Sunitinib-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUNITINIB-VISTA (SUNITINIB-VISTA)

Composition:

Active substance: 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:

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 orange cap and orange body, marked with white ink "12.5 mg" on the body, containing granules of yellow to orange color;

25 mg: gelatin capsules size 3 with caramel-colored cap and orange body, marked with white ink "25 mg" on the body, containing granules of yellow to orange color;

37.5 mg: gelatin capsules size 2 with yellow cap and yellow body, marked with black ink "37.5 mg" on the body, containing granules of yellow to orange color;

50 mg: gelatin capsules size 1 with caramel-colored cap and caramel-colored body, marked with white ink "50 mg" on the body, containing granules of yellow to orange 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 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 (Cmax) of sunitinib is generally observed within 6–12 hours (time to maximum plasma concentration [Tmax]) after oral administration. Food intake does not affect the bioavailability of sunitinib. Sunitinib-Vistu can be administered regardless of food intake.

Protein binding of sunitinib and its primary active metabolite to human plasma proteins in vitro was 95% and 90%, respectively, without concentration dependence 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 increased proportionally with dose. Sunitinib is primarily metabolized by the cytochrome P450 enzyme CYP3A4 to form the primary active metabolite, which is subsequently metabolized by CYP3A4. The major active metabolite accounts for 23% to 37% of total exposure. Elimination occurs primarily via feces. In a human mass balance study with [14C]sunitinib, 61% of the dose was excreted in 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, representing 91.5%, 86.4%, and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were detected in urine and feces but generally not in plasma. Total oral clearance (C/F) ranged from 34 to 62 L/h, with inter-individual variability of 40%.

After a single oral dose in healthy volunteers, terminal half-life of sunitinib and its primary active metabolite is 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 active metabolite were observed. Steady-state concentrations of sunitinib and its primary active metabolite are reached within 10–14 days. By day 14, the combined plasma concentration 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 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 GIST (gastrointestinal stromal tumor) and RCC (renal cell carcinoma). 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 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 was similar in patients with severe renal impairment (CLcr < 30 mL/min) and in patients with normal renal function (CLcr >80 mL/min). Despite the fact that sunitinib is not removed by hemodialysis, systemic exposure to sunitinib was 47% lower in patients with end-stage renal disease (ESRD) undergoing 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 liver function.

Cardiac Electrophysiology.

Sunitinib may cause dose-dependent QT interval prolongation, which could increase the risk of ventricular arrhythmias, including torsades de pointes (see section "Special Warnings and Precautions for Use").

Clinical Studies.

Gastrointestinal Stromal Tumor.

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 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 other reasons.

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)

Efficiency parameter	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; PR – partial response.

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-group, dose-escalation study conducted in patients with GIST after 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 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).

Untreated RCC.

Study 3 (NCT # 00083889) was a multicenter, international, randomized study comparing sunitinib monotherapy with interferon-α (IFN-α) in patients with previously untreated RCC. The objective was to compare PFS in patients receiving sunitinib versus those receiving IFN-α. Other 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 (IU) three times weekly. Patients received treatment until disease progression or study withdrawal. A statistically significant advantage of sunitinib over IFN-α was observed for the PFS endpoint (see Table 2). In prespecified stratification factors—lactate dehydrogenase (LDH) (> 1.5 ULN vs. ≤ 1.5 ULN), ECOG performance status (0 or 1), and prior nephrectomy (yes or no)—the hazard ratio demonstrated superiority of sunitinib over IFN-α. ORR was higher in the sunitinib group (see Table 2).

Table 2. Efficacy results in previously untreated RCC (interim analysis) from Study 3

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

Efficiency parameter	Sunitinib (N = 375)	IFN-α (N = 375)	p-value (log-rank test)	HR (95 % CI)
Progression-free survivala [median value, 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	NR

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 studies. All patients enrolled in these studies had previously failed cytokine therapy. In Study 4 (NCT # 00077974), failure of prior cytokine therapy was defined by radiographic 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 (IFN-α, interleukin-2, or IFN-α plus interleukin-2; patients receiving IFN-α alone were required to have received treatment for at least 28 days). In Study 5 (NCT # 00054886), failure of prior cytokine therapy was defined as disease progression or treatment-related unacceptable 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 were enrolled in Study 5. Patients received sunitinib 50 mg on a 4-week-on/2-week-off schedule.

ORR and DOR data from Studies 4 and 5 are presented in Table 3. In Study 4, 36 objective responses 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 objective responses 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 last response was observed in cycle 10. DOR data from Study 4 are considered preliminary, as only 9 of the 36 responding patients (25%) experienced disease progression or death at the time of data cutoff.

Table 3. Efficacy results in cytokine-refractory RCC from Studies 4 and 5

Efficiency parameter	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 value, weeks (95% CI)]	NE* (42.0, *)	54b (34.3, 70.1)

* Data not reliable for determining the upper limit of the confidence interval.

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

a Assessed by blinded independent radiology review.

b Assessed by investigators.

Adjuvant therapy of RCC.

Sunitinib was evaluated in the adjuvant setting in S-TRAC (NCT #00375674), a multicenter, international, randomized, double-blind, placebo-controlled trial involving patients at high risk of recurrent RCC following nephrectomy. Patients were required to have clear cell histology and 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 disease-free survival (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 placebo (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 mortality rate among patients being 141 out of 615 (23%).

Table 4. Disease-free survival results assessed by BICR in the adjuvant RCC therapy setting (treated 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 the prognostic group of the University of California, Los Angeles (UCLA) Integrated Staging System (UISS); HR is based on the Cox proportional hazards model stratified by UISS prognostic group.

Abbreviations: BICR – blinded independent central review; CI – confidence interval; EFS – event-free survival; HR – hazard ratio; N – number of patients; RCC – renal cell carcinoma.

Table 5. Event-free survival by baseline disease characteristics

	Number of cases/total n/N		Median PFS [years (95% CI)]		HRa (95% CI)
	Sunitinib	Placebo	Sunitinib	Placebo
T3 Moderateb	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 formd	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; PFS – progression-free survival; HR – hazard ratio; N – number of patients; n – number of events; NE – 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 PNET (pancreatic neuroendocrine tumor). Patients were required to have RECIST-documented disease progression 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 PFS in patients receiving sunitinib versus those receiving placebo. Secondary endpoints included OS, ORR, and safety. The use of somatostatin analogs was permitted in the study.

As recommended by the Independent Data Monitoring Committee, the study was terminated early prior to the prespecified interim analysis. This may have led to an overestimation of the magnitude of the PFS treatment effect. A clinically meaningful improvement in PFS with sunitinib compared to placebo was observed by both investigator assessment and independent review. A favorable hazard ratio for 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; RR – risk ratio; N – number of patients; NA – not applicable; pNET – pancreatic neuroendocrine tumors.

a Two-sided unstratified log-rank test.

b Fisher's exact test.

Clinical characteristics.

Indications.

Gastrointestinal stromal tumor (GIST).

Sunitinib-Vista is indicated for the treatment of gastrointestinal stromal tumor following disease progression or intolerance to imatinum mesylate.

Progressive renal cell carcinoma (RCC).

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

Sunitinib-Vista is indicated for adjuvant therapy in adult patients with high risk of recurrent RCC following nephrectomy.

Progressive pancreatic neuroendocrine tumors (pNET).

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

Contraindications.

Hypersensitivity to sunitinib malate 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 sunitinib plasma concentrations. It is recommended to select an alternative concomitant medicinal product with no or minimal enzyme inhibition potential. Concomitant administration of Sunitinib-Vista 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-Vista in healthy volunteers. Concomitant use of Sunitinib-Vista with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase sunitinib plasma concentrations. Dose reduction of Sunitinib-Vista should be considered when it must be co-administered with strong CYP3A4 inhibitors (see section "Dosage and administration").

Strong CYP3A4 inducers.

CYP3A4 inducers, such as rifampicin, may reduce sunitinib plasma concentrations. It is recommended to select an alternative concomitant medicinal product with no or minimal enzyme induction potential. Concomitant administration of sunitinib 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 sunitinib in healthy volunteers. Concomitant use of Sunitinib-Vista with CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, St. John's wort) may reduce sunitinib concentrations. Dose escalation of Sunitinib-Vista should be considered when it must be co-administered with CYP3A4 inducers (see section "Dosage and administration").

In vitro studies of CYP inhibition and induction.

In vitro studies have shown 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.

Drugs that prolong the QT interval.

Sunitinib may prolong the QT interval. In patients requiring treatment with medicinal products that prolong the QT interval, more frequent monitoring of the QT interval by ECG is recommended.

Special precautions for use.

Hepatotoxicity.

Sunitinib may cause severe hepatotoxicity, leading to liver failure or fatal outcome. Liver failure occurred at a frequency of < 1 % in clinical studies. Signs 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. Sunitinib-Vista should be discontinued in case of drug-related grade III or IV hepatic adverse reactions and permanently discontinued if they do not resolve. Reinitiation of sunitinib is not recommended in patients who develop severe abnormalities in liver function tests or symptoms of liver failure.

The safety of sunitinib has not been established in patients with ALT or AST levels > 2.5 times the upper limit of normal (ULN), or in patients with liver metastases and levels > 5 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 adverse events involving the pancreas have been reported, some of which were fatal. Sunitinib should be discontinued and appropriate supportive treatment initiated in patients presenting symptoms of pancreatitis.

Cardiovascular disorders.

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

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

In the adjuvant RCC study, left ventricular ejection fraction (LVEF) decline meeting CTCAE grade II criteria (LVEF 40–50 % and a decrease of 10–19 % from baseline) was observed in 11 patients in each group. No patient experienced grade III–IV LVEF decline. LVEF did not return to ≥ 50 % or baseline levels at the last measurement in three patients in the sunitinib group and two in the placebo group. No patient receiving sunitinib was diagnosed with congestive heart failure (CHF).

Patients with cardiovascular events within 12 months prior to sunitinib administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass grafting, symptomatic CHF, acute cerebrovascular accident, transient ischemic attack, or pulmonary artery thromboembolism, were excluded from clinical trials of sunitinib. It is unknown whether patients with these comorbidities may have an increased risk of drug-related left ventricular dysfunction.

Monitoring of LVEF at the beginning of treatment and periodically thereafter, as clinically indicated, should be considered. Patients should be closely monitored for clinical signs and symptoms of CHF. Sunitinib should be discontinued in patients who develop clinical manifestations of CHF. The drug should be interrupted and/or dose reduced in patients without clinical signs of CHF if LVEF decreases by more than 20 % but less than 50 % from baseline or falls below the lower limit of normal, when 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 observed in < 0.1 % of patients receiving sunitinib. Patients 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 (magnesium, potassium) should be considered during treatment with sunitinib. Concomitant use of strong CYP3A4 inhibitors may increase sunitinib plasma concentrations; therefore, dose reduction of sunitinib should be considered (see section "Dosage and administration").

Arterial hypertension.

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

Arterial hypertension was observed in 29 % of patients receiving sunitinib (N = 7527) in studies of GIST, advanced RCC, adjuvant therapy for RCC, and PRCC. Grade III hypertension occurred in 7 % of patients and grade IV in 0.2 %.

Hypersensitivity/angioedema.

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

Seizures.

Seizures have been reported in clinical trials of sunitinib and during post-marketing use. Patients experiencing seizures or symptoms of reversible posterior leukoencephalopathy syndrome (RPLS), such as arterial hypertension, headache, decreased alertness, cognitive impairment, or visual disturbances including cortical blindness, require monitoring and medical treatment, including control of hypertension. Temporary discontinuation of sunitinib is recommended; after resolution of the event, 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) included gastrointestinal, respiratory, tumor-related, urinary tract, and intracranial bleeding. Hemorrhagic events were observed in 30 % of patients receiving sunitinib (N = 7527) in studies of GIST, advanced RCC, adjuvant therapy for RCC, and PRCC, with grade III or IV events in 4.2 % of patients. The most common hemorrhagic adverse reaction was epistaxis, while gastrointestinal bleeding was the most common grade ≥ III event.

Bleeding related to tumors has been observed in patients receiving sunitinib. These events may occur suddenly and, in patients with lung tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, some fatal, have been reported 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 patients with lung cancer. 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.

Tumor lysis syndrome (TLS).

Cases of TLS, sometimes fatal, have been observed in clinical trials and during post-marketing use, primarily in patients with RCC or GIST receiving sunitinib. Overall, patients with high tumor burden prior to starting treatment are at risk of TLS. Such patients should be closely monitored and managed according to clinical indications.

Aneurysms and arterial dissection.

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

Thrombotic microangiopathy (TMA).

Thrombotic microangiopathy (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 should be discontinued in patients who develop TMA. Resolution of TMA effects has been observed after discontinuation of 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 development or worsening of proteinuria. Urinalysis should be performed at baseline and periodically during treatment, with 24-hour urine protein measurement as clinically indicated. Sunitinib should be interrupted and dose reduced if 24-hour urinary protein is ≥ 3 grams. Sunitinib should be discontinued in patients with nephrotic syndrome or recurrent episodes of urinary protein ≥ 3 grams despite dose reduction. The safety of continuing sunitinib 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 occur (e.g., progressive skin rash, often with blisters or mucosal involvement), sunitinib treatment should be discontinued. Reinitiation of sunitinib is not recommended if SJS or TEN is suspected.

Necrotizing fasciitis, including fatal cases, has been reported in patients receiving sunitinib, including perineal involvement and fistula formation. Sunitinib 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, cognitive impairment, and visual disturbances, including cortical blindness. Diagnosis should be confirmed by magnetic resonance imaging. Sunitinib should be withheld until resolution of symptoms. The safety of reinitiating sunitinib 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 starting sunitinib. All patients should be closely monitored for symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, during sunitinib treatment. Patients with signs suggestive of thyroid dysfunction should undergo laboratory monitoring of thyroid function and receive treatment according to standard medical practice.

Cases of hyperthyroidism, some followed by 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 and GIST, and in approximately 10 % of patients receiving sunitinib for PRCC in clinical studies. Hypoglycemia was not observed in patients receiving sunitinib in the adjuvant RCC study. In patients with PRCC and hypoglycemia, no abnormalities in glucose homeostasis were observed. Blood glucose reduction may be more pronounced in patients with diabetes. Blood glucose levels should be monitored regularly during and after discontinuation of sunitinib treatment. Anti-diabetic therapy should be adjusted as needed to minimize the risk of hypoglycemia.

Osteonecrosis of the jaw (ONJ).

Osteonecrosis of the jaw (ONJ) has been observed 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. An oral examination should be performed before starting Sunitinib-Vista and periodically during therapy. Patients should be advised on proper oral hygiene. Sunitinib-Vista treatment should be interrupted, if possible, at least 3 weeks before planned dental surgery or invasive dental procedures. Treatment with Sunitinib-Vista should be discontinued in case of ONJ development until complete healing.

Impaired wound healing.

Impaired wound healing has been observed in patients receiving sunitinib (see section "Adverse reactions"). Sunitinib therapy should be interrupted at least 3 weeks before planned major surgery. The drug should not be administered for at least 2 weeks after major surgery and until adequate wound healing has occurred. The safety of resuming sunitinib treatment after resolution of wound healing complications has not been established.

Embryo-fetal toxicity.

Based on animal studies and the mechanism of action, sunitinib 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 clinical systemic exposure (AUC) at the recommended daily dose (RDD) of 50 mg/day, respectively.

Pregnant women should be informed of the potential risk to the fetus. Women of reproductive potential should be advised to use effective contraception during sunitinib treatment and for 4 weeks after the last dose (see sections "Pharmacodynamics" and "Use in pregnancy or breastfeeding").

Pediatric use.

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

Use in elderly patients.

Among 825 patients with GIST or metastatic RCC receiving sunitinib in clinical studies, 277 (34 %) were aged 65 years or older. In the PRCC study, 22 patients (27 %) receiving 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 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, grade III–IV adverse reactions occurred in 50 patients (16 %) in the sunitinib group compared to 15 patients (5 %) in the placebo group.

Hepatic impairment.

No initial dose adjustment is required for sunitinib in patients with Child-Pugh class A or B hepatic impairment. Sunitinib and its primary metabolite are predominantly 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 sunitinib in patients with severe hepatic impairment (Child-Pugh class C) has not been studied. Patients with ALT or AST > 2.5×ULN or, in the presence of liver metastases, > 5.0×ULN were excluded from cancer trials.

Renal impairment.

No initial dose adjustment is required for sunitinib in 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. No initial dose adjustment is required in patients with end-stage renal disease (ESRD) on hemodialysis. However, sunitinib exposure is 47 % lower in patients with ESRD on hemodialysis compared to those 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"). In patients who develop unexplained lethargy or mental status changes, ammonia levels should be measured and appropriate pharmacological treatment initiated.

Use in pregnancy or breastfeeding.

Pregnancy.

Summary of 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 drug-related risk. 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 exposures approximately 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 reproductive potential should be advised of the potential risk to the fetus. The expected background risk of major congenital malformations and miscarriage is unknown for the specified populations. All pregnancies carry a background risk of congenital malformations, miscarriage, or other adverse outcomes. In the general US population, the estimated background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2–4 % and 15–20 %, respectively.

Lactation.

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

Men and women of reproductive potential.

Sunitinib may cause fetal harm when administered to pregnant women (see section "Pregnancy").

Pregnancy testing.

Pregnancy should be verified in women of reproductive potential before initiating Sunitinib-Vista treatment.

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 treatment with Sunitinib-Vista and for 7 weeks after the last dose.

Infertility.

Based on reproductive toxicity studies in animals, sunitinib may impair fertility in males and females.

Ability to drive and use machines.

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 sunitinib treatment.

Method of Administration and Dosage

Recommended dosage for GIST and advanced RCC

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

Recommended dosage for adjuvant therapy of RCC.

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

Recommended dosage for PNET.

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

Dose modification

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

Strong CYP3A4 inhibitors, such as ketoconazole, may increase sunitinib plasma concentrations. It is recommended to select an alternative concomitant medicinal product with no or minimal enzyme inhibition potential. Consideration should be given to reducing the dose of Sunitinib-Vista to at least 37.5 mg (GIST and RCC) or 25 mg (PNET) daily if coadministration with a strong CYP3A4 inhibitor is unavoidable (see section "Interactions with Other Medicinal Products and Other Forms of Interactions" and "Pharmacokinetics").

Strong 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. Consideration should be given to increasing the dose of Sunitinib-Vista up to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (PNET) daily if coadministration with a strong CYP3A4 inducer is unavoidable. If the dose is increased, patients should be closely monitored for signs of toxicity (see sections "Interactions with Other Medicinal Products and Other Forms of Interactions" and "Pharmacokinetics").

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

Paediatric population

The safety and efficacy of Sunitinib-Vista 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. In preclinical studies, mortality was observed at a dose of five times the daily dose 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 at lower doses when administered over a longer duration.

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

Adverse Reactions

The most important serious adverse reactions associated with sunitinib use (including fatal outcomes) are renal failure, heart failure, pulmonary embolism, gastrointestinal tract perforation, and hemorrhage (e.g., gastrointestinal bleeding, respiratory tract hemorrhage, tumor hemorrhage, urinary tract hemorrhage, or intracranial hemorrhage).

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

Common adverse drug reactions include hematologic 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.

Below is a list of adverse reactions reported in patients with gastrointestinal stromal tumors (GIST), metastatic renal cell carcinoma (mRCC), and pancreatic neuroendocrine tumors (pNET). Information on these adverse reactions was derived from pooled data from 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 in post-marketing clinical studies. Within each frequency group, adverse reactions are listed in descending order of frequency. 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 not known (cannot be estimated from available data). Adverse reactions recorded during clinical trials (publicly available information).

Infections and Infestations.

Common: viral infections^a, respiratory tract infections^b*, abscess^c*, fungal infections^d, urinary tract infections, skin infections^e (and phlegmon), sepsis^f*.

Uncommon: necrotizing fasciitis*.

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*.

Psychiatric Disorders.

Very common: insomnia.

Common: depression.

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*.

Not known: hyperammonemia encephalopathy.

Eye Disorders.

Common: periorbital edema, eyelid edema, increased lacrimation.

Cardiovascular 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 failure*, torsades de pointes.

Very common: arterial hypertension.

Common: deep vein thrombosis, hot flashes, hyperemia.

Uncommon: tumor hemorrhage*.

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 (also throat and larynx), nasal congestion, dryness of nasal mucosa.

Uncommon: pulmonary hemorrhage*, respiratory failure*.

Gastrointestinal Disorders.

Very common: stomatitis^o, abdominal pain^p, vomiting, diarrhea, dyspepsia, nausea, constipation.

Common: gastroesophageal reflux disease, dysphagia, gastrointestinal hemorrhage*, esophagitis*, abdominal distension, abdominal discomfort, rectal hemorrhage, gingival bleeding, oral ulcers, proctalgia, cheilitis, hemorrhoids, glossodynia, mouth pain, dry mouth, flatulence, mouth discomfort, belching.

Uncommon: gastrointestinal (and intestinal) perforation^q*, pancreatitis, anal fistula, colitis^s.

Hepatobiliary Disorders.

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

Rare: hepatitis.

Skin and Subcutaneous Tissue Disorders.

Very common: skin color changes^s, hand-foot syndrome (palmar-plantar erythrodysesthesia), 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: urinary tract hemorrhage.

Rare: nephrotic syndrome.

General Disorders and Administration Site Conditions.

Very common: mucosal inflammation, increased fatigue^w (and general weakness), edema^x (facial edema, edema, and peripheral edema), pyrexia.

Common: chest pain, pain, influenza-like illness, chills.

Uncommon: impaired healing.

Investigations.

Common: weight loss, decreased white blood cell count, increased lipase levels, decreased platelet count, decreased hemoglobin levels, increased amylase levels^y, increased aspartate aminotransferase (AST) levels, increased alanine aminotransferase (ALT) levels, increased blood creatinine levels, increased blood pressure, increased blood uric acid levels.

Uncommon: increased blood creatine phosphokinase levels, increased blood thyroid-stimulating hormone (TSH) levels.

* Includes fatal cases.

The following terms were combined:

a Pharyngitis, nasopharyngitis, and oral herpes.

b Bronchitis, lower respiratory tract infections, pneumonia, and respiratory tract infections.

c Abscess, limb abscess, anal abscess, gingival abscess, liver abscess, pancreatic abscess, perineal abscess, perirectal abscess, rectal abscess, subcutaneous abscess, and dental abscess.

d Esophageal candidiasis and oral candidiasis.

e Cellulitis and skin infections.

f Sepsis and septic shock.

g Intra-abdominal abscess, abdominal sepsis, diverticulitis, and osteomyelitis.

h Thrombotic microangiopathy, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome.

i Decreased appetite and anorexia.

j Altered taste sensation, loss of taste, and taste disturbance.

k Acute coronary syndrome, angina, unstable angina, coronary artery occlusion, and myocardial ischemia.

l Decreased or abnormal ejection fraction.

m Acute myocardial infarction, myocardial infarction, and asymptomatic myocardial infarction.

n Mouth and throat pain, throat and larynx pain.

o Stomatitis and aphthous stomatitis.

p Abdominal pain, lower and upper abdominal pain.

q Gastrointestinal perforation and intestinal perforation.

r Cholecystitis and acalculous cholecystitis.

s Jaundice, skin color change, and pigmentation disorder.

t Psoriasiform dermatitis, exfoliative rash, rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, papular rash, and pruritic rash.

u Skin reactions and skin disorders.

v Nail disorders and nail color change.

w Fatigue and asthenia.

x Facial edema, edema, and peripheral edema.

y Increased amylase levels.

Description of Selected Adverse Reactions.

Infections and Infestations.

Serious infections (with or without neutropenia), including fatal cases, have been reported. Cases of necrotizing fasciitis, including intra-abdominal necrotizing fasciitis, have been reported, some of which were fatal (see section "Special Warnings and Precautions for Use").

Blood and Lymphatic System Disorders.

Grade III and IV decreases in absolute neutrophil count 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 mRCC study, and in 13% and 2.4% of patients in the phase 3 pNET study. Grade III and IV thrombocytopenia was 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 pNET study (see section "Special Warnings and Precautions for Use").

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 mRCC compared to 11% of patients receiving interferon-α (IFN-α). Grade III or higher bleeding events were 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 mRCC. Bleeding events (excluding epistaxis) were reported in 21.7% of patients receiving sunitinib in the phase 3 pNET study compared to 9.85% of placebo recipients (see section "Special Warnings and Precautions for Use").

In clinical trials, tumor hemorrhage occurred in approximately 2% of patients with GIST.

Immune System Disorders.

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

Endocrine Disorders.

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

Additionally, elevated thyroid-stimulating hormone (TSH) levels were observed in 4 patients with cytokine-refractory mRCC (2%). Overall, 7% of mRCC patients had clinical or laboratory evidence of hypothyroidism developing during treatment. Acquired hypothyroidism occurred in 6.2% of GIST patients 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 studies among breast cancer patients, prospective monitoring of thyroid function was conducted; sunitinib is not approved for breast cancer treatment. In one study, hypothyroidism was reported in 15 patients (13.6%) receiving sunitinib and 3 (2.9%) 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%) patient receiving standard therapy. In another study, hypothyroidism occurred in 31 (13%) patients receiving sunitinib and 2 (0.8%) 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 occurred in 2 (0.8%) patients receiving sunitinib and 1 (0.4%) in the capecitabine group. Elevated T3 levels occurred in 1 (0.8%) patient receiving sunitinib and not in patients receiving capecitabine. All thyroid-related reactions were Grade I–II severity (see section "Special Warnings and Precautions for Use").

Metabolism and Nutrition Disorders.

Hypoglycemia occurred more frequently in patients with pancreatic neuroendocrine tumors 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 investigational treatment.

Nervous System Disorders.

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

Cardiac Function Disorders.

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

In GIST patients, heart failure, congestive heart failure, or left ventricular failure were reported in 1.2% of the sunitinib group and 1% of the placebo group. In the main phase 3 GIST study (N=312), fatal cardiac disorders related to the drug occurred in 1% of patients in each study group (sunitinib and placebo). In a phase 2 study of cytokine-refractory mRCC, fatal myocardial infarction related to the drug occurred in 0.9% of patients. In a phase 3 study of previously untreated mRCC, 0.6% in the IFN-α group and 0% in the sunitinib group experienced fatal cardiac disorders. In the phase 3 pNET 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. Dose reduction or temporary interruption of sunitinib occurred in approximately 2.7% of patients due to hypertension. In none of these patients was sunitinib permanently discontinued. Severe hypertension (systolic >200 mm Hg or diastolic >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 mRCC 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 pNET study compared to 4.9% of placebo recipients. Severe hypertension was reported in 10% of pNET patients receiving sunitinib and 3% of placebo patients.

Thromboembolic Events.

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 mRCC.

In the phase 3 GIST study, venous thromboembolic events occurred in 7 patients (3%) receiving sunitinib and in no patients in the placebo group; 5 of 7 had Grade III deep vein thrombosis (DVT) and 2 had Grade I or II DVT. Four of these 7 GIST patients discontinued treatment after the first DVT event.

Thirteen patients (3%) receiving sunitinib in the phase 3 previously untreated mRCC study and 4 patients (2%) from 2 cytokine-refractory mRCC studies reported venous thromboembolism. Nine of these patients had pulmonary embolism; one Grade II and eight Grade IV. Eight of these patients had DVT; one Grade I, two Grade II, four Grade III, and one Grade IV. One patient with pulmonary embolism in the cytokine-refractory mRCC study discontinued therapy. In patients with previously untreated mRCC receiving IFN-α, 6 (2%) cases of venous thromboembolism were recorded; one patient (<1%) had Grade III DVT and five patients (1%) had Grade IV pulmonary embolism.

Venous thromboembolism was reported in one (1.2%) patient in the sunitinib group and five (6.1%) patients in the placebo group in the phase 3 pNET study. Two patients in the placebo group had DVT: one Grade II and one Grade III.

No fatal cases were reported in the registration studies of GIST, mRCC, and pNET. Fatal cases occurred during post-marketing use.

Pulmonary embolism occurred in approximately 3.1% of GIST patients and 1.2% of mRCC patients receiving sunitinib in phase 3 studies. Pulmonary embolism was not reported in pNET patients receiving sunitinib in the phase 3 study. Rare fatal cases occurred during post-marketing use.

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

In patients receiving sunitinib in phase 3 registration studies, lung disorders (i.e., dyspnea, pleural effusion, pulmonary embolism, or pulmonary edema) were reported in approximately 17.8% of GIST patients, 26.7% of mRCC patients, and 12% of pNET patients.

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

Gastrointestinal Disorders.

Pancreatitis occurred uncommonly (<1%) in patients receiving sunitinib for GIST or mRCC. Pancreatitis related to the drug was not reported in the phase 3 pNET study (see section "Special Warnings and Precautions for Use").

Gastrointestinal hemorrhage with fatal outcome 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 hepatic failure, have been reported (see section "Special Warnings and Precautions for Use").

Skin and Subcutaneous Tissue Disorders.

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

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 practice standards.

Fistula formation, sometimes associated with tumor necrosis and regression, has been reported, occasionally leading to fatal outcomes. Osteonecrosis of the jaw has been described in patients receiving sunitinib, primarily in the presence of risk factors for osteonecrosis of the jaw (e.g., intravenous bisphosphonate use and/or history of dental disease requiring invasive dental procedures) (see section "Special Warnings and Precautions for Use").

Investigations.

Preclinical data (in vitro and in vivo) with sunitinib at doses exceeding the recommended human dose indicate that sunitinib may inhibit cardiac repolarization (e.g., QT interval prolongation). QTc interval increase >500 msec was observed in 0.5%, and changes from baseline >60 msec were observed 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 of 24 patients aged 20–87 years with advanced malignancies. Results showed sunitinib affected QTc (defined as mean change, placebo-corrected, >10 msec with 90% confidence interval [CI] upper limit >15 msec) at therapeutic concentration (day 3) using the baseline correction method over 24 hours and at supratherapeutic concentration (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 baseline correction method over 24 hours, the clinical significance of this finding is unclear. Comprehensive assessment of serial ECGs during periods corresponding to therapeutic or supratherapeutic drug concentrations showed no QTc prolongation considered "severe" (i.e., ≥ Grade III per Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) in any patient in the evaluable population or randomized patients (ITT). At therapeutic plasma concentrations, the maximum mean difference from baseline in QTcF (Fridericia-corrected) was 9 msec (90% CI: 15.1 msec). At concentrations approximately twice therapeutic, the maximum mean difference from baseline in QTcF was 15.4 msec (90% CI: 22.4 msec). Moxifloxacin (400 mg), used as positive control, showed a maximum mean difference from baseline in QTcF of 5.6 msec. No subject experienced QTc effect > Grade II (CTCAE, version 3.0) (see section "Special Warnings and Precautions for Use").

Long-term Safety in mRCC Treatment.

Long-term safety of sunitinib in mRCC 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 sunitinib-related adverse events (SRAEs) 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 SRAEs.

Pediatric Population.

A phase I dose-escalation study of oral sunitinib was conducted in 35 children and young adults (aged 2–21 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 risk of drug-related cardiac adverse reactions was higher in children previously exposed to cardiac irradiation and/or anthracyclines compared to those without such treatment. The maximum tolerated dose of sunitinib was not established for this patient group due to dose-limiting toxicity (see section "Pharmacodynamics"). In children not previously treated with anthracyclines or cardiac irradiation, the most common adverse reactions were gastrointestinal toxicity, neutropenia, increased fatigue, and elevated ALT levels.

Based on population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK/PD) analyses, sunitinib at 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 achieve plasma drug concentrations, and thus safety and efficacy profiles, similar to those in adult GIST patients receiving 50 mg/day on a 4/2 schedule.

Adjuvant Therapy in mRCC. Safety of sunitinib was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who underwent nephrectomy for mRCC received sunitinib 50 mg 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 reaction 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. Dose interruption or delay occurred in 166 (54%) and 84 (28%) patients receiving sunitinib and placebo, respectively. Dose reduction occurred in 140 patients (45.8%) of 306 in the sunitinib group and 15 (5%) of 304 in the placebo group. Table 7 compares the frequency of common (≥10%) adverse reactions occurring during treatment in patients receiving sunitinib versus placebo. Adverse reactions reported in S-TRAC in ≥10% of mRCC patients receiving sunitinib and more frequently than in placebo recipients are listed below*

	Adjuvant therapy for RCC
Adverse reaction	Sunitinib (N=306)		Placebo (N=304)
	All grades %	Grade III–IV %	All grades %	Grade III–IV %
Any adverse reaction	99	60	88	15
Systemic Fatigue/asthenia Localized edema Fever	57 18 12	8 < 1 < 1	34 < 1 6	2 0 0
Gastrointestinal Mucositis/stomatitis Diarrhea Nausea Dyspepsia Abdominal pain 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
Cardiac Arterial hypertension Edema/peripheral edema	39 10	8 < 1	14 7	1 0
Dermatological Hand-foot syndrome Hair color changes Rash Skin discoloration/yellowing of skin Dry skin	50 22 24 18 14	16 0 2 0 0	10 2 12 1 6	< 1 0 0 0 0
Neurological Taste alteration Headache	38 19	< 1 < 1	6 12	0 0
Musculoskeletal Limb pain Arthralgia	15 11	< 1 < 1	7 10	0 0
Endocrine system Hypothyroidism/elevated TSH	24	< 1	4	0
Metabolism/nutrition Anorexia/reduced appetite	19	< 1	5	0
Bleeding Bleeding events, all sites	24	< 1	5	< 1
* 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, swelling of face and eyes. 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, rash with desquamation, 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 tract bleeding, hematuria.

Adverse reactions of Grade IV in patients receiving sunitinib included palmar-plantar erythrodysesthesia (1%), fatigue (<1%), abdominal pain (<1%), stomatitis (<1%), and pyrexia (<1%). Adverse reactions of Grade IV in patients receiving placebo included asthenia (<1%) and hypertension (<1%). Laboratory abnormalities of Grade III–IV that occurred in ≥2% of patients receiving sunitinib included neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), increased alanine aminotransferase (2%), increased aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized 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.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach and sight of children.

Packaging.

7 capsules in a blister; 4 blisters in a cardboard box (for dosage strengths of 12.5 mg, 25 mg, 37.5 mg, and 50 mg) or 4 capsules in a blister; 7 blisters in a cardboard box (for dosage strengths of 37.5 mg and 50 mg).

Prescription status.

Prescription only.

Manufacturer.

Remedica Ltd

Manufacturer’s name and address of the place of business.
Acharnon Street, Lemesos Industrial Estate, Building 5 – Hormones and Corticosteroids, Building 10 – Antineoplastic and Immunomodulating Agents, Limassol, 3056, Cyprus

Manufacturer.

Pharmakea Premium Ltd

Manufacturer’s name and address of the place of business.

HCF003, Galphar Industrial Estate, Birkirkara, BGBG 3000, Malta