MAGNIU SUL'FAT

INSTRUCTIONS for medical use of the medicinal product SUNITINIB-MILI-12.5 SUNITINIB-MILI-25 SUNITINIB-MILI-37.5 SUNITINIB-MILI-50

Composition

The active substance is 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 composition: 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 physical and chemical properties

Capsules of 12.5 mg: hard gelatin capsules with an orange opaque cap and body, with white ink writing "SML" on the cap, and "20" on the body, containing an orange-colored granulated powder; capsules of 25 mg: hard gelatin capsules with a caramel-colored opaque cap and an orange-colored opaque body, with white ink writing "SML" on the cap, and "21" on the body, containing an orange-colored granulated powder; capsules of 37.5 mg: hard gelatin capsules with a yellow opaque cap and body, with white ink writing "SML" on the cap, and "22" on the body, containing an orange-colored granulated powder; capsules of 50 mg: hard gelatin capsules with a caramel-colored opaque cap and body, with white ink writing "SML" on the cap, and "23" on the body, containing an orange-colored granulated powder.

Pharmacotherapeutic group

Antineoplastic agents. Other protein kinase inhibitors.

ATC code

L01E X01.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathological angiogenesis, and metastatic progression of cancer. Sunitinib has been evaluated for its inhibitory activity against a variety of kinases (> 80 kinases) and has been identified as a platelet-derived growth factor receptor (PDGFRα and PDGFRβ), vascular endothelial growth factor receptor (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (RET) inhibitor.

Sunitinib inhibited the phosphorylation of many RTKs (PDGFRb, VEGFR2, KIT) in tumor xenografts expressing these target RTKs in vivo and demonstrated inhibition of tumor growth or regression of tumors and/or inhibition of metastases in some experimental cancer models. Sunitinib demonstrated the ability to inhibit the growth of tumor cells expressing unregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRb- and VEGFR2-dependent tumor angiogenesis in vivo.

Pharmacokinetics

The pharmacokinetics of sunitinib and its malate have been evaluated in healthy subjects and in patients with solid tumors.

The maximum plasma concentration of sunitinib (Cmax) is generally observed within 6-12 hours (time to maximum plasma concentration [Tmax]) after oral administration. Food does not affect the bioavailability of sunitinib.

The drug can be taken regardless of food intake.

The binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, without concentration-dependent binding within the range of 100-4000 ng/mL. The apparent volume of distribution (Vd/F) of sunitinib was 2230 L. Within the dose range of 25-100 mg, AUC and Cmax increased proportionally to the dose (0.5 to 2 times higher than the corresponding values with the approved recommended daily dose of 50 mg).

Sunitinib is metabolized primarily by CYP3A4 to its primary active metabolite, which is then metabolized by CYP3A4. The primary active metabolite accounts for 23-37% of the total exposure.

Elimination is primarily via the feces. In a mass balance study in humans, [14C] sunitinib, 61% of the dose was excreted in the feces, and renal excretion accounted for 16% of the administered dose. Sunitinib and its primary active metabolite were the major compounds detected in plasma, urine, and feces, accounting for 91.5%, 86.4%, and 73.8% of the radioactivity in the combined samples, respectively. Minor metabolites were detected in urine and feces but generally not in plasma. The total oral clearance (CL/F) ranged from 34 to 62 L/h, and interindividual variability was 40%.

After oral administration, the terminal elimination half-life of sunitinib and its primary active metabolite is approximately 40-60 hours and 80-110 hours, respectively.

With repeated daily administration of sunitinib, 3-4-fold accumulation was observed, while the primary metabolite accumulated 7-10-fold. Steady-state concentrations of sunitinib and its primary active metabolite were reached within 10-14 days. On 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 administration or with repeated cycles of dosing.

The pharmacokinetics were similar in healthy volunteers and in the patient population with solid tumors who participated in the study, including patients with GIST and RCC.

Pharmacokinetics in special patient groups

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

Patients with renal impairment.

Clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite in patients with mild (CLcr 50-80 mL/min), moderate (CLcr 30-50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis, compared to patients with normal renal function (CLcr >80 mL/min), were not predicted and were not observed. Although sunitinib and its primary metabolite are not cleared by hemodialysis, the total systemic exposure to sunitinib is 47% lower in patients with end-stage renal disease (ESRD) on hemodialysis compared to patients with normal renal function.

Hepatic impairment.

Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of sunitinib were similar in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment compared to patients with normal hepatic function. 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 paroxysmal ventricular tachycardia (see "Special warnings and precautions for use").

Clinical characteristics

Indications

Gastrointestinal stromal tumor (GIST).

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

Progressing renal cell carcinoma (RCC).

Sunitinib-MILI is indicated for the treatment of progressing renal cell carcinoma.

Adjuvant therapy for renal cell carcinoma (RCC).

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

Progressing neuroendocrine tumors of the pancreas (PNET).

Sunitinib-MILI is indicated for the treatment of progressing, well-differentiated neuroendocrine tumors of the pancreas in patients with unresectable, locally advanced, or metastatic disease.

Contraindications

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

Interactions with other medicinal products and other forms of interaction

Strong CYP3A4 inhibitors.

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

Strong CYP3A4 inducers.

CYP3A4 inducers, such as rifampin, may decrease the plasma concentration of sunitinib. It is recommended to choose an alternative concomitant medication with no or minimal potential for enzyme induction. Concomitant administration of a single dose of sunitinib with the strong CYP3A4 inducer rifampin 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. Concomitant administration of sunitinib with CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, St. John's Wort) may decrease the concentration of sunitinib. An increase in the dose of sunitinib should be considered when it is necessary to administer it with CYP3A4 inducers (see "Posology and method of 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 human liver microsomes and hepatocytes of CYP isoform activity (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11) demonstrated that sunitinib and its primary active metabolite have no clinically significant drug interactions with medications that may be metabolized by these enzymes.

Medicinal products that prolong the QT interval.

Sunitinib may prolong the QT interval. In patients who require treatment with medicinal products that prolong the QT interval, it is recommended to monitor the QT interval more frequently using ECG.

Special warnings and precautions for use

Hepatotoxicity.

Sunitinib-MILI may cause severe hepatotoxicity, leading to liver failure or a fatal outcome. In the overall safety population, <1% of patients experienced liver failure in clinical trials. Liver failure included 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. Administration of sunitinib should be interrupted in cases of hepatotoxicity grade 3 or 4 until normalization of the condition. Sunitinib should be discontinued in patients who do not experience normalization of the condition with hepatotoxicity grade 3 or 4, patients with serious changes in liver function tests, and patients with other signs and symptoms of liver failure.

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

Pancreatitis.

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

Serious pancreatitis-related events, some of which were fatal, have been reported. If symptoms of pancreatitis occur, sunitinib should be discontinued, and appropriate supportive care should be initiated.

Cardiovascular disorders.

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

Cardiac failure was observed in 3% of patients; in 71% of patients with cardiac failure, recovery was reported. Fatal cardiac failure was observed in <1% of patients.

In an adjuvant RCC study, 11 patients experienced a decrease in left ventricular ejection fraction (LVEF) to 40-50% (a decrease of 10-19% from baseline). No patient experienced a decrease in LVEF to grade 3-4. LVEF values in three of these 11 patients did not return to ≥50% or to baseline at the time of the last measurement. No patient who received sunitinib was diagnosed with congestive heart failure (CHF).

Patients with a history of cardiovascular events, such as myocardial infarction (including severe/unstable angina), coronary artery bypass grafting/peripheral artery revascularization, symptomatic CHF, acute cerebrovascular event, or pulmonary thromboembolism, were excluded from sunitinib clinical trials. Patients who received anthracyclines or had a history of radiation therapy to the chest were also excluded from some studies. It is unknown whether patients with these comorbidities may be at increased risk of developing left ventricular dysfunction.

Consideration should be given to monitoring LVEF at the beginning of treatment and periodically thereafter as clinically indicated. Patients should be carefully monitored for signs and symptoms of CHF. Sunitinib should be discontinued in patients who experience clinical signs of CHF. The administration of sunitinib should be interrupted and/or the dose reduced in patients without clinical signs of CHF who have an LVEF that is >20% but <50% below the institution's lower limit of normal or below the patient's baseline LVEF value if the baseline LVEF value was below the institution's lower limit of normal.

QT interval prolongation and paroxysmal ventricular tachycardia.

Sunitinib-MILI may cause dose-dependent QT interval prolongation, which may increase the risk of ventricular arrhythmias, including paroxysmal ventricular tachycardia. Paroxysmal ventricular tachycardia was observed in <0.1% of patients.

Patients who are at increased risk of QT interval prolongation, including those with a history of QT interval prolongation, those taking antiarrhythmic medications, or those with a history of significant cardiac dysfunction, bradycardia, or electrolyte disturbances, should be monitored. Consideration should be given to periodic monitoring of electrocardiograms and electrolytes (e.g., magnesium, potassium) during treatment with sunitinib. More frequent monitoring of the QT interval should be performed when sunitinib is administered concomitantly with strong CYP3A4 inhibitors or medicinal products that have a known effect of QT interval prolongation. Consideration should be given to reducing the dose of sunitinib (see "Posology and method of administration" and "Interactions with other medicinal products and other forms of interaction").

Hypertension.

In the overall safety population, 29% of patients experienced hypertension. Grade 3 hypertension was observed in 7% of patients, and grade 4 hypertension was observed in 0.2% of patients.

Blood pressure should be monitored at the beginning of treatment and periodically thereafter as clinically indicated. If necessary, antihypertensive therapy should be initiated and/or adjusted. In cases of hypertension, it is recommended to interrupt the administration of sunitinib until the hypertension is controlled.

Hypersensitivity/Giant urticaria.

If hypersensitivity reactions, including giant urticaria, occur, sunitinib treatment should be interrupted, and standard medical care should be provided (see "Adverse reactions").

Seizures.

Seizures have been reported in clinical trials and postmarketing experience with sunitinib. Patients with seizures and symptoms of posterior reversible leukoencephalopathy syndrome, such as hypertension, headache, decreased alertness, confusion, and visual loss, including cortical blindness, require monitoring and medical therapy, including blood pressure control. It is recommended to temporarily interrupt sunitinib; after resolution of the seizure, sunitinib treatment may be resumed at the discretion of the physician (see "Adverse reactions").

Hemorrhagic events and perforation of visceral organs.

Hemorrhagic events, some of which were fatal, included gastrointestinal bleeding, respiratory tract bleeding, tumor bleeding, urinary tract bleeding, and cerebral hemorrhage. In the overall safety population, 30% of patients experienced hemorrhagic events, 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 common grade ≥3 event.

In patients who received sunitinib, tumor-related bleeding events were observed. These events may occur suddenly, and in the case of lung tumors, they may manifest as severe and life-threatening hemoptysis or pulmonary hemorrhage. In clinical trials, pulmonary hemorrhage, some of which were fatal, were observed in patients who received sunitinib for metastatic RCC, GIST, and metastatic lung cancer. Sunitinib-MILI is not approved for use in patients with lung cancer.

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

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 postmarketing experience with sunitinib, mainly in patients with RCC or GIST. The risk of TLS exists for patients with high tumor burden prior to the initiation of treatment. These patients should be monitored for TLS and receive appropriate treatment.

Aneurysms and arterial dissections.

The use of vascular endothelial growth factor receptor inhibitors in patients with hypertension or without may contribute to the formation of aneurysms and/or arterial dissections. Before initiating sunitinib, this risk should be carefully considered in patients with risk factors, such as hypertension or aneurysm history.

Thrombotic microangiopathy.

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes resulting in renal failure or a fatal outcome, has been observed in clinical trials and postmarketing experience with sunitinib as monotherapy and in combination with bevacizumab. Sunitinib-MILI is not approved for use in combination with bevacizumab. Sunitinib should be discontinued in patients who develop TMA. The effects of TMA have been observed to resolve after discontinuation of sunitinib.

Proteinuria.

Proteinuria and nephrotic syndrome have been observed, some of which resulted in renal failure and fatal outcomes. Patients should be monitored for the development or worsening of proteinuria. Urinalysis should be performed at baseline and periodically during treatment as clinically indicated, with further measurement of urine protein levels as clinically indicated. Sunitinib should be interrupted and the dose reduced in patients who develop a urine protein level of ≥3 g or more. Sunitinib should be discontinued in patients with nephrotic syndrome or recurrent urine protein levels of ≥3 g or more despite dose reduction. The safety of continuing sunitinib in patients with moderate to severe proteinuria has not been evaluated.

Skin toxicity.

Severe skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, some of which were fatal, have been reported. If symptoms of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis occur, sunitinib should be discontinued. Necrotizing fasciitis, including fatal cases, has been reported in patients who received sunitinib, including cases involving the perineum and fistula formation. Sunitinib should be discontinued in patients who develop necrotizing fasciitis.

Posterior reversible leukoencephalopathy syndrome (PRES).

Cases of PRES have been reported in <1% of patients, some of which were fatal. Patients may experience hypertension, headache, decreased alertness, confusion, and visual loss, including cortical blindness. Magnetic resonance imaging is necessary to confirm the diagnosis. Sunitinib should be interrupted until the condition resolves. The safety of re-administering sunitinib in patients with PRES is unknown.

Dysfunction of the thyroid gland.

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

Thyroid function should be monitored at the beginning of treatment, periodically during treatment, and as clinically indicated. All patients should be carefully monitored for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, during treatment with sunitinib. If necessary, thyroid therapy should be initiated and/or adjusted.

Hypoglycemia.

Sunitinib-MILI may cause symptomatic hypoglycemia, which may result in loss of consciousness or require hospitalization. Hypoglycemia occurred in 2% of patients who received sunitinib for the treatment of advanced RCC and GIST and in approximately 10% of patients who received sunitinib for the treatment of PNET. In patients who received sunitinib for PNET, all cases of hypoglycemia were asymptomatic, and no abnormalities in glucose homeostasis were observed. Decreased blood glucose levels may be more pronounced 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. Patients with diabetes should be evaluated for the need to adjust their antidiabetic therapy to minimize the risk of hypoglycemia.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients who received sunitinib. Concomitant use of other risk factors, such as bisphosphonates or dental disease/invasive dental procedures, may increase the risk of ONJ. An oral examination should be performed before initiating sunitinib, and patients should be advised on proper oral hygiene. Treatment with sunitinib should be interrupted, if possible, at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. Sunitinib treatment should be discontinued in cases of ONJ until complete healing has occurred.

Impaired wound healing.

Impaired wound healing has been observed in patients who received sunitinib (see "Adverse reactions").

Prior to scheduled surgery, sunitinib treatment should be interrupted at least 3 weeks prior. The drug should not be administered for at least 2 weeks after major surgical procedures and until adequate wound healing has occurred. The safety of resuming sunitinib after the resolution of wound healing complications has not been established.

Embryo-fetal toxicity.

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

Pregnant women should be informed of the potential risk to the fetus. Women of childbearing potential should be advised to use effective contraception during treatment with sunitinib and for 4 weeks after the last dose (see "Pregnancy and lactation").

Use in children

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

Overdose

Treatment of overdose with sunitinib should consist of general supportive measures. There is no specific antidote for overdose with sunitinib. If indicated, elimination of the unabsorbed drug should be achieved by emesis or gastric lavage. Reports of accidental overdose have been received; these cases were associated with adverse reactions consistent with the known safety profile of sunitinib or were without adverse reactions. In preclinical studies, mortality was observed after administration of 5 daily doses of 500 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included muscle coordination disorders, head tremors, hypoactivity, eye discharge, piloerection, and gastrointestinal disorders. Mortality and similar signs of toxicity were observed at lower doses with longer administration.

Adverse Reactions

The most significant serious adverse reactions (including those with fatal outcomes) associated with sunitinib use are renal failure, cardiac failure, pulmonary embolism, gastrointestinal perforation, and hemorrhage (e.g., gastrointestinal bleeding, bleeding in the respiratory tract, from the tumor, in the urinary tract, or in the brain). The most common adverse reactions of any grade (reported during studies involving patients with renal cell carcinoma, gastrointestinal stromal tumors, and progressive neuroendocrine tumors of the pancreas) include decreased appetite, taste disturbances, arterial hypertension, fatigue, gastrointestinal disorders (i.e., diarrhea, nausea, stomatitis, dyspepsia, and vomiting), skin discoloration, and palmar-plantar erythrodysesthesia syndrome. The intensity of these symptoms may decrease during further treatment. Hypothyroidism may develop during treatment. Common adverse reactions to the drug include blood system disorders (e.g., neutropenia, thrombocytopenia, and anemia).

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

Most Frequent Adverse Reactions

Below is a list of adverse reactions that developed in patients with gastrointestinal stromal tumors, metastatic renal cell carcinoma, and progressive neuroendocrine tumors of the pancreas. This information on adverse reactions was taken from combined data on 7115 patients. Adverse reactions are presented by organ system, frequency, and severity (according to NCI-CTCAE criteria). The list also includes adverse reactions observed during post-marketing clinical trials. Within each frequency group, adverse reactions are listed in order of decreasing severity. Frequency is defined as: very common (≥ 1/10), common (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), rare (from ≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and unknown (cannot be established based on available information).

Adverse Reactions Recorded in Clinical Trials

Infections and invasions

• Common: viral infections, respiratory infections, abscess, fungal infections, urinary tract infections, skin infections, sepsis
• Uncommon: necrotizing fasciitis, bacterial infections

Blood and lymphatic system disorders

• Very common: neutropenia, thrombocytopenia, anemia, leukopenia
• Common: lymphopenia
• Uncommon: pancytopenia
• Rare: thrombotic microangiopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome

Immune system disorders

• Uncommon: hypersensitivity
• Rare: angioedema

Endocrine system disorders

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

Metabolism and nutrition disorders

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

Psychiatric disorders

• Very common: insomnia
• Common: depression

Nervous system disorders

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

Eye disorders

• Common: periorbital edema, eyelid edema, increased lacrimation

Cardiac disorders

• Common: myocardial ischemia, decreased ejection fraction
• Uncommon: congestive heart failure, myocardial infarction, cardiac failure, cardiomyopathy, pericardial effusion, QT interval prolongation on electrocardiogram
• Rare: left ventricular failure, ventricular tachycardia of the "pirouette" type

Vascular disorders

• Very common: arterial hypertension
• Common: deep vein thrombosis, flushing, hyperemia
• Uncommon: tumor bleeding
• Unknown: aneurysms and arterial dissection

Chest and mediastinal disorders

• Very common: dyspnea, epistaxis, cough
• Common: pulmonary embolism, pleural effusion, hemoptysis, dyspnea on exertion, pain in the mouth and throat, nasal congestion, dryness of the nasal mucosa
• Uncommon: pulmonary hemorrhage, respiratory failure

Gastrointestinal disorders

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

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

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

Musculoskeletal and connective tissue disorders

• Very common: limb pain, arthralgia, back pain
• Common: musculoskeletal pain, muscle spasms, myalgia, muscle weakness
• Uncommon: jaw osteonecrosis, anal fissure
• Rare: rhabdomyolysis, myopathy

Renal and urinary disorders

• Common: renal failure, acute renal failure, chromaturia, proteinuria
• Uncommon: bleeding from the urinary tract
• Rare: nephrotic syndrome

General disorders and administration site conditions

• Very common: mucosal inflammation, increased fatigue, edema
• Common: chest pain, pain, flu-like illness, chills
• Uncommon: impaired wound healing

Laboratory tests

• Common: weight loss, decreased white blood cell count, increased lipase level, decreased platelet count, decreased hemoglobin level, increased amylase level, increased aspartate aminotransferase level, increased alanine aminotransferase level, increased creatinine level in blood, increased blood pressure, increased uric acid level in blood
• Uncommon: increased creatine phosphokinase level in blood, increased thyrotropin level in blood

Description of Individual Adverse Reactions

Infections and invasions. There have been reports of serious infections (with and without neutropenia), including those with fatal outcomes. Cases of necrotizing fasciitis, including abdominal fasciitis, have been reported, sometimes with fatal outcomes.

Blood and lymphatic system disorders. In a phase 3 study, decreased absolute neutrophil count of grades 3 and 4 was observed in 10% and 1.7% of patients with GIST, 16% and 1.6% of patients with RCC, and 13% and 2.4% of patients with PNET. Decreased platelet count of grades 3 and 4 was observed in 3.7% and 0.4% of patients with GIST, 8.2% and 1.1% of patients with mRCC, and 3.7% and 1.2% of patients with PNET.

Bleeding occurred in 18% of patients with GIST receiving sunitinib in a phase 3 study, compared to 17% of patients receiving placebo. In 39% of patients receiving sunitinib for previously untreated RCC, bleeding was observed, compared to 11% of patients receiving interferon-alpha (IFN-α). Grade 3 or higher bleeding was observed in 17 (4.5%) patients receiving sunitinib, compared to 5 (1.7%) patients receiving IFN-α. Bleeding was observed in 26% of patients receiving sunitinib for cytokine-refractory RCC. Bleeding (excluding epistaxis) occurred in 21.7% of patients with PNET receiving sunitinib in a phase 3 study, compared to 9.85% of patients receiving placebo.

In clinical trials, approximately 2% of patients with GIST receiving sunitinib experienced tumor bleeding.

Immune system disorders. Hypersensitivity reactions, including angioedema, have been reported.

Endocrine system disorders. Hypothyroidism has been reported in 7 patients (4%) receiving sunitinib in 2 studies of cytokine-refractory RCC; in 61 patients (16%) receiving sunitinib and 3 patients (<1%) in the IFN-α group in a study of previously untreated RCC.

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

In two studies, prospective monitoring of thyroid function was conducted in patients with breast cancer; sunitinib is not approved for the treatment of breast cancer. In one study, hypothyroidism was observed in 15 patients (13.6%) receiving sunitinib and 3 (2.9%) patients receiving standard treatment. Elevated thyrotropin levels were observed in 1 (0.9%) patient receiving sunitinib and were not observed in patients receiving standard treatment. Hyperthyroidism was not observed in patients receiving sunitinib and was observed in 1 (1.0%) patient receiving standard treatment. In another study, hypothyroidism was observed in 31 (13%) patients receiving sunitinib and 2 (0.8%) patients receiving capecitabine. Elevated thyrotropin levels were observed in 12 (5%) patients receiving sunitinib and were not observed in patients receiving capecitabine. Hyperthyroidism was observed in 4 (1.7%) patients receiving sunitinib and was not observed in patients receiving capecitabine. Decreased thyrotropin levels were observed in 3 (1.3%) patients receiving sunitinib and were not observed in patients receiving capecitabine. Elevated T4 levels were observed in 2 (0.8%) patients receiving sunitinib and 1 (0.4%) patient receiving capecitabine. Elevated T3 levels were observed in 1 (0.8%) patient receiving sunitinib and were not observed in patients receiving capecitabine. All thyroid reactions were grade 1 or 2 in severity.

Metabolism and nutrition disorders. In patients with PNET, a higher frequency of hypoglycemia was observed compared to patients with metastatic RCC and GIST. However, most of these adverse reactions observed during clinical trials were considered unrelated to the study treatment.

Nervous system disorders. In clinical trials of sunitinib and during post-marketing use, there have been reports of seizures (<1%) and reversible posterior leukoencephalopathy syndrome, sometimes with fatal outcomes. Seizures were observed in patients with and without brain metastases.

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

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

Vascular disorders

Hypertension

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

Venous thromboembolism

In clinical trials of GIST and RCC, treatment-related venous thromboembolic events were reported in approximately 1.0% of patients with solid tumors receiving sunitinib.

In a phase 3 study of GIST, venous thromboembolic events were observed in 7 patients (3%) receiving sunitinib and no patients in the placebo group: 5 of 7 had deep vein thrombosis (DVT) grade 3 and 2 had grade 1 or 2. Four of these 7 patients with GIST discontinued treatment after the first DVT event.

In 13 patients (3%) receiving sunitinib in a phase 3 study of previously untreated RCC and 4 patients (2%) in 2 studies of cytokine-refractory RCC, venous thromboembolism occurred. Nine of these patients had pulmonary embolism: 1 had grade 2 and 8 had grade 4. Eight of these patients had DVT: 1 had grade 1, 2 had grade 2, 4 had grade 3, and 1 had grade 4. One patient with pulmonary embolism in a study of cytokine-refractory RCC interrupted therapy.

In patients with previously untreated RCC receiving IFN-α, 6 (2%) cases of venous thromboembolism were reported; 1 (<1%) patient had grade 3 DVT, and 5 (1%) patients had grade 4 pulmonary embolism.

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

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

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

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

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

Approximately 22.2% of patients with solid tumors, including GIST and RCC, receiving sunitinib in clinical trials experienced pulmonary disorders.

Gastrointestinal disorders. Pancreatitis occurred infrequently (<1%) in patients receiving sunitinib for GIST or RCC. In a phase 3 study of PNET, no treatment-related pancreatitis was reported.

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

Hepatobiliary disorders. There have been reports of liver function disorders, which may include liver function test abnormalities, hepatitis, or liver failure.

Skin and subcutaneous tissue disorders. There have been reports of gangrenous pyoderma, which is usually reversible after discontinuation of sunitinib.

Musculoskeletal and connective tissue disorders. There have been reports of myopathy and/or rhabdomyolysis, some of which were accompanied by acute renal failure. Patients with symptoms of muscle toxicity should receive care according to current medical practice standards.

There have been reports of fistula formation (including necrosis and regression of the tumor), which in some cases led to death.

In patients receiving sunitinib, there have been reports of jaw osteonecrosis, mostly in the presence of risk factors for osteonecrosis of the jaw (e.g., intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures).

Laboratory tests. Data from preclinical studies (in vitro and in vivo) of the drug at doses exceeding the recommended dose for humans showed that sunitinib may inhibit the repolarization process of cardiac activity (e.g., prolongation of the QT interval).

QTc interval prolongation to more than 500 ms was observed in 0.5%, and changes relative to baseline of more than 60 ms were observed in 1.1% of 450 patients with solid tumors; both of these parameters are considered potentially significant changes. Sunitinib at concentrations approximately twice the therapeutic concentrations prolonged the QTcF interval (QT interval corrected using Fridericia's formula).

QT interval prolongation was studied in a study involving 24 patients aged 20 to 87 years with advanced malignancies. The results of this study demonstrated that sunitinib affected the QTc interval (defined as the mean change from baseline, corrected for placebo, >10 ms with a 90% confidence interval [CI] upper limit >15 ms) at therapeutic concentrations (day 3) using a time-matched placebo correction and at concentrations exceeding therapeutic concentrations (day 9) using both time-matched and placebo corrections. No patient had a QTc interval >500 ms. Although an effect on the QTcF interval was observed on day 3, 24 hours after dosing (i.e., at therapeutic plasma concentrations expected after the recommended initial dose of 50 mg), using a time-matched placebo correction, the clinical significance of this finding is unknown.

Based on a comprehensive evaluation of serial ECGs at times corresponding to therapeutic or higher-than-therapeutic concentrations of the drug, no patient in the population evaluated or randomized patients (intent-to-treat [ITT]) had QTc interval 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 the QTcF interval (corrected using Fridericia's formula) was 9 ms (90% CI: 15.1 ms). At concentrations approximately twice the therapeutic concentrations, the maximum mean difference from baseline in the QTcF interval 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 the QTcF interval of 5.6 ms. No subject experienced a QTc interval change of more than 2 grades (CTCAE, version 3.0).

Long-term Safety in RCC

The long-term safety of sunitinib in patients with RCC was analyzed in 9 completed clinical trials conducted in first-line, cytokine-refractory, and refractory-to-bevacizumab treatment regimens in 5739 patients, of whom 807 (14%) received treatment for 2 to 6 years. In 807 patients who received prolonged sunitinib treatment, most treatment-related adverse reactions (TRAEs) initially developed within the first 6 to 12 months and then remained stable or decreased in frequency over time, with the exception of hypothyroidism, which gradually progressed over time, and new cases emerged during the 6-year period. Long-term sunitinib treatment was not associated with new types of TRAEs.

Pediatric Patients

A phase 1 study of oral sunitinib with dose escalation was conducted in 35 patients, 30 of whom were pediatric patients (aged 3 to 17 years) and 5 of whom were young adult patients (aged 18 to 21 years), with refractory solid tumors, most of whom had a primary diagnosis of brain tumor. All study participants experienced adverse reactions, most of which were severe (grade ≥3 toxicity) and included cardiotoxicity. The most common adverse reactions were gastrointestinal toxicity, neutropenia, increased fatigue, and increased alanine aminotransferase levels. The risk of adverse reactions to the drug from the heart was higher in children who had previously received radiation to the heart area and anthracyclines, compared to those who had not received such treatment. For the group of patients who had not previously received anthracyclines or radiation to the heart area, the maximum tolerated dose was established.

Adjuvant Treatment of RCC

The safety of sunitinib was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled study in which patients who had undergone nephrectomy for RCC received sunitinib 50 mg/day on a 4/2 schedule (n = 306) or placebo (n = 304). The median duration of treatment was 12.4 months (range: 0.13 to 14.9) for sunitinib and 12.4 months (range: 0.03 to 13.7) for placebo. Discontinuation of the drug due to an adverse reaction occurred in 28% of patients receiving sunitinib. Adverse reactions leading to discontinuation of the drug in >2% of patients included palmar-plantar syndrome and fatigue/asthenia. Interruption of treatment was observed in 54%, and dose reduction was observed in 46% of patients receiving sunitinib.

Grade 4 adverse reactions in patients receiving sunitinib included palmar-plantar syndrome (1%), fatigue (<1%), abdominal pain (<1%), stomatitis (<1%), and pyrexia (<1%). Changes in laboratory values of grade 3–4 that occurred 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 Suspected Adverse Reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and pharmacists are asked to report any suspected adverse reactions via the automated information system for pharmacovigilance at: https://aisf.dec.gov.ua/

Shelf Life

2 years.

Storage Conditions

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

Packaging

7 capsules in a blister pack; 4 blister packs in a carton box.

Release Category

Prescription only.

Manufacturer

Shilpa Medicare Limited.

Manufacturer's Location and Address

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