PRONORAN

INSTRUCTIONS FOR MEDICAL USE OF SUNITINIB-VISTA MEDICINE

COMPOSITION

The active substance is sunitinib; 1 capsule contains 12.5 mg or 25 mg, or 37.5 mg, or 50 mg of sunitinib; excipients: microcrystalline cellulose (E 460), mannitol (E 421), sodium croscarmellose, povidone (E 1201), magnesium stearate (E 470b); capsule shell: gelatin, for capsules of: 12.5 mg - red iron oxide (E 172), titanium dioxide (E 171); 25 mg and 50 mg - black iron oxide (E 172), red iron oxide (E 172), yellow iron oxide (E 172), titanium dioxide (E 171); 37.5 mg - yellow iron oxide (E 172), titanium dioxide (E 171).

PHARMACEUTICAL FORM

Hard capsules.

MAIN PHYSICOCHEMICAL PROPERTIES

12.5 mg: gelatin capsules size 4 with an orange cap and an orange body, with white ink writing "12.5 mg" on the body, which contain granules from yellow to orange in color; 25 mg: gelatin capsules size 3 with a caramel cap and an orange body, with white ink writing "25 mg" on the body, which contain granules from yellow to orange in color; 37.5 mg: gelatin capsules size 2 with a yellow cap and a yellow body, with black ink writing "37.5 mg" on the body, which contain granules from yellow to orange in color; 50 mg: gelatin capsules size 1 with a caramel cap and a caramel body, with white ink writing "50 mg" on the body, which contain granules from yellow to orange in color.

PHARMACOTHERAPEUTIC GROUP

Antineoplastic agents, protein kinase inhibitors. ATC code L01X E04.

PHARMACOLOGICAL PROPERTIES

PHARMACODYNAMICS

MECHANISM OF ACTION

Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are associated with tumor growth, pathological angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against various kinases (>80 kinases) and was identified as a platelet-derived growth factor receptor (PDGFRα and PDGFRβ), vascular endothelial growth factor receptor (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (RET). Inhibition of RTK activity by sunitinib has been demonstrated in biochemical and cellular analyses, and inhibition of function has been demonstrated in cell proliferation analysis. The main metabolite shows similar efficacy compared to sunitinib in biochemical and cellular analyses. Sunitinib inhibited the phosphorylation of many RTKs (PDGFRb, VEGFR2, KIT) in tumor xenografts expressing these RTKs in vivo and demonstrated inhibition of tumor growth or regression and/or inhibition of metastasis in some experimental cancer models. Sunitinib demonstrated the ability to inhibit the growth of tumor cells expressing unregulated target RTKs (PDGFR, RET, or KIT) in vitro and inhibit PDGFRb- and VEGFR2-dependent tumor angiogenesis in vivo.

PHARMACOKINETICS

The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors. The maximum concentration of sunitinib in plasma (Cmax) is generally observed within 6-12 hours (time to maximum plasma concentration [Tmax]) after oral administration. Food does not affect the bioavailability of sunitinib. Sunitinib-Vista can be taken independently of food intake. The binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, without concentration-dependent binding within the range of 100-4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. Within the dose range of 25-100 mg, AUC and Cmax increase proportionally to the dose. Sunitinib is metabolized primarily by the cytochrome P450 enzyme CYP3A4 to form the primary active metabolite, which is then metabolized by CYP3A4. The primary active metabolite accounts for 23-37% of the total exposure. Elimination is primarily via the feces. In a mass balance study in humans, 61% of the dose was excreted in the feces, and renal excretion accounted for 16% of the administered dose. Sunitinib and its primary active metabolite were the main drug-related compounds detected in plasma, urine, and feces, accounting for 91.5%, 86.4%, and 73.8% of the radioactivity in the combined samples, respectively. Secondary metabolites were detected in urine and feces but not in plasma.

PHARMACOKINETICS IN SPECIAL PATIENT GROUPS

A population pharmacokinetic analysis of demographic data indicates that there is no clinically significant effect of age, body weight, creatinine clearance, race, sex, or ECOG performance status on the pharmacokinetics of sunitinib or its primary active metabolite.

USE IN CHILDREN

The pharmacokinetics of sunitinib have not been evaluated in children.

RENAL IMPAIRMENT

Systemic exposure to sunitinib after a single dose of the drug was similar in patients with severe renal impairment (CLcr <30 mL/min) and patients with normal renal function (CLcr >80 mL/min). Although sunitinib was not cleared by hemodialysis, systemic exposure to sunitinib was 47% lower in patients with end-stage renal disease (ESRD) on hemodialysis compared to patients with normal renal function.

HEPATIC IMPAIRMENT

Systemic exposures after a single dose of sunitinib were similar in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment compared to patients with normal hepatic function.

CARDIAC ELECTROPHYSIOLOGY

Sunitinib may cause dose-dependent QT interval prolongation, which may lead to an increased risk of ventricular arrhythmias, including paroxysmal ventricular tachycardia of the "pirouette" type (see "Special warnings and precautions for use").

CLINICAL STUDIES

GASTROINTESTINAL STROMAL TUMOR (GIST)

STUDY 1

Study 1 (NCT #00075218) was an international randomized double-blind placebo-controlled study in 2 groups of sunitinib in patients with GIST who had disease progression during previous treatment with imatinib mesylate (imatinib) or who were intolerant to imatinib. The objective was to compare the time to tumor progression (TTP) in patients receiving sunitinib plus best supportive care versus patients receiving placebo plus best supportive care. Other objectives included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Patients were randomized (2:1) to receive either 50 mg of sunitinib or placebo orally once daily on a 4/2 schedule until disease progression or withdrawal from the study for other reasons.

In sunitinib, there was a statistically significant advantage over placebo in TTP, which corresponds to the primary endpoint. Efficacy results are presented in Table 1.

STUDY 2

Study 2 was an open-label, single-arm, dose-escalation study conducted in patients with GIST who had disease progression after treatment with or were intolerant to imatinib. After identifying the recommended regimen (50 mg once daily on a 4/2 schedule), 55 patients in this study received sunitinib at a dose of 50 mg on a 4/2 treatment schedule. Partial responses (PR) were observed in 5 of 55 patients (9.1% PR rate, 95% CI: 3.0%, 20.0%).

RENAL CELL CARCINOMA (RCC)

RCC WITHOUT PREVIOUS TREATMENT

Study 3 (NCT # 00083889) was a multicenter international randomized study comparing monotherapy with sunitinib to interferon-alpha (IFN-α) in patients with RCC without previous treatment. The objective was to compare PFS in patients receiving sunitinib versus patients receiving IFN-α. Other endpoints included ORR, OS, and safety. 750 patients were randomized (1:1) to receive either 50 mg of sunitinib once daily on a 4/2 schedule or IFN-α subcutaneously at a dose of 9 million international units (MIU) 3 times a week. Patients received treatment until disease progression or withdrawal from the study. A statistically significant advantage of sunitinib over IFN-α was observed in the PFS endpoint (see Table 2). In pre-specified stratification factors, such as lactate dehydrogenase (LDH) (> 1.5 ULN versus ≤ 1.5 ULN), ECOG performance status (0 or 1), and prior nephrectomy (yes or no), the hazard ratio showed an advantage of sunitinib over IFN-α. ORR was higher in the sunitinib group (see Table 2).

RCC REFRACTORY TO CYTOKINE THERAPY

The use of sunitinib as monotherapy in cytokine-refractory RCC was investigated in two single-arm studies. In all patients enrolled in these studies, previous cytokine therapy had been unsuccessful. In Study 4 (NCT # 00077974), the failure of previous cytokine therapy was based on radiographic evidence of disease progression, as determined by Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria within 9 months after completing 1 cytokine therapy (IFN-α, interleukin-2, IFN-α plus interleukin-2; patients who received only IFN-α had to have received treatment for at least 28 days). In Study 5 (NCT # 00054886), the failure of previous cytokine therapy was determined as disease progression or unacceptable toxicity related to treatment. The endpoint for both studies was ORR. Duration of response (DOR) was also evaluated. 106 patients were enrolled in Study 4 and 63 patients were enrolled in Study 5. Patients received 50 mg of sunitinib on a 4/2 schedule.

ORR and DOR data from Studies 4 and 5 are presented in Table 3. In Study 4, 36 PRs were identified by central radiology review for an ORR of 34.0% (95% CI: 25.0%, 43.8%). In Study 5, 23 PRs were identified by investigators for an ORR of 36.5% (95% CI: 24.7%, 49.6%). Most (> 90%) objective responses to disease were observed within the first 4 cycles; the last recorded response was observed in Cycle 10. DOR data from Study 4 are premature, as only 9 of 36 patients (25%) who responded to treatment had disease progression or died at the time of data cutoff.

ADJUVANT THERAPY FOR RCC

Sunitinib was investigated in S-TRAC (NCT # 00375674), a multicenter international randomized double-blind placebo-controlled study in patients with high-risk RCC after nephrectomy. Patients had to have clear cell histology and high risk of recurrence, defined as tumors ≥ T3 and/or N+. 615 patients were randomized 1:1 to receive either 50 mg of sunitinib once daily on a 4/2 schedule or placebo. Patients received treatment for 9 cycles (approximately 1 year) or until disease recurrence, unacceptable toxicity, or withdrawal of consent.

The primary efficacy endpoint was disease-free survival (DFS) in patients receiving sunitinib versus placebo, according to independent central review in a blinded manner. Overall survival was a secondary endpoint. A statistically significant improvement in DFS was observed in patients receiving sunitinib compared to placebo (Table 4). Pre-specified subgroup analyses are presented in Table 5. At the time of analysis, DFS data were mature, with a death rate of 141 of 615 patients (23%).

NEUROENDOCRINE TUMORS OF THE PANCREAS

Study 6 (NCT # 00428597) was a multicenter international randomized double-blind placebo-controlled study of sunitinib monotherapy in patients with unresectable neuroendocrine tumors of the pancreas (NET). Patients had to have documented disease progression according to RECIST criteria within the previous 12 months; they were randomized (1:1) to receive either 37.5 mg of sunitinib (N = 86) or placebo (N = 85) once daily without a planned break in treatment. The primary objective was to compare PFS in patients receiving sunitinib with PFS in patients receiving placebo. Other endpoints included OS, ORR, and safety. The use of somatostatin analogs was allowed.

As recommended by the Independent Data Monitoring Committee, the study was terminated prematurely prior to the pre-specified interim analysis. This may have resulted in an overestimation of the magnitude of the PFS effect. A clinically significant improvement in PFS was observed with sunitinib compared to placebo, as assessed by both the investigator and independent review. A hazard ratio favoring sunitinib was observed in all pre-specified baseline characteristic subgroups. OS data were not mature at the time of analysis. There were 9 deaths in the sunitinib group and 21 deaths in the placebo group. A statistically significant difference in ORR was observed, indicating a benefit of sunitinib compared to placebo. Efficacy results are presented in Table 6.

CLINICAL CHARACTERISTICS

INDICATIONS

Gastrointestinal stromal tumor (GIST). Sunitinib-Vista is indicated for the treatment of gastrointestinal stromal tumor after disease progression or intolerance to imatinib mesylate.

Progressive renal cell carcinoma (RCC). Sunitinib-Vista is indicated for the treatment of progressive renal cell carcinoma.

Adjuvant therapy for renal cell carcinoma (RCC). Sunitinib-Vista is indicated for adjuvant therapy in adult patients with high-risk recurrent RCC after nephrectomy.

Progressive neuroendocrine tumors of the pancreas (NET). Sunitinib-Vista is indicated for the treatment of progressive, well-differentiated neuroendocrine tumors of the pancreas in patients with unresectable, locally advanced, or metastatic disease.

CONTRAINDICATIONS

Hypersensitivity to sunitinib malate or any of the excipients of the medicinal product.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

STRONG INHIBITORS OF CYP3A4

Strong inhibitors of CYP3A4, such as ketoconazole, may increase the plasma concentration of sunitinib. It is recommended to choose an alternative concomitant medicinal product with no or minimal potential to inhibit enzymes. Concomitant administration of Sunitinib-Vista with the strong CYP3A4 inhibitor ketoconazole resulted in a 49% and 51% increase in the combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of Sunitinib-Vista in healthy volunteers. Concomitant administration of Sunitinib-Vista with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase the concentration of sunitinib. Grapefruit may also increase the plasma concentration of sunitinib. A reduction in the dose of Sunitinib-Vista should be considered when it is necessary to administer it with strong CYP3A4 inhibitors (see "Posology and method of administration").

STRONG INDUCERS OF CYP3A4

Inducers of CYP3A4, such as rifampin, may decrease the plasma concentration of sunitinib. It is recommended to choose an alternative concomitant medicinal product with no or minimal potential to induce enzymes. Concomitant administration of sunitinib with the strong CYP3A4 inducer rifampin resulted in a 23% and 46% decrease in the combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of sunitinib in healthy volunteers. Concomitant administration of Sunitinib-Vista with inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital, St. John's Wort) may decrease the concentration of sunitinib. An increase in the dose of Sunitinib-Vista should be considered when it is necessary to administer it with CYP3A4 inducers (see "Interactions with other medicinal products and other forms of interaction" and "Pharmacokinetic properties").

IN VITRO INHIBITION AND STIMULATION OF CYP STUDIES

In vitro studies have shown that sunitinib does not induce or inhibit the main CYP enzymes. In vitro studies in human liver microsomes and hepatocytes of CYP isoform activity CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 have shown that sunitinib and its primary active metabolite have no clinically significant drug interactions with medicinal products that may be metabolized by these enzymes.

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL

Sunitinib may cause dose-dependent QT interval prolongation, which may lead to an increased risk of ventricular arrhythmias, including paroxysmal ventricular tachycardia of the "pirouette" type. Paroxysmal ventricular tachycardia of the "pirouette" type was observed in < 0.1% of patients who received sunitinib treatment. Patients with a history of QT interval prolongation, patients taking antiarrhythmic medicinal products, or patients with relevant pre-existing cardiac conditions, bradycardia, or electrolyte disturbances should be monitored. When administering sunitinib, it is recommended to consider periodic monitoring of electrocardiograms and electrolytes (magnesium, potassium) during treatment. Concomitant treatment with strong CYP3A4 inhibitors may increase the plasma concentration of sunitinib; therefore, it is recommended to consider a reduction in the dose of sunitinib (see "Posology and method of administration").

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

HEPATOTOXICITY

Sunitinib may cause severe hepatotoxicity, leading to liver failure or a fatal outcome. Liver failure was observed with a frequency of < 1% in clinical studies. Symptoms of liver failure include jaundice, elevated transaminases, and/or hyperbilirubinemia in combination with encephalopathy, coagulopathy, and/or renal failure. Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) should be monitored before starting treatment, during each treatment cycle, and as clinically indicated. Administration of Sunitinib-Vista should be interrupted in cases of grade III or IV liver-related adverse reactions and discontinued if they do not resolve. Sunitinib should not be restarted in patients who have experienced severe changes in liver function tests or symptoms of liver failure.

PANCREATITIS

In patients with various solid tumors who received sunitinib, elevated serum lipase and amylase activities were observed. Elevated serum lipase was transient and usually asymptomatic in patients with various solid tumors (see "Adverse reactions").

CARDIOVASCULAR DISEASES

Reports of cardiovascular diseases, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been received.

In 3% of patients who received sunitinib (N = 7527) for GIST, advanced RCC, as adjuvant therapy for RCC, and NET, heart failure was observed; in 71% of patients with heart failure, recovery was reported. Fatal heart failure was observed in < 1% of patients.

In the adjuvant RCC study, in 11 patients in each group, a decrease in left ventricular ejection fraction (LVEF) corresponding to CTCAE grade II criteria (LVEF 40-50% and a decrease of 10-19% compared to baseline) was observed. No decrease in LVEF corresponding to CTCAE grade III-IV criteria was observed in any patient. LVEF values in 3 patients in the sunitinib group and 2 patients in the placebo group did not return to ≥ 50% or to baseline at the last measurement. No patient who received sunitinib was diagnosed with congestive heart failure (CHF).

Patients who had experienced cardiac events, such as myocardial infarction (including severe/unstable angina), coronary artery bypass grafting/peripheral arterial bypass surgery, symptomatic CHF, acute cerebrovascular event, or pulmonary embolism, within 12 months prior to sunitinib administration were excluded from clinical trials of sunitinib. It is unknown whether patients with these comorbid conditions may be at increased risk of developing sunitinib-related left ventricular dysfunction.

It is recommended to consider monitoring LVEF at the start of treatment and periodically thereafter based on clinical signs. Patients should be closely monitored for signs and symptoms of CHF. Administration of sunitinib should be discontinued in patients who experience clinical signs of CHF. Administration of the medicinal product should be interrupted and/or the dose reduced in patients without clinical signs of CHF who have an LVEF that is more than 20% but less than 50% below the baseline value or below the lower limit of normal, provided that the baseline LVEF is not obtained.

QT INTERVAL PROLONGATION AND PAROXYSMAL VENTRICULAR TACHYCARDIA OF THE "PIROUETTE" TYPE

Sunitinib may cause dose-dependent QT interval prolongation, which may lead to an increased risk of ventricular arrhythmias, including paroxysmal ventricular tachycardia of the "pirouette" type. Paroxysmal ventricular tachycardia of the "pirouette" type was observed in < 0.1% of patients who received sunitinib treatment. Patients with a history of QT interval prolongation, patients taking antiarrhythmic medicinal products, or patients with relevant pre-existing cardiac conditions, bradycardia, or electrolyte disturbances should be monitored. When administering sunitinib, it is recommended to consider periodic monitoring of electrocardiograms and electrolytes (magnesium, potassium) during treatment. Concomitant treatment with strong CYP3A4 inhibitors may increase the plasma concentration of sunitinib; therefore, it is recommended to consider a reduction in the dose of sunitinib (see "Posology and method of administration").

ARTERIAL HYPERTENSION

Patients should be monitored for signs of arterial hypertension and, if necessary, standard antihypertensive therapy should be administered. In cases of severe hypertension, it is recommended to temporarily discontinue administration of sunitinib until hypertension is controlled.

In 29% of patients who received sunitinib (N = 7527) for GIST, advanced RCC, as adjuvant therapy for RCC, and NET, arterial hypertension was observed. In 7% of patients, grade III hypertension was observed, and in 0.2% of patients, grade IV hypertension was observed. Hypersensitivity/angioedema.

If angioedema occurs due to hypersensitivity, sunitinib treatment should be interrupted and standard medical care should be provided (see "Adverse reactions").

SEIZURES

Reports of seizures have been received during clinical trials of sunitinib and in the post-marketing period. Patients who experience seizures and symptoms of reversible posterior leukoencephalopathy syndrome, such as arterial hypertension, headache, decreased activity, changes in thinking, and vision loss, including cortical blindness, require monitoring and medical therapy, including control of hypertension. It is recommended to temporarily discontinue administration of sunitinib; after the seizure has been controlled, treatment with sunitinib may be resumed at the discretion of the physician (see "Adverse reactions").

HEMORRHAGIC EVENTS AND PERFORATION OF INTERNAL ORGANS

Hemorrhagic events, some of which were fatal, have been reported in the post-marketing period, including gastrointestinal bleeding, bleeding from the respiratory tract, tumor bleeding, and urinary tract bleeding. In 30% of patients who received sunitinib (N = 7527) for GIST, advanced RCC, as adjuvant therapy for RCC, and NET, hemorrhagic events were observed, and in 4.2% of patients, grade III or IV hemorrhagic events were observed. The most common hemorrhagic adverse reaction was nosebleeds, and gastrointestinal bleeding was the most common grade ≥ III adverse reaction.

In patients who received sunitinib, tumor-related bleeding was observed. These events can occur suddenly, and in the case of lung tumors, they can manifest as severe and life-threatening hemoptysis or pulmonary hemorrhage. In clinical trials, cases of pulmonary hemorrhage, some of which were fatal, were observed; they were reported in the post-marketing period in patients who received sunitinib for metastatic RCC, GIST, and metastatic lung cancer. Sunitinib is not approved for use in patients with lung cancer. Clinical evaluation of hemorrhagic events should include a series of blood tests and physical examinations.

In patients with intra-abdominal malignant lesions who received sunitinib, serious and sometimes fatal gastrointestinal complications, including gastrointestinal perforation, were reported.

SYNDROME OF TUMOR LYSES (STL)

Cases of STL, sometimes fatal, have been observed in clinical trials and in the post-marketing period, mainly in patients with RCC or GIST who received sunitinib. In general, the risk of STL exists for patients who have a high tumor burden before starting treatment. Such patients should be closely monitored and treated according to clinical signs.

ANEURYSMS AND ARTERIAL DISSECTIONS

The use of vascular endothelial growth factor receptor inhibitors in patients with or without hypertension may contribute to the formation of aneurysms and/or arterial dissections. Before starting sunitinib, it is recommended to carefully consider this risk in patients with risk factors such as hypertension or aneurysm in their history. Thrombotic microangiopathy.

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been observed in clinical trials and in the post-marketing period with sunitinib as monotherapy and in combination with bevacizumab. Administration of sunitinib should be discontinued in patients who develop TMA. The effects of TMA have been observed to resolve after discontinuation of treatment.

PROTEINURIA

Proteinuria and nephrotic syndrome have been observed. Some of these cases have led to renal failure and fatal outcomes. Patients should be monitored for the development or worsening of proteinuria. Initial and periodic urinalysis should be performed during treatment, with further measurement of protein in a 24-hour urine sample as clinically indicated. Administration of sunitinib should be interrupted and the dose reduced to achieve a protein level in a 24-hour urine sample of ≥ 3 g. Administration of sunitinib should be discontinued in patients with nephrotic syndrome or recurrent protein levels in urine ≥ 3 g, despite dose reduction. The safety of continuing sunitinib therapy in patients with moderate to severe proteinuria has not been systematically evaluated.

SKIN TOXICITY

Reports have been received of serious skin reactions, including cases of multiform erythema (ME), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If symptoms of ME, SJS, or TEN (e.g., progressive skin rash, often with blisters or mucosal involvement) occur, treatment with sunitinib should be discontinued. If SJS or TEN is suspected, treatment with sunitinib should not be resumed.

NECROTIZING FASCITIS

Necrotizing fasciitis, including fatal cases, has been reported in patients who received sunitinib, including cases in the perineal area and fistula formation. Administration of sunitinib should be discontinued in patients who develop necrotizing fasciitis.

REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME

Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported in < 1% of patients, some of which were fatal. Patients may experience hypertension, headache, decreased activity, changes in thinking, and vision loss, including cortical blindness. Magnetic resonance imaging is necessary to confirm the diagnosis. Administration of sunitinib should be interrupted until the condition is controlled. The safety of resuming sunitinib in patients with RPLS is unknown.

THYROID DYSFUNCTION

It is recommended to perform laboratory measurements of thyroid function at baseline; patients with hypothyroidism or hyperthyroidism should receive treatment according to standard medical practice before starting sunitinib treatment. All patients should be closely monitored for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, during treatment with sunitinib. Patients with signs and symptoms suggestive of thyroid dysfunction should undergo laboratory evaluation of thyroid function and receive treatment according to standard medical practice.

CASES OF HYPERTHYROIDISM

Cases of hyperthyroidism, some of which were accompanied by hypothyroidism, have been reported in clinical trials and in the post-marketing period.

HYPOGLYCEMIA

Sunitinib may cause symptomatic hypoglycemia, which may lead to loss of consciousness or require hospitalization. Hypoglycemia occurred in 2% of patients who received sunitinib for the treatment of advanced RCC or GIST and in approximately 10% of patients who received sunitinib for the treatment of NET. In the adjuvant RCC study, hypoglycemia was not observed in patients who received sunitinib. In patients who received sunitinib for NET, hypoglycemia was not observed in patients with abnormal glucose homeostasis. The reduction in blood glucose levels in patients with diabetes may be more pronounced. Blood glucose levels should be regularly monitored during and after discontinuation of sunitinib treatment. It is recommended to evaluate the need to adjust the dose of antidiabetic medicinal products to minimize the risk of hypoglycemia.

OSTEONECROSIS OF THE JAW (ONJ)

Osteonecrosis of the jaw (ONJ) has been observed in patients who received sunitinib. The concomitant use of other risk factors, such as the use of bisphosphonates or dental diseases/invasive dental procedures, may increase the risk of ONJ. A dental examination should be performed before starting Sunitinib-Vista treatment and periodically during therapy. Patients should be advised on proper oral hygiene. It is recommended to interrupt, if possible, Sunitinib-Vista treatment at least 3 weeks before scheduled dental surgery or invasive dental procedures. Sunitinib-Vista treatment should be discontinued in cases of ONJ until complete healing.

WOUND HEALING IMPAIRMENT

Impaired wound healing has been observed in patients who received sunitinib (see "Adverse reactions"). Before planned surgical intervention, it is recommended to interrupt sunitinib therapy at least 3 weeks in advance. The medicinal product should not be administered for at least 2 weeks after major surgical intervention and until adequate wound healing. The safety of resuming sunitinib treatment after the resolution of wound healing complications has not been established.

USE DURING PREGNANCY OR BREASTFEEDING

PREGNANCY

Review of information on risks. Based on animal reproduction studies and the mechanism of action of sunitinib, sunitinib may cause harm to the fetus when administered to pregnant women (see "Pharmacodynamics"). There are no data on pregnant women to inform the risk associated with the medicinal product. In a developmental and reproductive toxicity study in animals, oral administration of sunitinib to pregnant female rats and rabbits during organogenesis resulted in teratogenic effects (embryonic, craniofacial, and skeletal malformations) that were 5.5 and 0.3 times higher, respectively, than the combined AUC (combined systemic exposure of sunitinib plus its active metabolite) in patients receiving the recommended daily dose of 50 mg. Women of childbearing potential should be warned of the potential risk to the fetus. The expected background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, miscarriage, or other adverse outcomes. In the general US population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

BREASTFEEDING

There is no information on the presence of sunitinib and its metabolites in human breast milk. Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12 times higher than in plasma. Due to the potential for serious adverse reactions in breastfed infants, women should not breastfeed during treatment with sunitinib and for at least 4 weeks after the last dose.

USE IN CHILDREN

The safety and efficacy of Sunitinib-Vista in children have not been established.

USE IN THE ELDERLY

Of 825 patients with GIST or metastatic RCC who received sunitinib in clinical trials, 277 (34%) were aged 65 years or older. In the NET study, 22 patients (27%) who received sunitinib were aged 65 years or older. No overall differences in safety and efficacy were observed between younger and older patients. Among 158 patients aged 65 years or older who received sunitinib or placebo as adjuvant therapy for RCC, the hazard ratio for disease-free survival was 0.59 (95% CI: 0.36, 0.95). Among patients aged 65 years or older who received sunitinib or placebo as adjuvant therapy for RCC, 50 patients (16%) in the sunitinib group and 15 patients (5%) in the placebo group experienced a grade III or IV adverse reaction.

HEPATIC IMPAIRMENT

No dose adjustment is required in patients with hepatic impairment of Child-Pugh class A or B. Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of sunitinib were similar in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) compared to patients with normal hepatic function. The use of sunitinib has not been studied in patients with severe (Child-Pugh class C) hepatic impairment. Patients with ALT or AST > 2.5 × ULN or with liver metastases > 5 × ULN were excluded from sunitinib cancer trials.

RENAL IMPAIRMENT

No dose adjustment is required in patients with renal impairment without dialysis with mild (CLcr 50-80 mL/min), moderate (CLcr 30-< 50 mL/min), or severe (CLcr < 30 mL/min) renal impairment. In patients with end-stage renal disease (ESRD) on hemodialysis, no dose adjustment is required. However, considering the reduced exposure to sunitinib in patients with ESRD compared to patients with normal renal function, subsequent doses may be gradually increased up to 2 times based on safety and tolerability data (see "Pharmacodynamics").

HYPERAMMONEMIC ENCEPHALOPATHY

Hyperammonemic encephalopathy has been observed with sunitinib (see "Adverse reactions"). In patients who develop unexplained lethargy or changes in mental status, it is necessary to measure the level of ammonia and initiate appropriate medical treatment.

ABILITY TO INFLUENCE REACTION RATE WHEN DRIVING VEHICLES OR OPERATING MACHINERY

Sunitinib-Vista has a minor influence on the ability to drive and use machines. Patients should be warned about the possible occurrence of dizziness during treatment with sunitinib.

POSLOGY AND METHOD OF ADMINISTRATION

RECOMMENDED DOSE FOR GIST AND ADVANCED RCC

The recommended dose of Sunitinib-Vista for GIST and advanced RCC is 50 mg orally once daily on a 4-week-on/2-week-off (4/2) schedule. Sunitinib-Vista can be taken independently of food intake.

RECOMMENDED DOSE FOR ADJUVANT THERAPY FOR RCC

The recommended dose of Sunitinib-Vista for adjuvant therapy for RCC is 50 mg orally once daily on a 4-week-on/2-week-off (4/2) schedule for 9 cycles of 6 weeks each. Sunitinib-Vista can be taken independently of food intake.

RECOMMENDED DOSE FOR NET

The recommended dose of Sunitinib-Vista for NET is 37.5 mg orally once daily continuously without a planned break in treatment. Sunitinib-Vista can be taken independently of food intake.

DOSE MODIFICATION

Administration should be interrupted and/or the dose modified, with an increase or decrease of 12.5 mg, depending on individual safety and tolerability. The maximum dose used in the NET study was 50 mg/day. In the adjuvant RCC study, the minimum dose used was 37.5 mg.

Strong CYP3A4 inhibitors, such as ketoconazole, may increase the plasma concentration of sunitinib. It is recommended to choose an alternative concomitant medicinal product with no or minimal potential to inhibit enzymes. Consideration should be given to reducing the dose of Sunitinib-Vista to a minimum of 37.5 mg (GIST and RCC) or 25 mg (NET) per day if Sunitinib-Vista is to be administered with a strong CYP3A4 inhibitor (see "Interactions with other medicinal products and other forms of interaction").

Strong CYP3A4 inducers, such as rifampin, may decrease the plasma concentration of sunitinib. It is recommended to choose an alternative concomitant medicinal product with no or minimal potential to induce enzymes. Consideration should be given to increasing the dose of Sunitinib-Vista to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (NET) per day if Sunitinib-Vista is to be administered with a strong CYP3A4 inducer. If the dose is increased, the patient should be closely monitored for signs of toxicity (see "Interactions with other medicinal products and other forms of interaction" and "Pharmacokinetic properties").

Patients with end-stage renal disease (ESRD) on hemodialysis do not require dose adjustment. However, considering the reduced exposure to sunitinib in patients with ESRD compared to patients with normal renal function, subsequent doses may be gradually increased up to 2 times based on safety and tolerability data (see "Pharmacodynamics").

OVERDOSE

Symptoms. Reports of accidental overdose have been received; these cases were associated with adverse reactions consistent with the known safety profile of sunitinib or were without adverse reactions. In preclinical studies, mortality was observed at doses of 5 daily doses of 500 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included muscle coordination disorders, head tremors, hypoactivity, eye discharge, blisters, erythema, alopecia, acne, pruritus, skin hyperpigmentation, skin lesions, and nail disorders. Mortality and similar signs of toxicity were observed at lower doses when administered for a longer period.

Treatment. Treatment of overdose with sunitinib should consist of general supportive measures. There is no specific antidote. If there are indications, elimination of the unabsorbed medicinal product should be achieved through emesis or gastric lavage.

Adverse Reactions

The most important serious adverse reactions (including fatal outcomes) associated with sunitinib are renal failure, cardiac failure, pulmonary embolism, gastrointestinal perforation, and hemorrhage (e.g., gastrointestinal bleeding, bleeding into the respiratory tract, tumor-related bleeding, or bleeding into the urinary tract or brain).

The most common adverse reactions of any grade (reported in clinical studies with patients with metastatic renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors) include decreased appetite, taste disturbances, arterial hypertension, fatigue, gastrointestinal disorders (i.e., diarrhea, nausea, stomatitis, dyspepsia, and vomiting), skin discoloration, and palmar-plantar erythrodysesthesia syndrome. The intensity of these symptoms may decrease during continued treatment. Hypothyroidism may develop during treatment.

Common adverse reactions to the drug include blood system disorders (e.g., neutropenia, thrombocytopenia, and anemia).

Fatal events considered possibly related to sunitinib include multi-organ failure, disseminated intravascular coagulation, peritoneal hemorrhage, adrenal insufficiency, pneumothorax, shock, and sudden death.

Below is a list of adverse reactions reported in patients with gastrointestinal stromal tumors, metastatic renal cell carcinomas, and pancreatic neuroendocrine tumors. The information on these adverse reactions was obtained from combined data on 7115 patients. Adverse reactions are listed by system organ class, frequency, and severity (according to NCI-CTCAE criteria). The list also includes adverse reactions observed during post-marketing clinical trials. Within each frequency group, adverse reactions are presented in order of decreasing severity. Frequency is defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and unknown (cannot be estimated from available data). Adverse reactions reported during clinical trials (publicly available information).

Infections and Infestations

Common: viral infections, respiratory infections, abscess, fungal infections, urinary tract infections, skin infections (including phlegmon), sepsis. Uncommon: necrotizing fasciitis.

Blood and Lymphatic System Disorders

Very common: neutropenia, thrombocytopenia, anemia, leucopenia. Common: lymphopenia. Uncommon: pancytopenia. Rare: thrombotic microangiopathy.

Immune System Disorders

Uncommon: hypersensitivity. Rare: angioedema.

Endocrine System Disorders

Very common: hypothyroidism. Uncommon: hyperthyroidism. Rare: thyroiditis.

Metabolism and Nutrition Disorders

Very common: decreased appetite. Common: dehydration, hypoglycemia. Rare: tumor lysis syndrome.

Psychiatric Disorders

Very common: insomnia. Common: depression.

Nervous System Disorders

Very common: dizziness, headache, taste disturbance. Common: peripheral neuropathy, paresthesia, hypesthesia, hyperesthesia. Uncommon: intracranial hemorrhage, stroke, transient ischemic attack. Rare: reversible posterior leukoencephalopathy syndrome. Unknown: hyperammonemic encephalopathy.

Eye Disorders

Common: periorbital edema, eyelid edema, increased lacrimation.

Cardiovascular Disorders

Common: myocardial ischemia, decreased ejection fraction. Uncommon: congestive heart failure, myocardial infarction, cardiac failure, cardiomyopathy, pericardial effusion, QT interval prolongation on electrocardiogram. Rare: left ventricular failure, ventricular tachycardia.

Very common: arterial hypertension. Common: deep vein thrombosis, flushing, hyperemia. Uncommon: tumor-related hemorrhage. Unknown: aneurysms and arterial dissection.

Respiratory, Thoracic, and Mediastinal Disorders

Very common: dyspnea, epistaxis, cough. Common: pulmonary embolism, pleural effusion, hemoptysis, dyspnea on exertion, oropharyngeal pain (and throat pain), nasal congestion, dryness of nasal mucosa. Uncommon: pulmonary hemorrhage, respiratory failure.

Gastrointestinal Disorders

Very common: stomatitis, abdominal pain, vomiting, diarrhea, dyspepsia, nausea, constipation. Common: gastroesophageal reflux disease, dysphagia, gastrointestinal bleeding, esophagitis, abdominal distension, abdominal discomfort, rectal hemorrhage, bleeding from gums, oral ulcers, proctalgia, cheilitis, hemorrhoids, glossodynia, oral pain, dry mouth, flatulence, oral discomfort, eructation. Uncommon: gastrointestinal perforation, pancreatitis, anal fissure, colitis.

Hepatobiliary Disorders

Uncommon: liver failure, cholecystitis, liver function disorders. Rare: hepatitis.

Skin and Subcutaneous Tissue Disorders

Very common: skin discoloration, palmar-plantar erythrodysesthesia syndrome, rash, hair color changes, dry skin. Common: skin exfoliation, skin reactions, eczema, blisters, erythema, alopecia, acne, pruritus, skin hyperpigmentation, skin lesions, hyperkeratosis, dermatitis, nail disorders. Rare: multiform erythema, Stevens-Johnson syndrome, gangrenous pyoderma, toxic epidermal necrolysis.

Musculoskeletal and Connective Tissue Disorders

Very common: limb pain, arthralgia, back pain. Common: musculoskeletal pain, muscle spasms, myalgia, muscle weakness. Uncommon: osteonecrosis of the jaw, fistula. Rare: rhabdomyolysis, myopathy.

Renal and Urinary Disorders

Common: renal failure, acute renal failure, chromaturia, proteinuria. Uncommon: urinary tract hemorrhage. Rare: nephrotic syndrome.

General Disorders and Administration Site Conditions

Very common: mucosal inflammation, increased fatigue (and general weakness), edema (including facial edema, edema, and peripheral edema), pyrexia. Common: chest pain, pain, flu-like illness, chills. Uncommon: impaired healing.

Laboratory Investigations

Common: weight loss, decreased white blood cell count, increased lipase levels, decreased platelet count, decreased hemoglobin levels, increased amylase levels, increased aspartate aminotransferase (AST) levels, increased alanine aminotransferase (ALT) levels, increased creatinine levels, increased blood pressure, increased uric acid levels. Uncommon: increased creatine phosphokinase levels, increased thyroid-stimulating hormone (TSH) levels.

* Including fatal cases.

Description of Selected Adverse Reactions

Infections and Infestations

Reports of serious infections (with and without neutropenia) including fatal outcomes have been received. Reports of necrotizing fasciitis, including Fournier's gangrene, which in some cases resulted in fatal outcomes (see "Special Warnings and Precautions for Use").

Blood and Lymphatic System Disorders

Absolute neutrophil count decreases of grade 3 and 4 were reported in 10% and 1.7% of patients in the phase 3 GIST study, 16% and 1.6% of patients in the phase 3 RCC study, and 13% and 2.4% of patients in the phase 3 PNET study. Platelet count decreases of grade 3 and 4 were observed in 3.7% and 0.4% of patients in the phase 3 GIST study, 8.2% and 1.1% of patients in the phase 3 mRCC study, and 3.7% and 1.2% of patients in the phase 3 PNET study (see "Special Warnings and Precautions for Use").

Bleeding was reported in 18% of patients receiving sunitinib in the phase 3 GIST study compared to 17% of patients receiving placebo. In 39% of patients receiving sunitinib for previously untreated RCC, bleeding was observed compared to 11% of patients receiving interferon-α (IFN-α). In 17 (4.5%) patients receiving sunitinib, compared to 5 (1.7%) patients receiving IFN-α, grade 3 or higher bleeding was observed. In 26% of patients receiving sunitinib for cytokine-refractory RCC, bleeding was observed. Bleeding (excluding epistaxis) was reported in 21.7% of patients receiving sunitinib in the phase 3 PNET study compared to 9.85% of patients receiving placebo (see "Special Warnings and Precautions for Use").

In clinical trials, tumor-related hemorrhage was observed in approximately 2% of patients with GIST.

Immune System Disorders

Hypersensitivity reactions, including angioedema, have been reported (see "Special Warnings and Precautions for Use").

Endocrine System Disorders

Hypothyroidism was reported in 7 patients (4%) receiving sunitinib in two cytokine-refractory RCC studies; in 61 patients (16%) receiving sunitinib and 3 patients (< 1%) in the IFN-α group in the previously untreated RCC study.

In addition, elevated TSH levels were reported in 4 patients with cytokine-refractory RCC (2%). Overall, 7% of patients with RCC had clinical or laboratory evidence of hypothyroidism that developed during treatment. Acquired hypothyroidism was observed in 6.2% of patients with GIST receiving sunitinib compared to 1% in the placebo group. In the phase 3 PNET study, hypothyroidism was reported in 6 patients (7.2%) receiving sunitinib and 1 patient (1.2%) receiving placebo.

In two breast cancer studies, prospective monitoring of thyroid function was conducted; sunitinib is not approved for the treatment of breast cancer. In one study, hypothyroidism was reported in 15 patients (13.6%) receiving sunitinib and 3 patients (2.9%) receiving standard treatment. Increased TSH levels were reported in 1 (0.9%) patient receiving sunitinib and not observed in patients receiving standard treatment. Hyperthyroidism was not reported in patients receiving sunitinib and was reported in 1 (1%) patient receiving standard treatment. In another study, hypothyroidism was observed in 31 (13%) patients receiving sunitinib and 2 (0.8%) patients receiving capecitabine. Increased TSH levels were reported in 12 (5%) patients receiving sunitinib and not observed in patients receiving capecitabine. Hyperthyroidism was observed in 4 (1.7%) patients receiving sunitinib and not observed in patients receiving capecitabine. Decreased TSH levels were reported in 3 (1.3%) patients receiving sunitinib and not observed in patients receiving capecitabine. Elevated T4 levels were reported in 2 (0.8%) patients receiving sunitinib and 1 (0.4%) patient receiving capecitabine. Elevated T3 levels were reported in 1 (0.8%) patient receiving sunitinib and not observed in patients receiving capecitabine. All thyroid-related reactions were grade 1 or 2 in severity (see "Special Warnings and Precautions for Use").

Metabolism and Nutrition Disorders

In patients with pancreatic neuroendocrine tumors, a higher incidence of hypoglycemia was observed compared to metastatic renal cell carcinoma and gastrointestinal stromal tumors. However, most of these adverse reactions observed during clinical trials were considered unrelated to the study treatment.

Nervous System Disorders

In clinical trials of sunitinib and during post-marketing use, there have been few reports (< 1%), some with fatal outcomes, of subjects with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome. Seizures have been observed in patients with and without evidence of brain metastases (see "Special Warnings and Precautions for Use").

Cardiac Disorders

In clinical trials, a decrease in left ventricular ejection fraction (LVEF) of ≥ 20% and below the lower limit of normal was observed in approximately 2% of patients with GIST receiving sunitinib, 4% of patients with cytokine-refractory RCC, and 2% of patients with GIST receiving placebo. These LVEF decreases are not progressive and often improve during continued treatment. In the previously untreated RCC study, a decrease in LVEF below the lower limit of normal was observed in 27% of patients receiving sunitinib and 15% of patients receiving IFN-α. Congestive heart failure was diagnosed in 2 (< 1%) patients receiving sunitinib.

In patients with GIST, cardiac failure, congestive heart failure, or left ventricular failure was reported in 1.2% of the sunitinib group and 1% of the placebo group. In the phase 3 GIST study (N=312), cardiac-related fatalities occurred in 1% of patients in each treatment group (i.e., sunitinib and placebo groups). In the phase 2 study, among patients with cytokine-refractory RCC, a fatal myocardial infarction related to the drug occurred in 0.9% of patients, and in the phase 3 study, among patients with previously untreated RCC, 0.6% of patients in the IFN-α group and 0% of patients in the sunitinib group had cardiac-related fatalities. In the phase 3 PNET study, 1 (1%) patient receiving sunitinib had a fatal cardiac failure related to the drug.

Vascular Disorders

Hypertension.

In clinical trials, hypertension was very commonly reported. The dose of sunitinib was reduced or its administration temporarily interrupted in approximately 2.7% of patients due to hypertension. In none of these patients was the administration of sunitinib permanently discontinued. Severe hypertension (> 200 mmHg systolic or 110 mmHg diastolic) was observed in 4.7% of patients with solid tumors. Hypertension was observed in approximately 33.9% of patients receiving sunitinib for previously untreated RCC compared to 3.6% of patients receiving IFN-α. Severe hypertension was observed in 12% of previously untreated patients and < 1% of patients receiving IFN-α. Hypertension was reported in 26.5% of patients receiving sunitinib in the phase 3 PNET study compared to 4.9% of patients receiving placebo. Severe hypertension was reported in 10% of patients with PNET receiving sunitinib and 3% of patients receiving placebo.

Venous thromboembolism.

In clinical trials, venous thromboembolic events related to the drug were reported in approximately 1.0% of patients with solid tumors receiving sunitinib.

In the phase 3 GIST study, venous thromboembolic events were observed in 7 patients (3%) receiving sunitinib and none in the placebo group; 5 of the 7 had deep vein thrombosis (DVT) grade 3 and 2 had grade 1 or 2. Four of these 7 patients with GIST discontinued treatment after the first DVT event.

Thirteen patients (3%) receiving sunitinib in the phase 3 previously untreated RCC study and 4 patients (2%) in 2 cytokine-refractory RCC studies reported venous thromboembolism. Nine of these patients had pulmonary embolism; 1 was grade 2 and 8 were grade 4. Eight of these patients had DVT; 1 was grade 1, 2 were grade 2, 4 were grade 3, and 1 was grade 4. One patient with pulmonary embolism in the cytokine-refractory RCC study interrupted therapy. In patients with previously untreated RCC receiving IFN-α, 6 (2%) cases of venous thromboembolism were reported; 1 (< 1%) patient had grade 3 DVT and 5 (1%) patients had grade 4 pulmonary embolism.

Venous thromboembolism was reported in 1 (1.2%) patient in the sunitinib group and 5 (6.1%) patients in the placebo group in the phase 3 PNET study. Two patients in the placebo group had DVT: 1 was grade 2 and 1 was grade 3.

In registration studies of GIST, RCC, and PNET, no fatal cases were reported. Fatal cases were observed during post-marketing use.

Pulmonary embolism was observed in approximately 3.1% of patients with GIST and approximately 1.2% of patients with RCC receiving sunitinib in phase 3 studies. In patients with PNET receiving sunitinib in the phase 3 study, no pulmonary embolism was reported. Rare fatal cases were observed during post-marketing use.

Patients with pulmonary embolism in the previous 12 months were excluded from clinical trials of sunitinib.

In patients receiving sunitinib in phase 3 registration studies, pulmonary-related events (i.e., dyspnea, pleural effusion, pulmonary embolism, or pulmonary edema) were reported in approximately 17.8% of patients with GIST, approximately 26.7% of patients with RCC, and 12% of patients with PNET.

Approximately 22.2% of patients with solid tumors, including GIST and RCC, receiving sunitinib in clinical trials reported pulmonary-related events.

Gastrointestinal Disorders

Pancreatitis was observed infrequently (< 1%) in patients receiving sunitinib for GIST or RCC. In the phase 3 PNET study, no pancreatitis related to the drug was reported (see "Special Warnings and Precautions for Use").

Gastrointestinal bleeding with fatal outcome was reported in 0.98% of patients receiving placebo in the phase 3 GIST study.

Hepatobiliary Disorders

Cases of liver dysfunction, which may include liver function test abnormalities, hepatitis, or liver failure, have been reported (see "Special Warnings and Precautions for Use").

Skin and Subcutaneous Tissue Disorders

Cases of gangrenous pyoderma, which is usually reversible after discontinuation of sunitinib, have been reported (see "Special Warnings and Precautions for Use").

Musculoskeletal and Connective Tissue Disorders

Cases of myopathy and/or rhabdomyolysis, some with acute renal failure, have been reported. Patients with symptoms of muscle toxicity should be managed according to standard medical practice.

Cases of fistula formation, sometimes associated with necrosis and tumor regression, which in some cases resulted in fatal outcomes, have been reported. In patients receiving sunitinib, cases of osteonecrosis of the jaw, mostly in the presence of risk factors for osteonecrosis of the jaw (e.g., intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures), have been described (see "Special Warnings and Precautions for Use").

Laboratory Investigations

Data from non-clinical studies (in vitro and in vivo) of sunitinib at doses exceeding the recommended dose for humans showed that sunitinib may inhibit the repolarization of cardiac action potential (e.g., prolongation of the QT interval). Prolongation of the QTc interval to > 500 ms was observed in 0.5%, and changes from baseline > 60 ms were observed in 1.1% of 450 patients with solid tumors; both parameters are considered potentially significant changes. Sunitinib at concentrations approximately twice the therapeutic concentrations prolonged the QTcF interval (QT interval corrected by the Fridericia formula).

QTc prolongation was studied in a study involving 24 patients aged 20 to 87 years with advanced malignancies. The results of this study demonstrated that sunitinib affected the QTc interval (defined as the mean change from baseline, adjusted for placebo, > 10 ms with a 90% confidence interval [CI] upper bound > 15 ms) at therapeutic concentrations (day 3) using the time-matched baseline method and at concentrations exceeding therapeutic concentrations (day 9) using both time-matched and 24-hour baseline-adjusted methods. No patient had a QTc interval > 500 ms. Although the effect on QTcF was observed on day 3, 24 hours after dosing (i.e., at therapeutic plasma concentrations expected after the recommended starting dose of 50 mg), using the time-matched baseline method, the clinical significance of this finding is unknown. Based on a comprehensive evaluation of serial ECGs at times corresponding to therapeutic or higher-than-therapeutic concentrations of the drug, no patient in the evaluable population or randomized patients (ITT) had QTc prolongation considered "severe" (i.e., ≥ grade 3 according to the Common Terminology Criteria for Adverse Events [CTCAE], version 3.0). At therapeutic plasma concentrations, the maximum mean change from baseline in QTcF (Fridericia-corrected) was 9 ms (90% CI: 15.1 ms). At concentrations approximately twice the therapeutic concentrations, the maximum mean change from baseline in QTcF was 15.4 ms (90% CI: 22.4 ms). Moxifloxacin (400 mg), used as a positive control, showed a maximum mean change from baseline in QTcF of 5.6 ms. No subject experienced a change in QTc > grade 2 (CTCAE, version 3.0) (see "Special Warnings and Precautions for Use").

Long-term Safety in RCC

The long-term safety of sunitinib in patients with RCC was evaluated in 9 completed clinical studies conducted in first-line, cytokine-refractory, and refractory-to-cytokine treatment settings in 5739 patients, of whom 807 (14%) received treatment for 2 to 6 years. In the 807 patients who received prolonged treatment with sunitinib, most sunitinib-related adverse reactions (SRARs) initially developed within the first 6 months to 1 year and then remained stable or decreased in frequency over time, with the exception of hypothyroidism, which gradually increased over time, and new cases emerged during the 6-year period. Prolonged treatment with sunitinib was not associated with new types of SRARs.

Pediatric Population

A phase 1 study of oral sunitinib with dose escalation was conducted in 35 pediatric and young adult patients (aged 2 to 21 years) with refractory solid tumors, most of whom had a primary diagnosis of brain tumor. All study participants experienced adverse reactions, and in patients who had previously received anthracyclines or had received radiation to the chest area, most reactions were severe (grade 3 or higher toxicity) and included cardiotoxicity. The risk of adverse reactions related to the heart was higher in children who had previously received radiation to the chest area and anthracyclines compared to those who had not received such treatment. For this patient group, the maximum tolerated dose of sunitinib was not established due to dose-limiting toxicity (see "Pharmacodynamics"). In children who had not previously received anthracyclines or radiation to the chest area, the most common adverse reactions were gastrointestinal toxicity, neutropenia, increased fatigue, and increased ALT levels.

Based on a population pharmacokinetic (PK) analysis and a pharmacokinetic-pharmacodynamic (PK/PD) analysis, sunitinib at a dose of 25 mg/m2/day on a 4/2 schedule in children (aged 6-11 and 12-17 years) with gastrointestinal stromal tumors is expected to provide a plasma concentration of the drug and, therefore, a safety and efficacy profile similar to that in adult patients with gastrointestinal stromal tumors receiving the drug at a dose of 50 mg/day on a 4/2 schedule.

Adjuvant Treatment of RCC

The safety of sunitinib was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled study in which patients with RCC who had undergone nephrectomy received sunitinib 50 mg/day (n=306) on a 4/2 schedule or placebo (n=304). The median duration of treatment was 12.4 months (range: 0.13-14.9) for sunitinib and 12.4 months (range: 0.03-13.7) for placebo. Discontinuation of the drug due to an adverse reaction occurred in 28% of patients receiving sunitinib and 6% of patients receiving placebo. Adverse reactions leading to discontinuation of the drug in > 2% of patients included palmar-plantar erythrodysesthesia syndrome and fatigue/asthenia. Dose interruptions or delays occurred in 166 (54%) and 84 (28%) patients receiving sunitinib and placebo, respectively. Dose reductions occurred in 140 patients (45.8%) in the sunitinib group and 15 patients (5%) in the placebo group.

Grade 4 adverse reactions in patients receiving sunitinib included palmar-plantar erythrodysesthesia syndrome (1%), fatigue (< 1%), abdominal pain (< 1%), stomatitis (< 1%), and pyrexia (< 1%). Grade 4 adverse reactions in patients receiving placebo included asthenia (< 1%) and arterial hypertension (< 1%). Changes in laboratory values of grade 3-4 severity that occurred in ≥ 2% of patients receiving sunitinib included neutropenia (13%), thrombocytopenia (5%), leucopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorization of the medicinal product is an important procedure. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf Life

3 years.

Storage Conditions

Store in the original packaging at a temperature not exceeding 25°C. Store in a place inaccessible to children.

Packaging

7 capsules in a blister pack; 4 blister packs in a carton (for 12.5 mg, 25 mg, 37.5 mg, and 50 mg dosages) or 4 capsules in a blister pack; 7 blister packs in a carton (for 37.5 mg and 50 mg dosages).

Legal Category

Prescription only.

Manufacturer

Remedica Ltd

Manufacturer's Address

Achnaton Street, Limassol Industrial Estate, Building 5-Hormones and Corticosteroids, Building 10-Antineoplastics and Immunomodulators, Limassol, 3056, Cyprus

Manufacturer

Pharmakea Premium Ltd

Manufacturer's Address

HCH003, Hal Far Industrial Estate, Birzebbugia, BBG3000, Malta