Sunitinib in patients with renal cell carcinoma after nephrectomy

Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits tumor growth, pathological angiogenesis, and metastasis. Indications for use are: gastrointestinal stromal tumors, renal cell carcinoma.

The purpose of the S-TRAC analysis was to determine the efficacy and safety profile of sunitinib in patients with high-recurrence locoregional renal cell carcinoma following nephrectomy.

Methods

The phase 3, randomized, double-blind study included 615 patients 18 years of age or older with high-risk locoregional clear cell renal cell carcinoma. Patients were randomized into 2 groups: sunitinib 50 mg daily or placebo for 4 weeks, then 2 weeks off, and then on a 4/2 schedule for one year or until disease relapse, severe drug toxicity, or the patient was excluded from the analysis.

The disease-free period was chosen as the primary endpoint; the disease-free period assessed by investigators, overall survival, and safety of therapy were selected as secondary endpoints.

Compound:

For 1 capsule:

results

• The median disease-free survival period was 6.8 years (95% CI, 5.8 - not reached the limit) in the group of patients receiving sunitinib and 5.6 years (95% CI, 3.8-6.6) in the placebo group (hazard ratio (HR) ), 0.76; 95% CI, 0.59 to 0.98; P=0.03).
• Dose reductions due to adverse events occurred more frequently in the sunitinib group compared with the control group (34.3% vs. 2%), as did dose interruptions (46.4% vs. 13.2%) and discontinuation of the drug (28.1% vs. 2%). 5.6%).
• Grade 3 and 4 adverse events were more frequently reported in subjects receiving sunitinib (48.4% grade 3 and 12.1% grade 4 events) compared with controls (15.8% and 3.6%, respectively).
• The incidence of serious adverse events was comparable in both groups (21.9% for sunitimab and 17.1% for placebo), and no deaths were attributed to treatment toxicities.

Instructions for use SUTENT

Leather and fabrics

Change in skin color due to the color of the drug's active ingredient (yellow) is a very common adverse reaction, occurring in approximately 30% of patients. Patients should be warned that depigmentation of hair or skin may also occur during treatment with sunitinib. Other possible adverse dermatologic reactions may include dry, thickened or cracked skin, blistering, or an occasional rash on the palms of the hands and soles of the feet.

The above-described adverse reactions did not accumulate, were usually reversible and did not lead to discontinuation of treatment.

Hemorrhagic reactions

Hemorrhagic reactions reported during post-marketing surveillance (some of which were fatal) included gastrointestinal bleeding, respiratory tract bleeding, tumor bleeding, urinary tract bleeding and cerebral hemorrhage. In clinical studies, treatment-related tumor bleeding was observed in approximately 2% of patients with gastrointestinal stromal tumors. These reactions can occur suddenly and, in the case of pulmonary tumors, can be the source of serious and life-threatening hemoptysis or pulmonary hemorrhage. In a clinical trial in patients with metastatic non-small cell lung cancer (NSCLC), fatal pulmonary hemorrhage occurred in 2 patients receiving sunitinib. In both patients, histology revealed squamous cell carcinoma. Sunitinib has not been approved for the treatment of patients with non-small cell lung cancer.

In the double-blind treatment phase of the gastrointestinal stromal tumor study, treatment-related bleeding occurred in 18% of patients receiving sunitinib and 17% of patients receiving placebo. Bleeding occurred in 39% of patients receiving sunitinib and in 11% of patients receiving interferon-alpha for previously untreated metastatic renal cell carcinoma. Eleven patients (1.9%) receiving sunitinib and one patient (0.3%) receiving interferon alfa experienced grade 3 or higher treatment-related hemorrhagic reactions. Bleeding events were reported in 26% of patients receiving sunitinib for metastatic renal cell carcinoma refractory to cytokine therapy. Standard evaluation of this adverse reaction should include a complete blood count and physical examination.

Gastrointestinal tract

Serious and fatal gastrointestinal complications, including perforation, have rarely been observed in patients with intra-abdominal tumors treated with sunitinib.

Reactions from the gastrointestinal tract

The most common gastrointestinal adverse reactions were nausea, diarrhea, stomatitis, dyspepsia and vomiting. Replacement therapy for gastrointestinal adverse events requiring treatment may include drugs with antiemetic or antidiarrheal effects.

Pancreatitis

Increases in serum lipase and amylase were observed in patients with various solid tumors who received sunitinib. Elevations in lipase levels were transient and were not accompanied by signs or symptoms of pancreatitis in subjects with various solid tumors. Pancreatitis was observed in 0.4% of patients with solid tumors. If symptoms of pancreatitis or liver failure occur, stop taking sunitinib and provide the patient with appropriate medical care.

Hepatotoxicity

Cases of hepatotoxicity have been reported in patients taking sunitinib.

Liver failure, some fatal, has been reported in <1% of patients with solid tumors. It is recommended to monitor liver function indicators (ALT, AST, bilirubin levels) before prescribing the drug, at the beginning of treatment, at the end of each cycle, and as clinically necessary. If adverse reactions of grade 3 and 4 from the liver develop, the drug should be suspended, and if there is no reverse dynamics, discontinued.

Hematological reactions

Grade 3 and grade 4 decreases in absolute neutrophil counts were reported in 13.1% and 0.9% of patients, respectively. Grade 3 and 4 platelet counts were reported in 4% and 0.5% of patients, respectively. The above-described adverse reactions did not accumulate, were usually reversible and did not lead to discontinuation of treatment. In addition, several cases of fatal bleeding associated with thrombocytopenia have been reported during post-marketing surveillance.

Patients receiving sunitinib treatment should have a complete blood count done at the start of each treatment cycle.

Cardiovascular reactions

During post-marketing surveillance, cases of cardiovascular manifestations have been reported, incl. heart failure, myocardiopathy and myocardial disorders; some of them were fatal. In clinical trials, a decrease in LVEF of ≥20% and below the lower limit of normal occurred in approximately 2% of patients with gastrointestinal stromal tumors, in 4% of patients with metastatic renal cell carcinoma refractory to cytokine therapy treated with sunitinib, and in 2% of patients who received placebo. These declines in LVEF were not progressive and often improved with continued treatment.

In a study of previously untreated metastatic renal cell carcinoma, 27% of patients receiving sunitinib and 15% of patients receiving interferon alfa had LVEF below the lower limit of normal. Two patients (<1%) receiving sunitinib were diagnosed with congestive heart failure.

Adverse reactions such as “heart failure”, “congestive heart failure” or “left ventricular failure” were observed in 0.7% of patients with solid tumors and in 1% of patients receiving placebo. In a phase 3 study of sunitinib for the treatment of pancreatic neuroendocrine tumors, one (1%) patient experienced treatment-related fatal heart failure.

Clinical studies with sunitinib excluded patients who experienced cardiac reactions, such as:

• myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass grafting, symptomatic congestive heart failure, stroke or transient ischemic attack or pulmonary embolism. It is unknown whether patients with these underlying conditions are at higher risk of developing drug-related left ventricular dysfunction. Doctors are advised to weigh this risk against the potential benefits of taking the drug. These patients should be closely monitored for clinical signs and symptoms of congestive heart failure while taking sunitinib. Patients receiving sunitinib should also take into account the results of baseline and periodic LVEF assessments. If patients do not have risk factors for heart disease, consideration should be given to performing a baseline assessment of ejection fraction.

If clinical signs of congestive heart failure appear, it is recommended to discontinue sunitinib. In the absence of clinical symptoms of congestive heart failure in patients, sunitinib should be discontinued or its dose should be reduced if the ejection fraction is <50% and its decrease is >20% of the initial value.

QT prolongation

At concentrations 2 times the therapeutic value, sunitinib has been demonstrated to prolong the QTcF interval (as adjusted using the Frederick formula). No patients with QT/QTc interval prolongation above grade 2 according to the Common Terminology Criteria v3.0 (CTCAE) were registered. Prolongation of the QT interval may lead to a higher risk of developing ventricular arrhythmias, including torsade de pointes. Torsade de pointes arrhythmia has been reported in <0.1% of patients treated with sunitinib. Sunitinib should be used with caution in patients with a history of QT prolongation, in patients using antiarrhythmic drugs, in patients with existing cardiac disease, bradycardia, or electrolyte disturbances. Co-administration of the drug with CYP3A4 inhibitors, which may lead to increased sunitinib plasma concentrations, should be used with caution and the dose of sunitinib should be reduced.

Hypertension

Treatment-related hypertension was observed in approximately 16% of patients with solid tumors. Sunitinib dosing was reduced or temporarily discontinued in approximately 2.7% of patients in this population. None of these patients discontinued sunitinib treatment. Severe hypertension (systolic pressure >200 mmHg or diastolic pressure >110 mmHg) occurred in 4.7% of patients in this population. Treatment-related hypertension was reported in approximately 30% of patients receiving sunitinib for the treatment of previously untreated metastatic renal cell carcinoma and in 6% of patients receiving interferon alfa. Severe hypertension occurred in 12% of patients with previously untreated metastatic renal cell carcinoma treated with sunitinib and in less than 1% of patients receiving interferon alfa. Treatment-related hypertension occurred in approximately 23% of patients treated with sunitinib in the phase 3 pNET study, compared with 4% of patients treated with placebo. Severe hypertension occurred in 10% of patients with pancreatic neuroendocrine tumor treated with sunitinib and in 3% of patients treated with placebo. It is necessary to monitor blood pressure in patients for arterial hypertension and, if necessary, take appropriate measures. For patients with severe hypertension that is not controlled with medication, a temporary suspension of treatment is recommended. Treatment may be resumed once hypertension is controlled.

Thyroid dysfunction

An initial laboratory assessment of thyroid function is recommended. Patients with symptoms of hypothyroidism should be treated according to medical standards before starting sunitinib. While taking sunitinib, patients should be closely monitored for signs and symptoms of thyroid dysfunction. In patients with symptoms of thyroid dysfunction, thyroid function should be monitored using laboratory methods and treated according to medical standards. Acquired treatment-emergent hypothyroidism was reported in 4% of patients with gastrointestinal solid tumors receiving sunitinib compared with 1% of patients receiving placebo. Hypothyroidism as an adverse event was reported in 16% of patients treated with sunitinib in a study with previously untreated metastatic renal cell carcinoma and in three patients (<1%) in the interferon-alpha group and 4% of patients in two studies with metastatic renal cell carcinoma refractory to cytokine therapy. In addition, TSH elevations have been reported in 2% of patients with metastatic renal cell carcinoma refractory to cytokine therapy. Overall, among a population of patients with metastatic renal cell carcinoma refractory to cytokine therapy, 7% had either clinical or laboratory reactions to treatment-emergent hypothyroidism. In a phase 3 study of pancreatic neuroendocrine tumor with sunitinib, treatment-emergent hypothyroidism was reported in 5 patients (6%) receiving sunitinib and one patient receiving placebo. Rare cases of hyperthyroidism, in some cases with subsequent development of hypothyroidism, have been reported in clinical studies and post-marketing surveillance.

Convulsions

In clinical studies with sunitinib, seizures were reported in patients with radiological evidence of brain metastases. In addition, there have been rare reports (<1%) of patients with seizures and radiographic evidence of reversible posterior leukoencephalopathy syndrome (RPLS). In none of these patients was death observed as an outcome of the reaction. Patients with seizures and signs/symptoms consistent with reversible posterior leukoencephalopathy syndrome, such as:

• hypertension, headache, decreased alertness, changes in mental capacity, and vision loss, including cortical blindness, should be monitored medically, including control of hypertension. Temporary discontinuation of sunitinib is recommended. After resolution of the process, according to the decision of the attending physician, treatment can be continued.

Surgery

Cases of impaired wound healing have been reported during sunitinib therapy. As a precaution, it is recommended that patients undergoing major surgery temporarily stop taking this drug.

The decision to restart therapy should be made taking into account a clinical assessment of the patient's recovery after surgery.

Osteonecrosis of the jaw
(ONJ)
​​Infrequent cases of ONJ have been reported in clinical trials and post-marketing experience. In most cases, these patients received concomitant or previous therapy in the form of intravenous bisphosphonates, which are a known risk factor for the development of ONJ. Caution should be exercised when administering sunitinib and intravenous bisphosphonates simultaneously or sequentially. Risk factors for developing ONJ also include invasive dental procedures. Before initiating treatment with sunitinib, a dental examination and, if necessary, prophylactic dental treatment should be performed. Patients who have previously received or are receiving intravenous bisphosphonates should avoid invasive dental procedures if possible.

Tumor lysis syndrome (TLS)

Rare, sometimes fatal, cases of TLS have been reported in clinical trials and post-marketing experience in patients receiving sunitinib. The high-risk group for developing TLS includes patients with a high degree of tumor decay, which was already observed before the start of treatment. Such patients should be closely monitored and treated only as indicated.

Impact on the ability to drive vehicles and operate machinery

There have been no studies examining the effect on the ability to drive a car or operate machinery. Patients should be advised that they may experience dizziness during treatment with sunitinib.

Preclinical safety data

Repeated dose toxicity studies in rats and mice for up to 9 months have identified major target organs such as: gastrointestinal tract (vomiting and diarrhea in monkeys), adrenal glands (cortical collection and/or hemorrhage in rats and monkeys, with necrosis accompanied by fibrosis in rats), hemolymphopoietic system (hypocellularity of the bone marrow and lymphoid depletion of the thymus, spleen and lymph nodes), exocrine glands (degranulation of acinar cells with necrosis of individual cells), salivary glands (acinar hypertrophy), bone joints (compaction of growth plates ), uterus (atrophy), ovaries (reduced follicular development). All data were obtained at clinically relevant sunitinib exposure levels. Additional effects that were observed in other studies included:

• prolongation of the QTc interval, decreased LVEF, pituitary hypertrophy and atrophy of the seminiferous tubules, increased mesangial matrix in the kidneys, bleeding in the gastrointestinal tract and oral mucosa, and hypertrophy of anterior pituitary cells. Changes in the uterus (endometrial atrophy) and bony growth plates (physeal thickening or cartilage dysplasia) are thought to be related to the pharmacological effects of sunitinib. Most of these events reversed 2-6 weeks after the end of treatment.

Genotoxicity

The genotoxic potential of sunitinib was assessed in vitro and in vivo. Sunitinib was not mutagenic in bacteria using rat liver-induced metabolic activation. Sunitinib did not induce structural chromosomal aberrations in human peripheral blood lymphocytes in vitro. Polyploidy (multiple chromosomal aberrations) has been observed in human peripheral blood lymphocytes in vitro, both in the presence and absence of metabolic activation. Sunitinib was not clastogenic in rat bone marrow in vivo. The genotoxic potential of the main active metabolite has not been assessed.

Carcinogenicity

Although specific carcinogenicity studies have not been conducted with sunitinib, development of carcinoma and hyperplasia.

Effect of toxicity on reproduction and development

There was no effect on fertility in male rats when administered for 58 days before mating with untreated females. In female rats, when taking the drug for 14 days before mating with untreated males at a dose leading to the development of systemic exposure 5 times higher than the systemic exposure in patients, no effect on reproduction was observed. However, in repeated dose toxicity studies in rats and monkeys, effects on female fertility in the form of follicular atresia, corpora lutea degeneration, endometrial changes in the uterus, and decreased uterine and ovarian weight were noted at levels of clinically significant systemic exposure. Effects on male fertility have been observed in the form of seminiferous tubule atrophy in the testes, decreased epididymal sperm count, and colloid wasting of the prostate and seminal vesicles, with plasma exposure levels 18 times higher than those observed in clinical practice. By the end of the recovery period (6 weeks), not all effects recorded in male rats had reversed.

No specifically designed animal studies examining the effects on perinatal and postnatal development have been conducted.

In rats, embryo-fetal mortality was evident. It was expressed in a significant decrease in the number of live litters, an increase in the number of resorptions (early and total), an increase in post-implantation mortality and loss of the entire litter in 8 of 28 pregnant females at exposure levels 5.5 times higher than those observed in the clinic. In rabbits, reductions in gravid uterine weight and number of live fetuses were observed due to increased resorption rates, increased postimplantation mortality, and complete litter loss in 4 of 6 pregnant females at exposure levels 3 times those observed in the clinic.

Treatment with sunitinib at a dose of ≥5 mg/kg/day in rats during organogenesis resulted in developmental effects manifested by an increase in the number of fetal skeletal malformations characterized by delayed ossification of the thoracic/lumbar vertebrae that occurred at plasma exposure levels blood 6 times higher than observed in the clinic. In rabbits, at exposure levels approximately equal to those observed in the clinic, the developmental effect was represented by an increased incidence of cleft lip, and at exposure levels 2.7 times higher than observed in the clinic, cleft lip and palate.

Specific studies examining the effects of toxicity on embryo-fetal development in rabbits have not been conducted since embryo-fetal effects have been clearly demonstrated in rats and reported in a preliminary study conducted in rabbits.

Interaction:

Drugs that increase the concentration of sunitinib in blood plasma The combined use of a single dose of sunitinib with the CYP3A4 isoenzyme inhibitor, ketoconazole, increases the Cmax and AUC0-∞ of the sunitinib complex and the main active metabolite by 49% and 51%, respectively.

The use of sunitinib in combination with other inhibitors of the CYP3A4 isoenzyme (for example, ritonavir, itraconazole, erythromycin, clarithromycin or grapefruit juice) may lead to increased sunitinib concentrations. Coadministration of CYP3A4 inhibitors with sunitinib should be avoided, or an alternative drug with minimal CYP3A4 inhibitory potential should be selected. If this is not possible, it will likely be necessary to reduce the daily dose of sunitinib by 12.5 mg to 37.5 mg per day for gastrointestinal stromal tumors and metastatic renal cell carcinoma and to 25 mg per day for pancreatic neuroendocrine tumors.

Drugs that reduce the plasma concentration of sunitinib

Co-administration of a single dose of sunitinib with the inducer of the CYP3A4 isoenzyme, rifampicin, reduces the Cmax and AUC0-∞ of the sunitinib complex and the main active metabolite by 23% and 46%, respectively.

Use of sunitinib in combination with other inducers of the CYP3A4 isoenzyme (for example, dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John's wort) may lead to decreased concentrations of sunitinib. Coadministration of CYP3A4 inducers with sunitinib should be avoided, or an alternative drug with minimal CYP3A4 inducing potential should be selected. If this is not possible, it will likely be necessary to increase the sunitinib dose by 12.5 mg while monitoring patient tolerance. The daily dose in this case should not exceed 87.5 mg for gastrointestinal stromal tumors and metastatic renal cell cancer and 62.5 mg for neuroendocrine tumors of the pancreas.

Pharmacokinetics:

Suction

Sunitinib is well absorbed when taken orally. The time to reach maximum concentration (Cmax) is 6-12 hours (Tmax) after administration. Food intake does not affect the bioavailability of sunitinib.

Distribution

The binding of sunitinib and its main metabolite to plasma proteins is 95% and 90%, respectively, with no apparent concentration dependence in the range from 100 to 4000 ng/ml. The estimated volume of distribution in tissues (Vd/F) is 2230 l.

Metabolism

Sunitinib is metabolized primarily by CYP3A4, a cytochrome P450 enzyme, resulting in the formation of the main active metabolite, which is further metabolized by the same CYP3A4 isoenzyme. The proportion of the active metabolite is 23-37% of the area under the curve “very often” ≥10%; “common” ≥ 1% and < 10%, “infrequently” ≥0.1% and < 1%, “rare” ≥ 0.01% < 0.1%, “very rare” - < 0.01%.

Disorders of the blood and lymphatic system: very often - anemia, neutropenia, thrombocytopenia; often - leukopenia, lymphopenia, decreased hemoglobin concentration; infrequently - pancytopenia.

Gastrointestinal tract disorders: very often - taste disturbance, diarrhea, nausea, vomiting, stomatitis (including aphthous), mucositis, dyspepsia, abdominal pain, anorexia, constipation, glossodynia (neuralgia of the tongue), flatulence, dryness oral mucosa; often - pain in the mouth, bloating, gastroesophageal reflux, loss of appetite, bleeding gums, dysphagia, ulceration of the oral mucosa, cheilitis, pain in the anus, hemorrhoids, rectal bleeding, belching; uncommon - pancreatitis; rarely - gastrointestinal perforation.

Disorders of the skin and subcutaneous tissues: very often - discoloration of the skin, palmar-plantar syndrome (erythrodysesthesia), rash (erythematous, macular, papular, pityriasis, generalized, psoriasis-like), blisters, discoloration of hair, dry skin, erythema; often - alopecia, peeling of the skin, itching, exfoliative dermatitis, impaired nail growth, yellow skin discoloration, hyperkeratosis, acne, skin hyperpigmentation, eczema; rarely - Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders: often - pain in the limbs, arthralgia, myalgia, muscle spasm, back pain, muscle weakness.

Nervous system disorders: very often - headache; often - dizziness, paresthesia, insomnia or increased drowsiness, peripheral neuropathy.

Cardiac disorders: often - decreased left ventricular ejection fraction (LVEF); uncommon - heart failure, including chronic, dysfunction of the left ventricle, pericardial effusion; rarely - prolongation of the QT interval, atrial fibrillation and atrial flutter of the “pirouette” type.

Vascular disorders: very often - increased blood pressure; often - venous thromboembolism (pulmonary embolism, deep vein thrombosis), "flushes" of blood.

Disorders of the kidneys and urinary tract: often - chromaturia (discoloration of urine); infrequently - acute renal failure.

Disorders of the respiratory system, chest and mediastinal organs: very often - nosebleeds, cough; often - shortness of breath, laryngopharyngeal pain, pleural effusion, dryness of the nasal mucosa; infrequently - hemoptysis.

Endocrine system disorders: often - hypothyroidism, increased concentration of thyroid-stimulating hormone.

Visual disturbances: often - increased lacrimation, periorbital edema, swelling of the eyelids.

Laboratory and instrumental data: very often - increased lipase activity in the blood serum; often - increased activity of liver enzymes, increased concentration of creatinine in the blood plasma, increased activity of creatine phosphokinase and amylase in the blood serum, increased concentration of uric acid in the blood plasma, decrease in body weight.

General disorders and disorders at the injection site: very often - asthenia, increased fatigue; often - flu, fever, chills, peripheral edema, dehydration, chest pain; infrequently - bleeding from tumors, delayed wound healing; rarely - tumor lysis syndrome (in some cases fatal).

In patients with brain metastases or reversible leukoencephalopathy syndrome, cases of seizures, in some cases with a fatal outcome, have been described.

Results of post-marketing studies of sunitinib

The following adverse events were recorded during the use of sunitinib after its registration:

Blood and lymphatic system disorders: Rare cases of thrombotic microangiopathy have been reported. In such cases, it is recommended to temporarily stop taking sunitinib; After symptoms resolve, the drug may be resumed at the discretion of the attending physician.

Respiratory, thoracic and mediastinal disorders: cases of pulmonary embolism, sometimes fatal, have been reported.

Endocrine disorders: Rare cases of hyperthyroidism progressing to hypothyroidism have been reported in clinical trials of sunitinib and during post-marketing use of sunitinib; infrequently - thyroiditis.

Immune system disorders: hypersensitivity reactions, including angioedema.

Infectious and parasitic diseases: Cases of serious infections (including those associated with neutropenia), some of which resulted in death, have been reported. Infections that develop during the use of sunitinib are common in cancer patients (often respiratory infections (pneumonia, bronchitis), urinary tract infections, skin infections (for example, inflammation of the subcutaneous fatty tissue), abscess (for example, oral cavity, genital area, anorectal area, skin, extremities, visceral abscess), infrequently - sepsis/septic shock). Often, infections can be bacterial (eg, intra-abdominal, osteomyelitis), viral (eg, nasopharyngitis, oral herpes) or fungal (eg, oral candidiasis, esophageal candidiasis). Rare cases of necrotizing fasciitis, including perineal involvement, have been reported, sometimes with fatal outcome.

Musculoskeletal and connective tissue disorders: There have been reports of rare cases of myopathy and/or rhabdomyolysis, with or without combination with acute renal failure, with rare cases of death. The majority of these patients had underlying risk factors and/or received concomitant therapy with drugs that are prone to adverse reactions of this kind. There are also case reports of fistula formation, sometimes associated with necrosis and/or tumor regression, some of which were fatal. Cases of necrosis of the jaw have been reported with the use of sunitinib. Most patients had risk factors for developing jaw necrosis, such as intravenous bisphosphonate use and/or previous dental treatment requiring invasive intervention.

Nervous system disorders: Cases of taste disorders, including ageusia, have been reported.

Renal and urinary tract disorders: There have been reports of cases of renal dysfunction/renal failure, some of which have been fatal. Cases of proteinuria and rare cases of nephrotic syndrome have been reported.

Cardiac disorders: Cases of cardiomyopathy have been reported, some of which have been fatal.

Vascular disorders: There have been reports of arterial thromboembolism (some fatal) in patients receiving sunitinib. The most common were: stroke, transient ischemic attack.

Risk factors, in addition to the underlying disease and the patient's age over 65 years, are: arterial hypertension, diabetes mellitus, history of thromboembolic complications. Cases of bleeding, sometimes fatal, have been reported, including gastrointestinal bleeding, respiratory tract bleeding and cerebral hemorrhage.

Skin and subcutaneous tissue disorders: There have been reports of rare cases of pyoderma gangrenosum, erythema multiforme, and toxic epidermal necrolysis.

Gastrointestinal disorders: esophagitis.

Disorders of the liver and biliary tract: hepatitis.

Impact on the ability to drive vehicles. Wed:

There is no data on the effect of Sunitinib-native on the ability to drive vehicles and operate machinery. In the event of the development of undesirable reactions from the musculoskeletal and connective tissue, visual organs or nervous system when using the drug Sunitinib-native, you should refrain from driving vehicles and machinery, as well as from engaging in other potentially hazardous activities that require increased concentration and speed. psychomotor reactions.

Pharmacodynamics:

Sunitinib is able to simultaneously inhibit the receptors of various tyrosine kinases (RTKs) involved in the processes of tumor growth, pathological angiogenesis and the formation of metastases. Shows inhibitory activity against many kinases (> 80 kinases). It has been shown to be a potent inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGRFβ), vascular endothelial growth factor receptors (VEGRF1, VEGRF2 and VEGRF3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 receptor (FLT), colony-stimulating factor receptor (CSF-1R) and glial-derived neurotrophic factor receptor (RET). The activity of the main metabolite was similar to that of sunitinib.

Sunitinib inhibited the phosphorylation of multiple RTKs (PDGRFβ, VEGRF2, and KIT) in tumor xenografts expressing target RTKs in vivo and demonstrated inhibition of tumor growth or regression and/or inhibition of metastasis in experimental models of various tumors. Sunitinib has demonstrated the ability to inhibit the growth of tumor cells expressing deregulated target PTKs (PDGFR, RET, or KIT) in vitro and PDGRFβ- and VEGRF2-dependent angiogenesis in vivo.