Visutin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VESUTIN (VISUTIN)

Composition:

Active substance: sunitinib;

1 capsule contains sunitinib malate equivalent to sunitinib 12.5 mg, 25 mg, 37.5 mg, 50 mg;
Excipients: microcrystalline cellulose, povidone, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

12.5 mg capsules: hard gelatin capsule size № 4 with orange body and orange cap, printed in white with "SNB" and "12.5" on the body; the capsule contains orange-colored powder;

25 mg capsules: hard gelatin capsule size № 3 with orange body and caramel-colored (light brown) cap, printed in white with "SNB" and "25" on the body; the capsule contains orange-colored powder;

37.5 mg capsules: hard gelatin capsule size № 2 with yellow body and yellow cap, printed in black with "SNB" and "37.5" on the body; the capsule contains orange-colored powder;

50 mg capsules: hard gelatin capsule size № 1 (elongated) with caramel-colored (light brown) body and cap, printed in black with "SNB" and "50" on the body; the capsule contains orange-colored powder.

Pharmacotherapeutic group.
Antineoplastic agents, protein kinase inhibitors. ATC code L01XE04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action.

Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are involved in tumor growth, pathological angiogenesis, and metastatic progression of cancer. Sunitinib has been evaluated for its inhibitory activity against various kinases (>80 kinases) and has been identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor type 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (RET). Inhibition of these RTKs by sunitinib has been demonstrated in biochemical and cellular assays, and functional inhibition has been shown in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. Sunitinib inhibited phosphorylation of several RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing these target RTKs in vivo, and demonstrated inhibition of tumor growth or tumor regression and/or inhibition of metastases in certain experimental cancer models. Sunitinib demonstrated the ability to inhibit tumor cell growth expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro, and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.

Pharmacokinetics.

The pharmacokinetics of sunitinib and sunitinib malate were evaluated in 135 healthy volunteers and 266 patients with solid tumors.

Maximum plasma concentration (C_max) of sunitinib is generally observed within 6–12 hours (time to reach C_max [T_max]) after oral administration. Food does not affect the bioavailability of sunitinib. Sunitinib can be administered independently of food intake.

Plasma protein binding of sunitinib and its primary active metabolite in human plasma in vitro was 95% and 90%, respectively, without concentration dependence within the range of 100–4000 ng/mL. The apparent volume of distribution (V_d/F) for sunitinib was 2230 L. Over the dose range of 25–100 mg, the area under the plasma concentration-time curve (AUC) and C_max increased proportionally with dose (0.5 to 2 times higher than corresponding values at the approved recommended daily dose of 50 mg).

Sunitinib is primarily metabolized by the cytochrome P450 enzyme CYP3A4, forming a primary active metabolite, which is subsequently metabolized by CYP3A4. The primary active metabolite accounts for 23% to 37% of total drug exposure. Elimination occurs primarily via feces. In a human mass balance study with [14C]sunitinib, 61% of the administered dose was excreted in feces and 16% in urine. Sunitinib and its primary active metabolite were the major drug-related components detected in plasma, urine, and feces, accounting for 91.5%, 86.4%, and 73.8% of total radioactivity in pooled samples, respectively. Minor metabolites were detected in urine and feces but generally not in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hour, with inter-individual variability of 40%. After a single oral dose in healthy volunteers, the terminal half-life of sunitinib and its primary active metabolite was approximately 40–60 hours and 80–110 hours, respectively. With repeated daily dosing of sunitinib, 3–4-fold accumulation of sunitinib and 7–10-fold accumulation of the primary metabolite were observed. Steady-state concentrations of sunitinib and its primary active metabolite are reached within 10–14 days. By day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 62.9 to 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or its primary active metabolite were observed with repeated daily dosing or across repeated cycles in dosing regimens. Pharmacokinetics were similar in healthy volunteers and in patient populations with solid tumors included in the study, including patients with gastrointestinal stromal tumor (GIST) and renal cell carcinoma (RCC).

Pharmacokinetics in Special Patient Populations.

Population pharmacokinetic analysis of demographic data indicates no clinically significant effect of age, body weight, creatinine clearance, race, gender, or Eastern Cooperative Oncology Group (ECOG) performance status score on the pharmacokinetics of sunitinib or its primary active metabolite.

Use in Children. Pharmacokinetics of sunitinib have not been evaluated in children.

Patients with Renal Impairment. No clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite were expected or observed in patients with mild (CL_cr 50–80 mL/min), moderate (CL_cr 30–50 mL/min), or severe (CL_cr < 30 mL/min) renal impairment not on dialysis, compared to patients with normal renal function (CL_cr > 80 mL/min). Although sunitinib is not removed 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. 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 (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment compared to patients with normal hepatic function. Use of sunitinib in patients with severe (Child-Pugh class C) hepatic impairment has not been studied.

Cardiac Electrophysiology.

Sunitinib may cause dose-dependent QT interval prolongation, which may increase the risk of ventricular arrhythmias, including torsades de pointes (see section "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, two-arm study of sunitinib in patients with GIST who had disease progression on prior imatinib mesylate (imatinib) therapy or who were intolerant to imatinib. The objective was to compare time to tumor progression (TTP) in patients receiving sunitinib plus best supportive care versus those receiving placebo plus best supportive care. Secondary endpoints 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-weeks-on/2-weeks-off schedule until disease progression or withdrawal from the study for another reason.

Sunitinib demonstrated a statistically significant advantage over placebo in TTP, the primary endpoint. Efficacy results are presented in Table 1.

Table 1

Efficacy Results in GIST from Study 1 (Double-Blind Treatment Phase)

Parameter of efficacy	Sunitinib (N=207)	Placebo (N=105)	p-value (log-rank test)	HR (95% CI)
Time to tumor progressiona [median value, weeks (95% CI)]	27.3 (16.0; 32.1)	6.4 (4.4; 10.0)	< 0.0001*	0.33 (0.23; 0.47)
Progression-free survivalb [median value, weeks (95% CI)]	24.1 (11.1; 28.3)	6.0 (4.4; 9.9)	< 0.0001	0.33 (0.24; 0.47)
Objective response rate (ORR) [%, (95% CI)]	6.8 (3.7; 11.1)	0	0.006c

*Comparison is considered statistically significant if the p-value < 0.00417 (O'Brien-Fleming early stopping criterion).

Abbreviations: CI – confidence interval; GIST – gastrointestinal stromal tumor; HR – hazard ratio; N – number of patients; ORR – objective response rate.

a Time from randomization to progression; deaths prior to documented progression were censored at the time of the last radiological assessment.

b Time from randomization to progression or death from any cause.

c Pearson's chi-square test.

Study 2.

Study 2 was an open-label, multicenter, single-arm trial (dose-escalation phase) conducted in patients with GIST following disease progression on or intolerance to imatinib. After identification of the recommended regimen (50 mg once daily on a 4-weeks-on/2-weeks-off schedule), 55 patients in this study received sunitinib 50 mg on a 4/2 schedule. ORR was observed in 5 of 55 patients (9.1% ORR, 95% CI: 3.0%, 20.0%).

Renal cell carcinoma (RCC).

Untreated RCC.

Study 3 (NCT#00083889) was a multicenter, international, randomized trial comparing sunitinib monotherapy with interferon-α (IFN-α) in patients with previously untreated RCC. The primary objective was to compare PFS in patients receiving sunitinib versus those receiving IFN-α. Secondary endpoints included ORR, OS, and safety. A total of 750 patients were randomized (1:1) to receive either sunitinib 50 mg once daily on a 4-weeks-on/2-weeks-off schedule or subcutaneous IFN-α at a dose of 9 million international units (MIU) three times per week. Patients were treated until disease progression or withdrawal from the study. A statistically significant improvement in PFS was demonstrated for sunitinib compared to IFN-α (see Table 2). Favorable hazard ratios for sunitinib over IFN-α were observed across prespecified stratification factors, including lactate dehydrogenase (LDH) (>1.5 ULN [upper limit of normal] vs. ≤1.5 ULN), ECOG performance status (0 or 1), and prior nephrectomy (yes or no). ORR was higher in the sunitinib group (see Table 2).

Table 2

Efficacy results in previously untreated RCC (interim analysis) from Study 3.

Parameter of efficacy	Sunitinib (N=375)	IFN-α (N=375)	p-value (log-rank test)	HR (95% CI)
Progression-free survivala [median, weeks (95% CI)]	47.3 (42.6; 50.7)	22.0 (16.4; 24.0)	< 0.000001b	0.415 (0.320; 0.539)
Objective response ratea [% (95% CI)]	27.5 (23.0; 32.3)	5.3 (3.3; 8.1)	< 0.001c	NA

Abbreviations: CI – confidence interval; RR – risk ratio; N – number of patients; IFN-α – interferon-alpha; NA – not applicable; RCC – renal cell carcinoma.

a Assessed by a blinded independent radiology review facility; images from 90 patients were not evaluated at the time of analysis.

b The comparison is considered statistically significant if the p-value < 0.0042 (O'Brien-Fleming stopping criterion).

c Pearson's chi-square test.

Cytokine-refractory RCC.

The use of sunitinib as monotherapy in cytokine-refractory RCC was evaluated in two multicenter, single-arm trials. All patients enrolled in these trials had previously received cytokine therapy that had proven ineffective. In Study 4 (NCT#00077974), failure of prior cytokine therapy was defined by radiological evidence of disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria within 9 months after completion of one cytokine therapy regimen (IFN-α, interleukin-2, or IFN-α plus interleukin-2; patients receiving only IFN-α were required to have received treatment for at least 28 days). In Study 5 (NCT#00054886), failure of prior cytokine therapy was defined as either disease progression or unacceptable treatment-related toxicity. The primary endpoint in both studies was ORR. Duration of response (DOR) was also assessed. A total of 106 patients were enrolled in Study 4, and 63 patients in Study 5. Patients received sunitinib 50 mg 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 the central radiology review facility, resulting in an ORR of 34.0% (95% CI: 25.0%, 43.8%). In Study 5, 23 PRs were identified by investigators, resulting in an ORR of 36.5% (95% CI: 24.7%, 49.6%). The majority (>90%) of objective responses occurred within the first 4 cycles; the latest response recorded was observed in cycle 10. DOR data from Study 4 are considered preliminary, as only 9 out of 36 patients (25%) who responded experienced disease progression or died at the time of data cutoff.

Table 3

Efficacy results in cytokine-refractory RCC from Studies 4 and 5.

Parameter of efficacy	Study 4 (N=106)	Study 5 (N=63)
Objective response rate [% (95 % CI)]	34.0a (25.0; 43.8)	36.5b (24.7; 49.6)
Duration of response [median, weeks (95 % CI)]	NR* (42.0, *)	54b (34.3; 70.1)

* Data not reliable for determining the upper limit of the CI.

Abbreviations: CI – confidence interval; N – number of patients; NR – not reached; RCC – renal cell carcinoma.

a Assessed by a blinded independent radiology review laboratory.

b Assessed by investigators.

Adjuvant Therapy in RCC

Sunitinib was evaluated in the adjuvant setting in the S-TRAC (NCT#00375674) trial, a multicenter, international, randomized, double-blind, placebo-controlled study involving patients at high risk of recurrence following nephrectomy for RCC. Patients were required to have clear cell histology and to be at high risk of recurrence, defined as tumors ≥ T3 and/or N+. A total of 615 patients were randomized in a 1:1 ratio to receive either sunitinib 50 mg once daily on a 4-weeks-on/2-weeks-off schedule or placebo. Patients received treatment for up to 9 cycles (approximately 1 year) or until disease recurrence, unacceptable toxicity, or withdrawal of consent.

The primary efficacy endpoint was DFS in patients receiving sunitinib compared to placebo, as assessed by blinded independent central review (BICR). Overall survival was a secondary endpoint.

A statistically significant improvement in DFS was observed in patients receiving sunitinib compared to those receiving placebo (see Table 4). Pre-specified subgroup analyses are presented in Table 5. At the time of the DFS analysis, overall survival data were not mature, with a mortality rate of 141 out of 615 patients (23%).

Table 4

DFS Results as Assessed by BICR in the Adjuvant RCC Setting (Treatment-Assigned Patient Population) from the S-TRAC Trial.

Parameter	Sunitinib (N=309)	Placebo (N=306)	p-valuea	HRa (95 % CI)
Median PFS [years (95 % CI)]	6.8 (5.8, NR)	5.6 (3.8; 6.6)	0.03	0.76 (0.59; 0.98)
PFS events	113 (36.6 %)	144 (47.1 %)
5-year PFS rate	59.3 %	51.3 %

a P-value based on the log-rank test, stratified by prognostic group of the University of California Los Angeles Integrated Scoring System (UISS); HR is based on the Cox proportional hazards model, stratified by UISS prognostic group. Abbreviations: IRC — independent central review; CI — confidence interval; PFS — progression-free survival; HR — hazard ratio; N — number of patients; RCC — renal cell carcinoma.

Table 5

PFS by baseline disease characteristics

	Number of events/total n/N		Median PFS [years (95 % CI)]		HRa (95 % CI)
	Sunitinib	Placebo	Sunitinib	Placebo
T3 Intermediateb	35/115	46/112	ND (5.2, ND)	6.4 (4.7, ND)	0.82 (0.53; 1.28)
T3 Highc	63/165	79/166	6.8 (5.0, ND)	5.3 (2.9, ND)	0.77 (0.55; 1.07)
T4/Nodular typed	15/29	19/28	3.5 (1.2, ND)	1.7 (0.4; 3.0)	0.62 (0.31; 1.23)

Abbreviations: CI – confidence interval; DFS – disease-free survival; HR – hazard ratio; N – number of patients; n – number of events; NR – not reached.

a HR based on Cox proportional hazards model.

b T3 Intermediate: T3, N0 or NX, M0, any Fuhrman grade, ECOG performance status 0 or T3, N0 or NX, M0, Fuhrman grade 1, ECOG performance status >1.

c T3 High: T3, N0 or NX, M0, Fuhrman grade >2, ECOG performance status >1.

d T4/Node-positive: T4, N0 or NX, M0, any Fuhrman grade, any ECOG performance status or any T, N1-2, M0, any Fuhrman grade, any ECOG performance status.

Pancreatic neuroendocrine tumors

Study 6 (NCT#00428597) was a multicenter, international, randomized, double-blind, placebo-controlled monotherapy trial of sunitinib in patients with unresectable pancreatic neuroendocrine tumors (pNET). Patients were required to have documented disease progression per RECIST criteria within the prior 12 months; they were randomized (1:1) to receive either sunitinib 37.5 mg (N=86) or placebo (N=85) once daily without a scheduled treatment interruption period. The primary objective was to compare progression-free survival (PFS) in patients receiving sunitinib versus those receiving placebo. Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. The use of somatostatin analogs was permitted in the study. As recommended by the Independent Data Monitoring Committee, the study was stopped early prior to a prespecified interim analysis. This may have led to an overestimation of the PFS treatment effect magnitude. A clinically meaningful improvement in PFS with sunitinib compared to placebo was observed both by investigator assessment and by independent review. The favorable risk-benefit profile of sunitinib was observed across all baseline patient 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, favoring sunitinib over placebo. Efficacy results are presented in Table 6.

Table 6

Efficacy results from Study 6 in pNET

Efficiency parameter	Sunitinib (N=86)	Placebo (N=85)	p-value	HR (95 % CI)
Progression-free survival [median value, months (95 % CI)]	10.2 (7.4; 16.9)	5.4 (3.4; 6.0)	0.000146a	0.427 (0.271; 0.673)
Objective response rate [%, (95 % CI)]	9.3 (3.2; 15.4)	0	0.0066b	NR

Abbreviations: CI – confidence interval; HR – hazard ratio; N – number of patients; NA – not applicable; pNET – pancreatic neuroendocrine tumor.

a Two-sided unstratified log-rank test.

b Fisher's exact test.

Clinical characteristics.

Indications.

Gastrointestinal stromal tumor (GIST)

Treatment of gastrointestinal stromal tumor following disease progression or intolerance to imatinib mesylate.

Progressive renal cell carcinoma (RCC)

Treatment of progressive renal cell carcinoma.

Adjuvant therapy of renal cell carcinoma (RCC)

Adjuvant therapy in adult patients with a high risk of recurrent RCC following nephrectomy.

Progressive pancreatic neuroendocrine tumors (pNET)

Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Strong CYP3A4 inhibitors.

Strong CYP3A4 inhibitors, such as ketoconazole, may increase plasma concentrations of sunitinib. It is recommended to select an alternative concomitant medicinal product with no or minimal enzyme inhibition potential. Concomitant administration of sunitinib with the strong CYP3A4 inhibitor ketoconazole resulted in a 49% and 51% increase in combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of sunitinib in healthy volunteers. Concomitant use of sunitinib with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit juice may also increase sunitinib plasma concentrations. Dose reduction of Visudyne should be considered when used concomitantly with strong CYP3A4 inhibitors (see section "Dosage and administration").

Strong CYP3A4 inducers.

CYP3A4 inducers, such as rifampicin, may decrease sunitinib plasma concentrations. It is recommended to select an alternative concomitant medicinal product with no or minimal enzyme induction potential. Concomitant administration of Visudyne with the strong CYP3A4 inducer rifampicin resulted in a 23% and 46% decrease in combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of Visudyne in healthy volunteers. Concomitant use of Visudyne with CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John's wort) may reduce sunitinib concentrations. St. John's wort may lead to unpredictable decreases in sunitinib plasma concentrations. Patients receiving Visudyne should not take St. John's wort concomitantly. Dose escalation of Visudyne should be considered when it must be used concomitantly with CYP3A4 inducers (see section "Dosage and administration").

In vitro studies of CYP inhibition and induction.

In vitro studies showed that sunitinib does not induce or inhibit major CYP enzymes. In vitro studies in liver microsomes and hepatocytes assessing the activity of CYP isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 demonstrated that sunitinib and its primary active metabolite are not expected to cause any clinically significant drug interactions with medicinal products metabolized by these enzymes.

Medicinal products that prolong the QT interval.

Sunitinib may prolong the QT interval. In patients requiring treatment with medicinal products that prolong the QT interval, QT interval should be monitored more frequently by ECG.

Special precautions for use.

Hepatotoxicity.

Sunitinib may cause severe hepatotoxicity leading to liver failure or fatal outcome. Liver failure was observed in <1% of patients in the overall safety cohort 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 initiating treatment, during each treatment cycle, and as clinically indicated. Treatment with Votrient should be interrupted for drug-related hepatic adverse reactions of grade 3 or 4 severity and discontinued if they do not resolve. Reinitiation of Votrient is not recommended in patients who experience severe abnormalities in liver function tests or symptoms of liver failure.

The safety of Votrient has not been established in patients with ALT or AST levels >2.5 times the upper limit of normal (ULN), or in the presence of liver metastases, >5.0 times ULN.

Pancreatitis.

Elevated serum lipase and amylase activity have been observed in patients with various solid tumors receiving sunitinib. Increased lipase activity was transient and generally not associated with symptoms of pancreatitis in patients with various solid tumors (see section "Adverse reactions").

Serious events involving the pancreas have been reported, some of which resulted in fatal outcomes. Sunitinib should be discontinued and appropriate supportive treatment initiated in patients who develop symptoms of pancreatitis.

Cardiovascular disorders.

Treatment with Votrient should be discontinued in patients with clinical manifestations of congestive heart failure (CHF). Votrient should be interrupted and/or the dose reduced in patients without clinical signs of CHF who experience a left ventricular ejection fraction (LVEF) decrease of >20%, but <50%, from baseline or below the lower limit of normal if baseline LVEF is not available.

Baseline assessment of LVEF should be considered in patients without cardiac risk factors. Patients should be carefully monitored for clinical signs and symptoms of CHF during treatment with Votrient. Baseline and periodic evaluation of LVEF should also be considered during treatment with Votrient in these patients.

Cardiovascular disorders, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, have been reported, some of which were fatal.

Heart failure occurred in 3% of patients receiving sunitinib (N=7527) in studies of GIST, advanced RCC, adjuvant therapy for RCC, and PNET. Recovery from heart failure was reported in 71% of these patients. Fatal heart failure occurred in <1% of patients.

In the adjuvant RCC study, LVEF reduction meeting CTCAE grade 2 criteria (LVEF 40–50% and a 10–19% decrease from baseline) occurred in 11 patients in each treatment group. No patient experienced grade 3–4 LVEF reduction. In three patients in the sunitinib group and two in the placebo group, LVEF did not return to ≥50% or baseline levels at the time of last measurement. No patient receiving sunitinib was diagnosed with congestive heart failure (CHF).

Patients with cardiovascular disease within 12 months prior to sunitinib administration, such as myocardial infarction (including severe/unstable angina), coronary or peripheral artery bypass grafting, symptomatic CHF, acute cerebrovascular accident, transient ischemic attack, or pulmonary artery thromboembolism, were excluded from clinical trials of sunitinib. Patients with prior anthracycline or radiation therapy to the heart were also excluded from some studies. It is unknown whether patients with these comorbidities may be at increased risk for left ventricular dysfunction associated with Votrient use.

Monitoring of LVEF at the start of treatment and periodically thereafter should be considered based on clinical indications. Patients should be closely monitored for clinical signs and symptoms of CHF. Treatment with Votrient should be discontinued in patients who develop clinical manifestations of CHF. Votrient should be interrupted and/or the dose reduced in patients without clinical signs of CHF who experience an LVEF decrease of >20% but <50% from baseline or below the lower limit of normal if baseline LVEF is not available.

QT interval prolongation and torsades de pointes.

Sunitinib may cause dose-dependent QT interval prolongation, which may increase the risk of ventricular arrhythmias, including torsades de pointes. Torsades de pointes has been reported in <0.1% of patients receiving sunitinib. Patients at increased risk of QT prolongation, including those with a history of QT prolongation, those taking antiarrhythmic drugs, or those with relevant pre-existing cardiac conditions, bradycardia, or electrolyte imbalances, should be monitored. Periodic monitoring of electrocardiograms and electrolytes (e.g., magnesium, potassium) should be considered during sunitinib treatment. QT interval should be monitored more frequently when sunitinib is used concomitantly with strong CYP3A4 inhibitors or drugs known to prolong the QT interval. Dose reduction of Votrient should be considered (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Arterial hypertension.

Patients should be monitored for signs of arterial hypertension and standard antihypertensive therapy should be initiated as needed. In case of severe hypertension, temporary discontinuation of Votrient is recommended until hypertension is controlled.

Arterial hypertension occurred in 29% of patients receiving sunitinib (N=7527) in studies of GIST, advanced RCC, adjuvant therapy for RCC, and PNET. Grade 3 hypertension occurred in 7% of patients and grade 4 hypertension in 0.2% of patients.

Hypersensitivity/angioedema.

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

Seizures.

Seizures have been reported in clinical trials and post-marketing experience with sunitinib. Patients who experience seizures or symptoms of reversible posterior leukoencephalopathy syndrome (RPLS), such as arterial hypertension, headache, decreased alertness, altered mental function, visual disturbances, including cortical blindness, require monitoring and medical treatment, including control of hypertension. Temporary discontinuation of sunitinib is recommended; after resolution of the seizure, treatment with sunitinib may be resumed at the physician's discretion (see section "Adverse reactions").

Hemorrhagic events and internal organ perforation.

Hemorrhagic events reported post-marketing (some of which were fatal) include gastrointestinal, respiratory tract, tumor-related, urinary tract, and intracranial bleeding. Hemorrhagic events occurred in 30% of patients receiving sunitinib (N=7527) in studies of GIST, advanced RCC, adjuvant therapy for RCC, and PNET, and grade 3 or 4 events occurred in 4.2% of patients. The most common hemorrhagic adverse reaction was epistaxis, and gastrointestinal bleeding was the most common grade ≥3 event.

Bleeding events related to tumors have been observed in patients receiving sunitinib. Bleeding may occur suddenly and, in the presence of lung tumors, may present as severe or life-threatening hemoptysis or pulmonary hemorrhage. Pulmonary hemorrhage (some fatal) has been observed in clinical trials and post-marketing experience in patients receiving sunitinib for metastatic RCC, GIST, and metastatic lung cancer. Sunitinib is not approved for use in lung cancer patients. Clinical evaluation of hemorrhagic events should include a series of clinical blood tests and physical examinations.

Serious, sometimes fatal, gastrointestinal complications, including gastrointestinal perforation, have been reported in patients with intra-abdominal malignancies receiving sunitinib.

A series of clinical blood tests and physical examinations should be included in the clinical assessment of bleeding events.

Tumor lysis syndrome (TLS).

Cases of TLS, sometimes fatal, have been observed in clinical trials and post-marketing use, primarily in patients with RCC or GIST receiving sunitinib. Overall, patients with high tumor burden prior to initiation of therapy are at risk of TLS. Such patients should be closely monitored and treated as clinically indicated.

Aneurysms and arterial dissection.

Use of vascular endothelial growth factor pathway inhibitors in patients with or without hypertension may promote the development of aneurysms and/or arterial dissections. The risk should be carefully considered before initiating sunitinib in patients with risk factors such as hypertension or a history of aortic aneurysm.

Thrombotic microangiopathy (TMA).

TMA, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or fatal outcome, has been observed in clinical studies and post-marketing use of sunitinib as monotherapy and in combination with bevacizumab. Sunitinib is not approved for use in combination with bevacizumab. Votrient should be discontinued in patients who develop TMA. Resolution of TMA effects has been observed after discontinuation of sunitinib treatment.

Proteinuria.

Proteinuria and nephrotic syndrome have been observed. Some of these cases led to renal failure and fatal outcomes. Patients should be monitored for the development or worsening of proteinuria. Baseline and periodic urinalysis should be performed during treatment, with subsequent 24-hour urine protein measurement as clinically indicated. Votrient should be interrupted and the dose reduced if 24-hour urine protein reaches ≥3 grams. Votrient should be discontinued in patients with nephrotic syndrome or recurrent episodes of urine protein ≥3 grams despite dose reduction. The safety of continuing Votrient therapy in patients with moderate to severe proteinuria has not been systematically evaluated.

Skin toxicity.

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

Necrotizing fasciitis, including fatal cases, has been reported in patients receiving sunitinib, including perineal area involvement and fistula formation. Votrient should be discontinued in patients who develop necrotizing fasciitis.

Reversible posterior leukoencephalopathy syndrome (RPLS).

Cases of RPLS have been reported in <1% of patients, some of which were fatal. Patients may experience hypertension, headache, decreased alertness, altered mental function, and visual disturbances, including cortical blindness. Diagnosis should be confirmed by magnetic resonance imaging. Votrient should be withheld until resolution of symptoms. The safety of re-administering Votrient in patients with RPLS is unknown.

Thyroid dysfunction.

Laboratory assessment of thyroid function at baseline is recommended. Patients with hypothyroidism or hyperthyroidism should receive appropriate treatment according to standard medical practice before initiating Votrient. All patients should be closely monitored for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, at baseline and throughout sunitinib treatment. Patients with signs suggestive of thyroid dysfunction should undergo laboratory monitoring of thyroid function and receive treatment according to standard medical practice. Initiation and/or adjustment of therapy for thyroid dysfunction should be considered as needed.

Cases of hyperthyroidism (some with subsequent hypothyroidism) have been reported in clinical trials and post-marketing experience.

Hypoglycemia.

Sunitinib may cause symptomatic hypoglycemia, which may lead to loss of consciousness or require hospitalization. Hypoglycemia occurred in 2% of patients receiving sunitinib for advanced RCC (Study 3) and GIST (Study 1), and in approximately 10% of patients receiving sunitinib for PNET (Study 6). Hypoglycemia was not observed in patients receiving sunitinib in the adjuvant RCC study. In patients with PNET and hypoglycemia, no glucose homeostasis abnormalities were observed. The reduction in blood glucose levels may be more pronounced in patients with diabetes. Blood glucose levels should be regularly monitored at the start of treatment, periodically during, and after discontinuation of sunitinib. Adjustment of antidiabetic medication dosage should be considered to minimize the risk of hypoglycemia.

Osteonecrosis of the jaw (ONJ).

ONJ has been observed in clinical trials and post-marketing experience in patients receiving sunitinib. Concurrent exposure to other risk factors, such as bisphosphonate use or dental disease/invasive dental procedures, may increase the risk of ONJ. A preventive dental examination and treatment should be considered before initiating Votrient. Patients should be advised on proper oral hygiene. Sunitinib should be interrupted, if possible, at least 3 weeks prior to planned dental surgery or invasive dental procedures. Invasive dental procedures should be avoided during sunitinib treatment, especially in patients receiving intravenous bisphosphonates. Sunitinib treatment should be discontinued in patients who develop ONJ until complete healing.

Impaired wound healing.

Impaired wound healing has been observed during sunitinib treatment (see section "Adverse reactions"). Votrient should be interrupted at least 3 weeks prior to planned major surgery. Votrient should not be administered for at least 2 weeks after major surgery and until adequate wound healing has occurred. The safety of resuming Votrient after resolution of wound healing complications has not been established.

Embryo-fetal toxicity.

Based on animal studies and the mechanism of action of sunitinib, the drug may cause fetal harm when administered to pregnant women. Administration of sunitinib to pregnant rats and rabbits during organogenesis resulted in teratogenicity at approximately 5.5 and 0.3 times the AUC, respectively, compared to the recommended daily dose (RDD) of 50 mg/day. Pregnant women should be advised of the potential risk to the fetus. Women of reproductive potential should use effective contraception during sunitinib treatment and for 4 weeks after the last dose (see sections "Pharmacodynamics" and "Use during pregnancy or breastfeeding").

Pediatric use.

The safety and efficacy of Votrient in children have not been established.

Use in elderly patients.

Among 825 patients with GIST or metastatic RCC who received sunitinib in clinical studies, 277 patients (34%) were aged 65 years or older. In the PNET study, 22 patients (27%) receiving sunitinib were aged 65 years or older. No overall differences in safety and efficacy between younger and older patients were observed. Among 158 patients aged 65 years or older receiving sunitinib/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 receiving sunitinib/placebo as adjuvant therapy for RCC, 50 patients (16%) in the sunitinib group experienced grade 3–4 adverse reactions compared to 15 patients (5%) in the placebo group.

Hepatic impairment.

No initial dose adjustment is required when Votrient is administered to patients with Child-Pugh class A or B hepatic impairment. 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 and B) compared to patients with normal hepatic function. The use of Votrient 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 >5.0×ULN were excluded from cancer studies.

Renal impairment.

No initial dose adjustment is required when Votrient is administered to patients without dialysis and with mild (CLcr 50–80 mL/min), moderate (CLcr 30–<50 mL/min), or severe (CLcr <30 mL/min) renal impairment (see section "Pharmacokinetics"). No dose adjustment is required in patients with end-stage renal disease (ESRD) on hemodialysis. However, sunitinib exposure is 47% lower in ESRD patients on hemodialysis compared to patients with normal renal function. Therefore, subsequent doses may be gradually increased up to 2-fold based on safety and tolerability.

Hyperammonemic encephalopathy.

Hyperammonemic encephalopathy has been observed with sunitinib use (see section "Adverse reactions"). Patients who develop unexplained lethargy or changes in mental status should have blood ammonia levels measured and receive appropriate clinical management.

Important information about excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per capsule, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Risk information.

Based on reproductive toxicity studies in animals and the mechanism of action, sunitinib may cause fetal harm when administered to pregnant women (see section "Pharmacodynamics"). There are no data in pregnant women to inform the risk associated with the drug. In animal developmental and reproductive toxicity studies, oral administration of sunitinib to pregnant rats and rabbits during organogenesis resulted in teratogenic effects (embryonic, craniofacial, and skeletal malformations) at approximately 5.5 and 0.3 times the combined AUC (combined systemic exposure of sunitinib plus its active metabolite) observed in patients receiving the recommended dose of 50 mg. Pregnant women and women of reproductive potential should be advised of the potential risk to the fetus.

The expected background risk of major congenital malformations and miscarriage for the indicated populations is unknown. All pregnancies carry a background risk of congenital malformations, miscarriage, or other adverse outcomes. However, it is estimated that the background risk of major congenital malformations in the general population in the United States (USA) is 2–4%, and of miscarriage is 15–20% of clinically recognized pregnancies.

Breastfeeding period.

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 from sunitinib, breastfeeding is not recommended during Votrient treatment and for at least 4 weeks after the last dose.

Pregnancy testing.

Women of reproductive potential should undergo a pregnancy test before initiating Votrient.

Contraception.

Women. Women of reproductive potential should be advised to use effective contraception during sunitinib treatment and for at least 4 weeks after the last dose.

Men. Based on reproductive toxicity studies in animals, male patients and their female partners of reproductive potential should be advised to use effective contraception during sunitinib treatment and for 7 weeks after the last dose.

Infertility.

Based on animal reproductive toxicity studies, fertility in males and females may be impaired by sunitinib treatment.

Ability to drive and use machines.

The medicinal product has minor influence on the ability to drive and use machines. Patients should be warned of the possible occurrence of dizziness during sunitinib treatment.

Method of Administration and Dosage.

Recommended dose for GIST and advanced RCC.

The recommended dose of Visutin for GIST and advanced RCC is 50 mg orally once daily according to a schedule of 4 weeks of treatment followed by a 2-week break (schedule 4/2) until disease progression or until unacceptable toxicity occurs. Visutin can be taken independently of food intake.

Recommended dose for adjuvant therapy of RCC.

The recommended dose of Visutin for adjuvant therapy of RCC is 50 mg orally once daily according to a schedule of 4 weeks of treatment followed by a 2-week break (schedule 4/2) for nine 6-week cycles. Visutin can be taken independently of food intake.

Recommended dose for PDR.

The recommended dose of Visutin for PDR is 37.5 mg orally once daily until disease progression or until unacceptable toxicity occurs. Visutin can be taken independently of food intake.

Dose modification.

Interruption and/or dose modification by increasing or decreasing by 12.5 mg depending on individual safety and tolerability. The maximum dose used in the PDR study was 50 mg per day. In the adjuvant RCC therapy study, the minimum administered dose was 37.5 mg per day.

Strong CYP3A4 inhibitors.

Select an alternative concomitant medication with no or minimal potential for enzyme inhibition. If co-administration of Visutin with a strong CYP3A4 inhibitor cannot be avoided, consider reducing the dose of Visutin to the minimum (see section "Interaction with other medicinal products and other forms of interaction") to 37.5 mg orally once daily according to the 4-weeks-on/2-weeks-off schedule (schedule 4/2) for GIST and RCC, or 25 mg orally once daily for PDR.

Strong CYP3A4 inducers.

Select an alternative concomitant medication with no or minimal potential for enzyme induction. If co-administration of Visutin with a strong CYP3A4 inducer cannot be avoided, consider increasing the dose of Visutin to the maximum (see section "Interaction with other medicinal products and other forms of interaction") to 87.5 mg orally once daily according to the 4-weeks-on/2-weeks-off schedule (schedule 4/2) for GIST and RCC, or 62.5 mg orally once daily for PDR. If the dose is increased, patients should be closely monitored for signs of adverse reactions (see sections "Interaction with other medicinal products and other forms of interaction").

For patients with ESRD on hemodialysis, no initial dose adjustment is required. However, due to reduced drug exposure in patients with ESRD compared to patients with normal renal function, subsequent doses may be gradually increased by up to two-fold based on safety and tolerability data (see section "Pharmacodynamics").

To open blisters, tear off a single dose of the medicinal product along the perforation line. Then peel back the foil on the blister and remove the capsule. Do not press on the capsule through the foil, as this may damage the capsule.

Children.

The safety and efficacy of Visutin in children have not been established.

Overdose.

Symptoms. Cases of accidental overdose have been reported. These cases were associated with adverse reactions consistent with the known safety profile of sunitinib or without adverse reactions. An intentional overdose of 1500 mg sunitinib was reported in a suicide attempt without resulting adverse reaction. In preclinical studies, mortality was observed with administration of 5 daily doses of 500 mg/kg (3000 mg/m²) in rats. At this dose, signs of toxicity included impaired muscle coordination, head tremors, hypoactivity, ocular discharge, piloerection, and gastrointestinal disturbances. Mortality and similar signs of toxicity were observed with administration of lower doses over a longer period.

Treatment. Management of sunitinib overdose should consist of general supportive measures. There is no specific antidote for overdose with Visutin. If indicated, elimination of unabsorbed drug should be achieved by inducing emesis or gastric lavage.

Adverse Reactions

The most important serious adverse reactions (including fatal outcomes) associated with sunitinib use are renal failure, heart failure, pulmonary embolism, gastrointestinal tract perforation, and hemorrhages (e.g., gastrointestinal bleeding, respiratory tract bleeding, tumor hemorrhage, urinary tract bleeding, or intracranial bleeding). The most commonly reported adverse reactions of any grade (observed in clinical trials involving patients with metastatic renal cell carcinoma, gastrointestinal stromal tumors, and progressive GIST) include decreased appetite, altered taste perception, arterial hypertension, fatigue, gastrointestinal disorders (diarrhea, nausea, stomatitis, dyspepsia, and vomiting), skin discoloration, and hand-foot syndrome (palmar-plantar erythrodysesthesia). With continued treatment, the intensity of these symptoms may decrease. Hypothyroidism may develop during treatment. Common adverse drug reactions include hematologic system disorders (e.g., neutropenia, thrombocytopenia, and anemia).

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

The list below presents adverse reactions reported in patients with gastrointestinal stromal tumors, metastatic RCC, and progressive GIST. Information on these adverse reactions was derived from pooled data of 7115 patients. Adverse reactions are listed by system organ class, frequency, and severity grade (according to NCI-CTCAE criteria). The list also includes adverse reactions observed during clinical trials and in the post-marketing period. Within each frequency group, adverse reactions are listed in descending order of severity. Frequency is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

Adverse reactions reported in clinical trials:

Infections and infestations.

Common: viral infections^a, respiratory infections^b*, abscess^c*, fungal infections^d, urinary tract infections, skin infections^e (including phlegmon), sepsis^f*.
Uncommon: necrotizing fasciitis*.
Rare: bacterial infections^g.

Blood and lymphatic system disorders.

Very common: neutropenia, thrombocytopenia, anemia, leukopenia.
Common: lymphopenia.
Uncommon: pancytopenia.
Rare: thrombotic microangiopathy^h*.

Immune system disorders.

Uncommon: hypersensitivity.
Rare: angioedema.

Endocrine disorders.

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

Metabolism and nutrition disorders.

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

Nervous system disorders.

Very common: dizziness, headache, altered taste perception^j.
Common: peripheral neuropathy, paresthesia, hypoesthesia, hyperesthesia.
Uncommon: intracranial hemorrhage*, stroke*, transient ischemic attack.
rare:* reversible posterior leukoencephalopathy syndrome*.
Frequency not known: hyperammonemic encephalopathy.

Eye disorders.

Common: periorbital edema, eyelid edema, increased lacrimation.

Cardiac disorders.

Common: myocardial ischemia^k*, decreased ejection fraction^l.
Uncommon: congestive heart failure, myocardial infarction^m*, heart failure*, cardiomyopathy*, pericardial effusion, QT interval prolongation on electrocardiogram.
Rare: left ventricular dysfunction*, torsades de pointes.

Vascular disorders.

Very common: arterial hypertension.
Common: deep vein thrombosis, flushing, hyperemia.
Uncommon: tumor hemorrhage*.
Frequency not known: aneurysms and arterial dissection*.

Respiratory, thoracic, and mediastinal disorders.

Very common: dyspnea, epistaxis, cough.
Common: pulmonary embolism*, pleural effusion*, hemoptysis, exertional dyspnea, mouth and throat painⁿ, nasal congestion, dryness of nasal mucosa.
Uncommon: pulmonary hemorrhage*, respiratory failure*.

Gastrointestinal disorders.

Very common: stomatitis, abdominal pain^p, vomiting, diarrhea, dyspepsia, nausea, constipation.
Common: gastroesophageal reflux disease, dysphagia, gastrointestinal bleeding*, esophagitis*, abdominal distension, abdominal discomfort, rectal hemorrhage, gingival bleeding, oral ulcers, proctalgia, cheilitis, hemorrhoids, glossodynia, mouth pain, dry mouth, flatulence, oral discomfort, eructation.
Uncommon: gastrointestinal (and intestinal) perforation^q*, pancreatitis, anal fistula, colitis**.

Hepatobiliary disorders.

Uncommon: liver failure*, cholecystitis^r*, hepatic function abnormalities.
Rare: hepatitis.

Skin and subcutaneous tissue disorders.

Very common: skin color changes^s, hand-foot syndrome, rash^t, hair color changes, dry skin.
Common: skin desquamation, skin reactions^u, eczema, blisters, erythema, alopecia, acne, pruritus, skin hyperpigmentation, skin lesions, hyperkeratosis, dermatitis, nail disorders^v.
Rare: erythema multiforme*, Stevens-Johnson syndrome*, pyoderma gangrenosum, 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: hemorrhage from urinary tract.
Rare: nephrotic syndrome.

General disorders and administration site conditions.

Very common: mucositis, fatigue^w (and general weakness), edema^x (facial edema, edema, and peripheral edema), fever.
Common: chest pain, pain, influenza-like illness, chills.
Uncommon: impaired healing.

Investigations.

Common: weight decrease, leukocyte count decrease, lipase level increased, platelet count decrease, hemoglobin decrease, amylase level increased^y, AST increased, ALT increased, creatinine blood increased, blood pressure increased, uric acid blood increased.
Uncommon: creatine kinase blood increased, thyroid-stimulating hormone increased.

* Includes fatal cases.

Combined terms:

a Pharyngitis, herpes oralis.
b Bronchitis, lower respiratory tract infections, pneumonia, respiratory tract infections.
c Abscess, limb abscess, anal abscess, gingival abscess, liver abscess, pancreatic abscess, perineal abscess, perirectal abscess, rectal abscess, subcutaneous abscess, dental abscess.
d Oral and esophageal candidiasis.
e Cellulitis and skin infections.
f Sepsis and septic shock.
g Abdominal abscess, abdominal sepsis, diverticulitis, osteomyelitis.
h Thrombotic microangiopathy, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome.
i Decreased appetite and anorexia.
j Altered taste sensation, taste loss, taste disturbance.
k Acute coronary syndrome, angina, unstable angina, coronary artery occlusion, myocardial ischemia.
l Decreased/abnormal ejection fraction.
m Acute myocardial infarction, myocardial infarction, asymptomatic myocardial infarction.
n Mouth and throat pain, throat and larynx pain.
o Stomatitis, aphthous stomatitis.
p Abdominal pain, lower and upper abdominal pain.
q Gastrointestinal and intestinal perforation.
** Colitis, ischemic colitis.
r Cholecystitis, acalculous cholecystitis.
s Skin jaundice, skin color change, pigmentation disorder.
t Psoriasiform dermatitis, exfoliative rash, rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash.
u Skin reactions, skin disorders.
v Nail disorders, nail color change.
w Fatigue, asthenia.
x Facial edema, edema, peripheral edema.
y Increased amylase level.

Description of selected adverse reactions.

Infections and infestations. Reports of serious infections (with and without neutropenia), including fatal cases, have been received. Cases of necrotizing fasciitis, including intra-abdominal, have been reported, some resulting in fatal outcomes (see section "Special precautions").

Blood and lymphatic system disorders. Grade 3 and 4 neutrophil count decreases were reported in 10% and 1.7% of patients, respectively, in the phase 3 GIST study, in 16% and 1.6% of patients in the phase 3 RCC study, and in 13% and 2.4% of patients in the phase 3 GIST study. Grade 3 and 4 thrombocytopenia were observed in 3.7% and 0.4% of patients in the phase 3 GIST study, in 8.2% and 1.1% of patients in the phase 3 mRCC study, and in 3.7% and 1.2% of patients in the phase 3 GIST study (see section "Special precautions").

Bleeding events were reported in 18% of patients receiving sunitinib in the phase 3 GIST study compared to 17% of placebo recipients. Bleeding occurred in 39% of patients receiving sunitinib for previously untreated RCC compared to 11% of patients receiving interferon-α (IFN-α). Grade 3 or higher bleeding was observed in 17 (4.5%) patients receiving sunitinib compared to 5 (1.7%) patients receiving IFN-α. Bleeding occurred in 26% of patients receiving sunitinib for cytokine-refractory RCC. Non-epistaxis bleeding was reported in 21.7% of patients receiving sunitinib in the phase 3 GIST study compared to 9.85% of placebo recipients (see section "Special precautions").

Bleeding from tumors was observed in approximately 2% of GIST patients in clinical trials.

Immune system disorders. Hypersensitivity reactions, including angioedema, have been reported (see section "Special precautions").

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

Additionally, elevated thyroid-stimulating hormone (TSH) levels were observed in 4 (2%) cytokine-refractory RCC patients. Overall, 7% of RCC patients developed clinical or laboratory evidence of hypothyroidism during treatment. Acquired hypothyroidism occurred in 6.2% of GIST patients receiving sunitinib compared to 1% in the placebo group. In the phase 3 GIST study, hypothyroidism was reported in 6 (7.2%) patients receiving sunitinib and 1 (1.2%) patient receiving placebo. In two breast cancer studies, prospective thyroid function monitoring was conducted. Sunitinib is not approved for breast cancer treatment. In one study, hypothyroidism occurred in 15 (13.6%) patients receiving sunitinib and 3 (2.9%) patients receiving standard therapy. Increased TSH levels were observed in 1 (0.9%) patient receiving sunitinib and not in patients receiving standard therapy. Hyperthyroidism was not reported in patients receiving sunitinib and in 1 (1.0%) patient receiving standard therapy. In another study, hypothyroidism occurred in 31 (13%) patients receiving sunitinib and 2 (0.8%) patients receiving capecitabine. Increased TSH levels were observed in 12 (5%) patients receiving sunitinib and not in patients receiving capecitabine. Hyperthyroidism occurred in 4 (1.7%) patients receiving sunitinib and not in patients receiving capecitabine. Decreased TSH levels were observed in 3 (1.3%) patients receiving sunitinib and not in patients receiving capecitabine. Elevated T4 levels were observed in 2 (0.8%) patients receiving sunitinib and 1 (0.4%) patient receiving capecitabine. Elevated T3 levels were observed in 1 (0.8%) patient receiving sunitinib and not in patients receiving capecitabine. All thyroid-related reactions were grade 1–2 severity (see section "Special precautions").

Metabolism and nutrition disorders. Hypoglycemia occurred more frequently in GIST patients compared to metastatic RCC and gastrointestinal stromal tumor patients. However, most of these adverse reactions observed during clinical trials were considered unrelated to the investigational treatment.

Nervous system disorders. A small number of reports (<1%), some fatal, of seizures and radiological findings of reversible posterior leukoencephalopathy syndrome have been received from sunitinib clinical trials and post-marketing use. Seizures occurred in patients with or without radiological evidence of brain metastases (see section "Special precautions").

Cardiac disorders. In clinical trials, a decrease in LVEF of ≥20% and below the lower limit of normal was reported in approximately 2% of GIST patients receiving sunitinib, 4% of cytokine-refractory RCC patients, and 2% of GIST patients receiving placebo. These LVEF abnormalities are not progressive and often improve with continued treatment. In the previously untreated RCC study, a decrease in LVEF below the lower limit of normal occurred in 27% of patients receiving sunitinib and 15% of patients receiving IFN-α. Two patients (<1%) receiving sunitinib were diagnosed with CHF.

Heart failure, CHF, or left ventricular dysfunction were observed in 1.2% of GIST patients receiving sunitinib and 1% of placebo recipients. In the main phase 3 GIST study (N=312), fatal cardiac events related to the drug occurred in 1% of patients in each study group (sunitinib and placebo). In a phase 2 study of cytokine-refractory RCC, 0.9% of patients experienced fatal myocardial infarction related to the drug. In a phase 3 study of previously untreated RCC, 0.6% of the IFN-α group and 0% of the sunitinib group had fatal cardiac events. In the phase 3 GIST study, 1 (1%) patient receiving sunitinib experienced fatal heart failure related to the drug.

Vascular disorders.

Hypertension.

Hypertension was very commonly reported in clinical trials. Sunitinib dose was reduced or temporarily discontinued in approximately 2.7% of patients due to hypertension. In none of these patients was sunitinib permanently discontinued. Severe hypertension (systolic pressure >200 mm Hg or diastolic pressure 110 mm Hg) occurred in 4.7% of patients with solid tumors. Hypertension occurred in approximately 33.9% of patients receiving sunitinib for previously untreated RCC compared to 3.6% of patients receiving IFN-α. Severe hypertension occurred 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 GIST study compared to 4.9% of placebo recipients. Severe hypertension was reported in 10% of GIST patients receiving sunitinib and 3% of placebo recipients.

Venous thromboembolism.

Venous thromboembolic events related to the drug were reported in approximately 1.0% of patients with solid tumors receiving sunitinib in clinical trials of GIST and RCC.

In the phase 3 GIST study, venous thromboembolic events occurred in 7 (3%) patients receiving sunitinib and in none of the placebo group; 5 of the 7 patients had grade 3 deep vein thrombosis (DVT) and 2 had grade 1 or 2 DVT. Four of these 7 GIST patients discontinued treatment after the first DVT event. Thirteen (3%) patients receiving sunitinib in the phase 3 previously untreated RCC study and 4 (2%) patients from two cytokine-refractory RCC studies reported venous thromboembolism. Nine of these patients had pulmonary embolism: 1 patient grade 2 and 8 patients grade 4. Eight of these patients had DVT: 1 patient grade 1, 2 patients grade 2, 4 patients grade 3, and 1 patient grade 4. One patient with pulmonary embolism in the cytokine-refractory RCC study discontinued therapy.

In previously untreated RCC patients receiving IFN-α, 6 (2%) venous thromboembolic events were recorded: 1 patient (<1%) had grade 3 DVT and 5 patients (1%) 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 GIST study. Two patients in the placebo group had DVT: 1 patient grade 2 and 1 patient grade 3.

No fatal cases were reported in registration trials for GIST, RCC, and GIST. Fatal cases occurred in the post-marketing period.

Pulmonary embolism occurred in approximately 3.1% of GIST patients and approximately 1.2% of RCC patients receiving sunitinib in phase 3 studies. In GIST patients receiving sunitinib in the phase 3 study, pulmonary embolism was not reported. Rare fatal cases occurred in the post-marketing period.

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

In patients receiving sunitinib in phase 3 registration trials, lung disorders (dyspnea, pleural effusion, pulmonary embolism, or pulmonary edema) were recorded in approximately 17.8% of GIST patients, 26.7% of RCC patients, and 12% of GIST patients.

Lung disorders occurred in approximately 22.2% of patients with solid tumors, including GIST and RCC, receiving sunitinib in clinical trials.

Gastrointestinal disorders. Pancreatitis occurred uncommonly (<1%) in patients receiving sunitinib for GIST or RCC. Pancreatitis related to the drug was not reported in the phase 3 GIST study (see section "Special precautions"). Fatal gastrointestinal bleeding was reported in 0.98% of patients receiving placebo in the phase 3 GIST study.

Hepatobiliary disorders. Cases of hepatic dysfunction, including abnormal liver function tests, hepatitis, or liver failure, have been reported (see section "Special precautions").

Skin and subcutaneous tissue disorders. Cases of pyoderma gangrenosum, usually reversible after discontinuation of sunitinib, have been reported (see section "Special precautions").

Musculoskeletal and connective tissue disorders. Cases of myopathy and/or rhabdomyolysis, some associated with acute renal failure, have been reported. Patients with symptoms of muscle toxicity should be managed according to current medical standards.

Cases of fistula formation, sometimes associated with tumor necrosis and regression, have been reported, occasionally resulting in fatal outcomes. Cases of osteonecrosis of the jaw (ONJ) have been described in patients receiving sunitinib, primarily in the presence of risk factors for ONJ (e.g., intravenous bisphosphonate use and/or history of dental disease requiring invasive dental procedures) (see section "Special precautions").

Investigations. Preclinical data (in vitro and in vivo) from studies using doses exceeding the recommended human dose indicate that sunitinib may inhibit cardiac repolarization processes (e.g., QT interval prolongation).

QTc prolongation >500 msec was observed in 0.5% and changes from baseline >60 msec in 1.1% of 450 patients with solid tumors; both parameters considered potentially significant. Sunitinib at concentrations approximately twice the therapeutic level prolonged QTcF (QT interval corrected by Fridericia's formula).

QTc prolongation was studied in a trial involving 24 patients aged 20 to 87 years with advanced malignancies. Results demonstrated that sunitinib affected QTc (defined as mean change, placebo-adjusted, >10 msec with 90% CI, upper limit >15 msec) at therapeutic concentration (day 3) using the baseline correction method over 24 hours and at concentrations exceeding therapeutic levels (day 9) using both baseline correction methods. No patient had QTc >500 msec. Although QTcF prolongation was observed on day 3, 24 hours after dosing (i.e., at therapeutic plasma concentration expected after the recommended initial dose of 50 mg) using the 24-hour baseline correction method, the clinical significance of this finding is unclear.

Based on comprehensive assessment of serial ECGs during periods corresponding to therapeutic or higher-than-therapeutic drug concentrations, no patient in the evaluable population or randomized patients (ITT) had QTc prolongation considered severe (i.e., ≥ grade 3 according to Common Terminology Criteria for Adverse Events [CTCAE], version 3.0). At therapeutic plasma concentrations, the maximum mean difference from baseline for QTcF (Fridericia-corrected) was 9 msec (90% CI: 15.1 msec). At concentrations approximately twice the therapeutic level, the maximum mean difference from baseline for QTcF was 15.4 msec (90% CI: 22.4 msec). Moxifloxacin (400 mg), used as a positive control, showed a maximum mean difference from baseline for QTcF of 5.6 msec. No patient experienced QTc changes greater than grade 2 (CTCAE, version 3.0) (see section "Special precautions").

Long-term safety in RCC treatment.

Long-term safety of sunitinib in RCC patients was analyzed in 9 completed clinical trials conducted in first-line, bevacizumab-refractory, and cytokine-refractory treatment settings involving 5739 patients, of whom 807 (14%) received treatment for 2 to 6 years. In the 807 patients receiving long-term sunitinib treatment, most drug-related adverse events initially developed within the first 6 months to 1 year and then remained stable or decreased in frequency over time, except for hypothyroidism, which progressively increased over time with new cases occurring throughout the 6-year period. Long-term sunitinib treatment was not associated with new types of drug-related adverse events.

Pediatric population.

A phase I dose-escalation study of oral sunitinib was conducted in 35 patients, 30 of whom were pediatric (aged 3 to 17 years) and 5 young adults (aged 18 to 21 years), with refractory solid tumors, most with primary brain tumor diagnosis. All study participants experienced adverse reactions, and in patients previously treated with anthracyclines or who received cardiac irradiation, most reactions were severe (toxicity grade ≥3) and included cardiotoxicity. The most common adverse reactions were gastrointestinal toxicity, neutropenia, increased fatigue, and elevated ALT levels. The risk of cardiac adverse reactions was higher in children previously exposed to cardiac irradiation or anthracyclines compared to those not receiving such treatment. The maximum tolerated dose of sunitinib was not established for this patient group due to dose-limiting toxicity (see section "Pharmacodynamics"). The maximum tolerated dose was established for the group of patients not previously treated with anthracyclines or not receiving cardiac irradiation.

Adjuvant therapy in RCC.

The safety of sunitinib was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial, in which patients who underwent nephrectomy for RCC received sunitinib 50 mg once daily (N=306) on a 4/2 schedule or placebo (N=304). Median treatment duration was 12.4 months (range: 0.13–14.9) for sunitinib and 12.4 months (range: 0.03–13.7) for placebo. Drug discontinuation due to adverse reactions occurred in 28% of patients receiving sunitinib and 6% of patients receiving placebo. Adverse reactions leading to drug discontinuation in >2% of patients included hand-foot syndrome and fatigue/asthenia. Drug interruption occurred in 54% and dose reduction in 46% of patients receiving sunitinib.

Table 7 summarizes adverse reactions observed in S-TRAC.

Table 7

Adverse reactions reported in S-TRAC in ≥10% of RCC patients receiving sunitinib and more frequently than in placebo recipients in S-TRAC.

Adverse reaction	Adjuvant therapy RCC
	Sunitinib (N=306)		Placebo (N=304)
	All grades, %	Grade 3–4, %	All grades, %	Grade 3–4, %
Any adverse reaction	99	60	88	15
Gastrointestinal. Mucositis/stomatitisb Diarrhea Nausea Dyspepsia Abdominal painc Vomiting Constipation	61 57 34 27 25 19 12	6 4 2 1 2 2 0	15 22 15 7 9 7 11	0 < 1 0 0 < 1 0 0
Systemic. Fatigue/asthenia Localized edemaa Fever	57 18 12	8 < 1 < 1	34 < 1 6	2 0 0
Skin-related. Palmar-plantar syndrome Hair color changes Rashe Skin discoloration/yellowing of skin Skin dryness	50 22 24 18 14	16 0 2 0 0	10 2 12 1 6	<1 0 0 0 0
Cardiac. Arterial hypertensiond Edema/peripheral edema	39 10	8 < 1	14 7	1 0
Nervous system. Altered tastef Headache	38 19	<1 <1	6 12	0 0
Endocrine system. Hypothyroidism/elevated TSH	24	<1	4	0
Bleeding Bleeding events, all sitesg	24	<1	5	<1
Metabolism/nutrition Anorexia/appetite decreased	19	<1	5	0
Musculoskeletal system. Limb pain Arthralgia	15 11	<1 <1	7 10	0 0

* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Abbreviations: AE – adverse events; N – number of patients; RCC – renal cell carcinoma.

a Includes localized edema, facial edema, eyelid edema, periorbital edema, facial swelling, and eye swelling.

b Includes mucosal inflammation, aphthous stomatitis, oral ulceration, tongue ulceration, oropharyngeal pain, and oral pain.

c Includes abdominal pain, lower abdominal pain, and upper abdominal pain.

d Includes hypertension, increased blood pressure, increased systolic blood pressure, increased diastolic blood pressure, and hypertensive crisis.

e Includes dermatitis, psoriasiform dermatitis, desquamative rash, genital rash, rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, papular rash, and pruritic rash.

f Includes ageusia, hypogeusia, and dysgeusia.

g Includes epistaxis, gingival bleeding, rectal bleeding, hemoptysis, anal bleeding, upper gastrointestinal bleeding, and hematuria.

Grade 4 adverse events in patients receiving sunitinib included hand-foot syndrome (1%), fatigue (<1%), abdominal pain (<1%), stomatitis (<1%), and pyrexia (<1%). Grade 4 adverse events in patients receiving placebo included asthenia (<1%) and arterial hypertension (<1%).

Grade 3–4 laboratory abnormalities occurring in ≥2% of patients receiving sunitinib included neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated ALT (2%), elevated AST (2%), hyperglycemia (2%), and hyperkalemia (2%).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Packaging. 7 capsules per blister; 4 blisters per cardboard box, or 10 capsules per blister; 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturers.

Sytone España, S.L.

and

Sytone B.V.

Manufacturers' locations and addresses of their business sites.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain

and

Microveg 22, Nijmegen, 6545 SM, The Netherlands.