Xalcory - instructions for use, dose, side effects, contraindications

Active substanceCrysotinibCrysotinib

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Xalcorie®

capsules inwards

Pfizer Inc. USA

Dosage form: & nbspcapsules

Composition:

Composition Mr.but 1 capsule:

active substance: cryotinib 200 mg, 250 mg.

Excipients: silicon dioxide colloid 2.00 / 2.50 mg, microcrystalline cellulose 83,00/103.75 mg, calcium phosphate 83.00 / 103.75 mg.

sodium carboxymethyl starch 20.00 / 25.00 mg. magnesium stearate 12.00 / 15.00 mg.

Composition of gelatin capsule:

Dosage 200 mg: capsule body-gelatin 44.27 mg. titanium dioxide 1.33 mg, cap capsule - gelatin 29.55 mg, titanium dioxide 0.60 mg. ferric iron oxide red (E 172) 0.25 mg.

Dosage of 250 mg: capsule body - gelatin 55.99 mg, titanium dioxide 1.14 mg, iron oxide red oxide (E 172) 0.47 mg.

capsule capsule - gelatin 37.33 mg, titanium dioxide 0.76 mg, ferric oxide red oxide (E 172) 0.31 mg.

Composition of ink: shellac 24-27%, ethanol 23-26%, isopropanol 1-3%, butanol 1-3%, n-propylene glycol 3-7%. ferric oxide black oxide (E 172) 24-28%. Ammonia solution concentrated 1-2%, potassium hydroxide 0.05-0.1%. purified water 15-18%.

Description:

Dosage 200 mg: hard gelatin capsules No. 1 with a pink lid and a white body, with a black overcoat "Pfizer" - on the lid and "CRZ200" - on the body.

The contents of the capsule are white or slightly yellow powder.

Dosage of 250 mg: hard gelatin capsules No. 0 with a lid and a pink body, with a black inscription "Pfizer" - on the top of the lid "CRZ250" - on the body.The contents of the capsule are a white or slightly yellowish powder.

Pharmacotherapeutic group:antitumor agent, inhibitor

ATX: & nbsp

L.01.X.E.16 Crysotinib

Pharmacodynamics:Crysotinib is a selective low-molecular inhibitor of tyrosine kinase reviewers (RTK), including anaplastic lymphoma kinase (ALK) and its oncogenic variants (i.e., the products of the fusion of AEK and its individual mutations). Kryozitnib is also an inhibitor of the receptors of the growth factor of geiatocytes (HGFR, c-Met), representatives of the family RTK. Kryozitnib in a concentration-dependent degree inhibits the activity of AEK. and c-Met in biochemical tests, and also inhibits phosphorylation and modulates kinase-dependent phenotypes within the framework of cellular assays. Crysotinib has potent and selective inhibitory activity and induces apoptosis of the lines of tumor cells expressing fusion products ALK (including EME4-ALK and NPM-ALK) either demonstrating amplification ALK or MET. The antitumor effect of krizotinp is dose-dependent and correlates with the severity of pharmacodynamics of a significant inhibition of phosphorylation of AEK fusion products (including EML4-ALK and NPM-ALK) in tumors in vivo.

Pharmacokinetics:

After a single oral intake of crisotinib on an empty stomach, the time to reach the maximum concentration in the blood plasma (TC_max) is from 4 to 6 hours. 11a background of taking 250 mg of cryosotinpb twice a day, the equilibrium concentration of cryotin is achieved within 15 days and remains unchanged, with an average accumulation coefficient of 4.8. Parameters of systemic exposure (maximum concentration in blood plasma (C_max ) and the area under the curve "concentration-time" (AUC)) in the dose range of 200 mg-300 mg 2 times a day increase more in proportion to the dose.

When taking krizotinib 2 times a day, the equilibrium concentration is reached within 15 days.

Absolute bioavailability of cryotinib with a single oral dose of 250 mg is 43%.

In healthy volunteers with a single oral intake of cryotinib 250 mg, a high-fat diet lowers AUCinf and C_max approximately on 14%. Thus, the krizotipib can be taken regardless of the intake of food.

Metabolism and excretion

In studies in vitro it was shown that the metabolic clearance of krizotinib is mainly carried out by isoenzymes CYP3A4 / 5. The main ways of metabolism in humans are the oxidation of the piperidine ring to the lactam of crizotinib and O-dealkylation, followed by conjugation of O-dealkylated metabolites of the 2-phase.

With a single administration of krizotinib, the terminal period of the vomiting from the blood plasma was 42 h.

With a single administration 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 the night, respectively. At the same time, approximately 53% and 2.3% of the accepted dose were due to unchanged cryotinib in the intestine and night, respectively. The average apparent clearance of cryotinib at equilibrium concentration was lower (60 l / h) after application of 250 mg cryotinib 250 mg twice a day than after application at a dose of 250 mg once a day (100 l / h). Most likely, this is due to increased inhibition of the isoenzyme CYP3A after applying several doses.

Distribution

Binding of cryotinib with plasma proteins in vitro is 91%. regardless of concentration.

Research results in vitro suggest that the krizotipib is a substrate of the P-glycoprotein.

The ratio of the concentration in the plasma or blood is approximately 1.

Patients with impaired renal function

There is no need for correction of the dose of cryotinib in patients with impaired renal function of mild severity (creatinine clearance from 60 ml / min to 90 ml / min) and moderate severity (QC from 30 ml / mp to 60 ml / min), both as equilibrium concentrations in these cases practically do not differ from the equilibrium concentration of krizotinib y patient "with normal renal function, and it was also found that QA had no effect on the pharmacokinetics of cryotinib.

After a single application of cryotinib 250 mg in patients with severe renal failure (CK <30 ml / min), the condition of which does not require peritoneal dialysis or hemodialysis. AUC and C_max Crizotinib increased by 79% and 34%, respectively. In such patients, the dosage of crizotinib should be adjusted (see section "Method of administration and dose"). It is impossible to give exact recommendations for dosing the drug in patients with terminal renal failure (not investigated).

The use of cryotinib in patients with severe renal dysfunction or who are on hemodialysis has not been investigated.From clinical studies, patients were excluded, with a serum creatinine concentration more than 2 times the upper limit of the norm (VGN).

Patients with impaired hepatic function

The use of cryotinib in patients with impaired hepatic function was investigated. From clinical studies, patients were excluded who reported increased activity of aspartate aminotransferase (ACT) or alanine aminotransferase (ALT) by more than 2.5 times with respect to IGN (more than 5 times with respect to IGN due to malignant neoplasm) or an increase in the concentration of total bilirubin by more than 1.5 times with respect to VGN. Based on population pharmacokinetic analysis, it was found that the basal concentration of total bilirubin or activity ACT do not affect the pharmacokinetics of cryotinib. As cryotinib is largely metabolized by the liver, we can expect an increase in the concentration of cryotinib in the blood plasma for violations of liver function.

Age

The pharmacokinetics of krizotinib ns varies with age.

Body weight and sex.

The sex and weight of the patient does not affect the pharmacokinetics of cryotinib.

Ethnicity

It was found that the estimated equilibrium APS in Asian residents is 23-37% higher than in representatives of other ethnic groups.

Use in children

The safety and efficacy of cryotinib in children have not been established.

Effect on heart function

In all patients who received cryotinib in a dose of 250 mg twice a day, the signs of lengthening of the interval QT. During the analysis of the pharmacokinetics and pharmacodynamics parameters, it was suggested that there is a connection between the concentration of cryotinib in the blood plasma and the duration of the interval QTc. In addition, it was found that the reduction in heart rate is associated with an increase in the concentration of cryotinib in the blood plasma.

Indications:

Common non-small cell lung cancer (NSCLC) expressing anaplastic lymphoma kinase (ALC).

Contraindications:

- hypersensitivity to krizotinib or to any auxiliary substance included in the preparation;

- impaired liver function - increased activity ACT or ALT more than 2.5 times with respect to IGN (more than 5 times with respect to IGN due to malignant neoplasm) or an increase in the total bilirubin concentration by more than 1.5 times with respect to IGN;

- impaired renal function of a serious degree or in patients on hemodialysis;

- simultaneous use with powerful inducers or inhibitors of isofermite CYP3A, as well as with isofermeity substrates CYP3A, characterized by a narrow therapeutic range (see section "Interaction with other medicinal products");

- pregnancy, the period of breastfeeding;

-baby age to 18 years (not enough data on safety and effectiveness).

Carefully:

Xalconi ® should be used with caution in patients who have a history of episodes of lengthening the interval QTc. predisposed to this condition (patients with congestive heart failure, bradycardia, electrolyte balance disorders) or receiving medications that lengthen the interval QT (see section "Special instructions"), as well as in case of violation of liver function.

Care should be taken when applying Xalcorie® in combination with preparations predominantly metabolized by isophrenic CYP3A (see the section "Interaction with other medicinal products").

Pregnancy and lactation:

Adequate and well-controlled studies of the use of crisotypes during pregnancy have not been conducted.

Cryotinib may cause fetal damage when applied during pregnancy. Women of childbearing age should be warned about the undesirability of pregnancy during the period of cryotinib therapy. To this end, during the treatment period and not less than 90 days after the completion of the woman of childbearing age, or their partners receiving Xalqori®. Adequate methods of contraception should be used.

When using Xalcorie® during pregnancy or at the onset of pregnancy during treatment with this drug of the patient or her sexual partner, they should be informed of the potential risks of adverse effects of the drug on the fetus.

It is not known whether cryotinib in breast milk. 13 period of breastfeeding should be either canceled cryotinib, or stop breastfeeding, depending on the degree of need for the drug the mother.

In accordance with the results of preclinical studies, it is assumed that cryotinib can affect the fertility of men and women.

Dosing and Administration:

Xalqori® apply inside, regardless of the reception of the poor. Capsules should be Pswallow whole.

Before using Xalcorie® in patients with NSCLC, an evaluation of tumor expression by ACC is necessary because it has been shown that the response to treatment is only achieved in these patients.

This research should be performed in a laboratory with relevant experience. Violation method of this analysis may be the reason for receiving false results.

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

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

In case of missed dose of Krizoginib, it should be taken immediately, as soon as the patient recalls it (if there are 6 hours or more remaining 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.

Correction of the dose.

Depending on individual tolerability and safety, a temporary withdrawal of the drug and / or a reduction in the dose of crizogynib may be required.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.

Recommendations for dose reduction in the development of hematological and non-hematological toxicity are given in Tables 1 and 2.

Table 1. Correction of the dose of cryotinib with the development of hematological toxicity^a

Degree of expression

СТСАЕ^b

Dosing regimen of cryotinib

Degree 3

Temporarily abolish the drug before the symptomatology is resolved to level <= 2 degrees, then resume therapy in the initial dosing regimen.

Degree 4

Temporarily abolish the drug before the symptomatology is resolved to level <= 2 degrees, then resume therapy at a dose of 200 mg 2 times a day^at.

^a except for lymphopenin (in case there is no connection with clinical manifestations, for example, opportunistic infections).

^b criteria for assessing the severity of the most frequent adverse events of the National Cancer Institute of the United States (NCI Common Terminology Criteria Gogh Adverse Events).

^at with the development of a relapse of an undesirable phenomenon, the drug should be temporarily discontinued until the symptomatology is resolved to a level <= 2 degrees, then resume therapy with a drug at a dose of 250 mg I once a day.Recurrent adverse events of 4 severity require complete reversal of therapy.

Table 2. Correction of the dose of cryotinib with the development of non-hematological toxicity.

Degree of expression^a	Dosing regimen cryotiniba
Increased ALT activity or ACT up to 3 or 4 degrees, associated with an increase in the concentration of total bilirubin to <= 1 degree	Temporarily abolish the drug before the symptomatology is resolved to a level of <= 1 degree or initial, then resume therapy at a dose of 200 mg 2 times a day ^b .
Increased ALT activity or ACT up to 2, 3 or 4 degrees, with the concomitant increase in the concentration of total bilirubin up to 2, 3 or 4 degrees (in the absence of cholestasis or hemolysis)	Complete withdrawal of the drug.
Interstitial lung diseases (PID) / pneumonitis of any with gravity^at	Complete withdrawal of the drug.
Interval lengthening QTc 3 degrees	Temporarily discontinue the drug until symptoms resolve to <= 1 degree, then resume therapy at a dose of 200 mg. 2 times a day ^b .
Interval lengthening QTc 4 degrees	Complete withdrawal of the drug.
Bradycardia 2, 3 degrees¹(are manifested concomitant symptoms (may be severe and clinically significant) requiring medical intervention)	Temporarily discontinue the drug until symptoms resolve to <= 1 degree or increase the heart rate to 60 beats / min or more. Evaluate the correctness of concomitant therapy with drugs that can lead to the development of bradycardia, as well as antihypertensive drugs. If the concomitant medication that affects the heart rate has been determined and canceled, or its dose is adjusted, then after resolution

symptomatology to level <= 1 degree or an increase in the heart rate to 60 beats / min or more should be resumed therapy with crizotinib in the initial dose.

If the concomitant medication that affects the heart rate has not been identified, or has not been canceled, or the dose has not been adjusted, then after resolving the symptomatology to <= 1 degree or increasing the heart rate to 60 beats / min or more, cryotinib therapy should be resumed less dose.

Bradycardia of the 4th degree ^{d d}(life-threatening consequences, immediate medical intervention is required)

It is necessary to completely cancel the reception of the cryotypib, unless another medication that affects the heart rate has been identified.

If the patient receives another medication that can affect the heart rate and is either canceled or corrected, then after resolving the symptomatology to <= 1 degree or increasing the heart rate to 60 beats / min or more, you should to resume therapy in a dose of 250 mg once a day.

^a criteria for assessing the severity of the most frequent adverse events of the National Cancer Institute of the United States (NCI Common Terminology Criteria for Adverse Events).

^b when the relapse of an unwanted phenomenon develops, the drug should be temporarily discontinued until the symptomatology is resolved to a level <I degree, then resume therapy with a drug at a dose of 250 mi I once a day. Recurrent adverse events of 3 or more severity require complete reversal of therapy.

^at not associated with the progression of NSCLC, other lung diseases, infections or previous radiation therapy.

^g the heart rate is less than 60 beats per minute.

^d permanent withdrawal of the drug for recovery.

Impaired liver function

The use of cryotinib was not investigated in patients with increased activity ACT or ALT more than 2.5 timeswith respect to IGN (more than 5 times that of IGN due to malignant neoplasm) or with an increase in the concentration of total bilirubin by more than 1.5 times with respect to IGN. Cryotideib in patients with impaired liver function should be applied with caution.

Impaired renal function

It is not necessary to correct the dose of the drug in patients with mild renal insufficiency (KK 60-90 ml / min) and medium (KK 30-60 ml / min) severity.

In patients with severe renal insufficiency (CK <30 ml / min), the concentration of the cryotypib in the blood plasma can increase. In patients with severe renal failure, the condition of which does not require peritoneal dialysis or hemodialysis, the dose of Xalcory should be adjusted® up to 250 mg once a day. After taking the drug for at least 4 weeks, the dose can be increased taking into account individual tolerance and safety up to 200 mg twice a day (see section "Pharmacological properties"). The use of cryotypib in patients with terminal renal failure was not investigated.

Elderly patients

In elderly patients, an initial dose adjustment is required.

Side effects:

Side effect

The most severe adverse reactions were gspatotoxicity, ISL or nnevmopit and lengthening of the interval QT.

The most frequent adverse reactions (recorded in> 25% of patients) were nausea, visual impairment, vomiting, diarrhea, constipation, swelling, increased transaminase activity. decreased appetite, increased fatigue, dizziness and neuropathy.

The frequency of undesired reactions is represented by the following classification:

Very Frequent	>=10%
Frequent	> = 1% and <10%
11th	> = 0.1% and <1%
Rare	> = 0.01% and <0.1%
Very rare	<0.01 %

From the cardiovascular system: very frequent - a bradycardia (including sinusovaja); frequent - reduction of heart rate, lengthening of the interval QT on an electrocardiogram, fainting.

From the senses: very frequent - Visual impairment (diplopia, photopsy, decreased vision, floating opacities of the vitreous, photophobia, defects in vision fields, the presence of iridescent circles around the light source in the field of vision, and a violation of the perception of the brightness of light).

From the digestive system: very frequent - nausea, diarrhea, vomiting, constipation,disorders of the esophagus (gastroesophageal reflux disease, dysphagia, pain in swallowing, pain in the esophagus, spasm of the esophagus, ulcer of the esophagus, esophagitis, reflux esophagitis), abdominal pain, stomatitis (glaeopathy, glossitis, heylntitis, inflammation and ulcers of the mucosa oral pain, oropharyngeal pain); frequent - indigestion; infrequent - hepatic insufficiency, perforation of the gastrointestinal tract.
Laboratory indicators: very frequent - increased activity of "liver" transaminases * (ALT, ACT, gamma glutamyl transferase), a violation of liver function; frequent - increased activity of alkaline phosphatase.

From the hematopoiesis: very frequent - neutropenia (febrile neutropenia, a decrease in the number of neutrophils), leukopenia, a decrease in the concentration of white blood cells; frequent - lymphopenia, anemia, decreased hemoglobin; infrequent - thrombocytopenia.

From the side of metabolism: very frequent - decreased appetite; frequent - hypophosphatemia.

From the nervous system: very frequent - Neuropathy (sensation of burning, neuralgia, peripheral neuropathy (including motor, sensory neuropathy and motor-sensory neuropathy),neurotoxicity dizssteziya, creeping sensation in the body, gait disturbance, hypotension, optic neuritis, paresthesia, hypoesthesia, hyperesthesia, sensory disturbances, motor disorder, paralysis of the peroneal nerve, zeros neuropathy), dizziness, balance disorders, postural dizziness, lightheadedness, dysgeusia, headache, insomnia.

On the part of the respiratory system: frequent - ILD (acute respiratory distress syndrome, pneumonitis, alveolitis), upper respiratory tract infection (nasopharyngitis, rhinitis, pharyngitis), breathlessness, cough.

From the skin: very frequent rash.

From the urinary system: frequent - multiple cysts of the kidneys, bleeding from the kidney cysts, infection of the cysts of the kidneys, abscess of the night.

On the side of the onorn-dvengatelnogo apparatus: very frequent - pain in the joints, back pain, musculoskeletal pain in the chest, muscle weakness, muscular atrophy.

Other: very frequent - edema (peripheral edema, facial edema, generalized edema, local edema, periorbital edema), fatigue, asthenia, chest pain, discomfort in the chest, fever.

* Increased transaminase activity was usually observed during the first two months of therapy. Episodes of increased transaminase activity in most cases were asymptomatic and stopped after a temporary cessation of therapy. After resumption of the drug, usually in a smaller dose, recurrence of changes was not recorded.

Overdose:

In case of an overdose, standard maintenance therapy should be given. The specific antidote of cryotinib is not known.

Interaction:

In studies in vitro on human hepatocytes, it was shown that clinically significant drug interaction as a result of krosotinib mediated inhibition of the metabolism of other drugs that are substrates of isoenzymes CYP1A2, CYP2C8. CYP2C9, CYP2C19 or CYP2D6, unlikely.

In vitro cryotobium is an inhibitor of the isoenzyme CYP2B6, therefore, it can potentially increase the plasma concentration of drugs, mainly isostabilized with isoenzyme CYP2B6.

In studies in vitro on microsomes of the human liver it was shown that the rhizobium inhibits the activity of isoenzymes CYP2B6 and CYP3A in a time-dependent degree. Crysotieib is a substrate of isoenzyme CYP3A4 / 5 and a moderate isoenzyme inhibitor CYP3A. In studies in vitro and in vivo it was shown that kryzotibib is an inhibitor of the isoenzyme CYP3A.

Simultaneous use with drugs that are substrates of uridine 5 '-diphosphate-glucuronoschransferase (UDF1T)

Research in vitro showed that the interaction between the preparations, due to the cryotinib-induced inhibition of the metabolism of UDPGT substrates, is unlikely.

Drugs that can increase the concentration of cryotinib in the blood plasma

Combination of cryotinib with potent inhibitors of isoenzyme CYP3A can lead to an increase in its concentration in the blood plasma. Therefore, combining krizotinib with potent inhibitors of isoenzyme should be avoided CYP3A, including atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, isfinavir, ritonavir, saquinavir, telithromycin, troleoaddomia and voriconazole.

Combined single oral intake of krizotypes in a dose of 150 mg and ketoconazole at a dose of 200 mg twice a day, leads to an increase in the systemic exposure of the cryotypes. The values AUCinf and Cmax increase approximately 3.2 and 1.4 times, respectively, compared with the reception of the cryptotype in mopotrapia. Nevertheless, the severity of the effect of inhibitors of the isoenzyme CYP3A on the values of the exposure of the cryotypes in the equilibrium state is not determined.

Grapefruit or grapefruit juice can also increase the concentration of cryotinib in the blood plasma, so you should avoid using it against the background of therapy with this drug. Care should be taken when applying the cryotypes with moderate isoenzyme inhibitors CYP3A.

Drugs that can reduce the concentration of cryotinib in the blood plasma.

Combination of cryotinib with powerful isoenzyme inducers CYP3A can lead to a decrease in its concentration in the blood plasma. Therefore, simultaneous application of cryotinib with powerful isoenzyme inducers should be avoided CYP3A, including carbamazepine, phenobarbital, fsitoyin, rifabutiyom, rifampicip and preparations of St. John's wort perfumed.

A single application of crizotinib 250 mg at the same time as rifampicamp (600 mg once a day) resulted in a decrease in the values AUCinf and Cmax of crizotinib by 82% and 69%, respectively, compared with the latter in monotherapy. However, the severity of the influence of inducers of isoenzyme CYP3A on the values of the exposure of the cryotinib in the equilibrium state is not determined.

Medicines, whose concentrations in the blood plasma can change when combined with cryotinib

Caution should be exercised when using cryotinib in combination with drugs, especially the isotropic isoenzyme CYP3A, it may be necessary to reduce the dose of these drugs. Combination of cryotinib with isozofermite substrates should be avoided CYP3A, characterized by a narrow therapeutic range (such as, alfentanil, ciclosporin, fentanyl, chiidine, sirolimus, tacrolimus), as well as with drugs, the use of which can be associated with the development of bile threatening arrhythmias (pimozide, dihydroergotamine ergotamine, and astemizole. tsizapprdom and terfenadip).

After taking krizotinib 250 mg twice a day with patients with malignant neoplasms for 28 days, AUC midazolam (with his oral intake) was 3.65 times (90% CI: 2.63-5.07) higher than that of monazole medication with midazolam.

Combination of krizotinib with drugs that increase and pH of gastric juice.
The solubility of cryotinib in water depends on pH: at low (acidic) pH values, its solubility increases. One-time administration of 250 mg krizotniba after administration of 40 mg ompsprazole once a day for 5 days leads to a decrease in total AUCinf crizotinib by about 10% and the absence of a change in C_max cryotinib in the blood plasma; the degree of increase in exposure is clinically insignificant. Thus, correction of the initial dose of krizotnib with simultaneous application 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.

Combination with substrates of conveyors.

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

In vitro Krizotinib is an inhibitor of transport proteins of OSB and OST2. Concerning cryotinib potentially can increase the concentration in the blood plasma of drugs that are substrates of these proteins.

In studies in vitro Cryotinib in therapeutic concentrations did not inhibit transport proteins of the liver OATP1B1 or OATP1B3. Therefore, clinically significant drug interaction as a result of cryotinib mediated inhibition of hepatic or renal capture of drugs that are substrates of these transports is unlikely.

In vitro in clinically significant concentrations cryotinib is not an inhibitor of the transport proteins of bile salts.

Special instructions:

There are reports of the development of a drug-induced gene i toxicity with fatal outcome in patients taking cryotinib. According to clinical studies, the incidence of this complication is less than 0.5%. The following symptoms are typical: weakness, fatigue, anorexia, nausea, vomiting, abdominal pain, jaundice, darkening of urine, generalized pruritus, hemorrhagic diathesis, especially in combination with fever and rash).

Against the background of cryotinib therapy, there were cases of development of severe, life-threatening or fatal IZL or pepmonitis. This condition developed in general within 3 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. If there are violations that may indicate the development of IZL or pepmonitis, it is necessary to perform a survey of patients in order to exclude alternative causes of this condition. After the diagnosis of IZL or pepmonitis, associated with ongoing therapy, cryotinib should be canceled.

With the appearance or aggravation of visual impairment, including diplopia, photopsy, reduced vision clarity, floating vitality, it is necessary to assess the need for an ophthalmological examination. These disorders usually appear during the first two weeks of taking the drug. 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. The cases of the necessity of temporary or complete withdrawal of krizotinib or a reduction in its dose due to the development of visual impairment were recorded.

The most frequent adverse reactions from the digestive system are nausea, diarrhea, vomiting and constipation. Nausea and vomiting develop on average within 2-3 days. Most of the reactions were mild or moderate in severity, and their frequency decreased after 3-4 weeks of therapy. With the development of side effects from the digestive system, standard maintenance therapy with antiemetic, anti-diarrhea and / or laxatives can be performed.

On the background of cryotinib therapy, monitoring of the values of functional liver samples, including ALT activity, ACT and the concentration of total bilirubin. Control should be carried out every two weeks during the first 2 months of therapy, then at intervals of at least once a month or more, if there are appropriate clinical indications, to increase these levels to level 2, 3 or 4 degrees of toxicity according to the classification of STAAE. The dose should be adjusted according to the recommendations in the section "Method of administration and dose".

During therapy with cryotinib, monitoring of the clinical blood test (e by counting the leukocyte formula) should be performed, the frequency of which should be increased when the deviations from the norm are graded 3 or 4 according to the classification of STAAE, increased body temperature or infection. Monitoring should be carried out according to clinical indications. The dose should be adjusted according to the recommendations in the section "Method of administration and dose".

When using cryotinin in patients who have a history of episodes of lengthening the interval QTc, predisposed to this condition or receiving medicines that extend the interval QT, should consider the issue of periodic monitoring of ECG and electrolyte concentration in the blood. The dose should be adjusted according to the recommendations in the section "Method of administration and dose".

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

There are reports of cases of bradycardia noted during clinical trials. Usually in these cases the bradycardia proceeds asymptomatically. The total effect of krizotinbn on the heart rate may not manifest itself within a few weeks after the start of therapy. In connection with the possible risk of developing clinical manifestations of bradycardia (fainting, dizziness,reduction in blood pressure), whenever possible, avoid concomitant use of cryotinin and other drugs that reduce the heart rate (for example, beta-blockers, non-dihydropyridine blockers of "slow" calcium channels, such as verapamil and diltiazem, clonidine, digoxain). It is recommended to monitor the heart rate and blood pressure monthly. In the case of asymptomatic bradycardia, dose adjustment it takes. When developing bradycardia, accompanied by with appropriate symptoms, it is necessary to suspend therapy with crizotinib and evaluate the correctness of prescribing concomitant therapy (see the section "Dosing and Administration" and "Side-effects").

Against the background of taking krizotinib, there have been cases of development of cystic kidney damage. These patients did not have clinically significant abnormalities in urinalysis or renal dysfunction, however, some patients reported spreading the cyst beyond the renal capsule. With the development of cystic kidney disease, monitoring is recommended, including laboratory and functional examination methods.

Effect on the ability to drive transp. cf. and fur:Studies of the influence of Xalcorie® on the ability to drive and work with machinery have not been carried out. However, against the background of taking krizotinib it is possible to develop side effects such as visual impairment, dizziness or fatigue, and therefore patients should develop potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions (driving, working with moving mechanisms etc.)

Form release / dosage:

Capsules 200 mg and 250 mg

For 10 capsules in a PVC / aluminum blister.

For 1 or 6 blisters together with instructions for use in a cardboard bundle.

Packaging:

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001917

Date of registration:29.11.2012

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

PFIZER MANUFACTURING DEUTSCHLAND, GmbH Germany

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp10.03.2014

Illustrated instructions

Instructions

Xalcorie® (Xalkori®)