Сутент®

General characteristics. Structure:

Capsule of 12,5 mg. A solid gelatin capsule with a lid and the basis of red-brown color on which lid "Pfizer" is printed, and on the case - "STN 12,5 mg". Capsule of 25 mg. A solid gelatin capsule with a lid of brownish-orange color and the basis of red-brown color on which lid "Pfizer" is printed, and on the case - "STN 25 mg". Capsule of 50 mg. A solid gelatin capsule of light brownish-orange color on which lid "Pfizer" is printed, and on the case - "STN 50 mg". The text on the capsule of any dosage is put with ink white. The capsule contains granules from yellow till orange color.

Pharmacological properties:

Pharmacodynamics. Сунитиниб it is capable to inhibit at the same time receptors of various tyrosinekinases (RTK) participating in processes of growth of tumors, a pathological angiogenesis and formation of metastasises. Shows the inhibiting activity concerning many kinases (> 80 kinases). It was shown that it is powerful inhibitor of receptors of a platelet growth factor (PDGFRa and PDGRFb), receptors of a growth factor of a vascular endothelium (VEGRF1, VEGRF2 and VEGRF3), a receptor of a factor of stem cells (KIT), a receptor of a Fms-like tyrosinekinase-3 (FLT), a receptor of a colony stimulating factor (CSF-1R) and a receptor of a neurotrophic glial factor (RET). Activity of the main metabolite was similar to that of a sunitinib. Сунитиниб inhibited phosphorylation of many RTK (PDGRFb, VEGRF2 and KIT) in ksenografta of the tumors expressing target RTK in vivo and showed suppression of growth of a tumor or its regression and/or suppression of metastasises on experimental models of various tumors. Сунитиниб showed ability to inhibit growth of the tumor cells expressing deregulirovanny target RTK (PDGFR, RET, or KIT) in vitro and PDGRFb- and VEGRF2-a dependent angiogenesis of in vivo.

Pharmacokinetics. Сунитиниб it is well soaked up at intake. Time of achievement of the maximum concentration of Smaks made 6-12 hours (Тмакс) after reception. Meal does not influence bioavailability of a sunitinib. Linkng of a sunitinib and its main metabolite with proteins of plasma made 95 and 90%, respectively, without explicit dependence on concentration ranging from 100 to 4000 ng/ml. The size of settlement volume of distribution in fabrics (Vd/F) made 2230 l. Metabolism of a sunitinib carries out generally CYP3A4 isoenzyme, P450 cytochrome enzyme therefore the main active metabolite which is metabolized further by the same isoenzyme of CYP3A4 is formed. The share of an active metabolite makes 23-37% of area size under a curve "concentration time" (AUC). Сунитиниб it is removed generally with a stake (61%); through kidneys in the form of drug and its metabolites about 16% of the entered dose are removed. The general clearance at intake reached 34-62 l/hour. After single oral administration of drug by healthy volunteers time of semi-removal of a sunitinib and its main active metabolite makes 40-60 and 80-110 hours, respectively. At repeated daily use there is a 3-4-fold accumulation of a sunitinib and 7-10-fold accumulation of its main metabolite. Equilibrium concentration of a sunitinib and its main active metabolite are reached in 10-14 days. By 14th day total concentration of a sunitinib and its main active metabolite in plasma makes 62,9-101 ng/ml. At repeated daily use or recycles with various mode of dosing no considerable changes in pharmacokinetics of a sunitinib and its main active metabolite are revealed. The age, weight, clearance of creatinine, race, floor or assessment according to classification of East joint group of oncologists (ECOG scale) do not exert clinically significant impact on pharmacokinetics of drug and its active metabolite. Body weight and quality of life: the population pharmacokinetic analysis showed that there is no need of correction of an initial dose of drug depending on body weight and quality of life on ECOG scale. Floor: the available data show that the seeming clearance of a sunitinib at women can be 30% lower, than at men, however this difference does not demand correction of an initial dose of a sunitinib.

Indications to use:

Gastrointestinal stromal tumors in the absence of effect of therapy imatiniby owing to resistance or intolerance; widespread and/or metastatic pochechnokletochny cancer at the patients who were not receiving earlier specific treatment; widespread and/or metastatic pochechnokletochny cancer in the absence of effect of therapy by cytokines.

Route of administration and doses:

Inside. Administration of drug does not depend on meal. The recommended dose of the drug Sutent® makes 50 mg a day inside within 4 weeks with the subsequent break in 2 weeks (mode 4/2). The full cycle of therapy makes, thus, 6 weeks. If administration of drug was missed, it is not necessary to fill the passed dose. The patient has to accept the usual appointed drug dose next day. Depending on individual portability and safety the daily dose of the drug Sutent® can be reduced or increased by 12,5 mg, and has to make no more than 87,5 mg and not less than 37,5 mg. Use for children: efficiency and safety of the drug Sutent® at children is not established. Use for patients of advanced age: dose adjustment is not required. Use for patients with an abnormal liver function: at increase in activities of the nuclear heating plant and/or ALT exceeding the upper bound of norm less than by 2,5 times or, in case of increase in these indicators owing to a basic disease, less than by 5 times dose adjustment is not required. Use for patients with a renal failure: at increase in concentration of serumal creatinine less than twice exceeding the upper bound of norm dose adjustment it is not required.

Features of use:

Treatment by the drug Sutent® should be carried out under observation of the doctor having experience with antineoplastic drugs. At the beginning of each cycle of therapy it is necessary to carry out by the drug Sutent® an integrated analysis of hematologic indicators. Messages on cases of bleedings, sometimes deadly, including gastrointestinal bleedings, bleedings from respiratory tracts, tumors, urinary tract and hemorrhage were hit in a brain. These phenomena can unexpectedly arise, and in case of the tumoral centers in lungs to be shown in the form of a heavy or zhizneugrozhayushchy pneumorrhagia or pulmonary bleeding. It is periodically necessary to perform medical examination and to estimate blood indicators for early identification of the first symptoms of bleeding and use of necessary therapeutic measures. At the accompanying therapy by anticoagulants it is necessary to watch indicators of coagulability of blood. Communication between inhibition of a receptor of a tyrosinekinase (PTK) and cordial function is not studied. It is unknown whether patients at whom cases of cardiovascular diseases within the last 12 months before purpose of treatment sunitiniby, such as a myocardial infarction (including heavy/unstable stenocardia), coronary/peripheral shunting, symptomatic congestive heart failure, cerebrovascular complications or tranzitorny ischemic disturbances, or a pulmonary embolism, to bigger risk of development of the dysfunction of a left ventricle connected with treatment were registered are exposed. At purpose of the drug Sutent® of this category of patients it is necessary to estimate carefully a ratio risk/advantage at purpose of the drug Sutent®. During therapy by the drug Sutent® of patients it is necessary to inspect periodically regarding detection of clinical signs and symptoms of the congestive heart failure (CHF). FVLZh is recommended to be estimated prior to therapy, and also periodically during treatment. At manifestation of clinical signs of ZSN treatment sunitiniby should be stopped. In the absence of clinical signs of ZSN, but with FVLZh indicators or reduction of this indicator more than for 20% in comparison with initial (prior to therapy), a dose of a sunitinib administration of drug is recommended to reduce or stop less than 50%. At the concentration approximately twice exceeding therapeutic сунитиниб promotes lengthening of an interval of QTcF (Frederik's correction). The clinical importance of this effect is not clear and depends on risk factors and a susceptibility of the specific patient. Сунитиниб it is necessary to apply with care at patients with lengthening of an interval of Q-T in the anamnesis, at the patients accepting antiarrhytmic drugs or at patients with the corresponding heart diseases, bradycardia or disturbances of electrolytic balance. It is required to be careful and reduce a dose of a sunitinib at a concomitant use of powerful inhibitors of an isoenzyme of CYP3A4 which can increase concentration of a sunitinib in plasma. Prior to therapy and in the course of treatment the drug Sutent® recommends ECG control. Patients should be inspected regarding developing of arterial hypertension, using standard control methods of arterial pressure. At patients with a severe form of the arterial hypertension which is not giving in to treatment the temporary termination of therapy is recommended by the drug Sutent®. Therapy is resumed as soon as it is possible to stop arterial hypertension. The background research of laboratory indicators of function of a thyroid gland at patients with a hypothyroidism or a hyperthyroidism is recommended. Treatment of patients with a hypothyroidism is carried out according to standard medical practice prior to therapy sunitiniby. Observation of all patients is recommended during therapy sunitiniby regarding development of dysfunction of a thyroid gland. Patients with signs and/or symptoms of dysfunction of a thyroid gland have to undergo laboratory control. Patients should be warned that during treatment by the drug Sutent® change of coloring of skin owing to existence in drug of dye can be observed (yellow). Also there can be a decolouration of hair or skin. As at use of the drug Sutent® there can be nausea and vomiting, it is necessary to provide preventive purpose of antiemetic drugs. When developing diarrhea appoint antidiarrheal means. During treatment by the drug Sutent® it is periodically necessary to check activity of a lipase and amylase in blood serum. At existence or emergence of symptoms of pancreatitis regular medical control is necessary. Patients with metastasises in a brain, spasms in the anamnesis and/or signs/symptoms of a reversible back leukoencephalopathy, such as arterial hypertension, headache, block, cerebration disturbance, sight loss, including a cortical blindness, it is necessary to control by standard methods, including control of arterial pressure. In case of these symptoms against the background of therapy it is recommended to stop administration of drug of Sutent® temporarily. After disappearance of symptoms treatment can be resumed according to the decision of the attending physician. At emergence of a trombotichesky mikroangiopatiya the temporary termination of treatment sunitiniby is recommended. After disappearance of symptoms treatment can be resumed according to the recommendation of the attending physician. The background research of function of kidneys prior to treatment, and also monitoring of indicators of function of kidneys is recommended during therapy sunitiniby. Safety of reception of a sunitinib at patients with a proteinuria of average or heavy weight was not estimated. Patients with a nephrotic syndrome sunitiniby should stop treatment. In time and within, at least, three months after the therapy termination by the drug Sutent® it is necessary to use reliable methods of contraception. Fertility on the basis of results of preclinical trials it is possible to draw a conclusion that therapy sunitiniby can have an adverse effect on fertility of men and women Influence on ability of driving of the car and control of mechanisms. Patients need to be warned about a possibility of emergence during treatment by the drug Sutent® of dizziness and other side effects which can affect ability of driving and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

The most important serious by-effects connected with treatment by the drug Sutent® were: pulmonary embolism (1%), thrombocytopenia (1%), tumoral bleeding (0,9%), febrile neutropenia (0,4%) and arterial hypertension (0,4%). In 2% of cases at patients with metastatic nephrocellular cancer venous thromboembolisms were described: a pulmonary embolism (4 degrees) - at two patients and a deep vein thrombosis (3 degrees) - at two patients. At the patients with gastrointestinal stromal tumors receiving сунитиниб venous thromboembolisms observed at seven patients (3%). At five of seven the deep vein thrombosis 3 degrees, and at two patients - 1 or 2 degrees was noted. The most frequent by-effects of all degrees connected with treatment by the drug Sutent® (noted at more than, 20% of patients), the fatigue, gastrointestinal disturbances, such as diarrhea, nausea, stomatitis, dyspepsia and vomiting, and also disturbance of a xanthopathy were; rash; syndrome of a ladonnopodoshvenny eritrodizesteziya; xeroderma; hair-dyeing change; inflammation of mucous membranes; adynamy, disturbance of taste and anorexia. Patients with solid tumors the most widespread by-effects connected with therapy by the drug Sutent® had a fatigue, arterial hypertension and a neutropenia up to the 3rd severity and increase in activity of a lipase up to the 4th degree. The by-effects connected with treatment sunitiniby, noted in clinical trials at least at> 5% of patients with solid tumors, are given below and systematized on system and organ classes, frequency and severity. In each group by-effects are located as severity reduction. Frequency: very often (≥ 1/10), it is frequent (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), is rare (≥ 1/10000 to <1/1000), is very rare (<1/10000). From bodies of a hemopoiesis: very often – anemia, a neutropenia, thrombocytopenia; often – a leukopenia.

From digestive organs: very often – a food faddism, diarrhea, nausea, vomiting, stomatitis, mukozita, dyspepsia, pains in a stomach, anorexia, a lock, a glossodynia (language neuralgia), a meteorism, dryness in a mouth; often – mouth pain, a gastroesophageal reflux; infrequently – pancreatitis; seldom – gastrointestinal perforation.

From skin and skin appendages: very often – change of coloring of skin, a palmar and bottom syndrome (eritrodizesteziya), rash (erythematic, spotty, papular, scaly, generalized, psoriazopodobny), blisters, discoloration of hair, a xeroderma, an erythema; often – an alopecia, a skin peeling, a skin itch, exfoliative dermatitis.

From a musculoskeletal system: often – extremity pain, an arthralgia, a mialgiya.

From a nervous system: very often – a headache; often – dizziness, paresthesias, sleeplessness or the increased drowsiness, a depression.

From cardiovascular system: very often – increase in arterial pressure; often – decrease in the fraction of emission of a left ventricle (FELV), venous thromboembolisms (a pulmonary embolism, a deep vein thrombosis); infrequently – heart failure, congestive heart failure, dysfunction of a left ventricle, it is rare – lengthening of an interval of Q-T, blinking and an atrial flutter on the pirouette type.

From an urinary system: often – a chromaturia (urine coloring change). 

From a respiratory organs: very often - nasal bleeding; often – short wind, laryngopharyngeal pains. 

From endocrine system: often – a hypothyroidism, increase in level of thyritropic hormone. Other: very often - an adynamy / increased fatigue, increase in activity of a lipase in blood serum; often – dacryagogue, a body degrowth, flu, fever, a fever, peripheral hypostases, periorbital hypostasis, dehydration, increase in blood serum of activity of a kreatinfosfokinaza and activity of amylase; infrequently – bleedings from tumors, a grippopodobny syndrome. At patients with metastasises in a brain or with a syndrome of a reversible leukoencephalopathy cases of spasms are described. Results of a post-market research during use of a sunitinib after its registration the following undesirable phenomena were recorded.

From bodies of a hemopoiesis: It is reported about exceptional cases of a trombotichesky mikroangiopatiya. In such cases it is recommended to suspend reception of a sunitinib temporarily; after permission of symptoms administration of drug can be resumed at the discretion of the attending physician.

From a respiratory organs: It is reported about cases of an embolism of a pulmonary artery, sometimes with a lethal outcome. From endocrine system: In clinical trials and during post-marketing use of drug exceptional cases of a hyperthyroidism with transition to a hypothyroidism were recorded.

From immune system: It is reported about hypersensitivity reactions, including a Quincke's disease. Infections and invasions: It is reported about cases of serious infections (against the background of a neutropenia or without), a part of which came to the end with a lethal outcome.

From a musculoskeletal system: There are messages on exceptional cases of a myopathy and/or a rabdomioliz in a combination or without combination to an acute renal failure, to exceptional cases of a lethal outcome. Most of such patients had initial risk factors and/or they received the accompanying therapy by drugs for which undesirable reactions of this sort are inherent. Messages on cases educations of the fistulas sometimes connected with a necrosis and/or regression of a tumor some of which came to the end with a lethal outcome are had.

From a nervous system: There are messages on cases of disorders of flavoring sensitivity, including an ageusia.

From an urinary system: There are messages on cases of dysfunction of kidneys / a renal failure some of which came to the end with a lethal outcome. It is reported about cases of a proteinuria and exceptional cases of a nephrotic syndrome.

From cardiovascular system: It was reported about cardiomyopathy cases some of which came to the end with a lethal outcome.

Interaction with other medicines:

The drugs increasing concentration of a sunitinib in plasma. Combined use of a single dose of a sunitinib with CYP3A4 isoenzyme inhibitor, ketokonazoly, raises Cmax and AUC0-∞ a complex of a sunitinib and the main active metabolite at healthy volunteers for 49% and 51%, respectively. Use of the drug Sutent® together with other inhibitors of an isoenzyme CYP3A4 (for example, ritonaviry, itrakonazoly, erythromycin, klaritromitsiny or grapefruit juice) can lead to increase in concentration of a sunitinib. It is necessary to avoid joint reception of inhibitors of an isoenzyme of CYP3A4 with the drug Sutent® or it is necessary to choose alternative drug with the minimum ability to CYP3A4 isoenzyme inhibition. If it is not possible probably it is necessary to reduce a daily dose of a sunitinib by 12,5 mg. In this case the daily dose has to be not less than 37,5 mg. The drugs reducing concentration of a sunitinib in plasma. Combined use of a single dose of a sunitinib with CYP3A4 isoenzyme inductor, rifampicin, lowers Cmax and AUC0-∞ at healthy volunteers by 23% and 46%, respectively. Use of the drug Sutent® together with other inductors of an isoenzyme CYP3A4 (for example, dexamethasone, Phenytoinum, karbmazepiny, the rifampicin, phenobarbital or a St. John's Wort which is made a hole) can lead to reduction of concentration of a sunitinib. It is necessary to avoid joint reception of inductors of an isoenzyme of CYP3A4 with the drug Sutent® or it is necessary to choose alternative drug with the minimum ability to induction of an isoenzyme of CYP3A4. If it is not possible probably it is necessary to increase a dose of a sunitinib by 12,5 mg, controlling portability of drug the patient. The daily dose in this case should not exceed 87,5 mg.

Contraindications:

Hypersensitivity to a sunitinib or other components of drug; pregnancy and period of feeding by a breast; children's age (efficiency and safety of the drug Sutent® at children is not established).

Overdose:

The specific antidote does not exist. At overdose a symptomatic treatment. If necessary, it is recommended to cause vomiting or to carry out a gastric lavage.

Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children!

Issue conditions:

According to the recipe

Packaging:

Capsules on 12,5 mg, 25 mg and 50 mg. Primary packaging: On 28 or 30 capsules in a bottle from polyethylene of high density with the protecting laying from a foil with the Pfizer logos with the screw-on cover protecting from opening by children. The label is applied on a bottle. On 7 capsules in the blister from a PVC film / Aklar and aluminum foil. Secondary packaging: On one bottle or on 4 blisters on 7 capsules together with the application instruction in a cardboard pack.