Nilotinib-native (Nilotinib-native)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceNilotinibNilotinib
Similar drugsTo uncover
  • Nilotinib-native
    capsules inwards 
    NATIVA, LLC     Russia
  • Tacsin®
    capsules inwards 
    Novartis Pharma AG     Switzerland
  • Tacsin®
    capsules inwards 
    Novartis Pharma AG     Switzerland
    • Dosage form: & nbspcapsules
    Composition:

    Composition per 1 capsule:

    Ingredient name

    Contents in 1 capsule


    150 mg

    200 mg

    Active substance:

    Nilotinib hydrochloride monohydrate

    165.45 mg

    220.60 mg

    In terms of nilotinib basis

    150.00 mg

    200.00 mg

    Excipients:

    Mannitol

    117.05 mg

    156.00 mg

    Crospovidone

    12.00 mg

    16.00 mg

    Poloxamer

    2.50 mg

    3.40 mg

    Silica colloidal dioxide

    1.50 mg

    2.00 mg

    Magnesium stearate

    1.50 mg

    2.00 mg

    Capsules gelatinous:

    Composition of the capsule body (content of ingredients in% per capsule)

    Titanium dioxide

    2,0 %

    2,0 %

    Gelatin

    up to 100%

    up to 100%

    Composition of cap capsule (content of ingredients in% per capsule)

    Indigocarmine

    0,13 %

    -

    Titanium dioxide

    1,0%

    2,0 %

    Gelatin

    up to 100%

    up to 100 %
    Description:

    Dosage of 150 mg: Hard gelatin capsules number 1. The case is white, the lid is blue.

    Dosage of 200 mg: Hard gelatin capsules number 0. The body is white, the lid is white.
    The contents of the capsules are white or white with a yellowish tinge powder.
    Pharmacotherapeutic group:Antitumor agent, protein tyrosine kinase inhibitor
    ATX: & nbsp

    L.01.X.E   Protein kinase inhibitors

    L.01.X.E.08   Nilotinib

    Pharmacodynamics:

    Nilotinib effectively inhibits tyrosine kinase activity BCR-ABL oncoprotein of cell lines and primarily positive for the Philadelphia chromosome (Ph+) leukemic cells.

    Nilotinib has a high affinity for binding sites with ATP and, thus, has a pronounced inhibitory effect on BCR-ABL wild-type oncoprotein, and also shows activity against 32 and 33 main imatinib-resistant mutant forms BCR-ABL-tyrosine kinase, with the exception of the T3151 mutation. Nilotinib selectively inhibits proliferation and induces apoptosis of cell lines and Ph+ leukemia cells in patients with chronic myelogenous leukemia (CML). Nilotinib does not or has little effect on other known protein kinases (including family kinase Src), except for kinases that have receptors for platelet growth factors (PDGRF), KIT-, CSF-1R, DDRreceptors and efrino receptors. Inhibition of protein kinases of this type occurs at drug concentrations within the range of therapeutic doses recommended for the treatment of CML for oral administration.

    There is evidence that against the background of nilotinib therapy at a dose of 400 mg twice a day in adult patients with Ph+ CML in the chronic phase with intolerance or ineffectiveness of previous therapy, including imatinib, the frequency of achieving a large cytogenetic response was 59%, and this response was achieved fairly quickly (during the first three months of therapy) (median - 2.8 months) and persisted against the background of continued use of the drug (within 24 months) in 77% of patients. The overall survival after 24 months of therapy was 87 %.

    When nilotinib is used at a dose of 400 mg twice a day in adult patients with Ph+ CML in the accelerated phase with intolerance or resistance to prior therapy, including imatinib, the frequency of achieving a complete hematologic response was 55%, and this response was achieved rather quickly (during the first month of therapy) (median - 1 month) and persisted against the background of continuing reception of nilotinib (within 24 months) in 49 % patients. The rate of achievement of a large cytogenetic response was 32%, and this response was preserved in 66% of patients with continued use of nilotinib (within 24 months).

    Pharmacokinetics:

    Suction

    The mean time to reach the maximum concentration of nilotinib in the blood plasma (tmax) is about 3 hours. Absorption of nilotinib after oral administration is about 30%.Absolute bioavailability of nilotinib is not defined. Compared to the solution for oral administration (pH 1.2 to 1.3), the relative bioavailability of the nilotinib capsules is about 50%.

    With the simultaneous administration of nilotinib with food, the maximum concentration (CmOh) and the area under the curve "concentration-time" (AUC) Nilotinib increased by 112% and 82%, respectively, compared with fasting nilotinib. The use of nilotinib 30 minutes or 2 hours after ingestion increases the bioavailability of nilotinib by 29% and 15%, respectively. In patients undergoing total or partial gastrectomy, the absorption of nilotinib (relative bioavailability) decreases by approximately 48% and 22%, respectively.

    A single application of 400 mg of nilotinib in the form of an apple sauce dissolved in a teaspoon of the contents of two 200 mg capsules is bioequivalent to the use of 2 intact 200 mg capsules.

    Distribution

    The ratio of concentrations of nilotinib in the blood and blood plasma is 0.71. Connection with plasma proteins in vitro is about 98%.

    In the equilibrium state, the systemic exposure of nilotinib is dose-dependent. However, when the drug is used at a dose exceeding 400 mg once a day, an increase in the exposure of nilotinib, depending on the increase in the dose of the drug, is less pronounced.The daily plasma concentration of nilotinib in the equilibrium state was 35% higher when administered at a dose of 400 mg 2 times a day than when applied at a dose of 800 mg 1 time per day. AUC nilotinib at a dose of 400 mg twice a day is approximately 13.4% higher than when administered nilotinib 300 mg twice daily. When taking nilotinib for 12 months at a dose of 400 mg twice a day, the minimum and maximum concentrations of nilotinib are 15.7% and 14.8% higher than those for application of nilotinib in a dose of 300 mg 2 times a day, respectively. There was no significant increase in the equilibrium concentration of nilotinib with an increase in the dose from 400 mg twice a day to 600 mg twice a day.

    Plasma exposure of nilotinib in the period between the application of the first dose and the attainment of an equilibrium concentration increases approximately 2-fold with the administration of the drug once a day and 3.8 times with the administration twice a day. The equilibrium concentration is reached by the eighth day.

    Metabolism

    The main ways of metabolism of nilotinib are oxidation and hydroxylation. In the blood plasma nilotinib circulates basically unchanged. All metabolites of nilotinib have little pharmacological activity.

    Excretion

    After a single application of nilotinib in healthy volunteers, more than 90% of the dose is excreted within 7 days mainly with feces. In unchanged form, 69% of nilotinib is excreted. The half-life (T1/2) with repeated application of a daily dose is approximately 17 hours.

    Pharmacokinetics in selected patient groups

    Patients with hepatic impairment

    When nilotinib is used in patients with impaired hepatic function, there is no significant change in the pharmacokinetic parameters of nilotinib. With a single administration of nilotinib, a decrease AUC nilotinib by 35%, 35% and 19% in patients with impaired liver function of mild, moderate and severe, respectively (compared with patients without violations of the liver function). FROMmOh Nilotinib in the equilibrium state is increased by 29%, 18% and 22%, respectively. Individual differences in pharmacokinetics among patients were moderate to severe.

    Indications:

    - The newly identified positive for the Philadelphia chromosome (Ph+) chronic myeloid leukemia in the chronic phase in adults.

    - Ph+ CML in the chronic phase and the phase of acceleration in adult patients with intolerance or resistance to prior therapy, including imatinib.

    Contraindications:

    - Hypersensitivity to the active substance or any other component of the drug.

    - Pregnancy and the period of breastfeeding.

    - Age under 18 years (no application data available).

    Carefully:

    Nilotinib should be used with caution in patients with risk factors for lengthening the interval QT on an electrocardiogram (ECG): with congenital lengthening of the interval QT, with medically uncontrolled or severe heart disease (including recent myocardial infarction, chronic heart failure, unstable angina, or clinically significant bradycardia); with impaired liver function; with pancreatitis (including in the anamnesis).

    It should be used with caution nilotinib in patients who are chronic carriers of the hepatitis B virus (it is possible to reactivate the hepatitis B virus after using a tyrosine kinase inhibitor BCR-ABL, such as nilotinib).

    Nilotinib should not be used concurrently with drugs that are potent inhibitors of the isoenzyme CYP3A4 or extending the interval QT, especially patients with hypokalemia and hypomagnesemia (perhaps more pronounced lengthening of the interval QT).

    It should avoid the simultaneous use of nilotinib with grapefruit juice and other products that are known inhibitors of the isoenzyme CYP3A4.
    Pregnancy and lactation:

    The use of nilotinib during pregnancy and during breastfeeding is contraindicated.

    During therapy with nilotinib and at least two weeks after completion of therapy, reliable methods of contraception should be used for patients, especially women of childbearing age.

    Dosing and Administration:

    Nilotinib-native should be taken 2 times a day (every 12 hours), 2 hours after eating. After using the drug Nilotinib-native Take food should not be earlier than 1 hour later. Capsules must be swallowed whole, washed down with water.

    For patients with difficulty swallowing, it is possible to dissolve the contents of the capsules in one teaspoon of apple puree immediately before taking. To dissolve the contents of capsules, use only apple puree! The contents of capsules should not be dissolved in more than one teaspoon of apple puree!

    In case of missing the next dose, do not take additional medication, it is necessary to take the next prescribed dose of the drug Nilotinib-native.

    Before starting, 7 days after the beginning and during the treatment with the drug, it is recommended to conduct an ECG study.

    Before applying the drug, if necessary, should be corrected hypomagnesemia and hypokalemia. During the treatment it is recommended to monitor the potassium and magnesium content in the blood serum, especially in patients at risk of developing metabolic disorders.

    Against the background of taking the drug Nilotinib-native there was an increase in the concentration of total cholesterol in the blood serum. It is recommended to determine the lipid profile before the start of therapy with the drug Nilotinib-native, and also 3 and 6 months after the start of treatment and at least once a year with prolonged use.

    Against the background of the drug Nilotinib-native there was an increase in the concentration of glucose in the blood plasma. It is necessary to assess the concentration of glucose in the blood plasma before the start of treatment, and also, if necessary, during treatment with the drug Nilotinib-native.

    Due to the risk of development of tumor lysis syndrome, the clinical manifestation of dehydration and increased uric acid concentration in patients should be corrected, if necessary.

    Routine monitoring of response to therapy in patients with Ph+ CML, both during the use of the drug and in the case of a change in therapy, in order to identify a suboptimal response to treatment, loss of response, insufficient adherence of the patient to treatment (compliance) or possible drug interaction. Correction of therapy should be based on monitoring results.

    For the treatment of newly diagnosed RI + CML in the chronic phase the adult patients recommended dose of the drug Nilotinib-native is 300 mg 2 times a day.

    For treatment Ph+ CML in the chronic phase and the acceleration phase the adult patients with intolerance or resistance to prior therapy, including Imatinib, recommended dose of the drug Nilotinib-native is 400 mg 2 times a day. Treatment with the drug is carried out as long as the clinical effect remains.

    Patients with hepatic impairment

    Since the application of nilotinib in patients with impaired hepatic function did not show a significant change in the pharmacokinetic parameters of nilotinib, this category of patients does not require a correction of the dosing regimen of the drug Nilotinib-native. However, apply Nilotinib-native these patients should be treated with caution.

    Patients with impaired renal function

    There is no data on the use of nilotinib in patients with impaired renal function (creatinine concentration in the blood plasma is 1.5 times> the upper limit of the norm (VGN)). Since the kidneys do not play a significant role in the excretion of nilotinib and its metabolites, overall clearance is not expected to decrease with the use of the drug Nilotinib-native in this category of patients.

    Patients with cardiovascular disorders

    Since clinical data on the use of nilotinib in patients with severe heart disease (including unstable angina, uncontrolled chronic heart failure, severe bradycardia, or recent myocardial infarction) are absent, caution should be used in these patients.

    Patients ≥65 years of age

    In clinical trials, patients aged> 65 years with newly diagnosed Ph+XML in the chronic phase and with Ph+XMJI in the chronic phase and the phase of acceleration with intolerance or resistance to prior therapy, including imatinib, accounted for 12% and 30% of the total number of patients, respectively.

    Significant differences in the efficacy and safety of nilotinib in this category of patients compared with patients aged 18 to 65 years were not identified.

    Use in children and adolescents (under 18 years)

    The safety and efficacy of nilotinib in children and adolescents under 18 years of age have not been studied. Correction of the dosing regimen in the development of serious adverse events from the blood and lymphatic system (thrombocytopenia, severe neutropenia)

    When neutropenia and thrombocytopenia are not associated with the underlying disease, a temporary withdrawal of the drug or a decrease in its dose is required, depending on the severity of these undesirable events (Table 1).

    Table 1. Correction of the dose of the drug in the case of neutropenia and thrombocytopenia

    Indication and method of application

    Unwanted

    phenomena

    Correction of dose

    - First identified Ph+ CML in the chronic phase - 300 mg 2 times a day.

    - Ph+ CML in the resistance or intolerance of previous therapy in the chronic phase - 400 mg 2 times a day.

    Reduction of the absolute number of neutrophils <1x109/ l and / or the number of platelets < 50x109/ l.

    1 Drug withdrawal Nilotinib-native and conducting regular clinical blood tests.

    2. Renewal within two weeks of treatment with the drug Nilotinib-native in the dose used before the interruption of therapy, if the absolute number of neutrophils> 1x109/ l and / or platelet count> 50x109/ l.

    3. If the cytopenia is maintained, a dose reduction may be required Nilotinib-native up to 400 mg once a day.

    - Ph+ CML in the resistance or intolerance of previous therapy in the accelerating phase - 400 mg 2 times a day.

    Reduction of the absolute number of neutrophils < 0,5x109/ l and / or the number of platelets <1 Ox 109/ l.

    1. Abolition of the drug Nilotinib-native and conducting regular clinical blood tests.

    2. Resumption of drug treatment Nilotinib-native for two weeks at a dose used before the interruption of therapy, if the absolute number of neutrophils> 1x109/ l and / or the number of platelets> 20x109/ l.

    3. If the cytopenia is maintained, a dose reduction may be required Nilotinib-native up to 400 mg once a day.

    Correction of the dosing regimen in the development of serious non-hematological undesirable phenomena

    With the development of moderately severe or severe non-hematological adverse events associated with taking the drug, drug therapy Nilotinib-native should be interrupted. After the disappearance of adverse events, treatment with the drug can be resumed at a dose of 400 mg once a day. If necessary, it is possible to increase the dose of the drug to 300 mg twice a day in patients with newly diagnosed Ph+ CML in the chronic phase and up to 400 mg twice a day with therapy Ph+ CML in the chronic phase and the phase of acceleration in adult patients with intolerance or resistance to prior therapy, including imatinib.

    When the blood lipase activity is increased 2 times higher than the IGN, the bilirubin concentration is 3 times higher than the IGN or hepatic transaminases 5 times higher than the IGN dose of the drug Nilotinib-native it is recommended to reduce to 400 mg once a day or temporarily interrupt therapy.

    Side effects:

    In patients with newly diagnosed Ph+XMJI, who received nilotinib at a dose of 300 mg twice a day, the most frequent non-hematological adverse events associated with the use of the drug were: skin rash, itchy skin, headache, nausea, fatigue, alopecia, myalgia and upper abdominal pain . Most of the side effects were mildly expressed.Less frequent (<10% and ≥5%) showed mild adverse events, such as constipation, diarrhea, dry skin, muscle spasms, joint pain, abdominal pain, peripheral edema, vomiting and asthenia. When nilotinib was used at a dose of 300 mg twice daily, pleural and pericardial effusions, regardless of their etiology, were observed in 1% and <1% of patients, respectively. Gastrointestinal bleeding, regardless of etiology, was observed in 3% of patients.

    Hematologic adverse events, including myelosuppression: thrombocytopenia, neutropenia, anemia. Disorders of biochemical laboratory indicators include: increased activity of alanine aminotransferase (ALT), hyperbilirubinemia, increased activity of aspartate aminotransferase (ACT), increased lipase activity, increased bilirubin concentration in the blood, hyperkalemia, hypercholesterolemia, hypertriglyceridemia.

    In patients with Ph+XMJI in the chronic phase and the acceleration phasewho received nilotinib in a dose of 400 mg twice a day, the most frequent non-hematological adverse events associated with the use of the drug were: skin rash, itchy skin, nausea, headache, fatigue, constipation, diarrhea, vomiting and myalgia.Most of the above adverse events were mildly expressed. Less frequent (<10% and ≥5%) showed moderate undesirable effects, such as: alopecia, muscle spasms, decreased appetite, joint pain, bone pain, abdominal pain, peripheral edema and asthenia. Heart failure was observed in <1% of patients. Pleural and pericardial effusions, as well as their complications, were observed in <1% of patients taking nilotinib in a dose of 400 mg 2 times a day. Gastrointestinal bleeding and cerebral hemorrhage were observed in 1% and <1% of patients, respectively.

    Interval lengthening QTcF more than 500 ms was observed in <1% of patients. Episodes of ventricular tachysystolic arrhythmia such as "pirouette" (torsade des pointes), short-term and long-term, were not observed.

    Hematologic adverse events, including myelosuppression: thrombocytopenia, neutropenia, anemia.

    Adverse events are listed below for organs and systems, indicating the frequency of their occurrence: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), separately Undesirable phenomena with unknown frequency are presented.

    Violations from the blood and lymphatic system: very often - thrombocytopenia *, neutropenia *, anemia *; often - eosinophilia, febrile neutropenia, pancytopenia, lymphopenia; frequency unknown - Thrombocythemia, leukocytosis.

    Immune system disorders: frequency unknown - hypersensitivity.

    Disorders from the endocrine system: infrequently - hyperthyroidism, hypothyroidism; frequency unknown - secondary hyperparathyroidism, thyroiditis.

    Disorders from the metabolism and nutrition: very often - hypophosphatemia; often - decreased appetite, disorders of water and electrolyte balance (hypomagnesaemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), hyperglycemia, diabetes mellitus, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia; infrequently - gout, dehydration, increased appetite, dyslipidemia; frequency unknown - hyperuricemia, hypoglycemia.

    Mental disorders: often - Depression, insomnia, anxiety; frequency unknown - Disorientation, confusion, amnesia, dysphoria.

    Disorders from the nervous system: very often - headache; often - dizziness, peripheral neuropathy, hypoesthesia, paresthesia; infrequently - intracranial hemorrhage, ischemic stroke, transient cerebral circulation, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, impaired concentration, hyperesthesia; frequency unknown - Acute cerebrovascular accident, stenosis of the basilar artery, cerebral edema, optic neuritis, inhibition, dysesthesia, restless leg syndrome.

    Disorders from the side of the organ of vision: often - intraocular hemorrhage, periorbital edema, conjunctivitis, itching in the eyes, dry eye syndrome (including xerophthalmia); infrequently - impaired vision, blurred vision, decreased visual acuity, eyelid edema, photopsy, flushing (sclera, conjunctiva, eyeball), eye irritation, conjunctival hemorrhage; frequency unknown - edema of the optic disc, diplopia, photophobia, eyelid swelling, blepharitis, pain in the eye, chorioretinopathy, allergic conjunctivitis, diseases of the mucous membrane of the eye.

    Hearing disorders and labyrinthine disturbances: often - Vertigo; frequency unknown - decreased hearing aches, pain in the ears, tinnitus.

    Disorders from the heart: often - angina pectoris, arrhythmia (including atrioventricular block, atrial and ventricular flutter, extrasystole, tachycardia, bradycardia, atrial fibrillation), palpitations, lengthening of the interval QT on the ECG; infrequently - heart failure, myocardial infarction, ischemic heart disease, the appearance of heart murmurs, pericardial effusion, cyanosis; frequency unknown - Violations of the function of the ventricles, pericarditis, reduction of the ejection fraction, diastolic dysfunction, blockage of the left branch of the bundle.

    Vascular disorders: often - Increase in blood pressure (BP), "hot flashes" of blood; infrequently - hypertensive crisis, occlusion of peripheral arteries, intermittent claudication, arterial stenosis of limbs, formation of hematomas, arteriosclerosis; frequency unknown - hemorrhagic shock, decreased blood pressure, thrombosis, stenosis of peripheral arteries.

    Disturbances from the respiratory, thoracic and mediastinal systems: often - shortness of breath at rest and with physical activity, nosebleeds, cough, dysphonia; infrequently - pulmonary edema, pleural effusion, interstitial lung diseases,pleural pain, pleurisy, pain in the throat and / or larynx, irritation of the pharyngeal mucosa; frequency unknown - pulmonary hypertension, wheezing, pain in the mouth and pharynx.

    Disorders from the gastrointestinal tract: very often - nausea, constipation, diarrhea, vomiting, pain in the upper abdomen; often - discomfort in the abdomen, bloating, dyspepsia, dysgeusia, pancreatitis, flatulence; infrequently - gastrointestinal bleeding, melena, ulceration of the oral mucosa, esophageal reflux, stomatitis, pain in the esophagus, xerostomia, gastritis, increased sensitivity of tooth enamel; frequency unknown - perforation of the gastrointestinal ulcers, retroperitoneal bleeding, vomiting blood, stomach ulcer, ulcerative oesophagitis, partial bowel obstruction, enterocolitis, haemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis.

    Disorders from the liver and bile ducts: very often - hyperbilirubinemia; often - impaired liver function; infrequently - Hepatitis, jaundice, toxic liver damage; frequency unknown - cholestasis, hepatomegaly. Disturbances from the skin and subcutaneous tissues: very often - rash, itching, alopecia, dry skin; often - erythema, increased sweating at night, eczema, urticaria, hyperhidrosis, dermatitis (allergic, exfoliative and acneiform), subcutaneous hemorrhage, acne; infrequently - exfoliative rash, swelling of the face, drug rash, tenderness of the skin, ecchymosis; frequency unknown psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blisters, skin cyst, sebaceous gland hyperplasia, skin atrophy, skin discoloration, skin peeling, hyperpigmentation of the skin, skin hypertrophy, hyperkeratosis.

    Disorders from the musculoskeletal and connective tissue: very often - myalgia, arthralgia; often - muscle spasms, bone pain, pain in the limbs, pain in the iliac region, musculoskeletal pain (including musculoskeletal pain in the chest), back pain, neck pain, sore; infrequently - stiffness, muscle weakness, swelling of the joints; frequency unknown - arthritis.

    Disorders from the kidneys and urinary tract: often - pollakiuria; infrequently - dysuria, imperative urge to urinate, nocturia; frequency unknown - Renal failure, hematuria, urinary incontinence, chromaturia.

    Violations of the genitals and mammary gland: infrequently - pain in the breast, gynecomastia, erectile dysfunction; frequency unknown - Densification of mammary glands, menorrhagia, swelling of nipples.

    General disorders and disorders at the injection site: very often - increased fatigue; often - asthenia, fluid retention and swelling, fever, chest pain (including non-cardiac pain), chest discomfort, general malaise; infrequently - edema of the face, gravitational edema, flu-like syndrome, chills, sensation of changes in body temperature (alternation of "sensation of heat" and "sensation of cold"); frequency unknown - Local edema.

    Infectious and parasitic diseases: often - folliculitis, infections of the upper respiratory tract (including, pharyngitis, nasopharyngitis, rhinitis); infrequently - pneumonia, bronchitis, urinary tract infections, herpetic infection, candidiasis (including candidiasis of the oral cavity), gastroenteritis; frequency unknown - sepsis, subcutaneous abscess, abscess of perianal region, furunculosis, mycosis of smooth skin of feet, reactivation of hepatitis B virus.

    Benign, malignant and unspecified neoplasms: often - papilloma of the skin; frequency unknown - papilloma of the oral mucosa, paraproteinaemia.

    Laboratory and instrumental data: very often - increased activity of "liver" transaminases, increased activity of blood lipase, increased concentration of lipoprotein cholesterol (including high and low density lipoproteins), increased total cholesterol concentration, increased concentration triglycerides of blood; often - decrease in hemoglobin concentration, increase in amylase activity, gamma-glutamintransferase, creatine phosphokinase, alkaline phosphatase, increase in insulin concentration in blood plasma, decrease or increase in body weight, decrease in globulin concentration in the blood; infrequently - Increase in lactate dehydrogenase activity, increase in urea concentration in blood plasma; frequency unknown - an increase in the concentration of troponins in the blood plasma, the concentration of unconjugated bilirubin,a decrease in the concentration of insulin and C-peptide of blood, an increase in the concentration of parathyroid hormone in the blood plasma. There is evidence of the onset of tumor lysis syndrome in patients using nilotinib, without indication of a causal relationship with the use of nilotinib (the incidence of adverse events is not established).

    * - 3 and 4 degrees of severity according to the STACEA classification (Common Terminology Criteria for Adverse Events) in patients with newly diagnosed Ph+ CML in the chronic phase.

    Overdose:

    There were reported cases of intentional overdose with nilotinib, in which an unaccepted number of capsules were administered simultaneously with alcohol and other medications. There was a development of neutropenia, vomiting and drowsiness. Changes in the ECG and signs of toxic liver damage were not observed. In all cases, recovery was noted.

    In case of an overdose of the drug Nilotinib-native it is necessary to ensure observation of the patient, as well as apply appropriate symptomatic therapy.

    Interaction:

    Nilotinib is metabolized mainly in the liver, and is also a substrate for the system of removing many drugs - P-glycoprotein (P-GP).Absorption and subsequent elimination of nilotinib may be affected by drugs acting on the isoenzyme CYP3A4 and / or P-GP.

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

    In clinical studies with nilotinib plus imatinib (substrate and isoenzyme moderator CYP3A4 and P-GP), both drugs slightly inhibited the isoenzyme CYP3A4 and P-GP, in this case AUC Imatinib increased by 18-39%, a AUC nilotinib - by 18-40%.

    Bioavailability of nilotinib in healthy volunteers increased by 3 times with simultaneous application with a potent inhibitor of isoenzyme CYP3A4 ketoconazole. Therefore, simultaneous use of nilotinib with preparations that are potent inhibitors of the isoenzyme should be avoided CYP3A4 (eg, ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin), and consider the possibility of alternative therapy with drugs that do not inhibit or slightly inhibit the isoenzyme CYP3A4. If necessary, treatment with drugs that are potent inhibitors of the isoenzyme CYP3A4, treatment with nilotinib should, if possible, be suspended if nilotinib do not cancel, it is necessary to carry out a careful individual control to detect possible lengthening of the interval QTcF.

    It should also avoid the simultaneous use of nilotinib with grapefruit juice and other products that are known inhibitors of the isoenzyme CYP3A4.

    Drugs that can reduce the concentration of nilotinib in the blood plasma

    When nilotinib is used together with the isoenzyme inducer CYP3A4 rifampicin (at a dose of 600 mg / day for 12 days) there was a decrease in the systemic exposure of nilotinib (AUC) approximately 80%.

    Inductors of isoenzyme CYP3A4 can enhance the metabolism of nilotinib and reduce its concentration in the blood plasma. With the simultaneous administration of nilotinib with drugs that are inducers of the isoenzyme CYP3A4 (incl. phenytoin, rifampicin, carbamazepine, phenobarbital and St. John's wort pitted), a decrease in the concentration of nilotinib is possible. If necessary, therapy with drugs that are inductors of the isoenzyme CYP3A4, should consider the possibility of therapy with alternative drugs or use of agents that have less inducing effect on the isoenzyme CYP3A4.

    Solubility of nilotinib pH-dependent - with increasing pH (lower acidity) the solubility of the drug decreases. In healthy individuals with a marked increase in pH against esomeprazole (40 mg once daily for 5 days), the decrease in absorption of nilotinib was moderate (a decrease in CmOh and AUC by 27% and 34%, respectively). If necessary nilotinib can be used concurrently with esomeprazole or other proton pump inhibitors.

    In the study, healthy volunteers showed no significant changes in the pharmacokinetics of nilotinib when taken at a dose of 400 mg 10 hours after taking famotidine and 2 hours before taking famotidine. Thus, if against the background of drug therapy Nilotinib-native the use of H2-histamine receptor blockers is necessary, they should be taken 10 hours before or 2 hours after taking the drug Nilotinib-native.

    In the same study, it was shown that the use of antacids (aluminum hydroxide / magnesium hydroxide / simethicone) 2 hours before or 2 hours after taking nilotinib at a dose of 400 mg also did not alter the pharmacokinetics of nilotinib. Therefore, if antacids are necessary, they should be taken 2 hours before or approximately 2 hours after taking the drug Nilotinib-native.

    The effect of nilotinib on the concentration in the blood plasma of drugs, used as concomitant therapy

    Nilotinib is a competitive inhibitor of isoenzymes CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, with the lowest value of the inhibition constant (Ki) is 0.13 μmol for CYP2C9. In healthy individuals, the use of nilotinib with warfarin (substrate CYP2C9) does not have a clinically significant effect on the pharmacokinetics or pharmacodynamics of warfarin. If necessary nilotinib It should be used simultaneously with warfarin without increasing the anticoagulant effect of the latter.

    There are data that in patients with CML with simultaneous application of 400 mg of nilotinib twice daily for 12 days and midazolam (substrate CYP3A4) the system exposure of the latter when ingested increases 2.6 times. Nilotinib is a moderate inhibitor of isoenzyme CYP3A4, in connection with this, with simultaneous use of drugs metabolized mainly with the participation of isoenzyme CYP3A4 (eg, some HMG-CoA reductase inhibitors), their systemic exposure may increase. With the simultaneous use of nilotinib and preparations that are substrates of the isoenzyme CYP3A4, having a narrow therapeutic index (including, alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, sirolimus, tacrolimus, etc.), it may be necessary appropriate control and dose adjustment.

    Antiarrhythmic drugs and other medicines, The elongation of the OT interval

    Do not use nilotinib with antiarrhythmic drugs (for example, amiodarone, disopyramide, procainamide, quinidine and sotalol, etc.) and other drugs that cause lengthening of the interval QT (for example, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide, etc.).

    Other types of interactions that may affect the concentration of serum nilotinib

    With simultaneous intake with food, there is an increase in absorption and bioavailability of nilotinib, leading to an increase in the plasma concentration of the drug.

    If necessary, it is possible to use the drug Nilotinib-native together with hemopoiesis stimulants, such as erythropoietins, granulocyte colony stimulating factor, as well as with hydroxycarbamide and anagrelide.

    Special instructions:

    The treatment of patients should be performed by specialists with experience in the treatment of CML.

    Myelosuppression

    Since the use of nilotinib may lead to thrombocytopenia, neutropenia and anemia (most often in patients with CML in the acceleration phase), a clinical blood test should be performed every 2 weeks during the first 2 months of therapy with the drug, and then monthly or clinically. Myelosuppression is usually reversible and controlled. Normalization of the number of platelets and neutrophils can be achieved after a temporary cessation of therapy with nilotinib or a reduction in the dose of the drug.

    Cases of sudden death

    When nilotinib was used, there were cases (frequency 0.1-1%, gradation - "infrequently") sudden death of patients with heart disease or a high risk of complications from the cardiovascular system. These patients often had concomitant diseases and received concomitant therapy. Violations of repolarization of the ventricles can be an additional risk factor. According to clinical studies of nilotinib, the estimated frequency of spontaneous reports of sudden deaths was 0.02% per patient per year.

    Complications of the cardiovascular system

    When nilotinib was used in clinical trials in patients with newly diagnosed CML, cases of development of complications from the cardiovascular system were noted. HA 3 and 4 degrees included occlusion of peripheral arteries, ischemic heart disease and ischemic cerebrovascular events. If there are corresponding complaints or symptoms of acute cardiovascular disorders, the patient should immediately seek medical help. Before the beginning, 7 days after the beginning and during the treatment with the drug Nilotinib-native It is recommended that an ECG study be conducted to monitoring the function of the cardiovascular system, as well as for assessing risk factors for the development of complications from the cardiovascular system.

    Fluid retention

    In clinical trials, severe forms of fluid retention, such as pleural effusion, pulmonary edema and effusion into the pericardial cavity, were infrequent (0.1-1%) in patients with newly diagnosed CML. Similar cases have also been observed with the use of nilotinib in clinical practice.With sudden and rapid increase in body weight in patients receiving treatment with the drug Nilotinib-native, a thorough examination should be conducted to find out the cause. When symptoms of severe fluid retention occur, the etiology of the phenomenon should be clarified and appropriate treatment should be performed.

    Monitoring of laboratory data

    Lipid profile of blood serum

    In a clinical study, 1.1% of patients with newly diagnosed Ph+XMJI, who received nilotinib in a dose of 400 mg twice a day, there was a significant increase in the concentration of total cholesterol in the serum. However, in patients who received nilotinib in a dose of 300 mg twice a day, there was no such increase in serum cholesterol concentration. It is recommended to determine the lipid profile before starting therapy with the drug Nilotinib-native, and also 3 and 6 months after the start of treatment and at least once a year with prolonged use. Care should be taken when using HMG-CoA reductase inhibitors (lipid-lowering drugs) simultaneously with the drug Nilotinib-native, since the pathway of metabolic transformations of inhibitorsHMG-CoA reductase occurs with the participation of isoenzyme CYP3A4 (see section "Interaction with other drugs").

    The concentration of glucose in the blood plasma

    In a clinical trial, 6.9% of patients with newly diagnosed Ph+XMJI, who received nilotinib in a dose of 400 mg twice a day, and in 7% of patients who received nilotinib in a dose of 300 mg twice a day, there was a significant increase in the concentration of glucose in the blood plasma. It is necessary to assess the concentration of glucose in the blood plasma before the start of treatment, and also, if necessary, during treatment with the drug Nilotinib-native.

    Increased activity of blood plasma lipase

    When the lipase activity in the blood plasma increases, accompanied by abdominal symptoms, the drug intake Nilotinib-native should be discontinued and an appropriate examination of the patient should be conducted to exclude pancreatitis.

    Dysfunction of the liver

    When using the drug Nilotinib-native it is recommended to carry out monthly monitoring of liver function (transaminase, bilirubin).

    Chronic carriers of the hepatitis B virus

    In patients who are chronic carriers of the hepatitis B virus, it is possible to reactivate the hepatitis B virus after using a tyrosine kinase inhibitor (NTC) BCR- ABL, such as nilotinib. For such patients, the following recommendations exist:

    - A patient should be examined for hepatitis B virus infection before starting therapy with nilotinib.

    - Patients receiving nilotinib therapy should be tested for hepatitis B virus to detect chronic carriers.

    - Patients with positive serology to hepatitis B virus prior to the use of nilotinib, as well as patients who received positive serology to hepatitis B during treatment with nilotinib, should consult with experts in liver disease and the treatment of patients with hepatitis B.

    - Hepatitis B virus carriers receiving nilotinib therapy should be carefully monitored for symptoms and signs of active hepatitis B infection during the entire time of the drug, as well as for several months after discontinuation of therapy nilotinib.

    A review of the clinical trial data revealed the possibility of reactivation of the hepatitis B virus in chronic carriers after the use of ITC BCR-ABL. In some cases, acute liver failure or fulminant hepatitis developed, necessitating liver transplantation or death. Reactivation of the hepatitis B virus can develop at any time during treatment BCR-ABL. Some of these patients had a documented history of hepatitis B, in others the initial serological status was unknown. With the reactivation of the hepatitis B virus, an increase in the viral load was diagnosed or a positive serological test was obtained. Reactivation of the hepatitis B virus is a class effect of ITC BCR-ABL in the territory of the European Union, although the mechanism and frequency of reactivation of the hepatitis B virus against the background of NTC application BCR-ABL remain unknown.

    Patients who underwent gastrectomy

    Since patients who undergone gastrectomy, the bioavailability of nilotinib can be reduced, careful monitoring of the condition of these patients is necessary.

    Tumor lysis syndrome

    Due to the risk of development of tumor lysis syndrome before prescribing the drug Nilotinib-native if necessary, correct clinically pronounced dehydration and increased concentration of uric acid in patients.
    Effect on the ability to drive transp. cf. and fur:

    There is no data on the effect of nilotinib on the ability to drive vehicles and mechanisms. In the case of development of adverse reactions from the nervous system, the organs of vision and psyche with the use of the drug Nilotinib-native should refrain from driving vehicles and mechanisms, as well as other classes of potentially hazardous activities that require high concentration and psychomotor speed reactions.

    Form release / dosage:Capsules 150 mg and 200 mg.
    Packaging:

    For 4 or 8 capsules in a contour mesh box made of aluminum foil foil and polyvinyl chloride film.

    By 28, 40, 112 or 120 capsules in polyethylene terephthalate bottles, sealed with polyethylene covers. On the vials stick a self-adhesive label.

    At 7 or 28, the contour of cellular packages of 4 capsules of 15 5 or contour of cellular packages for 8 capsules, or bottle 1 together with instructions for use in a cardboard pack.

    Storage conditions:

    In the dark place at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003879
    Date of registration:05.10.2016
    Expiration Date:05.10.2021
    The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp19.10.2016
    Illustrated instructions
      Instructions
      Up