Sunitinib-mili- 25

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUNITINIB-MILI-12.5 SUNITINIB-MILI-25 SUNITINIB-MILI-37.5 SUNITINIB-MILI-50 (SUNITINIB-MILI-12.5 SUNITINIB-MILI-25 SUNITINIB-MILI-37.5 SUNITINIB-MILI-50)

Composition:

Active substance: sunitinib;

1 capsule contains sunitinib malate equivalent to 12.5 mg, 25 mg, 37.5 mg, or 50 mg of sunitinib;

Excipients:
Capsule contents: mannitol (E 421), sodium croscarmellose, povidone K-25, magnesium stearate, purified water;

Capsule shell: gelatin;
for 12.5 mg capsules — titanium dioxide (E 171), red iron oxide (E 172), purified water;
for 25 mg and 50 mg capsules — titanium dioxide (E 171), black iron oxide (E 172), red iron oxide (E 172), yellow iron oxide (E 172), purified water;
for 37.5 mg capsules — titanium dioxide (E 171), yellow iron oxide (E 172), purified water.

Pharmaceutical form. Hard gelatin capsules.

Main physicochemical properties:

12.5 mg capsules: hard gelatin capsules with an opaque orange cap and body, marked with white ink "SML" on the cap and "20" on the body, containing orange granular powder;

25 mg capsules: hard gelatin capsules with an opaque caramel-colored cap and orange opaque body, marked with white ink "SML" on the cap and "21" on the body, containing orange granular powder;

37.5 mg capsules: hard gelatin capsules with an opaque yellow cap and body, marked with white ink "SML" on the cap and "22" on the body, containing orange granular powder;

50 mg capsules: hard gelatin capsules with an opaque caramel-colored cap and body, marked with white ink "SML" on the cap and "23" on the body, containing orange granular powder.

Pharmacotherapeutic group. Antineoplastic agents. Other protein kinase inhibitors.

ATC code L01EX01.

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 multiple 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 the growth of tumor cells 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 have been evaluated in healthy subjects and in 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.

The drug can be administered independently of food intake.

Plasma protein binding of sunitinib and its primary active metabolite 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) of sunitinib was 2230 L. In the dose range of 25–100 mg, AUC and Cmax increased proportionally with dose (0.5 to 2 times higher than corresponding values following the approved recommended daily dose of 50 mg).

Sunitinib is primarily metabolized by CYP3A4 to a primary active metabolite, which is subsequently metabolized by CYP3A4. The primary active metabolite accounts for 23% to 37% of total exposure.

Elimination is 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 compounds detected in plasma, urine, and feces, representing 91.5%, 86.4%, and 73.8% of radioactivity in combined 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/h, with inter-individual variability of approximately 40%.

After oral dosing in healthy volunteers, the 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 schedules.

Pharmacokinetics were similar in healthy volunteers and in patient populations with solid tumors enrolled in studies, 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 ECOG (Eastern Cooperative Oncology Group) performance status score on the pharmacokinetics of Sunitinib-Mili or its primary active metabolite.

Patients with renal impairment.

No clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite were predicted or observed in patients with mild (CLcr 50–80 mL/min), moderate (CLcr 30–50 mL/min), or severe (CLcr <30 mL/min) renal impairment not on dialysis, compared to patients with normal renal function (CLcr >80 mL/min). Although sunitinib and its primary metabolite are not removed by hemodialysis, total 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 predominantly metabolized in 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. The use of sunitinib in patients with severe (Child-Pugh class C) hepatic impairment has not been studied.

Cardiac electrophysiology.

Sunitinib-Mili may cause dose-dependent QT interval prolongation, which may increase the risk of ventricular arrhythmias, including torsades de pointes (see section "Special precautions").

Clinical characteristics.

Indications.

Gastrointestinal stromal tumor (GIST).

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

Progressive renal cell carcinoma (RCC).

Sunitinib-Mili is indicated for the treatment of progressive renal cell carcinoma.

Adjuvant therapy of renal cell carcinoma (RCC).

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

Progressive pancreatic neuroendocrine tumors (pNET).

Sunitinib-Mili 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 types of interactions.

Strong CYP3A4 inhibitors.

Strong CYP3A4 inhibitors, such as ketoconazole, may increase sunitinib plasma concentrations. It is recommended to select an alternative concomitant medication with no or minimal enzyme inhibition potential. Coadministration of Sunitinib-Mili 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-Mili in healthy volunteers. Coadministration of Sunitinib-Mili with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir) may increase sunitinib concentrations. Grapefruit juice may also increase sunitinib plasma concentrations. Dose reduction of Sunitinib-Mili should be considered when coadministration with strong CYP3A4 inhibitors is necessary (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 medication with no or minimal enzyme induction potential. Coadministration of a single dose of sunitinib with the strong CYP3A4 inducer rifampicin in healthy volunteers 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. Coadministration of sunitinib with CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, St. John's wort) may reduce sunitinib concentrations. Dose escalation of Sunitinib-Mili should be considered when coadministration with CYP3A4 inducers is necessary (see section "Dosage and administration").

In vitro CYP inhibition and induction studies.

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 agents metabolized by these enzymes.

Drugs that prolong the QT interval.

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

Special precautions for use.

Hepatotoxicity.

Sunitinib-Mili 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 trials. Liver failure includes 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 at the beginning of treatment, during each treatment cycle, and as clinically indicated. Treatment with Sunitinib-Mili should be interrupted in case of grade 3 or 4 hepatotoxicity until normalization. Sunitinib-Mili should be discontinued in patients who do not achieve normalization of liver function tests with grade 3 or 4 hepatotoxicity, in patients with severe abnormalities in liver function tests, and in patients with other signs and symptoms of liver failure.

The safety of Sunitinib-Mili has not been established in patients with ALT or AST levels > 2.5 times the upper limit of normal (ULN), or with levels > 5 times ULN in the presence of liver metastases.

Pancreatitis.

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

Serious pancreatic events, some of which were fatal, have been reported. In case of symptoms suggestive of pancreatitis, sunitinib should be discontinued and appropriate supportive therapy initiated.

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 in the overall safety cohort; recovery was reported in 71 % of patients with heart failure. Fatal heart failure occurred in < 1 % of patients.

In the adjuvant renal cell carcinoma (RCC) study, left ventricular ejection fraction (LVEF) decline of grade 2 (LVEF 40–50 %, a decrease of 10–19 % from baseline) was observed in 11 patients. No patient experienced grade 3–4 decline in LVEF. LVEF did not return to ≥ 50 % or baseline levels in three of these eleven patients at the time of last measurement. No patient receiving sunitinib was diagnosed with congestive heart failure (CHF).

Patients with cardiovascular disorders within 12 months prior to sunitinib administration, such as myocardial infarction (including serious/unstable angina), coronary/peripheral artery bypass grafting, symptomatic CHF, acute cerebrovascular accident or transient ischemic attack, or pulmonary artery thromboembolism, were excluded from sunitinib clinical trials. 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 of left ventricular dysfunction.

Assessment 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-Mili should be discontinued in patients with clinical manifestations of CHF. Treatment should be interrupted and/or dose reduced in patients without clinical signs of CHF who experience an LVEF decline of more than 20 % but less than 50 % from baseline, or below the lower limit of normal if baseline LVEF is not available.

QT interval prolongation and torsades de pointes.

Sunitinib-Mili 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.

Patients at increased risk of QT interval 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 ECG and electrolyte monitoring (e.g., magnesium, potassium) during sunitinib treatment should be considered. 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 Sunitinib-Mili should be considered (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Arterial hypertension.

Arterial hypertension was observed in 29 % of patients in the overall safety cohort. Grade 3 hypertension occurred in 7 % of patients and grade 4 in 0.2 %.

Blood pressure should be monitored at the beginning of treatment and periodically thereafter as clinically indicated. Antihypertensive therapy should be initiated and/or adjusted as needed. In case of hypertension, temporary interruption of Sunitinib-Mili is recommended until hypertension is controlled.

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 hypertension, headache, decreased level of consciousness, cognitive impairment, or visual disturbances including cortical blindness, require monitoring and medical therapy, 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 gastrointestinal perforation.

Hemorrhagic events, some of which were fatal, included gastrointestinal, respiratory tract, tumor-related, genitourinary, and intracranial bleeding. Hemorrhagic events were observed in 30 % of patients in the overall safety cohort, including grade 3 or 4 events in 4.2 % of patients. The most common hemorrhagic adverse reaction was epistaxis, and gastrointestinal bleeding was the most frequent grade ≥ 3 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 or life-threatening hemoptysis or pulmonary hemorrhage. Pulmonary hemorrhages, some fatal, have been observed in clinical trials in patients receiving sunitinib for metastatic RCC, GIST, and metastatic non-small cell lung cancer. Sunitinib-Mili is not approved for use in patients with lung cancer.

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 evaluation of bleeding events.

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. In general, patients with high tumor burden prior to treatment initiation are at risk of TLS. Such patients should be monitored for TLS and managed appropriately.

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.

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 during post-marketing use of sunitinib as monotherapy and in combination with bevacizumab. Sunitinib-Mili is not approved for use in combination with bevacizumab. Sunitinib-Mili should be discontinued in patients who develop TMA. Resolution of TMA effects has been observed after discontinuation of sunitinib.

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 measurement of 24-hour urinary protein as clinically indicated. Sunitinib-Mili should be interrupted and the dose reduced if 24-hour urinary protein reaches 3 g or more. Sunitinib-Mili should be discontinued in patients with nephrotic syndrome or recurrent episodes of 24-hour urinary protein ≥ 3 g despite dose reduction. The safety of continuing sunitinib therapy in patients with moderate to severe proteinuria has not been evaluated.

Skin toxicity.

Serious skin adverse reactions, including 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, sunitinib should be discontinued. Necrotizing fasciitis, including fatal cases, has been reported in patients receiving sunitinib, including perineal involvement and fistula formation. Sunitinib-Mili should be discontinued in patients who develop necrotizing fasciitis.

Reversible posterior leukoencephalopathy syndrome.

Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported in < 1 % of patients, some of which were fatal. Patients may experience hypertension, headache, decreased level of consciousness, cognitive impairment, and visual disturbances, including cortical blindness. MRI is required to confirm the diagnosis. Sunitinib-Mili should be temporarily discontinued until resolution. The safety of reinitiating sunitinib in patients with RPLS is unknown.

Thyroid dysfunction.

Cases of hyperthyroidism, sometimes followed by hypothyroidism, have been reported in clinical trials and post-marketing experience with sunitinib.

Thyroid function should be monitored at the beginning of treatment, periodically during treatment, and as clinically indicated. All patients should be closely monitored for symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, during treatment with Sunitinib-Mili. Thyroid dysfunction therapy should be initiated and/or adjusted as needed.

Hypoglycemia.

Sunitinib-Mili 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 pancreatic neuroendocrine tumors (pNET). In pNET patients receiving sunitinib, no glucose homeostasis abnormalities were observed in those with hypoglycemia. Blood glucose reduction may be greater in patients with diabetes. Blood glucose levels should be monitored at the beginning of treatment, regularly during treatment, as clinically indicated, and after discontinuation of Sunitinib-Mili. Diabetic patients should have their antidiabetic therapy evaluated to minimize the risk of hypoglycemia.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw (ONJ) has been observed in patients receiving sunitinib. Concurrent 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 initiating Sunitinib-Mili and periodically during therapy. Patients should be advised on proper oral hygiene. Treatment with Sunitinib-Mili should be interrupted, if possible, at least 3 weeks prior to planned dental surgery or invasive dental procedures. Sunitinib-Mili treatment should be discontinued in case of ONJ development until complete healing.

Impaired wound healing.

Impaired wound healing has been observed in patients receiving sunitinib treatment (see section "Adverse reactions"). Therapy with Sunitinib-Mili should be interrupted at least 3 weeks prior to 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 therapy after resolution of wound healing complications has not been established.

Embryo-fetal toxicity.

Based on animal studies and mechanism of action, Sunitinib-Mili may cause fetal harm when administered to pregnant women. Administration of sunitinib to pregnant rats and rabbits during organogenesis resulted in teratogenicity, approximately 5.5 and 0.3 times higher than that observed with combined systemic exposure [combined area under the curve (AUC) of sunitinib and its active metabolite] in patients receiving the recommended daily dose (RDD) of 50 mg.

Pregnant women should be informed of the potential risk to the fetus. Women of reproductive potential should be advised to use effective contraception during treatment with Sunitinib-Mili and for 4 weeks after the last dose (see section "Pregnancy and breastfeeding").

Pediatric use.

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

Use in elderly patients.

Among 825 patients with GIST or metastatic RCC who received sunitinib in clinical trials, 277 (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 were observed between these patients and younger patients. Among 158 patients aged ≥ 65 years who received sunitinib/placebo as adjuvant therapy for RCC, 50 patients (16 %) were aged 65 years or older. The hazard ratio for disease-free survival was 0.59 (95 % CI: 0.36, 0.95). Among patients aged ≥ 65 years receiving sunitinib/placebo as adjuvant therapy for RCC, grade 3–4 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 when administering Sunitinib-Mili to patients with Child-Pugh class A or B hepatic impairment. No dose adjustment is required when administering Sunitinib-Mili to patients with mild or moderate hepatic impairment (Child-Pugh class A or B). The use of sunitinib in patients with severe (Child-Pugh class C) hepatic impairment has not been studied.

Renal impairment.

No dose adjustment is required when administering Sunitinib-Mili to patients not on dialysis 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 initial dose adjustment is required in patients with end-stage renal disease (ESRD) on hemodialysis. However, sunitinib exposure in ESRD patients on hemodialysis is 47 % lower compared to patients with normal renal function. Therefore, subsequent doses may be gradually increased up to 2-fold based on safety and tolerability.

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

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 during pregnancy or breastfeeding.

Pregnancy.

Overview of risk information.

Based on reproductive toxicity studies in animals and the mechanism of action, Sunitinib-Mili may cause fetal harm when administered to pregnant women (see section "Pharmacodynamics"). There are no data available in pregnant women to inform the risk associated with the medicinal product. In developmental and reproductive toxicity studies in animals, oral administration of sunitinib to pregnant rats and rabbits during organogenesis resulted in teratogenic effects (embryonic, craniofacial, and skeletal malformations) that were 5.5 and 0.3 times higher, respectively, than those observed with 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 for the indicated populations is unknown. 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.

Breastfeeding.

There is no information on the presence of sunitinib and its metabolites in human breast milk. Sunitinib and its metabolites are 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-Mili are advised not to breastfeed during treatment and for at least 4 weeks after the last dose.

Men and women of reproductive potential.

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

Pregnancy testing.

Pregnancy testing should be performed in women of reproductive potential prior to initiating treatment with Sunitinib-Mili.

Contraception.

Women. Women of reproductive potential should be advised to use effective contraception during treatment with Sunitinib-Mili 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-Mili and for 7 weeks after the last dose.

Infertility.

Based on reproductive toxicity studies in animals, sunitinib may impair fertility in men and women.

Ability to drive and use machines.

Sunitinib-Mili 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-Mili 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), until disease progression or unacceptable toxicity occurs. Sunitinib-Mili can be taken with or without food.

Recommended dosage for adjuvant therapy of RCC.

The recommended dose of Sunitinib-Mili 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-Mili can be taken with or without food.

Recommended dosage for PNET.

The recommended dose of Sunitinib-Mili for PNET is 37.5 mg orally once daily until disease progression or unacceptable toxicity occurs. Sunitinib-Mili can be taken with or without food.

Dose Modification.

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

Strong CYP3A4 Inhibitors

Select an alternative concomitant medication with no or minimal enzyme inhibition potential. If co-administration of Sunitinib-Mili with a strong CYP3A4 inhibitor cannot be avoided, consider reducing the dose of Sunitinib-Mili to the minimum (see section "Interaction with other medicinal products and other types of interactions"): 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 PNET.

Strong CYP3A4 Inducers

Select an alternative concomitant medication with no or minimal enzyme induction potential. If co-administration of Sunitinib-Mili with a strong CYP3A4 inducer cannot be avoided, consider increasing the dose of Sunitinib-Mili to the maximum: 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 once daily for PNET. If the dose is increased, patients should be closely monitored for signs of adverse reactions (see section "Interaction with other medicinal products and other types of interactions").

No initial dose adjustment is required for patients with ESRD on hemodialysis. However, due to decreased 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").

Children.

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

Overdose.

Management of overdose with Sunitinib-Mili should consist of general supportive measures. There is no specific antidote for overdose with Sunitinib-Mili. If indicated, elimination of unabsorbed drug should be achieved by inducing emesis or gastric lavage. 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 doses of 5 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.

Adverse Reactions

The most significant serious adverse reactions associated with sunitinib use (including fatal outcomes) are renal failure, heart failure, pulmonary embolism, gastrointestinal perforation, and hemorrhages (e.g., gastrointestinal bleeding, respiratory tract hemorrhage, tumor-related hemorrhage, urinary tract hemorrhage, or intracerebral hemorrhage). The most commonly observed adverse reactions of any severity (reported in clinical trials involving patients with renal cell carcinoma, gastrointestinal stromal tumors, and progressive pancreatic neuroendocrine tumors) include: decreased appetite, altered taste perception, 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 with continued treatment. Hypothyroidism may develop during treatment. Common adverse drug reactions also include hematologic disorders (e.g., neutropenia, thrombocytopenia, and anemia).

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

Below is a list of adverse reactions observed in patients with gastrointestinal stromal tumors, metastatic renal cell carcinoma, and progressive pancreatic neuroendocrine tumors. Information on these adverse reactions was derived from pooled data of 7,115 patients. Adverse reactions are categorized by system organ class, frequency, and severity (according to NCI-CTCAE criteria). The list also includes adverse reactions reported in post-marketing experience. 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 (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Adverse Reactions Observed in Clinical Trials

Infections and Infestations

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

Uncommon: necrotizing fasciitis*, 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*

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: hyperammonemic encephalopathy

Eye Disorders

Common: periorbital edema, eyelid edema, increased lacrimation

Cardiac Disorders

Common: myocardial ischemia^k*, reduced 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*

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 pain), nasal congestion, dry 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 hemorrhage, oral ulcers, proctalgia, cheilitis, hemorrhoids, glossodynia, mouth pain, dry mouth, flatulence, mouth discomfort, belching

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

Hepatobiliary Disorders

Uncommon: hepatic failure*, cholecystitis^s*, liver function abnormalities

Rare: hepatitis

Skin and Subcutaneous Tissue Disorders

Very common: skin color changes^t, hand-foot syndrome (palmar-plantar erythrodysesthesia), rash^u, hair color changes, dry skin

Common: skin desquamation, skin reactions^v, eczema, blisters, erythema, alopecia, acne, pruritus, skin hyperpigmentation, skin disorders, hyperkeratosis, dermatitis, nail disorders^w

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*, hematuria, proteinuria

Uncommon: urinary tract hemorrhage

Rare: nephrotic syndrome

General Disorders and Administration Site Conditions

Very common: mucositis, fatigue^x (and general weakness), edema^y (facial edema, edema, and peripheral edema), pyrexia

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

Uncommon: impaired healing

Investigations

Common: weight decreased, white blood cell count decreased, lipase increased, platelet count decreased, hemoglobin decreased, amylase increased^z, aspartate aminotransferase increased, alanine aminotransferase increased, blood creatinine increased, blood pressure increased, blood uric acid increased

Uncommon: creatine phosphokinase increased in blood, thyroid-stimulating hormone increased in blood

_____________________________________________________________________________

* Includes fatal cases.

Combined terms:

a Pharyngitis 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, taste loss, and taste disturbance.

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

l Decreased/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 Colitis and ischemic colitis.

s Cholecystitis and acalculous cholecystitis.

t Jaundice, skin color change, and pigmentation disorder.

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

v Skin reactions and skin disorders.

w Nail disorders and nail color changes.

x Fatigue and asthenia.

y Facial edema, edema, and peripheral edema.

z 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, have been reported, sometimes with fatal outcomes (see section "Special Warnings and Precautions").

Blood and Lymphatic System Disorders. In a phase 3 trial, grade 3 and 4 reductions in absolute neutrophil count were observed in 10% and 1.7% of GIST patients, 16% and 1.6% of RCC patients, and 13% and 2.4% of pNET patients, respectively. Grade 3 and 4 thrombocytopenia were observed in 3.7% and 0.4% of GIST patients, 8.2% and 1.1% of mRCC patients, and 3.7% and 1.2% of pNET patients, respectively (see section "Special Warnings and Precautions").

Bleeding occurred in 18% of GIST patients receiving sunitinib in a phase 3 trial, compared to 17% of placebo recipients. In 39% of patients receiving sunitinib for previously untreated RCC, bleeding occurred compared to 11% of interferon-α (IFN-α) recipients. Grade 3 or higher bleeding occurred in 17 (4.5%) sunitinib recipients versus 5 (1.7%) IFN-α recipients. Bleeding occurred in 26% of patients receiving sunitinib for cytokine-refractory RCC. Bleeding (excluding epistaxis) occurred in 21.7% of pNET patients receiving sunitinib in a phase 3 trial, compared to 9.85% of placebo recipients (see section "Special Warnings and Precautions").

Tumor hemorrhage occurred in approximately 2% of GIST patients in clinical trials.

Immune System Disorders. Hypersensitivity reactions, including angioedema, have been reported (see section "Special Warnings and Precautions").

Endocrine Disorders. Hypothyroidism was reported in 7 patients (4%) receiving sunitinib in 2 cytokine-refractory RCC trials; in 61 patients (16%) receiving sunitinib and 3 patients (<1%) in the IFN-α group in a previously untreated RCC trial.

Additionally, increased thyroid-stimulating hormone (TSH) levels were recorded in 4 patients with cytokine-refractory RCC (2%). Overall, 7% of RCC patients developed clinical or laboratory signs of hypothyroidism during treatment. Acquired hypothyroidism occurred in 6.2% of GIST patients receiving sunitinib, compared to 1% in the placebo group. In a phase 3 pNET trial, hypothyroidism was reported in 6 patients (7.2%) receiving sunitinib and 1 patient (1.2%) receiving placebo.

In two trials involving breast cancer patients, prospective thyroid function monitoring was conducted; sunitinib is not approved for breast cancer treatment. In one trial, hypothyroidism was reported in 15 patients (13.6%) receiving sunitinib and 3 (2.9%) receiving standard therapy. Increased TSH levels were recorded in 1 (0.9%) sunitinib recipient and not observed in standard therapy recipients. Hyperthyroidism was not observed in sunitinib recipients and in 1 (1.0%) standard therapy recipient. In another trial, hypothyroidism occurred in 31 (13%) sunitinib recipients and 2 (0.8%) capecitabine recipients. Increased TSH levels were recorded in 12 (5%) sunitinib recipients and not observed in capecitabine recipients. Hyperthyroidism occurred in 4 (1.7%) sunitinib recipients and not in capecitabine recipients. Decreased TSH levels were observed in 3 (1.3%) sunitinib recipients and not in capecitabine recipients. Elevated T4 levels occurred in 2 (0.8%) sunitinib recipients and 1 (0.4%) capecitabine recipient. Elevated T3 levels occurred in 1 (0.8%) sunitinib recipient and not in capecitabine recipients. All thyroid-related reactions were grade 1–2 severity (see section "Special Warnings and Precautions").

Metabolism and Nutrition Disorders. Hypoglycemia occurred more frequently in pNET patients compared to metastatic RCC and GIST patients. However, most of these events observed in clinical trials were considered unrelated to the investigational treatment.

Nervous System Disorders. In clinical trials and post-marketing experience, isolated cases (<1%) of seizures and reversible posterior leukoencephalopathy syndrome, sometimes fatal, have been reported. Seizures occurred in patients with or without radiological evidence of brain metastases (see section "Special Warnings and Precautions").

Cardiac Function Disorders. In clinical trials, a reduction in left ventricular ejection fraction (LVEF) of ≥20% and below the lower limit of normal was observed in approximately 2% of GIST patients receiving sunitinib, 4% of cytokine-refractory RCC patients, and 2% of placebo-treated GIST patients. These LVEF changes are not progressive and often improve with continued treatment. In a previously untreated RCC trial, reduced LVEF below the lower limit of normal occurred in 27% of sunitinib recipients and 15% of IFN-α recipients. Heart failure was diagnosed in 2 patients (<1%) receiving sunitinib.

Heart failure, congestive heart failure, or left ventricular dysfunction occurred in 1.2% of GIST patients receiving sunitinib and 1% of placebo recipients. In the main phase 3 GIST trial (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 trial of cytokine-refractory RCC, drug-related fatal myocardial infarction occurred in 0.9% of patients. In a phase 3 trial of previously untreated RCC, 0.6% of IFN-α recipients and 0% of sunitinib recipients experienced fatal cardiac events. In a phase 3 pNET trial, 1 (1%) sunitinib recipient experienced fatal heart failure related to the drug.

Vascular Disorders

Hypertension

Hypertension was very commonly reported in clinical trials. Sunitinib dose reductions or temporary discontinuations occurred in approximately 2.7% of patients due to hypertension. In none of these cases was sunitinib permanently discontinued. Severe hypertension (>200 mmHg systolic or >110 mmHg diastolic) 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 IFN-α recipients. Severe hypertension occurred in 12% of previously untreated patients and <1% of IFN-α recipients. Hypertension was reported in 26.5% of patients receiving sunitinib in a phase 3 pNET trial, compared to 4.9% of placebo recipients. Severe hypertension occurred in 10% of pNET 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 GIST and RCC clinical trials.

In a phase 3 GIST trial, venous thromboembolism occurred in 7 patients (3%) receiving sunitinib and in none receiving placebo: 5 of 7 had grade 3 deep vein thrombosis (DVT), and 2 had grade 1 or 2. Four of these 7 GIST patients discontinued treatment after the first DVT event.

Venous thromboembolism occurred in 13 patients (3%) receiving sunitinib in a phase 3 previously untreated RCC trial and in 4 patients (2%) across 2 cytokine-refractory RCC trials. Nine of these patients had pulmonary embolism: 1 grade 2 and 8 grade 4. Eight had DVT: 1 grade 1, 2 grade 2, 4 grade 3, and 1 grade 4. One patient with pulmonary embolism in the cytokine-refractory RCC trial 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%) sunitinib recipient and 5 (6.1%) placebo recipients in a phase 3 pNET trial. Two placebo recipients had DVT: 1 grade 2 and 1 grade 3.

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

Pulmonary embolism occurred in approximately 3.1% of GIST patients and 1.2% of RCC patients receiving sunitinib in phase 3 trials. Pulmonary embolism was not observed in pNET patients receiving sunitinib in a phase 3 trial. Rare fatal cases were reported in the post-marketing period.

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

Among patients receiving sunitinib in phase 3 registration trials, pulmonary disorders (i.e., 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 pNET patients.

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

Gastrointestinal Disorders. Pancreatitis occurred infrequently (<1%) in patients receiving sunitinib for GIST or RCC. No pancreatitis related to the drug was reported in a phase 3 pNET trial (see section "Special Warnings and Precautions").

Gastrointestinal hemorrhage with fatal outcome was recorded in 0.98% of placebo recipients in a phase 3 GIST trial.

Hepatobiliary Disorders. Cases of liver function impairment, including abnormal liver function tests, hepatitis, or hepatic failure, have been reported (see section "Special Warnings and Precautions").

Skin and Subcutaneous Tissue Disorders. Cases of pyoderma gangrenosum, usually reversible upon discontinuation of sunitinib, have been reported.

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, occasionally leading to death, have been reported.

Osteonecrosis of the jaw has been reported in patients receiving sunitinib, primarily in the presence of risk factors (e.g., intravenous bisphosphonates and/or history of dental disease requiring invasive dental procedures) (see section "Special Warnings and Precautions").

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

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

QTc prolongation was studied in a trial of 24 patients aged 20–87 with advanced malignancies. Results showed sunitinib affected QTc (defined as placebo-corrected mean change >10 ms with 90% confidence interval [CI] upper limit >15 ms) at therapeutic concentration (day 3) using the baseline correction method over time and at supratherapeutic concentration (day 9) using both baseline correction methods. No patient had QTc >500 ms. 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 time, the clinical significance of this finding is unclear.

Based on comprehensive serial ECG assessment at times corresponding to therapeutic or supratherapeutic drug concentrations, no patient in the evaluable population or the intent-to-treat (ITT) population 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 in QTcF (corrected by Fredericia’s formula) was 9 ms (90% CI: 15.1 ms). At concentrations approximately twice the therapeutic level, the maximum mean difference from baseline in QTcF was 15.4 ms (90% CI: 22.4 ms). Moxifloxacin (400 mg), used as a positive control, showed a maximum mean difference from baseline in QTcF of 5.6 ms. No subject experienced a QTc change greater than grade 2 (CTCAE, version 3.0) (see section "Special Warnings and Precautions").

Long-term Safety in RCC Treatment

The long-term safety of sunitinib in RCC patients was analyzed in 9 completed clinical trials conducted in first-line, bevacizumab-refractory, and cytokine-refractory settings involving 5,739 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 (DRAEs) developed within the first 6–12 months 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 DRAEs.

Pediatric Population

A phase I dose-escalation study of oral sunitinib was conducted in 35 patients, including 30 pediatric patients (aged 3–17 years) and 5 young adults (aged 18–21 years), with refractory solid tumors, most of whom had primary brain tumors. All study participants experienced adverse reactions, most of which 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 treated with cardiac irradiation and anthracyclines compared to those without such treatment. The maximum tolerated dose was established for patients not previously exposed to anthracyclines or 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 daily on a 4-weeks-on/2-weeks-off schedule (n = 306) or placebo (n = 304). Mean treatment duration was 12.4 months (range: 0.13–14.9) for sunitinib and 12.4 months (range: 0.03–13.7) for placebo. Discontinuation due to adverse reactions occurred in 28% of sunitinib recipients. Adverse reactions leading to discontinuation in >2% of patients included hand-foot syndrome and fatigue/asthenia. Treatment interruption occurred in 54% and dose reduction in 46% of sunitinib recipients. Table 1 summarizes adverse reactions in the S-TRAC trial.

Table 1. Adverse reactions reported in ≥ 10 % of patients with RCC receiving sunitinib and more frequently than in patients receiving placebo in S-TRAC*
	Adjuvant therapy in RCC
Adverse reaction	SUNITINIB (N = 306)		Placebo (N = 304)
	All grades %	Grade 3–4 %	All grades %	Grade 3–4 %
Any adverse reaction	99	60	88	15
Gastrointestinal disorders Mucositis/stomatitis Diarrhea Nausea Dyspepsia Abdominal painb 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 edema Fever	57 18 12	8 < 1 < 1	34 < 1 6	2 0 0
Dermatological Palmar-plantar syndrome Rashd Changes in hair color Skin discoloration/yellowing of skin Skin dryness	50 24 22 18 14	16 2 0 0 0	10 12 2 1 6	< 1 0 0 0 0
Cardiac Arterial hypertensione Edema/peripheral edema	39 10	8 < 1	14 7	1 0
Neurological Altered taste sensationf Headache	38 19	< 1 < 1	6 12	0 0
Endocrine system Hypothyroidism/elevated TSH	24	< 1	4	0
Bleeding/hemorrhage Bleeding events, all sitesg	24	< 1	5	< 1
Metabolism/nutrition Anorexia/reduced appetite	19	< 1	5	0
Musculoskeletal disorders 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 mucosal inflammation, aphthous stomatitis, oral mucosal ulceration, tongue ulcer, oropharyngeal pain, and mouth pain. b Includes abdominal pain, lower abdominal pain, and upper abdominal pain. c Includes localized edema, facial edema, eyelid edema, periorbital edema, facial swelling, and eye swelling. d Includes dermatitis, psoriasiform dermatitis, desquamating rash, genital rash, rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, pathological rash, and pruritic rash. e Includes hypertension, increased blood pressure, increased systolic blood pressure, increased diastolic blood pressure, and hypertensive crisis. f Includes ageusia, hypogeusia, and dysgeusia. g Includes epistaxis, gingival bleeding, rectal bleeding, hemoptysis, anal bleeding, upper gastrointestinal hemorrhage, and hematuria.
Grade 4 adverse reactions in patients receiving sunitinib included palmar-plantar syndrome (1 %), fatigue (< 1 %), abdominal pain (< 1 %), stomatitis (< 1 %), and pyrexia (< 1 %). Grade 3–4 laboratory abnormalities occurring in ≥ 2 % of patients receiving sunitinib included neutropenia (13 %), thrombocytopenia (5 %), leukopenia (3 %), lymphopenia (3 %), elevated alanine aminotransferase (2 %), elevated aspartate aminotransferase (2 %), hyperglycemia (2 %), and hyperkalemia (2 %).

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua/

Shelf life. 2 years.

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

Packaging.

7 capsules in a blister; 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Shilpa Medicare Limited.

Manufacturer's address and location of business operations.

Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India.