Krizotinib - instructions for use, reviews, analogs and forms of release (capsules or tablets 200 mg and 250 mg) of the drug for the treatment of lung and bronchial cancer in adults, children and pregnancy. Composition

In this article, you can read the instructions for using the drug Crysotinib. There are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors specialists on the use of Crysotinib in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Krizotinib in the presence of existing structural analogs. Use for the treatment of lung and bronchial cancer in adults, children, as well as during pregnancy and lactation.Composition of the preparation.

Crysotinib an antitumor agent, a selective low molecular weight inhibitor of tyrosine kinase receptors (RTK), including anaplastic lymphoma (ALK) kinase and its oncogenic variants (ie, ALK fusion products and its individual mutations). Cryotinib is also an inhibitor of hepatocyte growth factor receptors (HGFR, c-Met, representatives of the RTK family). Cryotinib in a concentration-dependent degree inhibits the activity of ALK and c-Met in biochemical tests, and also inhibits phosphorylation and modulates kinase-dependent phenotypes within the framework of cellular assays. Cryotinib possesses potent and selective inhibitory activity and induces apoptosis of the lines of tumor cells expressing ALK fusion products (including EML4-ALK and NPM-ALK) or demonstrating the amplification of ALK or MET. The antitumor effect of crizotinib is dose-dependent and correlates with the severity of pharmacodynamic inhibition of the phosphorylation of ALK fusion products (including EML4-ALK and NPM-ALK) in tumors in vivo.

Composition

Crysotinib + auxiliary substances.

Pharmacokinetics

Absolute bioavailability of cryotinib with a single oral dose of 250 mg is 43%. The binding of cryotinib with plasma proteins is 91% and does not depend on its concentration.In in vitro studies, it has been shown that the metabolism of crizotinib occurs predominantly with the participation of CYP3A4 / 5 isoenzymes. With a single intake of 250 mg of cryotinib labeled with a radioactive isotope, healthy volunteers 63% and 22% of the dose taken are excreted through the intestine and kidneys, respectively. At the same time, approximately 53% and 2.3% of the accepted dose accounted for unchanged kristotinib when excreted through the intestine and kidneys, respectively. The pharmacokinetics of krizotinib does not change with age, it is not affected by the sex and body weight of the patient.

Indications

• malignant neoplasms of the bronchi and lung, including advanced non-small cell lung cancer (NSCLC) expressing anaplastic lymphoma kinase (ALK).

 Forms of release

Capsules 200 mg and 250 mg (sometimes mistakenly called pills).

Instructions for use and dosing regimen

Cryotinib used inside, regardless of the meal. Capsules should be swallowed whole.

Before the use of the drug Crysotinib in patients with NSCLC, an evaluation of ALK tumor expression is necessary, as it has been shown that the response to treatment is achieved only in these patients.This research should be performed in a laboratory with relevant experience. Violation of the methodology of this analysis may be the reason for receiving false results.

The recommended dose of cryotinib is 250 mg twice a day.

Treatment with the drug is carried out for a long time, until there is a positive effect of therapy.

If you miss the dose of Krizotinib, you should take it immediately, as soon as the patient has thought of it (if there are 6 hours or more left until the next dose is taken), or do not take it at all (if less than 6 hours remain until the next dose is received). Do not double the next dose as compensation missed.

Depending on the individual tolerability and safety, a temporary discontinuation of the drug and / or a reduction in the dose of Crysotinib may be necessary. If it is necessary to reduce the dose, it should be reduced to 200 mg twice a day. If it is necessary to further reduce the dose, it is reduced to 250 mg once a day.

Side effect

• bradycardia (decrease in heart rate);
• prolongation of QT interval on electrocardiogram (ECG);
• Diplopia (visual impairment, in which as a result of the deviation of the visual axis of the eye, the image of the visible object doubles);
• photopsy (appearance in the field of vision of non-objective images: moving points, spots, figures, lightning, more often luminous, shining);
• decreased vision, floating opacities of the vitreous, photophobia, visual field defects, the presence of iridescent circles around the light source in the field of vision, a violation of the perception of the brightness of light;
• nausea, vomiting;
• diarrhea, constipation;
• disorders of the esophagus (gastroesophageal reflux disease, pain during swallowing, pain in the esophagus, spasm of the esophagus, ulcer of the esophagus, esophagitis, reflux esophagitis);
• abdominal pain;
• stomatitis (inflammation and ulcers of the oral mucosa);
• glossitis (inflammation of the tongue);
• cheilitis (an inflammatory process that affects the red border, mucous membrane and skin of the lips);
• dyspepsia (abnormal activity of the stomach, difficult and painful digestion);
• liver failure;
• increase in the activity of enzymes alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyltransferase (GGT), alkaline phosphatase (FA);
• violation of hepatic functional tests, impaired liver function;
• neutropenia (febrile neutropenia, decreased neutrophil count), leukopenia, lymphopenia, thrombocytopenia;
• decreased appetite;
• motor and / or sensory peripheral neuropathy (degenerative and distrophic changes in peripheral nerves);
• a sensation of crawling along the body;
• violation of gait;
• hypotension (decreased muscle tone);
• dizziness, balance disorder, postural dizziness;
• pre-fainting condition;
• dysgeusia (a disorder of taste in which taste sensations are partially absent or distorted);
• headache, insomnia;
• interstitial lung diseases (acute respiratory distress syndrome, pneumonitis);
• infection of the upper respiratory tract (nasopharyngitis, rhinitis, pharyngitis);
• shortness of breath, cough;
• rash on the skin;
• multiple cysts of the kidneys;
• pain in the joints, back pain, musculoskeletal pain in the chest;
• muscle weakness, muscular atrophy;
• edema (peripheral edema, facial swelling, generalized edema, local edema, periorbital edema);
• fatigue;
• discomfort in the chest area;
• fever.

Contraindications

• impaired liver function - increased ACT or ALT activity by more than 2.5 times with respect tothe upper limit of the norm (VGN) or more than 5 times the VGN due to malignant neoplasm;
• increasing the concentration of total bilirubin by more than 1.5 times relative to VGN;
• impaired renal function of a serious degree or in patients on hemodialysis;
• simultaneous application with powerful inducers or inhibitors of the CYP3A isoenzyme, as well as with substrates of the CYP3A isoenzyme, characterized by a narrow therapeutic range;
• pregnancy;
• lactation period (breastfeeding);
• children and adolescents under 18;
• increased sensitivity to krizotinibu.

Application in pregnancy and lactation

Contraindicated in the use of Cryotinib in pregnancy and lactation (breastfeeding).

Use in children

Contraindicated the appointment of the drug to children and adolescents under the age of 18 years.

Application in elderly patients

Older patients do not need an initial dose adjustment.

special instructions

Caution should be applied to the use of Cryotinib in patients with a history of episodes of prolonged QT interval predisposed to this condition (patients with congestive heart failure,bradycardia, electrolyte balance disorders) or receiving medications that extend the QT interval, as well as in case of liver dysfunction; in combination with preparations, predominantly metabolized isoenzymes CYP3A; in patients with impaired liver function.

When using Crysotinib in patients who have a history of episodes of prolonged QT interval, predisposed to this condition or receiving medicines that extend the QT interval, consideration should be given to periodic monitoring of ECG and electrolyte concentration in the blood. The dose should be adjusted according to a special scheme.

It is recommended to avoid the use of crizotinib in patients with congenital syndrome of QT interval prolongation.

In connection with the possible risk of developing clinical manifestations of bradycardia (syncope, dizziness, lowering blood pressure (BP)), whenever possible, avoid concomitant use of crizotinib and other medications that reduce the heart rate (heart rate), for example, beta-blockers, nondihydropyridine calcium blockers channels, such as Verapamil and diltiazem, clonidine, digoxin. It is recommended to monitor heart rate and blood pressure on a monthly basis.In the case of asymptomatic bradycardia, dose adjustment is not required. With the development of bradycardia, accompanied by the corresponding symptoms, it is necessary to suspend therapy with Cryotinib and evaluate the correctness of the appointment of concomitant therapy.

There have been reports of the development of drug-induced hepatotoxicity with a fatal outcome in patients receiving cryotinib. According to clinical studies, the incidence of this complication is less than 1%. The following symptoms are typical: weakness, fatigue, anorexia, nausea, vomiting, abdominal pain, jaundice, darkening of urine, generalized itching, hemorrhagic diathesis, especially in combination with fever and rash.

Against the background of cryotinib therapy, there have been cases of development of severe, life-threatening or fatal interstitial lung diseases or pneumonitis. This condition developed in general within 2 months after the initiation of therapy. Continuous monitoring of the patients' condition for the development of clinical manifestations from the side of the lungs should be carried out. When there are violations that may indicate the development of interstitial lung disease or pneumonitis,It is necessary to perform a survey of patients in order to exclude alternative causes of this condition. After the diagnosis of interstitial lung disease or pneumonitis associated with ongoing therapy, cryotinib should be discontinued.

With the appearance or aggravation of visual impairment, including diplopia, photopsy, reduced vision clarity, floating vitality, it is necessary to evaluate the need for an ophthalmological examination. These disorders usually appear within the first 2 weeks of taking cryotinib. It should be borne in mind that the development of floating vitreous opacities and / or severe photopsy or deterioration of these disorders may be a sign of rupture of the retina or threat of detachment of the retina. Cases of the need for temporary or complete withdrawal of krizotinib or reduction of its dose due to the development of visual impairment has not been recorded.

With the development of side effects from the digestive system, standard maintenance therapy with antiemetic, anti-diarrhea and / or laxatives can be performed.

Against the backdrop of Crozotinib therapy, it is necessary to monitor the values ​​of functional liver samples, including ALT activity and total bilirubin concentration, at a frequency of at least once a month during the first 3 months of therapy or more often, if there are appropriate clinical indications, to increase these indicators to the level 2, 3 or 4 toxicity according to the classification of STAE. If necessary, the dose adjustment is carried out according to a special scheme.

During the treatment with crizotinib, a regular blood test (with leukocyte counting) should be performed regularly, the frequency of which should be increased by developing abnormalities of grade 3 or 4 according to the classification of STAAE, an increase in body temperature or infection. Monitoring should be carried out according to clinical indications. If necessary, the dose adjustment is carried out according to a special scheme.

There are limited data on the safety and efficacy of cryotinib in elderly patients compared to younger patients.

Impact on the ability to drive vehicles and manage mechanisms

Studies of the influence of Crysotinib on the ability to drive vehicles and work with mechanisms have not been carried out. During the treatment period, patients should be cautious when performing such activities, especially in cases of visual impairment, dizziness or fatigue.

Drug Interactions

In in vitro studies on human hepatocytes, it has been shown that clinically significant drug interactions due to a Krisotinib-mediated inhibition of the metabolism of other drugs that are substrates of the isoenzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6 are unlikely. In vitro, cryotinib is an inhibitor of the CYP2B6 isoenzyme, so it can potentially increase the plasma concentration of drugs, mainly metabolized by the CYP2B6 isoenzyme.

In in vitro studies on human liver microsomes, it has been shown that crizotinib inhibits the activity of CYP2B6 and CYP3A isoenzymes in a time-dependent manner. Cryotinib is a substrate of the CYP3A4 / 5 isoenzyme and a moderate inhibitor of CYP3A. In in vitro and in vivo studies, it has been shown that cryotinib is an inhibitor of CYP3A.

In vitro studies have shown that interaction between drugs, due to cryotinib-mediated inhibition of the metabolism of uridine diphosphate-glucunonyltransferase substrates (UDPGT), is unlikely.

Combination of cryotinib with powerful inhibitors of CYP3A can lead to an increase in its concentration in the blood plasma. Therefore, a combination of crizotinib with potent inhibitors of CYP3A, including atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole should be avoided.

Caution is needed when concomitantly using cryotinib with moderate inhibitors of CYP3A.

Grapefruit or grapefruit juice can also increase the concentration of cryotinib in the blood plasma, so avoid using it during the treatment period.

With the simultaneous use of cryotinib with powerful inducers of CYP3A, its concentration in the blood plasma decreases. Therefore, simultaneous use of crizotinib with powerful inducers of CYP3A should be avoided, including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's wort preparations.

Caution should be exercised when using cryotinib in combination with drugs that are predominantly metabolized by CYP3A, a dose reduction of these drugs may be necessary.

Combination of cryotinib with CYP3A isoenzyme substrates having a narrow therapeutic range (such as, alfentanil, cyclosporin, fentanyl, quinidine, sirolimus, tacrolimus) should be avoided, as well as with preparations whose use may be associated with the development of life-threatening arrhythmias (pimozide, dihydroergotamine, ergotamine, as well as with astemizole, cisapride and terfenadine).

After taking 250 mg twice a day of cryotinib with malignant tumors for 28 days, the full absorption of midazolam (when administered orally) was 3.65 times higher than that of midazolam monotherapy.

The solubility of cryotinib in water depends on pH: at low (acidic) pH values, its solubility increases. A single administration of crizotinib 250 mg after taking Omeprazole 40 mg once a day for 5 days leads to an increase in the total AUCinf crisotinib by approximately 10%, with the maximum concentration of cryotinib in the blood plasma unchanged; the degree of increase in exposure is clinically insignificant.Thus, correction of the initial dose of cryotinib with simultaneous use with drugs that cause an increase in the pH of the gastric juice (such as proton pump inhibitors, H2-histamine receptor blockers or antacids) is not required.

Cryotinib is an inhibitor of P-glycoprotein. Therefore, it can increase the concentration in the blood plasma of co-administered drugs, which are substrates of P-glycoprotein.

Cryotinib is an inhibitor of the transport proteins OCT1 and OCT2. In this regard, krizotinib potentially can increase the concentration in the blood plasma of drugs that are substrates of these proteins.

Analogues of the drug Crysotinib

Structural analogs for the active substance:

• Xalqori.

Analogues of the preparation Crysotinib by pharmacological group (antitumor agents - inhibitors of protein kinases):

• Albitinib;
• The Athlete;
• Bosulif;
• Vargatef;
• Votrient;
• Genfatinib;
• Gefitinib;
• Giotrip;
• Histamel;
• Gleihib;
• Glivec;
• Dasatinib;
• Djakavi;
• Zelborough;
• Ibrans;
• Iglib;
• Imagliv;
• Imatib;
• Imatinib;
• Imbruvik;
• Imvek;
• Inlita;
• Iressa;
• Capresa;
• Cotellus;
• Xalqori;
• Lenwima;
• Mechinist;
• Nexavar;
• Neopax;
• Nilotinib;
• Sorafenib;
• Sprysel;
• Steiverg;
• Sunitinib;
• Sutent;
• Tagrisso;
• Tayverb;
• Tarlenib;
• Tarceva;
• Taxis;
• Tafinlar;
• Thorizel;
• Filachromine;
• Everolimus;
• Erlotinib.

Review of the oncologist's doctor

Treatment of advanced lung cancer with Cryotinib is a long process, especially when there is a pronounced positive effect. But without the development of side effects of therapy is not always done. In my practice, patients often have visual impairment. They complain of doubling in their eyes, floating dark spots or glowing dots before their eyes. There have been cases of development of an infection of the upper respiratory tract in the form of pharyngitis with a strong cough. Almost all patients receiving Crysotinib complain of nausea, weakness, fatigue. There are always changes in blood tests: a decrease in the number of leukocytes, platelets.

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