Composition, form of production and packaging
Hard gelatin capsules, size 1, with a pink lid and white body, with a black inscription "Pfizer" - on the lid and "CRZ200" on the casing; the contents of the capsules are a white or slightly yellowish powder.
1 caps.
cryotinib 200 mg
Excipients: silicon dioxide colloid - 2 mg, microcrystalline cellulose - 83 mg, calcium phosphate - 83 mg, sodium carboxymethyl starch - 20 mg, magnesium stearate - 12 mg.
The composition of the gelatin capsule body: gelatin - 44.27 mg, titanium dioxide - 1.33 mg.
Composition of the cap of the gelatin capsule: gelatin - 29.55 mg, titanium dioxide - 0.6 mg, iron oxide red (E172) - 0.25 mg.
Ink composition: shellac - 24-27%, ethanol - 23-26%, isopropanol - 1-3%, butanol 1-3%, propylene glycol - 3-7%, ferrous oxide black oxide (E172) - 24-28%, ammonia solution concentrated - 1-2%, potassium hydroxide - 0.05-0.1%, purified water - 15-18%.
10 pieces. - PVC blisters / Aluminum (1) - packs of cardboard.
10 pieces. - PVC blisters / Aluminum (6) - cardboard packs.
Hard gelatin capsules, size No. 0, with a lid and a pink body, with a black inscription "Pfizer" - on the lid and "CRZ250" on the body; the contents of the capsules are a white or slightly yellowish powder.
1 caps.
cryotinib 250 mg
Excipients: silicon dioxide colloid - 2.5 mg, cellulose microcrystalline - 103.75 mg, calcium phosphate - 103.75 mg, sodium carboxymethyl starch - 25 mg, magnesium stearate - 15 mg.
The composition of the gelatin capsule body: gelatin - 55.99 mg, titanium dioxide - 1.14 mg, iron oxide red (E172) - 0.47 mg.
The composition of the cap of the gelatin capsule: gelatin - 37.33 mg, titanium dioxide - 0.76 mg, iron oxide red oxide (E172) - 0.31 mg.
Ink composition: shellac - 24-27%, ethanol - 23-26%, isopropanol - 1-3%, butanol 1-3%, propylene glycol - 3-7%, ferrous oxide black oxide (E172) - 24-28%, ammonia solution concentrated - 1-2%, potassium hydroxide - 0.05-0.1%, purified water - 15-18%.
10 pieces. - PVC blisters / Aluminum (1) - packs of cardboard.
10 pieces. - PVC blisters / Aluminum (6) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antitumor drug. Cryotinib is a selective low molecular weight inhibitor of tyrosine kinase receptors (RTK), incl. kinase anaplastic lymphoma (ALK) and its oncogenic variants (ie products of ALK fusion 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.
PHARMACOKINETICS
Suction and distribution
After a single oral intake of cryotinib, fasting time for reaching the maximum plasma concentration (TC max ) is 4 to 6 hours. Against the background of taking 250 mg cryotinib 250 mg 2 times / day, the equilibrium concentration of cryotinib is reached within 15 days and remains unchanged, while the average coefficient of accumulation is 4.8. System exposure parameters (maximum plasma concentration (C max ) and area under the concentration-time curve (AUC)) increase in the dose range 200 mg-300 mg 2 times / day to a greater extent with respect to the accepted dose.
When taking krizotinib 2 times / 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, high-fat food intake reduces the AUC inf and C max values ​​by approximately 14%. Thus, krizotinib can be taken regardless of the meal.
The binding of cryotinib with plasma proteins in vitro is 91%, regardless of the concentration. Results of in vitro studies suggest that cryotinib is the substrate of P-glycoprotein. The ratio of the concentration in the plasma or blood is approximately 1.
Metabolism and excretion
In vitro studies It was shown that the metabolic clearance of cryotinib is mainly carried out by CYP3A4 / 5 isoenzymes. The main ways of metabolism in humans are the oxidation of the piperidine ring to the lactam of cryotinib and O-dealkylation followed by the conjugation of O-dealkylated metabolites of the 2-phase.
With a single administration of cryotinib, the terminal T 1/2 from the blood plasma was 42 hours.
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 average apparent clearance of cryotinib at equilibrium concentration was lower (60 l / h) after application of cryotinib 250 mg twice daily than after application at a dose of 250 mg 1 time / day (100 l / h). Most likely, this is due to increased inhibition of the CYP3A isoenzyme after several doses.
Pharmacokinetics in specific patient groups
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 (CK) from 60 ml / min to 90 ml / min) and moderate severity (QC from 30 ml / min to 60 ml / min), t .to. the equilibrium concentrations in these cases practically do not differ from the equilibrium concentration of cryotinib in patients with normal renal function. In addition, it was found that QA in no way affects the pharmacokinetics of cryotinib.
After a single application of 250 mg cryotinib in patients with severe renal insufficiency (QC <30 ml / min), the condition of which does not require peritoneal dialysis or hemodialysis, AUC and C max cryotinib 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 liver function has not been studied. Clinical studies excluded patients who reported an increase in activity of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) by more than 2.5 times with respect to IGN (more than 5 times that of IGN due to malignant neoplasm) or an increase in the total bilirubin concentration by more than 1.5 times with respect to VGN. Based on the population pharmacokinetic analysis, it was found that the basal concentration of total bilirubin or ACT activity does not affect the pharmacokinetics of cryotinib. Because Krizotinib 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 does not change with age.
Body weight and sex
The sex and body weight of the patient do not affect the pharmacokinetics of cryotinib.
Ethnicity
It was found that the estimated equilibrium AUC in Asian residents is 23-37% higher than in representatives of other ethnic groups.
Use in children
Safety and efficacy of cryotinib in children have not been established.
Effect on heart function
In all patients who received cryotinib 250 mg twice daily, the signs of prolongation of the QT interval were evaluated. 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 QT cinterval. In addition, it was found that a decrease in heart rate is associated with an increase in the concentration of cryotinib in the blood plasma.
INDICATIONS
- advanced non-small cell lung cancer (NSCLC) expressing anaplastic lymphoma kinase (ALK).
DOSING MODE
Xalcorie В® is used inside, regardless of food intake. Capsules should be swallowed whole.
Before using Xalcory В® in patients with NSCLC, an evaluation of ALK tumor expression is necessary, as it has been shown that treatment response is only achieved 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 2 times / day.
Treatment with the drug is carried out for a long time, as long as there is a positive effect of therapy.
If you miss the dose of krizotinib, it should be taken immediately, as soon as the patient has thought of it (if there is 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 individual tolerability and safety, a temporary withdrawal of the drug and / or a reduction in the dose of cryotinib may be required. If it is necessary to reduce the dose, it should be reduced to 200 mg 2 times / day. If it is necessary to further reduce the dose, it is reduced to 250 mg 1 time / 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 severity STAAE b Dosage regimen of cryotinib
Degree 3 Temporarily discontinue the drug until symptoms resolve to grade 2, then resume therapy in the initial dosing regimen.
Degree 4 Temporarily discontinue the drug until symptomatology is resolved to grade 2, then resume therapy at a dose of 200 mg twice daily.
and with the exception of lymphopenia (in case there is no connection with clinical manifestations, for example, opportunistic infections).
b criteria for assessing the severity of the most common adverse events of the National Cancer Institute (NCI).
in the development of a relapse of an undesirable phenomenon, the drug should be temporarily discontinued until the symptomatology is resolved to level 2, then resume therapy with a dose of 250 mg once a day. Recurrent adverse events of 4 severity require complete reversal of therapy.
Table 2. Correction of the dose of krizotinib with the development of non-hematologic toxicity.
Degree of severity of STAAE a Dosage regimen of cryotinib
Increase ALT or ACT activity to grade 3 or 4, associated with an increase in the total bilirubin concentration to? 1 degree. Temporarily discontinue the drug until symptoms resolve to grade 1 or baseline, then resume therapy at a dose of 200 mg 2 times / day b .
Increase ALT or ACT activity to grade 2, 3 or 4, with concomitant increase in total bilirubin concentration to grade 2, 3 or 4 (in the absence of cholestasis or hemolysis) Complete withdrawal of the drug.
Interstitial lung disease (PUL) / pneumonitis of any severity in complete withdrawal of the drug.
Elongation of the interval QT c 3 degrees Temporarily abolish the drug until the symptomatology is resolved to a level of? 1 degree, then resume therapy at a dose of 200 mg, 2 times / day b .
Elongation of the QT interval from grade 4 Complete withdrawal of the drug.
Bradycardia 2, 3 degrees g (accompanying symptoms requiring medical intervention) Temporarily discontinue the drug until symptoms resolve to grade 1 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 resolving the symptoms to grade 1 or increasing the heart rate to 60 beats / min or more, resuscitate the therapy with crizotinib at the starting dose. If the concomitant medication that affects the heart rate has not been identified or has not been canceled or the dose is not corrected, then after treatment of symptomatology to grade 1 or increase in heart rate to 60 beats / min or more, treatment with crizotinib at a lower dose should be resumed.
Bradycardia 4 degrees g, d (life-threatening consequences, immediate medical intervention is required) The reception of crizotinib should be completely abolished unless another medication that affects the heart rate has been identified. In case the patient receives another medication that can affect the heart rate and he either was canceled or his dose was corrected, then after the symptomatology had been resolved to the level of 1 degree or the heart rate increased to 60 beats / min or more, the therapy should be resumed in a dose 250 mg once a day.
and criteria for assessing the severity of the most frequent adverse events of the National Cancer Institute (NCI).
b with the development of a relapse of an undesirable phenomenon, the drug should be temporarily discontinued until the symptomatology is resolved to level 1, then resume therapy with a dose of 250 mg 1 time / day. Recurrent adverse events of 3 or more severity require complete reversal of therapy.
in unrelated to the progression of NSCLC, other lung diseases, infections or previous radiation therapy.
g 2 degree - accompanying symptoms appear, medical intervention is necessary; 3 degree - severe, medical intervention is necessary; 4 degree - life-threatening, urgent medical intervention is necessary.
d permanent withdrawal of the drug for recovery.
Impaired liver function
The use of crizotinib has not been studied in patients with an increase in AST or ALT activity more than 2.5 times with respect to IGN (more than 5 times with respect to 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. Cryotinib in patients with impaired liver function should be used 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 failure (CK <30 ml / min), the concentration of cryotinib in the blood plasma may increase. In patients with severe renal failure, the condition of which does not require peritoneal dialysis or hemodialysis, the dose of XalcoryВ® preparation should be adjusted 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 2 times / day (see section "Pharmacological properties"). The use of cryotinib in patients with terminal renal failure was not investigated.
Elderly patients
Older patients do not need an initial dose adjustment.
SIDE EFFECT
The most severe adverse reactions were hepatotoxicity, CLD or pneumonitis and QT interval elongation.
The most frequent adverse reactions (recorded in ≥25% of patients) were nausea, visual impairment, vomiting, diarrhea, constipation, swelling, increased transaminase activity, decreased appetite, fatigue, dizziness and neuropathy.
The frequency of unwanted reactions is represented by the following classification:
Very often? 10%
Often? 1% and <10%
Not infrequently, 0.1% and <1%
Rarely 0.01% and <0.1%
Very rarely <0.01%
From the cardiovascular system: very often - bradycardia (including sinus); often - a decrease in heart rate, prolongation of the QT interval on an electrocardiogram, fainting.
From the sense organs: very often - visual impairment (diplopia, photopsy, decreased vision, floating opacities, 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).
On the part of the digestive system: very often - nausea, diarrhea, vomiting, constipation, disorders of the esophagus (gastroesophageal reflux disease, dysphagia, swallowing pain, esophagus pain, esophageal spasm, esophagus ulcers, esophagitis, reflux esophagitis), pain in the abdomen, stomatitis (glossodinia, glossitis, cheilitis, inflammation and ulcers of the oral mucosa, oropharyngeal pain); often - indigestion; infrequently - hepatic insufficiency, perforation of the gastrointestinal tract.
Laboratory indicators: very often - an increase in the activity of hepatic transaminases * (ALT, AST, gammaglutamyltransferase), a violation of liver function; often - increased alkaline phosphatase activity.
On the part of the organs of hematopoiesis: very often - neutropenia (febrile neutropenia, a decrease in the number of neutrophils), leukopenia, a decrease in the concentration of white blood cells; often - lymphopenia, anemia, decreased hemoglobin; rarely - thrombocytopenia.
From a metabolism: often - loss of appetite; often - hypophosphatemia.
From the nervous system: very often - neuropathy (burning sensation, neuralgia, peripheral neuropathy (including motor, sensory neuropathy and motosensornaya neuropathy), neurotoxicity, dysesthesia, creeping sensation in the body, gait disturbance, hypotension, optic neuritis, paresthesia , hypoesthesia, hyperesthesia, sensory disturbances, motor disorder, paralysis of the peroneal nerve, polyneuropathy), dizziness, balance disorders, postural dizziness, lightheadedness, dysgeusia, headache, and insomnia.
The respiratory system:often - ILD (acute respiratory distress syndrome, pneumonitis, alveolitis), upper respiratory tract infection (nasopharyngitis, rhinitis, pharyngitis), breathlessness, cough.
For the skin: very often - a rash.
From the urinary system: often - multiple cysts of the kidneys, bleeding from the renal cysts, renal cysts infection, kidney abscess.
On the part of the musculoskeletal system: very often - joint pain, back pain, musculoskeletal chest pain, muscle weakness, muscle atrophy.
Other: often - edema (peripheral edema, facial edema, generalized edema, local edema, periorbital edema), fatigue, asthenia, chest pain, discomfort in the chest, fever.
* Increase of transaminases usually observed during the first two months of therapy. Episodes of increased activity of transaminases, in most cases were asymptomatic and were stopped after a temporary discontinuation of therapy. Upon resumption of the drug, typically in a lower dose, recurrent changes are recorded.
CONTRAINDICATIONS
- abnormal liver function - improving activity ACT ALT or more than 2.5 times the ULN (greater than 5 times the CAH due to malignancy) or increased concentration of total bilirubin more than 1.5 times the ULN;
- impaired renal function, severe or patients undergoing hemodialysis;
- simultaneous application of potent inducers or inhibitors isoenzyme CYP3A, as well as substrates isoenzyme CYP3A, characterized by a narrow therapeutic range (see "Interaction with other drugs.");
- Pregnancy;
- the period of breastfeeding;
- child and adolescence to 18 years (not enough data on the safety and effectiveness);
- hypersensitivity to krizotinibu or any auxiliary substance included in the preparation.
Carefully
Preparation Ksalkori В® should be used with caution in patients with a history of episodes lengthening QT interval c , predisposed to the condition (patients with congestive heart failure, bradycardia, disorders of electrolyte balance) or receiving drugs that prolong the interval QT (see. The section " Cautions "), as well as with abnormal liver function. Caution must be exercised when applying Ksalkori preparation В® in combination with drugs predominantly metabolized isoenzyme CYP3A (see. The section "Interaction with other drugs").
PREGNANCY AND LACTATION
There are no adequate and well-controlled studies of the use of krizotiniba during pregnancy was conducted. Krizotinib can cause fetal loss when used during pregnancy.
Women of childbearing age should be warned about the undesirability of pregnancy during therapy krizotinibom. To this end, during the period of therapy and at least for 90 days after the completion of women of childbearing age or their partners taking Ksalkori В® , you have to use an adequate method of contraception.
In applying the drug Ksalkori В®during pregnancy or if pregnancy occurs during treatment with this drug the patient or her sexual partner, they should be informed about the potential risk of adverse effects of the drug on the fetus.
It is unknown whether krizotinib excreted in breast milk. During the period of breast-feeding should either cancel krizotinib or stop breast-feeding, depending on the extent of the need for the mother of the drug.
According to the results of pre-clinical studies suggest that krizotinib can affect fertility in males and females.
APPLICATION FOR FUNCTIONS OF THE LIVER
Not required dose adjustment for patients with mild renal failure (creatinine clearance of 60-90 ml / min) and average (CC 30-60 ml / min) severity.
In patients with severe renal failure (creatinine clearance <30 mL / min) krizotiniba concentration in plasma may increase. In patients with severe renal failure condition which does not require a peritoneal dialysis or hemodialysis, should be adjusted medication dose Ksalkori В® 250 mg 1 time / day. After taking the drug for at least four weeks, the dose can be increased with the individual tolerance and safety of 200 mg of 2 times / day (see. The section "Pharmacological properties"). Application krizotiniba in patients with end-stage renal failure has not been studied.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Application krizotiniba not been studied in patients with an increase in the activity of AST or ALT more than 2.5 times the ULN (greater than 5 times the CAH due to malignancy) or with increasing concentrations of total bilirubin more than 1.5 times the ULN. Krizotinib in patients with impaired hepatic function should be used with caution.
APPLICATION FOR CHILDREN
Contraindicated appointment at the age of 18 years of the drug for children and adolescents (insufficient data on safety and efficacy).
APPLICATION IN ELDERLY PATIENTS
Elderly patients do not require an initial dose adjustment.
SPECIAL INSTRUCTIONS
There are reports of the development of drug-induced hepatotoxicity with fatal outcome in patients receiving krizotinib. According to clinical studies of the frequency of complications is less than 0.5%. Characterized by the following symptoms: weakness, fatigue, anorexia, nausea, vomiting, abdominal pain, jaundice, dark urine, generalized itching, bleeding diathesis, especially in combination with fever and rash).
Against the background of krizotinibom therapy there have been cases of severe, life-threatening or fatal ILD or pneumonitis. This state is developed generally within 3 months after initiation of therapy. There should be a constant monitoring of patients for the development of clinical manifestations in the lungs. When the violations, which may indicate the development of ILD or pneumonitis, performance of surveys of patients to exclude alternative causes of this condition. After setting ILD or pneumonitis diagnosis related to study medication, krizotinib should be abolished.
When exacerbating or impairment, including diplopia, photopsias, reduced visual acuity, vitreous floaters should assess the need to perform ophthalmologic examination. These disorders usually occur within the first 2 weeks of treatment. It should be borne in mind that the development of floating vitreous opacities and / or photopsias severe or worsening of these disorders can be a sign of retinal tear or retinal detachment threat. Where necessary, provisional or complete abolition krizotiniba or reduce doses because of the development of violations were recorded view.
The most common adverse reactions of the digestive system are nausea, diarrhea, vomiting and constipation. Nausea and vomiting on average develop over 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 of the digestive system may be carried out by standard supportive antiemetic therapy, antidiarrheal and / or laxatives.
The therapy requires krizotinibom monitoring liver function tests values, including ALT activity, AST and bilirubin concentration. Monitoring should be performed every 2 weeks during the first 2 months of therapy, thereafter at intervals not less than 1 time per month or more frequently in the presence of appropriate clinical indications for these indicators to improve the level of 2, 3 or 4 according to the classification CTCAE toxicities. The dosage should be adjusted accordingly recommendations under "Dosing and dose."
During therapy should be monitored krizotinibom CBC (with leukocyte counting) whose frequency must be increased in the development of abnormalities 3 or 4 on CTCAE classification, fever or infection. Monitoring should be performed as clinically indicated. The dosage should be adjusted accordingly recommendations under "Dosing and dose."
In applying krizotiniba in patients with a history of episodes of the interval lengthening QT cPredisposed to the condition or receiving medicinal products that prolong the QT interval, it should consider holding periodic performance monitoring ECG and electrolyte concentration in the blood. The dosage should be adjusted accordingly recommendations under "Dosing and dose."
It is recommended to avoid the use of krizotiniba in patients with congenital prolongation of the QT interval syndrome.
There are reports of bradycardia observed during clinical trials. Usually in these cases are asymptomatic bradycardia. Krizotiniba full effect on heart rate may not be apparent for several weeks after initiation of therapy. In connection with the possible risk of developing clinical manifestations of bradycardia (syncope, dizziness, decreased blood pressure) should be possible to avoid the simultaneous application krizotiniba and other drugs which reduce heart rate (e.g., beta-blockers, nedigidropiridinovyh blockers, slow calcium channel blockers, such as verapamil and diltiazem, clonidine, digoxin). Recommended monthly to monitor heart rate and blood pressure. In the case of asymptomatic bradycardia correction dose is not required. If bradycardia development accompanied by the relevant symptomsshould suspend therapy krizotinibom and assess correct destination concomitant therapy (see. the section "Dosage and administration" and "Side effect").
While taking krizotiniba cases of cystic renal lesions were observed. In these patients, no clinically significant abnormalities in the urinalysis or renal dysfunction, however, some patients had cysts spread beyond the kidney capsule. With the development of cystic kidney lesions recommended monitoring, including laboratory and functional examination methods.
Impact on the ability to drive vehicles and manage mechanisms
Studies of the effect of the drug Ksalkori В® on ability to drive and operate machinery have not been conducted. However, in patients receiving krizotiniba may develop side effects such as blurred vision, dizziness and fatigue, therefore the patients in the event described adverse events should refrain from performing potentially hazardous activities that require high concentration and speed of psychomotor reactions (driving, work with moving machinery, etc.).
OVERDOSE
In the case of an overdose should be the standard supportive care. Krizotiniba specific antidote is not known.
DRUG INTERACTION
In in vitro studies in human hepatocytes have shown that clinically significant drug interactions result in inhibition krizotinibom mediated metabolism of other drugs that are substrates of isozymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6, unlikely.
In vitro krizotinib is an inhibitor of isozyme CYP2B6, however it could potentially increase the plasma concentrations of drugs metabolized mainly isoenzyme CYP2B6.
In in vitro studies on human liver microsomes, it was shown that krizotinib inhibits the activity of CYP3A isozymes CYP2B6 and in degree dependent on the time.
Krizotinib a substrate isoenzyme CYP3A4 / 5 and a moderate inhibitor of isoenzyme CYP3A. The in vitro and in vivo studies have shown that an inhibitor krizotinib isoenzyme CYP3A.
Concomitant use with drugs that are substrates of uridine-5-diphosphate-glucuronosyltransferase (UDFGT)
Studies in vitro show that the interaction between the drugs, due krizotinib-mediated inhibition of metabolism UDFGT substrates improbable.
Drugs that can increase the concentration in the blood plasma krizotiniba
Combining krizotiniba with potent inhibitors of CYP3A isoenzyme may lead to an increase in its concentration in plasma. It should therefore be avoided krizotiniba combination with potent inhibitors isoenzyme CYP3A, including atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole and troleandomycin.
Combined krizotiniba single oral dose of 150 mg and ketoconazole at a dose of 200 mg of 2 times / day leads to an increase in systemic exposure krizotiniba. The values of AUC inf and C maxincreased approximately 3.2 and 1.4 times, respectively, compared with the reception krizotiniba in monotherapy. However, the severity of impact isoenzyme CYP3A inhibitors krizotiniba exposure value in the equilibrium state is not defined.
Grapefruit and grapefruit juice may also increase krizotiniba concentration in the blood plasma, so you should avoid its use during therapy with this drug. Caution must be exercised while the use krizotiniba isoenzyme inhibitors with moderate CYP3A.
The medicaments capable of lowering the concentration of plasma krizotiniba
Combining krizotiniba with potent CYP3A isoenzyme inducers may reduce its blood plasma concentration. Therefore, to avoid the simultaneous application krizotiniba with potent inducers isoenzyme CYP3A, including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John's wort preparations.
Krizotiniba single application of 250 mg simultaneously with rifampicin (600 mg 1 time / day) resulted in a decrease in AUC values inf and C max krizotiniba 82% and 69%, respectively, compared with the reception of the latter in monotherapy. However, the severity of impact on CYP3A isoenzyme inducers krizotiniba exposure values not defined in an equilibrium state.
Drugs whose concentrations in plasma cr
