Tasigna - instructions for use, doses, side effects, contraindications

Active substanceNilotinibNilotinib

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Nilotinib-native

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NATIVA, LLC Russia

Tacsin®

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Novartis Pharma AG Switzerland

Tacsin®

capsules inwards

Novartis Pharma AG Switzerland

Dosage form: & nbspcapsules

Composition:

1 capsule contains: for a dosage of 150 mg

active substance: 165.45 mg of nilotinib hydrochloride monohydrate, corresponding to 150 mg of nilotinib;

Excipients: lactose monohydrate 117.08 mg, crospovidone 11.93 mg, poloxamer 188 2.39 mg. silicon colloidal dioxide 1.58 mg, magnesium stearate 1.58 mg; ink composition: shellac (E904), iron dye oxide black (E172), water, propylene glycol. for a dosage of 200 mg

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

Excipients: 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; shell: gelatin 98.82%. titanium dioxide (E171) 1.00%, iron oxide dye yellow (El72) 0,18%;

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

Description:

Capsules 150 mg - red-brown opaque hard gelatin capsules No. 1 with axial marking "NVR" and "BCR" in black ink.

Contents of capsules: powder from white to yellowish white color.

Capsules 200 mg - opaque hard gelatin capsules №0 of light yellow color with axial marking "NVR" and "ТК1" red color.

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 tyrosine kinase activity BCR-ABL oncoprotein of cell lines and primarily positive for the Philadelphia chromosome (Ph +) 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-tyrosine kinase, with the exception of the T3151 mutation. Nilotinib selectively inhibits proliferation and induces apoptosis of cell lines and Ph- positive 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 therapeutic dose range,recommended for the treatment of CML for oral administration.

Against the background of therapy pilotibom in a dose of 400 mg 2 times 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 quite 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% 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 quite quickly - during the first month of therapy (median - I 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 (t_max) 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 (C_max) 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 apple spore 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 for 12 months inside 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 ways of metabolizing 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). Cmax of nilotinib in the equilibrium state 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 (CML) in the chronic phase in adults.

- Ph + XMJl 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 feeding period piles.

Children and adolescence under 18 years (no application data). Hereditary intolerance to galactose, deficiency of lactase or pokozo-galactose malabsorption, t. the dosage form contains lactose.

Carefully:

Tacigia ® 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 history).

Tasigne® should not be used concomitantly with preparations 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 be avoided simultaneous application of Tasignon ® with grapefruit juice and other products, which are known inhibitors of isoenzyme CYP3A4.

Pregnancy and lactation:

Application of the preparation® during pregnancy and during breastfeeding is contraindicated.

During therapy with Tasigne® and at least 2 weeks after the completion of therapy, patients, especially women of childbearing age, should use reliable contraceptive methods.

Dosing and Administration:

Taksia preparation® should be taken 2 times a day (every 12 hours), 2 hours after eating. After applying the preparation® Take the food should not be earlier than 1 hour. 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 blanchard.

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, should be corrected hypomagnesemia and giokalemia. 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 Tasigne ®, 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. The plasma glucose concentration should be assessed before the start of treatment, and also, if necessary, during treatment with Taciox®.

Due to the risk of developing a tumor lysis syndrome, the drug should be administered, if necessaryto correct clinically pronounced dehydration and increased concentration of uric acid in patients.

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 to the patient's treatment (compliance), or possible drug interaction. Correction of therapy should be based on monitoring results.

For the treatment of newly diagnosed Ph + XMJI in the chronic phase in adults The recommended dose of Tasignon ® in a dose of 300 mg 2 times a day.

For the treatment of RI + CML in the chronic phase and the acceleration phase in adult patients with intolerance or resistance to prior therapy, including imatinib, the recommended dose of Tasigne® is 400 mg twice a day.

Treatment with the drug is carried out as long as the clinical effect remains.

Patients with impaired hepatic function

Since nilotinib in patients with hepatic impairment did not show a significant change in the pharmacokinetic parameters of nilotinib, no correction of the dosage regimen of the Taciox® preparation was required in this category of patients.Nevertheless, use of TacIsin® in these patients should be carried out with caution.

Patients with impaired renal function

There is no data on the use of Tasigne ® in patients with renal dysfunction (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, it is not expected to reduce the overall clearance with Tasigne® in this category of patients.

Patients with cardiovascular disorders Since clinical data on the use of Taciox® 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 newly diagnosed Ph + XMJI 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 the Tasigna preparation® in this category of patients compared with patients aged 18 to 65 years was not found.

Use in children (under 18 years): The safety and effectiveness of the drug in children and adolescents under 18 years old have not been studied.

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 are not associated with the underlying disease, a temporary withdrawal of the drug or a decrease in its dose, depending on the severity of these undesirable phenomena, is required.

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

First identified Ph + XMJI in the chronic phase - 300 mg twice daily

Ph+ CML in the resistance or intolerance of previous therapy in the chronic phase - 400 mg twice daily

Decrease

absolute number of neutrophils <1x10% and / or number of platelets <50x10'7l

1 Cancellation® and conducting regular clinical blood tests.

2. Renewal within 2 weeks of treatment with Tasigne * at the dose used before the interruption of therapy, if the absolute number of neutrophils > 1x10% and / or the number of platelets > 50x10%.

3. With the preservation of cytopathy, it may be necessary to reduce the dosage of Taciox® to 400 mg once daily

Ph+ CML in the resistance or intolerance of previous therapy in the acceleration phase - 400 mg twice daily

Decrease

absolute number of neutrophils <0.5x10% and / or number of platelets <10x10%

1. Abolition of Tasigna * preparation and regular clinical blood tests.

2. The resumption of treatment with Tasigne * for 2 weeks at a dose used before the interruption of therapy, if the absolute number of neutrophils> 1 x 10% and / or the number of platelets > 20x10%.

3. At preservation of a dose, it may be necessary to reduce the dose of Tasigne * to 400 mg once a 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 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 + XMJI in the chronic phase and up to

400 mg 2 times 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, it is recommended to dose the dose of Tasox® to 400 mg once a day or temporarily to interrupt therapy.

Side effects:

In patients with newly diagnosed Ph+ CML, who received the drug Tazigna® at a dose of 300 mg twice a day, the most frequent (> = 10%) non-hematological adverse events associated with the use of the drug were: skin rash, itchy skin, headache, nausea, fatigue, alopecia, myalgia and pain upper abdomen. Most side effects were mild. Less frequently (<10% and> = 5%), moderate adverse events were observed, such as: constipation, diarrhea, dry skin, muscle spasms, joint pain, abdominal pain, peripheral edema, vomiting and asthenia.With the use of Tasigne® 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 (18%), neutropenia (15%), anemia (8%). Disorders of biochemical laboratory indicators include: increased activity of alanine aminotransferase (ALT) (24%), hyperbilirubinemia (16.5%), an increase in activity of aspartate aminotransferase (ACT) (12%), an increase in lipase activity (11%), an increase in bilirubin concentration in the blood (10%), hyperglycemia (4%), hypercholesterolemia (3%), hypertriglyceridemia (<1%).

In patients with Ph + XMJI in the chronic phase and the acceleration phasewho received Tasigno® 400 mg twice a day, the most frequent (> = 10%) 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 mild.Less frequently (<10% and> = 5%), moderate adverse events 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 Tasigna® in a dose of 400 mg 2 times a day. Gastrointestinal bleeding and hemorrhages in the brain 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 or long-term, were not observed.

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

Undesirable phenomena are listed below in the 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 oral cavity), gastroenteritis; frequency unknown - sepsis, subcutaneous abscess, perianal abscess, furuncle, tinea corporis stop. Benign, malignant and unspecified neoplasms: often - papilloma of the skin; frequency unknown - papilloma of the oral mucosa. paraproteinemia. Disorders from the metabolism and nutrition: Often - hypophosphatemia; often - reduction of appetite (4%), disorders of water and electrolyte balance (Ia giperkaliem hypomagnesemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia..), Hyperglycemia, diabetes mellitus, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia; infrequently - gout, dehydration, increased appetite, dyslipidemia; frequency unknown hyperuricemia, hypoglycemia.

Disorders from the nervous system: very often - headache (16%); often - dizziness, peripheral neuropathy, gipsstsziya, 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 musculoskeletal and connective tissue: very often - myalgia (10%), arthralgia (8%); often - muscular spasms (9%), pain in the legs (4%), pain in the extremities (5%), pain in the iliac region, musculoskeletal pain (including musculoskeletal pain in the chest), back pain, pain in the neck, pain in the side; infrequently - stiffness, muscle weakness, swelling of the joints; frequency unknown - arthritis. Disorders from the blood and lymphatic system: very often - Thrombocytopenia (30%), neutropenia (31%), anemia (11% *); often - eosinophilia, febrile neutropenia, panzoniemia, lymphopenia; frequency unknown - thrombocythemia, leukocytosis.

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

Mental disorders: 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 - Visual impairment, blurred vision, decreased visual acuity, eyelid edema, photonesis, hyperemia (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 eye mucosa.

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

Heart Disease: 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 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 (14%), constipation (10%), diarrhea (9%). vomiting (6%), pain in the upper abdomen (10%); often - discomfort in the abdomen, bloating, dyspepsia, dysgeusia, pancreatitis, flatulence; infrequently - gastrointestinal hemorrhage, 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 from the lump, 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 bile ducts: Often - hyperbilirubinemia; often - abnormal liver function; infrequently - Hepatitis, jaundice, toxic liver damage; frequency unknown - cholestasis, hematomegaly.

Disturbances from the skin and subcutaneous tissues: very often - rash (33%), itching (18%), alopecia (10%), dry skin (10%); often - erythema (3%), 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 kidneys and urinary tract: often - pollakiuria; infrequently - dysuria, imperative urge to urinate, nocturia; frequency unknown - kidney 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 (12%); often - asthenia (9%), fluid retention and swelling (5%), fever, chest pain (including non-cardiological pain), chest discomfort, general malaise; infrequently - edema of the face, gravitational edema, influenza-like syndrome, chills, sensation of changes in body temperature (alternation of "sensation of heat" and "sensation of cold"); frequency not known - local edema.

Laboratory and instrumental data: very often - an increase in the activity of "liver" transaminases, an increase in the activity of blood lipase, an increase in the concentration of lipoprotein cholesterol (including high and low density lipoproteins), an increase in the concentration of total cholesterol, an increase in the concentration of triglycerides of the 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-psistide blood, an increase in the concentration of parathyroid 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 the use of nilotinib (frequency there are no undesirable phenomena): cases of tumor lysis syndrome.

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

Overdose:It has been reported about single cases of intentional drug overdose, in which an unaccepted number of capsules were administered simultaneously with alcohol and other drugs. 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 Tasigne® 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). The absorption and subsequent elimination of Taciox® can 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. It should avoid the simultaneous use of nilotinib with drugs that are potent inhibitors of the isoenzyme 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 Taciox® should, if possible, be suspended. 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 Tasignon® with grapefruit juice and other products that are known inhibitors of the isoenzyme CYP3A4.

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

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%.

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, rifamgschin, 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.

The solubility of nilotinib is 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 (40 mg once daily for 5 days), the decrease in absorption of nilotinib was moderate (a decrease in C_max and AUC by 27% and 34%, respectively). If necessary, Tasigne® 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 famotidip and 2 hours before taking famotidine. Therefore, if the use of H2-histamine receptor blockers is necessary in the context of therapy with Tasigne®, they should be taken 10 hours before or 2 hours after taking the Taciox® drug.

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 ilotinib. Therefore, if antacids are needed, they should be taken 2 hours before or about 2 hours after taking Taciox®.

Influence and nilotinib on the concentration in the blood plasma of drugs used as concomitant therapy

Nilotimibe, being a competitive inhibitor of isoenzymes CYP3A4. CYP2C8, CYP2C9, CYP2D6 and UGTIAI in vitro, the lowest value of the inhibition constant (Ki) is 0.13 μmol for CYP2C9. In healthy individuals, the use of nilotinib along with warfarin (a 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 concomitantly with warfarin without increasing the anti-inflammatory 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. Nilothymib is a moderate inhibitor of the 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, dihydroergomamine, ergotamine, fentanyl, sirolimus, tacrolimus , etc.), appropriate monitoring and dose adjustment may be required. Antiarrhythmics and other medicines, The elongation of the QT interval

Do not use nilothimib with antiarrhythmic drugs (eg, amiodarone, disopyramide, procainamide, quinidine and sotalol, etc.) and other drugs that cause lengthening of the interval QT (for example, chloroquine, halofantrine, clarygromycin, 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 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 the use of Tacigpa® possibly development of loud-bloodedness, neutropenia and anemia (most often in patients with CML in the accelerated 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. as a rule, was reversible and controlled. The normalization of platelets and neutrophils was usually achieved after the temporary discontinuation of therapy with Tasigne® or reduce the dose of the drug.

Cases of sudden death

With the use of the Tasigna preparation® in clinical studies, cases (frequency 0.1-1%, gradation - "infrequently") of sudden death of patients with heart disease or a high risk of complications from the cardiovascular system were noted.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 the Tasigna preparation® 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. 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. It is necessary to monitor the function of the cardiovascular system, as well as assess the risk factors for the development of complications from the cardiovascular system throughout the duration of therapy with Tasox® .

Fluid retention

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 postmarketering 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.

Control of laboratory data Lipid profile of blood serum

In a clinical study, 1.1% of patients with newly diagnosed Ph+ 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 the Tasox preparation® , and also 3 and 6 months after the beginning of treatment with the drug, and at least I times a year with prolonged use.

Caution should be exercised when using HMG-CoA reductase inhibitors (lipid-lowering drugs) concomitantly with the preparation of Tacis® , since the pathway of metabolic transformations of HMG-CoA reductase inhibitors occurs with the participation of an isoenzyme CYP3A4 (see section "Interaction with Other Drugs and Other Interactions").

The concentration of glucose in the blood plasma

In a clinical study, 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, as well as, if necessary, during treatment with Tasigne® .

Increased activity of blood plasma lipase

When the activity of lipase in the blood plasma is increased, accompanied by abdominal symptoms, the drug should be stopped and an appropriate examination of the patient to exclude pancreatitis.

Dysfunction of the liver

With the use of the Tasigna preparation® it is recommended to carry out monthly monitoring of liver function (trapsaminase, bilirubin).

Patients who underwent gastrectomy

Since patients who undergone gastrectomy, the bioavailability of nilotipib 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 clinically significant dehydration and increased uric acid concentration in patients should be corrected, if necessary.

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

Some side effects of the drug, including dizziness or visual disturbances, can adversely affect the ability to drive vehicles and carry out potentially dangerous activities that require increased concentration and speed of psychomotor reactions. When these undesirable phenomena appear, one should refrain from these activities.

Form release / dosage:

Capsules 150 mg and 200 mg.

Packaging:

Primary packaging

For 4 or 8 capsules per blister of PVC / PVDC.

Secondary packaging

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

For 5 blisters but 8 capsules together with instructions for use in a cardboard box - 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.

Terms of leave from pharmacies:On prescription

Registration number:LP-000574

Date of registration:26.08.2011 / 11.04.2014

Expiration Date:26.08.2016

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA, AG Switzerland

Representation: & nbspPHARMSTANDART-Ufa-VITA, JSCPHARMSTANDART-Ufa-VITA, JSC

Information update date: & nbsp13.08.2015

Illustrated instructions

Instructions

Tacsin® (Tasigna®)