Tacsin® (Tasigna®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceNilotinibNilotinib
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  • 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:

    1 capsule contains:

    active substance: 200 mg of nilotinib, corresponding to 220.60 mg of nilotinib hydrochloride monohydrate;

    auxiliary matter: lactose monohydrate 156.11 mg, crospovidone 15.91 mg, poloxamer 188 3.18 mg, silicon dioxide colloid 2.10 mg, magnesium stearate 2.10 mg, gelatin 98.82%, titanium dioxide (E171) 1.00%, ferric oxide yellow oxide (E172) 0.18%;

    ink composition: shellac (E904), propylene glycol, iron dye red oxide (E172), potassium hydroxide, water.

    Description:

    Opaque hard gelatin capsules №0 of light yellow color with axial marking "NVR" and "TKI" red.

    The contents of the capsule are white or almost white 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 gyrosine kinase activity BCR-ABL oncoprotein of cell lines and primarily positive for the Philadelphia chromosome (Pli+) leukemic cells.

    The drug 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-terosipkinase, except for T3I5I mutations. Nilotinib selectively inhibits proliferation and induces apoptosis of cell lines and Ph- positive leukemia cells in patients with chronic myelogenous leukemia (CML). Nilotinib has little or no effect on other known protein kinases (including family kinase proteins Src), except for kinases that have receptors for platelet growth factors (PDGRF), KIT-, CSF-I-, DDR-recenters 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.

    Against the backdrop of therapy with nilotinib 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 3 months of therapy (median - 2.8 months) - and persisted against the background of continued use of the drug (within 24 months) in 77% 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 quite quickly - during the first month of therapy (median - 1 month) - and persisted against the background of continued use of the drug (within 24 months) in 49% of patients. The rate of achievement of a large cytogenetic response was 32%, and this response persisted in 66% of patients with continued use of the drug (within 24 months).

    Pharmacokinetics:

    Absorption

    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 - 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%.

    In healthy volunteers, while taking the drug with food, the maximum concentration (Cmax) and the area under the curve "concentration-time" (AUC) nilotinib increased by 112% and 82%, respectively, compared with the administration of nilotinib on an empty stomach. The use of the drug 30 minutes or 2 hours after ingestion increased 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 plasma is 0.71. Connection with plasma proteins in vitro is about 98%.

    In the equilibrium state, the systemic exposure of nilotinib was dose-dependent. However, when using the drug 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, was 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 administered 400 mg twice daily was approximately 13.4% higher when administered at a dose of 300 mg twice daily. When taking the drug inside for 12 months at a dose of 400 mg twice a day, the minimum and maximum concentrations of nilotinib by 15.7% and 14.8% were higher than those with the drug at 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 was reached by the 8th day.

    Metabolism

    In healthy volunteers, the main routes 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. 69% of the drug is excreted unchanged.The half-life with repeated use of the daily dose was approximately 17 hours.

    When nilotinib was used in patients with impaired hepatic function, there was no significant change in the pharmacokinetic parameters of nilotinib. With a single administration of the drug, there was a decrease AUC nilotinib by 35%, 35% and 19% in patients with impaired liver function of mild, moderate and severe degree (compared with patients without violations of the liver function). FROMmax Nilotinib in the equilibrium state increased by 29%, 18% and 22%, respectively.

    Individual differences in pharmacokinetics among patients were moderate to severe.

    Indications:Treatment of a positive myeloid leukemia in the chronic phase and an accelerated phase in adult patients with intolerance or resistance to prior therapy, including in the Philadelphia chromosome imatinib.
    Contraindications:

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

    Pregnancy and the period of breastfeeding.

    Children and adolescence under 18 years (no application data).

    Hereditary intolerance to galactose, deficiency of lactase or glucose-galactose malabsorption, because the dosage form contains lactose.

    Carefully:

    Taksia preparation® 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 recently suffered myocardial infarction, chronic cardiac insufficiency, unstable angina, or clinically significant bradycardia), with impaired hepatic function, with pancreatitis (including in the anamnesis).

    The Tasigna preparation should not be used concomitantly with preparations that are potent inhibitors of the isoenzyme CYP3A4 or extending the interval QT, especially in patients with hypokalemia and hypomagnesemia (perhaps more pronounced lengthening of the interval QT).

    It should avoid the simultaneous use of Tasignon ® with grapefruit juice and other products that are known inhibitors CYP3A4.

    Pregnancy and lactation:

    Use of Taciox® during pregnancy and during breastfeeding it is contraindicated.

    During therapy with Tacino® and at least 2 weeks after completion of therapy, reliable methods of contraception should be used in patients, especially women of childbearing age.

    Dosing and Administration:

    Tasigne ® should be taken 2 times a day (every 12 hours), 2 hours after eating. After applying Tasigne ® take food should not be earlier than 1 h. 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 Taksi® .

    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, correct hypomagnesemia and giocaemia.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 the application of the preparation of Taci® there was an increase in the concentration of total cholesterol in the blood serum. It is recommended to determine the lipid profile before the beginning of therapy with the Tasox preparation®, 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 application of the preparation of Taci® 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 if necessary during treatment with Tasigne® .

    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 interactions. Correction of therapy should be based on monitoring results.

    For treatment Ph+ CML in the chronic phase and the phase of acceleration in adult patients with intolerance or resistance to prior therapy, including imatinib, recommended dose of the product® is 400 mg 2 times a day. Treatment with the drug is carried out until then. while the clinical effect remains.

    Patients with impaired hepatic function

    Since no significant changes in the pharmacokinetic parameters of nilotinib were observed in patients with hepatic dysfunction when nilotinib was used, this category of patients did not require correction of the dosage regimen of the Tasox preparation® . Nevertheless, use the preparation of Tasign® these patients should be treated with caution.

    Patients with impaired renal function

    Data on the application of the preparation® in patients with impaired renal function (concentration of creatinine 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,It is not expected to reduce the overall clearance with the use of the Tasigna preparation® in this category of patients.

    Patients with cardiovascular disorders Since the clinical data on the use of the Ta-® 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 aged> = 65 years

    In clinical trials, patients aged> = 65 years 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 the Tasigna preparation® This category of patients was not detected in comparison with patients aged 18 to 65 years.

    Correction of the dosing regimen in the development of serious adverse events on the part of the hemopoietic system (thrombocytopenia, severe neutropenia) When neutropenia and thrombocytopenia occur. ns associated with the underlying disease, it is necessary to temporarily stop the drug or reduce its dose, depending on the severity of these undesirable events.

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

    Ph+ XMJI in chronic

    Reduction of the absolute number of neutrophils

    1 Cancellation® and regular

    phase 400 mg 2 times in

    <1 x 109 /l and / or number of platelets

    clinical blood tests

    day

    <50 x 109 /l

    2. Resumption within 2 weeks of treatment with Tasigne® in the dose used before the interruption of therapy, if the absolute number of neutrophils >1x 109 /l and / or the number of platelets >50x 109 l.

    3 If intopenia persists, a reduction in the dosage of the Thalessone preparation may be required® up to 400 mg once a day.


    Ph+ XMJI at phase


    Reduction of the absolute number of neutrophils

    1. Cancellation of Tacigia® and regular

    accelerations


    < 0.5 x 109 /l and / or numbers platelets

    clinical blood tests.

    400 mg 2 times per day


    < 10 х 109 /l

    2. Resumption within 2 weeks of treatment with Tacigia® in the dose used before the interruption of therapy, if the absolute number of neutrophils> 1x 109 /l and / or thrombocyte count> 20x 109 /l .

    3.While maintaining tsntopennn it may be necessary to reduce the dose of Tacigia® up to 400 mg 1 time per day

    Correction of the dosing regimen in the development of serious nonhematological adverse events

    With the development of moderately severe or severe non-hematologic adverse events associated with taking the drug, Taksi® should be interrupted. After the disappearance of side effects, treatment with the drug could be resumed at a dose of 400 mg once a day. If necessary, it is possible to increase the dose to 400 mg twice a day.

    When the activity of blood lipase is increased 2 times higher than VGP, the concentration of bilirubin is 3 times higher than that of VGP or hepatic transaminases is 5 times higher than the VGP dose of the Tasox preparation® it is recommended to reduce to 400 mg once a day or temporarily interrupt therapy.

    Side effects:

    Patients receiving Tacigia® 400 mg twice a day, the most frequent (> = 10%) non -hematological adverse events associated with the use of the drug were: skin rash, itching, nausea, headache, fatigue, constipation, diarrhea, vomiting and myalgia. Most of the above adverse events were mild.Less frequently (<10% and> = 5%), moderate undesirable effects were observed, 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 Tacigia® 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 tachycardia of the type torsade des pointes (short-term or long-term) were not observed.

    Hematologic adverse events, including myelosuppression: thrombocytopenia (31%), neutropenia (17%), anemia (14%).

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

    The incidence of adverse events noted in more than 5% of cases is shown in parentheses.
    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 horny cavity), gastroenteritis; frequency unknown - sepsis, subcutaneous abscess, abscess of perianal area, boils, mycosis of smooth skin moaning. Benign, malignant and unspecified neoplasms: often - papilloma of the skin; frequency unknown - papilloma of the oral mucosa, paraproteinaemia. Disorders from the metabolism and nutrition; Often - hypophosphatemia; often - decreased appetite (8%), disturbances of water-electrolyte balance (hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), hyperglycemia, diabetes mellitus, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia; infrequently - gout, dehydration, increased appetite, dyslipidemia; frequency unknown hyperuricemia, hypoglycemia.
    Impaired nervous system:
    Often - headache (15%); often - dizziness, peripheral neuropathy, hypoesthesia, paresthesia;
    infrequently -

    intracranial hemorrhage, ischemic stroke, transient impairment of cerebral circulation, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, impaired concentration, hyperesthesia; frequency unknown - acute disturbance of cerebral circulation, stenosis of the basilar artery, cerebral edema, optic neuritis, inhibition, dysesthesia, restless leg syndrome.

    Disorders from the musculoskeletal and connective tissue: very often - myalgia (10%); often - arthralgia (7%), muscular spasm (8%), bone pain (6%), limb pain, pain in the iliac fossa, musculoskeletal pain (including musculoskeletal chest pain), pain in the back, pain in the neck, pain in the side, muscle weakness; infrequently - stiffness, swelling of the joints; frequency unknown - arthritis.

    Disorders from the blood and lymphatic system: very often - Thrombocytopenia (30% *), neutropenia (31% *), anemia (11% *); often - leukopenia, 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 of the psyche: often - depression, insomnia, anxiety; frequency unknown - disorientation, confusion, amnesia, dysphoria.

    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 acuity, pain in the ears, tinnitus.

    Violations from hand heart: often - angina pectoris. arrhythmia (including atrioventricular blockade, atrial and ventricular flutter, extrasystole and ju, 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 - abnormal ventricular function, pericarditis, reduction of ejection fraction, diastolic dysfunction, left bundle branch blockade of the bundle.

    Violations from the vessels: often - increase in blood pressure (BP), "hot flashes" of blood; infrequently - hypertensive crisis, occlusion of peripheral arteries, intermittent lameness, stenosis arteries of the extremities, education hematomas, arteriosclerosis; frequency unknown - hemorrhagic shock, decreased blood pressure, thrombosis, stenosis of peripheral arteries.

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

    Disorders from the digestive system: very often - nausea (20%), constipation (12%), diarrhea (11%), vomiting (10%), pain in the upper abdomen (5%); often - discomfort in the abdomen, bloating, dyspepsia, dysgeusia, pancreatitis, flatulence; infrequently - gastrointestinal bleeding, melena, ulceration of the oral mucosa, gastro-esophageal reflux, stomatitis, pain in the esophagus, dry mouth, gastritis, increased sensitivity of tooth enamel; frequency unknown - perforation of gastrointestinal ulcers, retroperitoneal hemorrhage, vomiting with blood, stomach ulcer, ulcerative esophagitis, partial intestinal obstruction, enterocolitis, hemorrhoids, hernia of the esophageal opening of the diaphragm, rectal bleeding, gingivitis.

    Disorders from the liver and biliary tract: 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 (28%), itching (24%), alopecia (9%); often - increased sweating at night, eczema, urticaria, hyperhidrosis, dermatitis (allergic, exfoliative and acne), 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 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 (17%); often - asthenia (6%), fluid retention and edema (6%). fever, chest pain (including non-cardiological 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.

    Laboratory and instrumental data: very often - Increased activity of "hepatic" trapsaminases, increased activity of blood lipase, increased concentration of blood lipoprotein cholesterol (including low and high density lipoproteins), an increase in the concentration of total cholesterol, an increase in the concentration of triglycerides of blood; often - decrease in hemoglobin concentration, increase in amylase activity, gamma-glutamine transferase, 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 - increased lactate dehydrogenase activity, increased urea concentration in blood plasma; frequency unknown - an increase in the concentration of thrononins 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.

    Experience in clinical practice.

    Against the background of therapy with Tasigne® The following undesirable phenomena were noted without evidence of a causal relationship with pilotinib (frequency there are no undesirable phenomena): cases of tumor lysis syndrome.

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

    Overdose:There were reported cases of deliberate drug overdose, in which an unspecified number of capsules were administered simultaneously with alcohol and other drugs. There was a development of neutropenia, vomiting and drowsiness. Changes ECG and signs of toxic damage to the liver was noted ns was. In all cases, recovery was noted. In the case of an overdose of Tacigia, it is necessary to monitor the patient and apply appropriate symptomatic therapy.
    Interaction:

    Nilotinib is mostly destabilized in the liver, and it is also a substrate for the system for the removal of many drugs - P-glycoprotein (P-GP). The absorption and subsequent elimination of Taciox® can be affected by drugs acting on the isoenzyme CYP3A4 and / or P-GP.

    Medicinal products, which can increase the concentration of nilotinib in the blood plasma

    In clinical trials with nilotinib plus imatinib (substrate and inhibitor of the isoenzyme 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. It should avoid the simultaneous use of nilotinib with drugs that are potent inhibitors of isofermene CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, ritopavir, clarithromycin, and helminthin gels) 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 Taciox® should be suspended as far as possible. If it is necessary to simultaneously apply Tasigne® with preparations that are potent inhibitors of the isoenzyme CYP3A4, It is necessary to carry out a thorough individual control to identify possible lengthening of the interval QTcF.

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

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

    Inductors of isoenzyme CYP3A4 can enhance the metabolism of nilotinib and reduce its concentration in the blood plasma. With simultaneous administration with drugs that are inducers of 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 the use of other agents that have less inducing effect on the isoenzyme CYP3A4.

    When nilotinib is used in healthy volunteers together with an 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%.

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

    In the study, healthy volunteers did not show any significant changes in the pharmacokinetics of nilotinib with the use of the Ta-® in a dose of 400 mg 10 hours after taking famotidine and 2 hours before taking famotidine. Thus, if against the background of therapy with Tasigne® the use of H2-blockers of histamine receptors is necessary, they should be taken 10 hours before or 2 hours after taking the Tasox preparation® .

    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 the drug® in a dose of 400 mg also does not change the pharmacokinetics of nilotinib. Therefore, if antacids are needed, they should be taken 2 hours before or about 2 hours after taking Taciox®.

    The effect of nilotinib on the plasma concentration of a drug, used as a concomitant therapy

    Nilotinib, being a competitive inhibitor of isoenzymes CYP3A4. CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, the lowest value of the inhibition constant (Ki) is 0.13 μmol for CYP2C9. In healthy volunteers, the use of nilotinib along with warfarin (substrate CYP2C9) had no clinically significant effect on the pharmacokinetics or pharmacodynamics of warfarin. If necessary, the preparation of the Taxi® It should be used simultaneously with warfarin without increasing the anticoagulant effect of the latter. In patients with CML with simultaneous application of 400 mg of nilotinib 2 times a day for 12 days and midozolam (substrate CYP3A4) Systemic exposure of the latter with ingestion increased 2.6 times. Nilotinib is a moderate isoenzyme inhibitor 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, alfentapil, ciclosporin, dihydroergotamp, ergotamine, fentanyl, sirolimus, gacrolimus, etc.), appropriate monitoring and dose adjustment may be required. Antiarrhythmic drugs and other drugs that cause prolongation of the RT interval.

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

    Other 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 preparation of Taci® together with hemopoiesis stimulants, such as erythropoietins, granulocyte colony stimulating factor, as well as with hydroxycarbamide and anagrelide.

    Special instructions:

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

    Myelosuppression

    Since Tacigia * can develop thrombocytopenia, neutropenia, and anemia (most often in patients with CML in the accelerated phase), a clinical blood test should be performed every 2 weeks for the first 2 months of therapy drug, and then - monthly or in case of clinical necessity. Myelosuirscia. as a rule, was reversible and controlled. The normalization of the number of platelets and neutrophils was usually achieved after the temporary discontinuation of therapy with Tasigne * or a decrease in the dose of the drug.

    Cases of sudden death

    With the use of Tasigne ® in clinical studies, 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 post-marketing studies, the estimated frequency of spontaneous reports of sudden deaths was 0.02% per patient per year.

    Complications of the cardiovascular system

    With the use of Tasigne ® in clinical studies, as well as in post-marketing studies in patients with newly diagnosed CML cases of development of complications from the cardiovascular system were noted. The 3rd and 4th 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. It is necessary to monitor the function of the cardiovascular system,and also to assess the risk factors for the development of cardiovascular complications throughout the duration of therapy with Taciox®. The delay is liquid and

    In clinical trials in patients with newly diagnosed CML infrequent (0.1-1%) severe forms of fluid retention, such as effusion to the pleural cavity, pulmonary edema and effusion into the pericardial cavity. Similar cases were also noted when the drug was used in clinical practice in the postmarketing period. With a sudden and rapid increase in body weight in patients receiving treatment with nilotinib, 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 trial, 1.1% of patients with newly diagnosed RI + CML, 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 blood 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 the beginning of therapy with Tasigne ®, 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-CoD-reductase inhibitors (hypolipidemic agents) concomitantly with Tasigne * preparation, since the pathway of metabolic transformations of HMG-CoL reductase inhibitors occurs with the participation of the isoenzyme CYP3A4 (see section "Interaction with Other Drugs and Other Interactions").

    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 7.2% 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 preparation I alarm. Increased activity of blood plasma lipase

    With an increase in lipase activity in the blood plasma, accompanied by abdominal symptoms, the drug should be stopped and a proper examination of the patient to exclude pancreatitis.

    Dysfunction of the liver

    When using Tasigna, it is recommended to perform monthly monitoring of liver function (transaminase, bilirubin).

    Patients who underwent gastrectomy

    Because patients undergoing total 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, the clinical manifestation of dehydration and increased uric acid concentration in patients should be corrected, if necessary.

    Effect on the ability to drive transp. cf. and fur:

    Some of the side effects of the drug, such as dizziness or visual disturbances, as well as other undesirable effects, can adversely affect the ability to drive vehicles and carry out potentially dangerous activities requiring increased attention and speed of psychomotor reactions.Therefore, during the treatment period, care should be taken when driving vehicles and performing potentially hazardous activities. When these undesirable phenomena appear, one should refrain from these activities.

    Form release / dosage:Capsules 200 mg.
    Packaging:

    Primary packaging

    For 4 or 8 capsules in a blister of 11VX / PVDC.

    Secondary packaging

    For 7 blisters, 4 capsules together with instructions for use in a cardboard package - a weekly package (28 capsules).

    For 5 blister packs of 8 capsules, along with instructions for use in a cardboard box - a 10-day package (40 capsules).

    For four week packages (4 x 28) put in a cardboard box - a monthly package (112 capsules).

    Three 10-day packages (3 x 40) are placed in a cardboard box - a 30-day package (120 capsules).

    Storage conditions:

    At a temperature of no higher than 30 ° C.

    The drug should be stored out of the reach of children.

    Shelf life:

    3 years.

    Do not use the drug after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-000830/08
    Date of registration:18.02.2008
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspPHARMSTANDART-Ufa-VITA, JSCPHARMSTANDART-Ufa-VITA, JSC
    Information update date: & nbsp13.08.2015
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