CYP3A4 / 5 were the major enzymes involved in the metabolic clearance of crizotinib. The main metabolic pathways in humans were the oxidation of the piperidine ring to crizotinb lactam and O-dealkylation followed by the conjugation of phase 2 O-dealkylated metabolites. T_0,5 is 42 hours. Approx. 53% and 2.3% of the administered dose of crizotinib appeared unchanged, respectively, in faeces and urine.

Hypersensitivity to crizotinib or to any of the excipients. Severe liver dysfunction.

In clinical trials, less than 1% of patients reported a drug-induced hepatotoxicity leading to death, as well as a concomitant increase in ALT, up to 3 x ULN (upper limit of normal) and total bilirubin up to 2 x ULN without increasing alkaline phosphatase activity. Increases in laboratory parameters grade 3 and 4 were generally asymptomatic and resolved after discontinuation of the drug. Elevations of aminotransferases generally occurred within the first 2 months of treatment. The drug should not be used in patients with severe hepatic impairment. Liver function tests should be performed including ALT, AST and total bilirubin twice a month during the first 2 months of treatment, followed by once a month and in case of clinical indication, with more frequent testing if these grade 2 parameters are increased, 3. and 4. In clinical trials, in 1% of patients, the use of the drug was associated with the development of severe, life-threatening or fatal pneumonia. Patients should be monitored for respiratory symptoms that indicate pneumonitis. If you suspect pneumonia, the drug should be discontinued. Other causes of pneumonia should be ruled out and permanently discontinued in patients with pneumonia associated with the treatment. In addition, prolongation of the QTc interval has been observed, which may lead to an increased risk of ventricular tachyarrhythmias (e.g.torsade de pointes) or sudden death. The risk of QTc prolongation may be higher in patients receiving concomitant anti-arrhythmic therapy and in patients with existing cardiac disease, bradycardia or electrolyte disorders (eg secondary to diarrhea and vomiting); caution should be exercised in these patients and the use of the drug should be considered for periodic monitoring of electrocardiograms and electrolytes.If visual disturbances persist or their severity should be considered, an ophthalmological consultation should be considered. There are no data on patients over 85 years of age. Limited data are available for patients aged 65 years and above and for patients diagnosed with ALK-positive NSCLC other than adenocarcinoma (the clinical benefit may be lower in this subgroup of patients, which should be taken into consideration before deciding on individual treatment).

Do not use this medicine during pregnancy unless the clinical condition of the woman requires treatment. It may harm the fetus when used during pregnancy. Animal studies have shown reproductive toxicity. Pregnant women or women who become pregnant while taking crizotinib and treated men whose partners are pregnant with potential risks to the fetus should be informed. It is not known whether crizotinib and its metabolites are excreted in human milk - breastfeeding should be avoided while taking the drug. Women of childbearing potential should be advised not to become pregnant while taking the medicine. During treatment and for at least 90 days after the end of treatment, appropriate methods of contraception should be used.

Very common: neutropenia, decreased appetite, neuropathy, dizziness, disturbed taste, blurred vision, vomiting, nausea, diarrhea, constipation, fatigue, edema, increased ALT. Common: leukopenia, lymphopenia, anemia, hypophosphataemia, bradycardia, pneumonia, abnormal esophagus, indigestion, rash, QT prolongation in ECG, increased AST, increased alkaline phosphatase in the blood. Uncommon: kidney cyst.

Orally. When qualifying patients for treatment, it is necessary to perform an accurate and validated test for ALK. The assessment of ALK-positive NSCLC should be carried out in laboratories with proven experience in specialized technology that is used in such studies. Adults: 250 mg twice daily, treatment should be continued until disease progression or unacceptable toxic effects occur. After objective progression of the disease, some patients may be considered for prolongation of treatment but no additional benefit has been demonstrated. If you miss a dose, take the medicine as soon as possible, unless you have less than 6 hours left until the Next dose.Dose adjustment. Depending on your individual safety and tolerability, you may need to stop taking the medicine and / or reduce the dose. When dose reduction is required, the dose should be reduced to 200 mg 2 times a day. If it is necessary to reduce the dose further, it can be modified to 250 mg once a day, taking into account individual safety and tolerability. In the case of haematological adverse reactions (except lymphopenia): Grade 3 - the drug should be discontinued until grade ≤2, then return to the same dosing schedule; Grade 4 - the drug should be discontinued until grade ≤2, then return to the 200 mg dose twice a day and in the case of relapse to the degree ≤2, then return to the dose of 250 mg once a day, leave permanently in Grade 4 recurrence. In case of non-haematological toxicities: increase in Grade 3 or 4 ALT or AST with an increase in total grade bilirubin ≤1. - discontinue the medicine until it reaches ≤1. or the initial value, then return to the 200 mg dose twice daily; increase in ALT or AST grade 2, 3 or 4 with simultaneous increase in total bilirubin level 2, 3 or 4 (in the absence of cholestasis or haemolysis) - discontinue the drug permanently; pneumonia of any grade (not associated with NSCLC progression, other lung disease, infection or photoprotection effect) - discontinue the drug if suspected, and discontinue if diagnosed; QTc Grade 3 prolongation - discontinue the drug to grade ≤1, then return to 200 mg twice daily; QTc 4 step prolongation - discontinue the drug permanently. There are no dose recommendations in patients with impaired hepatic function, severe and end-stage renal disease, and in the elderly (no data available). In patients with mild and moderate renal impairment, adjustment of the starting dose is not recommended.
The drug can be administered with or without food. Kaps.do not crush, dissolve or open.