Sunitinib-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Sunitinib-Teva (Sunitinib-Teva)

Composition:

Active substance: sunitinib;

1 hard capsule contains sunitinib 12.5 mg or 25 mg or 50 mg;

Excipients:

capsule contents: mannitol (E 421), povidone K 25, sodium croscarmellose, magnesium stearate;

capsule shell: gelatin, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

12.5 mg hard capsules: hard gelatin capsule with an opaque moderately orange cap and an opaque moderately orange body, marked with "12.5" in black ink on the cap;

25 mg hard capsules: hard gelatin capsule with an opaque light orange cap and an opaque moderately orange body, marked with "25" in black ink on the cap;

50 mg hard capsules: hard gelatin capsule with an opaque light orange cap and an opaque light orange body, marked with "50" in black ink on the cap.

Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors.

ATC code L01E X01.

Pharmacological Properties

Pharmacodynamics

Sunitinib inhibits multiple receptor tyrosine kinases (RTKs) involved in tumor growth, tumor angiogenesis, and cancer metastasis. Sunitinib is 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 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (RET). The primary metabolite exhibits activity similar to that of sunitinib, as confirmed by biochemical and cellular assay results.

Pharmacokinetics

The pharmacokinetics of sunitinib were evaluated in 135 healthy volunteers and 266 patients with solid tumors. Pharmacokinetic parameters were similar across all studied groups of patients with solid tumors and in healthy volunteers.

Over the dose range of 25–100 mg, the area under the concentration-time curve (AUC) and Cmax increased dose-proportionally. With repeated daily administration, sunitinib accumulated 3–4-fold, while its primary active metabolite accumulated 7–10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are reached within 10–14 days. On day 14 of treatment, the combined plasma concentration of sunitinib and its active metabolite ranges from 62.9 to 101 ng/mL, which represents the target concentration that, according to preclinical data, inhibits receptor phosphorylation in vitro and results in tumor growth arrest/reduction in vivo. The primary active metabolite accounts for 23% to 37% of the total concentration. With repeated daily dosing or repeated cycles in dosing schedules, the pharmacokinetics of sunitinib or its primary active metabolite are not substantially altered.

Absorption

After oral administration, Cmax of sunitinib is typically reached within 6–12 hours (time to maximum concentration, tmax). Food does not affect the bioavailability of sunitinib.

Distribution

The in vitro plasma protein binding of sunitinib and its primary active metabolite in human plasma is 95% and 90%, respectively, with no apparent concentration dependence. The apparent volume of distribution (Vd) is large, at approximately 2230 L, indicating extensive tissue distribution.

Metabolic Interactions

Calculated in vitro Ki values for all tested cytochrome P450 (CYP) isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11) indicate that sunitinib and its primary active metabolite are unlikely to induce clinically significant metabolism of other drugs metabolized by these enzymes.

Biotransformation

Sunitinib is primarily metabolized by the CYP3A4 isoform to form its primary active metabolite, desethylsunitinib, which undergoes further metabolism by the same isoform.

Concomitant use of sunitinib with strong inducers or inhibitors of CYP3A4 should be avoided due to the potential for altered plasma levels of sunitinib (see sections "Special Warnings and Precautions for Use," "Interaction with Other Medicinal Products and Other Forms of Interaction").

Elimination

Elimination occurs primarily via feces (61%), with 16% of the administered dose excreted in urine as unchanged drug and metabolites. Sunitinib and its primary active metabolite were the major components detected in plasma, urine, and feces, accounting for 91.5%, 86.4%, and 73.8% of the total radioactivity, respectively. Minor metabolites were detected in urine and feces but were generally absent in plasma. The total oral clearance (CL/F) was 34–62 L/h. After oral administration to healthy volunteers, the elimination half-life of sunitinib and its primary active desethyl metabolite was approximately 40–60 hours and 80–110 hours, respectively.

Concomitant Use with Medicinal Products that are Inhibitors of Breast Cancer Resistance Protein (BCRP)

In vitro, sunitinib is a substrate of the efflux transporter BCRP. In study A6181038, concomitant administration of the BCRP inhibitor gefitinib did not result in clinically significant changes in Cmax or AUC of sunitinib or the combined sunitinib and metabolite levels (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

This multicenter, open-label phase 1/2 study evaluated the safety/tolerability, maximum tolerated dose, and antitumor activity of sunitinib in combination with gefitinib in patients with metastatic renal cell carcinoma (RCC). The pharmacokinetics of gefitinib (250 mg once daily) and sunitinib (37.5 mg [cohort 1, n=4] or 50 mg [cohort 2, n=7] once daily for 4 weeks followed by a 2-week break) were assessed as a secondary study objective.

Changes in sunitinib pharmacokinetic parameters were not clinically significant and did not indicate any interaction between the study drugs. However, given the relatively small number of trial participants (i.e., N=7+4) and moderate to high inter-subject variability in pharmacokinetic parameters, the results of this trial regarding pharmacokinetic interaction between the drugs should be interpreted with caution.

Special Patient Populations

Hepatic Impairment. Sunitinib and its primary metabolite are predominantly metabolized in the liver. Systemic exposure to sunitinib after a single dose was similar in patients with mild or moderate (Child-Pugh class A and B) hepatic impairment and in patients with normal liver function. The use of sunitinib in patients with severe (Child-Pugh class C) hepatic impairment has not been studied.

Patients with ALT or AST levels > 2.5 × ULN (upper limit of normal), or > 5.0 × ULN if elevated due to liver metastases, were excluded from oncology clinical trials.

Renal Impairment. Population pharmacokinetic analysis demonstrated that creatinine clearance (CLcr) within the studied range (42–347 mL/min) did not affect the apparent total clearance (CL/F) of sunitinib. Systemic exposure to sunitinib after a single dose was similar in patients with severe renal impairment (CLcr < 30 mL/min) and in patients with normal renal function (CLcr > 80 mL/min). Although sunitinib and its primary metabolite are not removed by hemodialysis in patients with end-stage renal disease, a 47% reduction in total body sunitinib and a 31% reduction in its primary metabolite were observed compared to patients with normal renal function.

Body Weight, Performance Status. Population pharmacokinetic analysis of demographic data showed no need for initial dose adjustment based on body weight or performance status according to the Eastern Cooperative Oncology Group (ECOG) scale.

Gender. Available data suggest that the apparent total clearance (CL/F) of sunitinib in women may be approximately 30% lower than in men; however, this difference does not require initial dose adjustment.

Pediatric Population. Experience with sunitinib in children is limited (see section "Dosage and Administration"). Population pharmacokinetic analyses of pooled data from adult patients with gastrointestinal stromal tumors (GIST) and solid tumors, and children with solid tumors, have been completed. Sequential analyses of independent variables were performed to evaluate the impact of age and body size (total body weight or body surface area) and other covariates on key pharmacokinetic parameters of sunitinib and its active metabolite. Among the evaluated age- and weight-related variables, age was a significant covariate for the apparent clearance of sunitinib (lower age in children associated with lower apparent clearance). Similarly, body surface area was a significant covariate for the apparent clearance of the active metabolite (smaller body surface area associated with lower apparent clearance).

Additionally, a comprehensive population pharmacokinetic analysis of pooled data from three pediatric studies (two involving pediatric patients with solid tumors and one with GIST; age: 6–11 years and 12–17 years) showed that baseline body surface area was a significant covariate for the apparent clearance of sunitinib and its active metabolite. Based on the results of this analysis, a daily dose of approximately 20 mg/m² is expected to achieve plasma levels of sunitinib and its active metabolite in children with body surface area of 1.10–1.87 m² comparable (75–125% of AUC) to those in adults with GIST receiving 50 mg daily according to the 4-weeks-on/2-weeks-off schedule (AUC 1233 ng·h/mL). The initial dose of sunitinib used in pediatric studies was 15 mg/m² (based on the maximum tolerated dose determined in a phase 1 dose-escalation study) and was later increased to 22.5 mg/m² and subsequently to 30 mg/m² (without exceeding a total daily dose of 50 mg) according to individual safety/tolerability in patients. Furthermore, according to published data in pediatric patients with GIST, the calculated initial dose ranged from 16.6 mg/m² to 36 mg/m², escalated up to 40.4 mg/m² (without exceeding a total daily dose of 50 mg).

Clinical characteristics.

Indications.

Gastrointestinal stromal tumors (GIST)

Sunitinib-Teva is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumors in adults following ineffective therapy with imatinib due to resistance or intolerance.

Metastatic renal cell carcinoma (mRCC)

Sunitinib-Teva is indicated for the treatment of progressive/metastatic renal cell carcinoma in adults.

Pancreatic neuroendocrine tumors (pNET)

Sunitinib-Teva is indicated for the treatment of progressive unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors in adults.

Contraindications.

Hypersensitivity to sunitinib or to any of the excipients (see section "Composition").

Interaction with other medicinal products and other forms of interactions.

Interaction studies have been conducted only in adults.

Medicinal products that may increase sunitinib plasma concentrations

Effect of CYP3A4 inhibitors

In healthy volunteers, co-administration of a single dose of sunitinib with the potent CYP3A4 inhibitor ketoconazole increased the combined [sunitinib + primary metabolite] maximum concentration (Cmax) and area under the pharmacokinetic curve (AUC0–∞) by 49% and 51%, respectively.

Concomitant use of sunitinib with potent CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) may increase sunitinib concentrations. Therefore, concomitant use with CYP3A4 inhibitors should be avoided or consideration should be given to using an alternative concomitant medicinal product that has no or minimal CYP3A4 inhibitory activity.

If avoidance is not possible, dose reduction of sunitinib may be required down to the minimum dose of 37.5 mg once daily for the treatment of GIST and mRCC and 25 mg once daily for the treatment of pNET, with close monitoring of tolerability (see section "Posology and method of administration").

Effect of breast cancer resistance protein (BCRP) inhibitors

Limited clinical data are available on the interaction between sunitinib and BCRP inhibitors; the potential for interaction between sunitinib and other BCRP inhibitors cannot be excluded.

Medicinal products that may decrease sunitinib plasma concentrations

Effect of CYP3A4 inducers

In healthy volunteers, administration of a single dose of sunitinib concomitantly with the CYP3A4 inducer rifampicin resulted in a reduction of the combined [sunitinib + primary metabolite] Cmax and AUC0–∞ by 23% and 46%, respectively.

Concomitant use of sunitinib with potent CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or herbal preparations containing St. John's wort [Hypericum perforatum]) may reduce sunitinib concentrations. Therefore, concomitant use with CYP3A4 inducers should be avoided or consideration should be given to selecting an alternative concomitant medicinal product that does not induce or minimally induces CYP3A4 activity. If avoidance is not possible, a stepwise dose increase of sunitinib by 12.5 mg (up to 87.5 mg once daily for the treatment of GIST and mRCC and 62.5 mg once daily for the treatment of pNET) may be required, with close monitoring of tolerability (see section "Posology and method of administration").

Special precautions for use.

Concomitant use of the medicinal product with strong CYP3A4 inducers should be avoided, as this may lead to decreased plasma concentrations of sunitinib.

Concomitant use with strong CYP3A4 inhibitors should be avoided due to the potential for increased sunitinib plasma concentrations (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interactions").

Skin and tissue disorders

Patients should be informed about the possibility of hair or skin depigmentation during treatment with sunitinib. Other potential dermatological disorders include dryness, thickening or cracking of the skin, and the development of blisters or rashes on the palms and soles.

The aforementioned reactions were noncumulative, usually reversible, and generally did not require discontinuation of treatment. Cases of pyoderma gangrenosum, typically reversible and resolving after discontinuation of sunitinib, have been reported. Serious skin reactions have been reported, including cases of erythema multiforme (EM), symptoms characteristic of Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of SJS, TEN, or EM (e.g., progressive skin rashes, often with blistering, or mucosal involvement) occur, sunitinib treatment should be discontinued. If SJS or TEN is confirmed, treatment should not be resumed. In some cases of suspected EM, rechallenge with sunitinib at a lower dose after resolution of the reaction has been tolerated; some patients also received concomitant therapy with corticosteroids or antihistamines (see section "Undesirable effects").

Haemorrhage and tumour-related bleeding

Haemorrhagic events, sometimes fatal, reported in clinical trials with sunitinib and during post-marketing surveillance, include gastrointestinal bleeding, respiratory tract bleeding, urinary tract bleeding, and intracranial haemorrhage (see section "Undesirable effects").

Routine assessment for haemorrhagic events should include complete blood count and physical examination.

Epistaxis was the most common haemorrhagic adverse reaction, reported in nearly half of patients with solid tumours who experienced haemorrhagic events. In some cases, epistaxis was severe, but rarely led to fatal outcomes.

Cases of tumour bleeding, sometimes associated with tumour necrosis, have been reported; some of these haemorrhagic events were fatal. Bleeding from tumours may occur suddenly, and in patients with lung tumours may present as severe, life-threatening haemoptysis or pulmonary haemorrhage. Cases of pulmonary haemorrhage, some fatal, have been observed in clinical trials and during post-marketing surveillance in patients receiving sunitinib for mRCC, GIST, or lung cancer.

Sunitinib is not approved for use in patients with lung cancer.

Patients receiving concomitant anticoagulant therapy (e.g., warfarin, acenocoumarol) may require periodic monitoring of complete blood count (platelets), coagulation parameters (PT/INR), and physical examination.

Gastrointestinal disorders

The most frequently reported gastrointestinal adverse reactions include diarrhoea, nausea/vomiting, abdominal pain, dyspepsia, and stomatitis/oral pain; cases of oesophagitis have also been reported (see section "Undesirable effects").

Supportive therapy for gastrointestinal adverse reactions may include antiemetic, antidiarrhoeal, or antacid agents. Serious, sometimes fatal, gastrointestinal complications, including perforation of gastrointestinal organs, have been reported in patients with intra-abdominal malignant tumours treated with sunitinib.

Arterial hypertension

Arterial hypertension, including severe cases (systolic pressure > 200 mm Hg or diastolic pressure > 110 mm Hg), has been reported during sunitinib treatment. Patients should be screened for arterial hypertension and appropriate control measures implemented. Temporary interruption of treatment is recommended in patients with severe, uncontrolled hypertension. Treatment may be resumed once adequate control of arterial hypertension is achieved (see section "Undesirable effects").

Haematological disorders

Decreased absolute neutrophil count and reduced platelet count have been reported during sunitinib treatment (see section "Undesirable effects"). These events were noncumulative, usually reversible, and generally did not lead to treatment discontinuation. None of these events were fatal in phase 3 trials; however, rare post-marketing reports of fatal haematological disorders, including bleeding associated with thrombocytopenia and neutropenic infections, have been received. Cases of anaemia have occurred during both early and late stages of sunitinib therapy. Complete blood count should be monitored at the beginning of each treatment cycle in patients receiving sunitinib (see section "Undesirable effects").

Cardiac disorders

Cardiovascular disorders, including heart failure, cardiomyopathy, reduced left ventricular ejection fraction (LVEF) below the lower limit of normal, myocarditis, myocardial ischaemia, and myocardial infarction, sometimes fatal, have been reported in patients treated with sunitinib. These data indicate that sunitinib increases the risk of cardiomyopathy. No specific additional risk factors for sunitinib-induced cardiomyopathy, apart from drug-specific effects, have been identified in patients treated with the drug. Sunitinib should be used with caution in patients with an increased risk of or history of the aforementioned disorders (see section "Undesirable effects").

Patients with cardiac disorders within 12 months prior to starting sunitinib treatment, including myocardial infarction (including severe/unstable angina), coronary artery bypass grafting or peripheral artery bypass, symptomatic congestive heart failure, acute cerebrovascular accident, transient ischaemic attack, or pulmonary artery embolism, were excluded from clinical trials of sunitinib. It is unknown whether patients with such comorbidities have an increased risk of left ventricular dysfunction associated with sunitinib use.

Physicians are advised to evaluate the risk-benefit ratio before initiating sunitinib. Close monitoring for clinical signs and symptoms of congestive heart failure during sunitinib treatment is recommended, especially in patients with risk factors for cardiac disorders and/or a history of ischaemic heart disease. Assessment of LVEF at baseline and periodically during treatment should be considered. In patients without cardiac risk factors, baseline assessment of ejection fraction should be considered.

If clinical signs of congestive heart failure develop, sunitinib should be discontinued. In patients without clinical signs of congestive heart failure but with an LVEF < 50% and > 20% below baseline, sunitinib treatment should be interrupted and/or the dose reduced.

QT interval prolongation

Prolongation of the QT interval and paroxysmal ventricular tachycardia of the "torsades de pointes" type have been observed in patients receiving sunitinib. QT interval prolongation may increase the risk of ventricular arrhythmias, including paroxysmal ventricular tachycardia of the "torsades de pointes" type.

Sunitinib should be used with caution in patients with a history of QT interval prolongation, those taking antiarrhythmic drugs or other medicinal products that may prolong the QT interval, and in patients with pre-existing cardiac conditions, bradycardia, or electrolyte imbalances. Concomitant use of sunitinib with strong CYP3A4 inhibitors should be limited due to the potential for increased sunitinib plasma concentrations (see sections "Posology and method of administration", "Interaction with other medicinal products and other forms of interactions", and "Undesirable effects").

Venous thromboembolic events

Venous thromboembolic events related to treatment, including deep vein thrombosis and pulmonary embolism, have been reported in patients receiving sunitinib (see section "Undesirable effects"). Fatal cases of pulmonary embolism have been reported during the post-marketing period.

Arterial thromboembolic events

Arterial thromboembolic events, sometimes fatal, have occurred in patients treated with sunitinib. The most common events include acute cerebrovascular accident, transient ischaemic attack, and ischaemic stroke. Risk factors for arterial thromboembolic events, apart from the underlying malignancy and age ≥ 65 years, include arterial hypertension, diabetes mellitus, and prior thromboembolic disease.

Aneurysms and arterial dissection

Use of VEGF (vascular endothelial growth factor) pathway inhibitors in patients with or without arterial hypertension may promote the development of aneurysms and/or arterial dissection. The likelihood of these disorders should be carefully evaluated before initiating sunitinib treatment in patients with risk factors such as arterial hypertension or a history of aneurysm.

Thrombotic microangiopathy (TMA)

TMA, including thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS), sometimes leading to renal failure or death, should be considered if haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological symptoms, renal dysfunction, or fever occur. Sunitinib therapy should be discontinued in patients who develop TMA, and immediate treatment is required. Reversible TMA effects have been observed after discontinuation of treatment (see section "Undesirable effects").

Thyroid dysfunction

All patients should undergo laboratory evaluation of thyroid function at the start of treatment. Patients with pre-existing hypothyroidism or hyperthyroidism should receive standard treatment prior to initiating sunitinib. Routine monitoring of thyroid function during sunitinib treatment should be performed every 3 months. Additionally, patients should be closely observed for signs and symptoms of thyroid dysfunction during treatment, and laboratory evaluation of thyroid function should be performed if any signs or symptoms suggestive of thyroid dysfunction occur, according to clinical indications. Patients who develop thyroid dysfunction should receive standard treatment.

Cases of hypothyroidism have been observed at both early and late stages of sunitinib treatment (see section "Undesirable effects").

Pancreatitis

Elevated serum lipase and amylase activity have been observed in patients with various solid tumours receiving sunitinib. Increased lipase activity was transient and generally not associated with signs or symptoms of pancreatitis in patients with solid tumours (see section "Undesirable effects").

Serious pancreatic disorders, some fatal, have been reported. Sunitinib should be discontinued and appropriate supportive treatment initiated if symptoms of pancreatitis occur.

Hepatotoxicity

Hepatotoxicity has been observed in patients treated with sunitinib. Cases of liver failure, some fatal, have been reported in < 1% of patients with solid tumours receiving sunitinib. Liver function tests (ALT, AST, bilirubin levels) should be monitored before treatment initiation, during each treatment cycle, and as clinically indicated. Sunitinib should be discontinued and appropriate supportive treatment initiated if signs or symptoms of liver failure occur (see section "Undesirable effects").

Renal function

Cases of impaired renal function, renal failure, and/or acute renal failure, sometimes fatal, have been reported.

Risk factors associated with impaired renal function/renal failure in patients receiving sunitinib, apart from the underlying disease—renal cell carcinoma—include advanced age, diabetes mellitus, pre-existing renal impairment, heart failure, arterial hypertension, sepsis, dehydration/hypovolemia, and rhabdomyolysis. The safety of continuing sunitinib treatment in patients with moderate or severe proteinuria has not been systematically studied.

Cases of proteinuria and isolated cases of nephrotic syndrome have been reported. Urinalysis is recommended at baseline, and patients should be monitored for the development or worsening of proteinuria. Sunitinib treatment should be discontinued in patients with nephrotic syndrome.

Fistulae

Sunitinib treatment should be discontinued if fistulae develop. Information on continuing sunitinib in patients with fistulae is limited (see section "Undesirable effects").

Impaired wound healing

Cases of impaired wound healing have been reported during sunitinib treatment.

No formal clinical studies have evaluated the effect of sunitinib on wound healing. As a precautionary measure, it is recommended to temporarily discontinue sunitinib treatment in patients undergoing major surgical procedures. Clinical experience regarding the timing of resuming therapy after major surgery is limited; therefore, the decision to resume sunitinib therapy after major surgery should be based on clinical assessment of postoperative recovery.

Osteonecrosis of the jaw (ONJ)

Cases of ONJ have been reported in patients treated with sunitinib. Most of these cases occurred in patients who had received or were concurrently receiving intravenous bisphosphonates, for which ONJ is an identified risk. Therefore, caution should be exercised when using sunitinib concomitantly or sequentially with intravenous bisphosphonates.

Invasive dental procedures are also an identified risk factor. Dental examination and appropriate preventive measures should be considered before initiating sunitinib treatment. Invasive dental procedures should be avoided, if possible, in patients who have previously received or are receiving intravenous bisphosphonates (see section "Undesirable effects").

Hypersensitivity/angioedema

If angioedema occurs due to hypersensitivity, sunitinib treatment should be discontinued and standard medical management initiated (see section "Undesirable effects").

Seizures

Seizures have been reported in clinical trials with sunitinib and during the post-marketing period. Patients with seizures and signs/symptoms characteristic of reversible posterior leukoencephalopathy syndrome, such as hypertension, headache, decreased concentration, worsening cognitive function, and visual loss, including cortical blindness, require monitoring and medical treatment, including control of arterial hypertension. Temporary discontinuation of sunitinib is recommended. After resolution of the seizure, treatment may be resumed at the physician's discretion (see section "Undesirable effects").

Tumour lysis syndrome (TLS)

Cases of TLS, sometimes fatal, have been rarely observed in clinical trials and during the post-marketing period in patients treated with sunitinib. Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, arterial hypotension, and acidic urine. Close monitoring of such patients and treatment as clinically indicated should be ensured, and prophylactic hydration should be considered.

Infections

Serious infections, with or without neutropenia, including some fatal cases, have been reported. Rare cases of necrotizing fasciitis, including perineal, sometimes fatal, have been reported (see section "Undesirable effects").

Sunitinib therapy should be discontinued if necrotizing fasciitis occurs, and appropriate treatment should be initiated immediately.

Hypoglycaemia

Decreased blood glucose levels have been reported in patients treated with sunitinib, in some cases associated with clinical symptoms and requiring hospitalization due to loss of consciousness. Sunitinib treatment should be temporarily discontinued in cases of symptomatic hypoglycaemia. Blood glucose levels should be regularly monitored in patients with diabetes mellitus to determine the need for dose adjustment of antidiabetic agents to minimize the risk of hypoglycaemia (see section "Undesirable effects").

Hyperammonaemic encephalopathy

Hyperammonaemic encephalopathy has been observed with sunitinib use (see section "Undesirable effects"). In patients who develop unexplained lethargy or altered mental status, ammonia levels should be measured and appropriate clinical management initiated.

Sodium

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

Use during pregnancy or breastfeeding

Contraception in men and women. Women of reproductive potential should be advised to use effective contraception and to avoid pregnancy during sunitinib treatment.

Pregnancy. Studies with sunitinib in pregnant women have not been conducted. Reproductive toxicity, including fetal malformations, has been observed in animal studies. Sunitinib should not be used in pregnant women or in women not using effective contraception, except when the potential benefit justifies the potential risk to the fetus. If the medicinal product is used during pregnancy or if a patient becomes pregnant while receiving sunitinib, she should be informed of the potential risks to the fetus.

Breastfeeding. Sunitinib and/or its metabolites are excreted in rat milk. It is unknown whether sunitinib or its major active metabolite is excreted in human breast milk. Since active substances are generally excreted in human breast milk and considering the potential for serious adverse reactions in infants, women should discontinue breastfeeding during sunitinib treatment.

Fertility. Preclinical data indicate that fertility in both men and women may be impaired by sunitinib treatment.

Ability to affect reaction speed when driving or operating machinery.

Sunitinib has a minor influence on the ability to drive and use machines. Patients should be warned about the possibility of experiencing dizziness during sunitinib treatment.

Method of Administration and Dosage

Treatment with sunitinib should be prescribed by a physician experienced in the use of anticancer agents. The medicinal product is administered orally and may be taken regardless of food intake. If a dose is missed, an additional dose should not be taken; the next day, the usual prescribed dose should be taken.

Recommended Dose for GIST and mRCC

For GIST and mRCC, the recommended dose of Sunitinib-Teva is 50 mg orally once daily for 4 weeks, followed by a 2-week treatment break (schedule "4/2").

A complete treatment cycle is 6 weeks.

Recommended Dose for pNET

For pNET, the recommended dose of Sunitinib-Teva is 37.5 mg orally once daily without a planned treatment break.

Dose Modifications

Safety and Tolerability. In GIST and mRCC, dose modifications may be performed with stepwise increases or reductions by 12.5 mg depending on individual safety and tolerability. The daily dose should not exceed 75 mg and should not be less than 25 mg.

For pNET, dose modifications may be performed with stepwise increases or reductions by 12.5 mg depending on individual safety and tolerability. The maximum dose used in the phase 3 pNET study was 50 mg daily.

Temporary discontinuation of therapy may be required based on individual safety and tolerability.

Inhibitors/Inducers of CYP3A4. Concomitant use of sunitinib with strong CYP3A4 inducers such as rifampicin should be avoided (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). If concomitant use is unavoidable, dose escalation of sunitinib by 12.5 mg increments may be considered (up to 87.5 mg daily for GIST and mRCC and up to 62.5 mg daily for pNET), with careful monitoring of tolerability.

Concomitant use of sunitinib with strong CYP3A4 inhibitors such as ketoconazole should be avoided (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). If concomitant use is unavoidable, dose reduction of sunitinib to the minimum dose—37.5 mg daily for GIST and mRCC and 25 mg daily for pNET—should be considered, with careful monitoring of tolerability.

Alternative concomitant medications that have no or minimal effect on CYP3A4 induction or inhibition should be considered.

Special Patient Populations

Children. The safety and efficacy of sunitinib in patients under 18 years of age have not been established.

Available data are described in sections "Pharmacological Properties" and "Undesirable Effects," but no dosage recommendations can be provided.

Elderly Patients. Approximately one-third of all patients in clinical trials receiving sunitinib were aged 65 years or older. No significant differences in safety or efficacy were observed between younger and older patients.

Hepatic Impairment. Dose adjustment of the initial dose is not required in patients with mild or moderate (Child-Pugh classes A and B) hepatic impairment. Sunitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and is therefore not recommended (see section "Pharmacological Properties").

Renal Impairment. Dose adjustment of the initial dose is not required in patients with mild or moderate renal impairment or in those with end-stage renal disease on hemodialysis. Subsequent dose adjustments should be based on individual safety and tolerability (see section "Pharmacological Properties").

Children. The safety and efficacy of sunitinib in patients under 18 years of age have not been established.

Overdose.

There is no specific antidote for sunitinib overdose. Management of overdose should consist of general supportive measures. If indicated, unabsorbed active substance may be removed by inducing emesis or gastric lavage. Cases of overdose have been reported, some of which were associated with adverse reactions consistent with the known safety profile of sunitinib.

Adverse Reactions

Summary of safety profile

The most serious adverse reactions associated with sunitinib, sometimes fatal, include renal failure, heart failure, pulmonary embolism, gastrointestinal perforation, and hemorrhage (e.g., respiratory tract hemorrhage, gastrointestinal bleeding, tumor hemorrhage, urinary tract bleeding, and intracranial hemorrhage). The most common adverse reactions of any grade (observed in patients in the RCC, GIST, and PNET registration trials) were decreased appetite, taste disturbance, hypertension, fatigue, gastrointestinal disorders (diarrhea, nausea, stomatitis, dyspepsia, and vomiting), skin color changes, and hand-foot syndrome. These symptoms may improve with continued treatment.

Hypothyroidism may develop during treatment. Hematologic disorders (e.g., neutropenia, thrombocytopenia, and anemia) are among the most common adverse reactions to sunitinib.

Fatal cases, in addition to those mentioned in the section "Special precautions for use" or in the section "Adverse reactions", considered likely related to sunitinib treatment, included multi-organ failure, disseminated intravascular coagulation, peritoneal hemorrhage, adrenal insufficiency, pneumothorax, shock, and sudden death.

List of adverse reactions

The following adverse reactions were observed in the combined population of patients with GIST, mRCC, and PNET (7115 patients), categorized by organ systems, frequency, and severity (according to NCI-CTCAE classification). This list also includes adverse reactions identified in clinical trials during the post-marketing period. Within each frequency category, adverse reactions are presented in decreasing order of severity.

Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Infections and infestations. Common: viral infections^a, respiratory infections^b*, abscess^c*, fungal infections^d, urinary tract infections, skin infections^e, sepsis^f*. Uncommon: necrotizing fasciitis*.

Blood and lymphatic system disorders. Very common: neutropenia, thrombocytopenia, anemia, leukopenia. Common: lymphopenia. Uncommon: pancytopenia. Rare: thrombotic microangiopathy^h*.

Immune system disorders. Uncommon: hypersensitivity. Rare: angioedema.

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

Metabolism and nutrition disorders. Very common: decreased appetiteⁱ. Common: dehydration, hypoglycemia. Rare: tumor lysis syndrome*.

Psychiatric disorders. Very common: insomnia. Common: depression.

Nervous system disorders. Very common: dizziness, headache, taste alteration^j. Common: peripheral neuropathy, paresthesia, hypoesthesia, hyperesthesia. Uncommon: intracranial hemorrhage*, cerebral hemorrhage*, stroke*, transient ischemic attack. Rare: reversible posterior leukoencephalopathy syndrome*. Frequency not known: hyperammonemia encephalopathy.

Eye disorders. Common: periorbital edema, eyelid edema, increased lacrimation.

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

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

Respiratory, thoracic and mediastinal disorders. Very common: dyspnea, epistaxis, cough. Common: pulmonary embolism*, pleural effusion*, hemoptysis, exertional dyspnea, oropharyngeal painⁿ, nasal congestion, dry nose. 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 bleeding, gingival bleeding, oral ulceration, proctalgia, cheilitis, hemorrhoids, glossodynia, oral pain, dry mouth, flatulence, oral discomfort, eructation. Uncommon: gastrointestinal perforation^q*, pancreatitis, anal fistula, colitis^r, ischemic 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, palmar-plantar erythrodysesthesia, rash, hair color changes, dry skin. Common: skin desquamation, skin reaction^v, eczema, blistering, 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: bone and muscle pain, muscle spasms, myalgia, muscle weakness. Uncommon: osteonecrosis of the jaw, fistulae*. Rare: rhabdomyolysis*, myopathy.

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

General disorders and administration site conditions. Very common: mucositis, fatigue^x, edema^y, pyrexia. Common: chest pain, pain, influenza-like symptoms, chills. Uncommon: impaired healing.

Investigations. Common: weight loss, decreased white blood cell count, increased lipase, decreased platelet count, decreased hemoglobin, increased amylase^z, increased AST, increased ALT, increased blood creatinine, increased blood pressure, increased blood uric acid. Uncommon: increased blood creatine phosphokinase, increased blood thyroid-stimulating hormone.

* Includes fatal cases.

The following terms were grouped:

a Pharyngitis, nasopharyngitis, and oral herpes.

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

c Abscess, limb abscess, anal abscess, gingival abscess, liver abscess, pancreatic abscess, perineal abscess, perirectal abscess, rectal abscess, subcutaneous abscess, 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 Dysgeusia, ageusia, and taste disturbance.

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

l Decreased/impaired ejection fraction.

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

n Oropharyngeal pain and pharyngolaryngeal pain.

o Stomatitis and aphthous stomatitis.

p Abdominal pain, lower abdominal pain, upper abdominal pain.

q Gastrointestinal perforation and intestinal perforation.

r Colitis and ischemic colitis.

s Cholecystitis and acalculous cholecystitis.

t Yellow skin discoloration, skin color change, and pigmentation disorder.

u Psoriasis-like dermatitis, exfoliative rash, rash, erythematous rash, vesicular rash, generalized rash, macular rash, maculopapular rash, papular rash, and pruritic rash.

v Skin reaction 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), sometimes fatal, have been reported. Cases of necrotizing fasciitis, including perineal necrotizing fasciitis, sometimes fatal, have been reported (see section "Special precautions for use").

Blood and lymphatic system disorders

Grade 3 and 4 decreases in absolute neutrophil count were reported in 10% and 1.7% of patients, respectively, in the phase 3 GIST study, 16% and 1.6% in the phase 3 mRCC study, and 13% and 2.4% in the phase 3 PNET study. Grade 3 and 4 thrombocytopenia was observed in 3.7% and 0.4% of patients, respectively, in the phase 3 GIST study, 8.2% and 1.1% in the phase 3 mRCC study, and 3.7% and 1.2% in the phase 3 PNET study (see "Special precautions for use").

Bleeding events were reported in 18% of patients receiving sunitinib in the phase 3 GIST study, compared to 17% of placebo recipients. Among patients receiving sunitinib for untreated mRCC, bleeding occurred in 39% compared to 11% of patients receiving IFN-α. Grade 3 or higher bleeding events occurred in 17 (4.5%) patients receiving sunitinib compared to 5 (1.7%) patients receiving IFN-α. Among patients receiving sunitinib for cytokine-refractory mRCC, 26% experienced bleeding. Bleeding events, including epistaxis, were observed in 21.7% of patients receiving sunitinib in the phase 3 PNET study compared to 9.85% of placebo recipients (see "Special precautions for use").

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

Immune system disorders

Hypersensitivity reactions, including angioedema, have been reported (see "Special precautions for use").

Endocrine disorders

Hypothyroidism as an adverse reaction was observed in 7 patients (4%) receiving sunitinib in two cytokine-refractory mRCC studies, and in 61 patients (16%) receiving sunitinib and 3 patients (<1%) in the IFN-α group in the untreated mRCC study.

Additionally, increased thyroid-stimulating hormone levels were observed in 4 patients with cytokine-refractory mRCC (2%). Overall, 7% of mRCC patients developed clinical or laboratory evidence of hypothyroidism during treatment. Acquired hypothyroidism occurred in 6.2% of GIST patients receiving sunitinib and in 1% of placebo group patients. In the phase 3 PNET study, hypothyroidism occurred in 6 patients (7.2%) in the sunitinib group and 1 patient (1.2%) in the placebo group.

Prospective monitoring of thyroid function was conducted in two studies in breast cancer patients; sunitinib is not approved for use in breast cancer patients. In one study, hypothyroidism occurred in 15 (13.6%) patients in the sunitinib group and 3 (2.9%) patients in the standard therapy group. Increased blood thyroid-stimulating hormone levels occurred in 1 (0.9%) patient in the sunitinib group and were not observed in the standard therapy group. Hyperthyroidism was not observed in patients treated with sunitinib, while it occurred in 1 (1.0%) patient in the standard therapy group. In another study, hypothyroidism was detected in 31 (13%) patients in the sunitinib group and 2 (0.8%) patients in the capecitabine group. Increased blood thyroid-stimulating hormone levels were observed in 12 (5.0%) patients treated with sunitinib and were not detected in the capecitabine group. Hyperthyroidism occurred in 4 (1.7%) patients in the sunitinib group; it was not observed in the capecitabine group. Decreased blood thyroid-stimulating hormone concentration occurred in 3 (1.3%) patients in the sunitinib group and was absent in the capecitabine group. Increased T4 concentration was observed in 2 (0.8%) patients in the sunitinib group and 1 (0.4%) patient in the capecitabine group. Increased T3 concentration was observed in 1 (0.8%) patient in the sunitinib group and was absent in the capecitabine group. All thyroid disorders were grade 1 or 2 in severity (see section "Special precautions for use").

Metabolism and nutrition disorders

A higher incidence of hypoglycemia was observed in PNET patients compared to mRCC and GIST patients. Despite this, most adverse events reported in clinical trials were considered unrelated to the investigational treatment (see section "Special precautions for use").

Nervous system disorders

During sunitinib clinical trials and in the post-marketing period, several reports (<1%) of seizures and radiologically confirmed reversible posterior leukoencephalopathy syndrome, sometimes fatal, were received. Seizures occurred in patients with and without radiological evidence of brain metastases (see section "Special precautions for use").

Cardiac disorders

In clinical trials, a decrease in LVEF of ≥20% and below the lower limit of normal was observed in approximately 2% of GIST patients treated with sunitinib, 4% of cytokine-refractory mRCC patients, and 2% of GIST patients receiving placebo. This decrease in LVEF did not progress and often improved with continued treatment. In a trial involving untreated mRCC patients, LVEF values below the lower limit of normal were observed in 27% of patients on sunitinib and 15% on IFN-α. Two patients (<1%) receiving sunitinib were diagnosed with congestive heart failure. In GIST patients, "heart failure," "congestive heart failure," or "left ventricular dysfunction" occurred in 1.2% of sunitinib-treated patients and 1% of placebo-treated patients. In the phase 3 GIST baseline study (N=312), fatal cardiac reactions related to treatment were reported in 1% of patients in each group (sunitinib and placebo). In a phase 2 trial involving cytokine-refractory mRCC patients, 0.9% of patients experienced fatal myocardial infarction related to treatment, and in a phase 3 trial involving untreated mRCC patients, 0.6% in the IFN-α group and 0% in the sunitinib group had fatal cardiac disorders. In the phase 3 PNET trial, one (1%) patient receiving sunitinib experienced fatal heart failure related to treatment.

Vascular disorders

Arterial hypertension. Arterial hypertension is a very common adverse reaction reported in clinical trials. Sunitinib dose was reduced or temporarily interrupted in approximately 2.7% of patients with hypertension. Treatment with sunitinib was not discontinued in any of these patients. Severe arterial hypertension (>200 mmHg systolic or >110 mmHg diastolic) was reported in 4.7% of patients with solid tumors. Arterial hypertension occurred in nearly 33.9% of patients receiving sunitinib for untreated mRCC compared to 3.6% of patients receiving IFN-α. Severe arterial hypertension was reported in 12% of previously untreated patients in the sunitinib group and <1% in the IFN-α group. Arterial hypertension was observed in 26.5% of patients receiving sunitinib in the phase 3 PNET study compared to 4.9% of placebo recipients. Severe arterial hypertension was reported in 10% of PNET patients in the sunitinib group and 3% in the placebo group.

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

Seven patients (3%) in the sunitinib group and no patients in the placebo group in the phase 3 GIST study experienced venous thromboembolic events, of which 5 patients had grade 3 deep vein thrombosis (DVT) and 2 had grade 1 or 2 DVT. Four of these 7 GIST patients discontinued treatment after DVT diagnosis.

Thirteen (3%) patients receiving sunitinib in the phase 3 trial involving untreated mRCC patients and 4 patients (2%) from two trials involving untreated cytokine-refractory mRCC patients experienced venous thromboembolic events. Pulmonary embolism occurred in nine of these patients: one grade 2 and eight grade 4 cases. Eight of these patients had DVT: one grade 1, two grade 2, four grade 3, and one grade 4. One patient with pulmonary embolism in the trial involving cytokine-refractory mRCC patients had temporary interruption of treatment.

Among untreated mRCC patients receiving IFN-α, 6 (2%) venous thromboembolic events were observed. One patient (<1%) had grade 3 DVT, and 5 patients (1%) had grade 4 pulmonary embolism.

In the phase 3 trial involving PNET patients, venous thromboembolic events were reported in 1 (1.2%) patient in the sunitinib group and 5 (6.1%) patients in the placebo group. Two of these placebo group patients had DVT: one grade 2 and one grade 3.

No fatal cases were recorded in registration trials involving GIST, mRCC, and PNET patients. Fatal cases occurred in the post-marketing period.

Approximately 3.1% of GIST patients and approximately 1.2% of mRCC patients receiving sunitinib in phase 3 trials experienced pulmonary embolism. Pulmonary embolism was not observed in PNET patients treated with sunitinib in the phase 3 trial. Isolated fatal cases were reported during post-marketing surveillance.

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

Lung disorders (such as dyspnea, pleural effusion, pulmonary embolism, or pulmonary edema) occurred in approximately 17.8% of GIST patients, 26.7% of mRCC patients, and 12% of PNET patients receiving sunitinib in phase 3 registration trials.

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

Gastrointestinal disorders

Pancreatitis occurred infrequently (<1%) in patients receiving sunitinib for GIST or mRCC. No treatment-related pancreatitis cases were reported in the phase 3 PNET trial (see section "Special precautions for use").

Fatal gastrointestinal hemorrhage was known in 0.98% of GIST patients receiving placebo in the phase 3 trial.

Hepatobiliary disorders

Cases of liver function impairment, including abnormal liver function tests, hepatitis, or hepatic failure, have been reported (see section "Special precautions for use").

Skin and subcutaneous tissue disorders

Cases of pyoderma gangrenosum, usually reversible after discontinuation of sunitinib, have been reported (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders

Cases of myopathy and/or rhabdomyolysis, some with acute renal failure, have been reported. Patients with signs or symptoms of muscle toxicity should receive standard treatment (see section "Special precautions for use").

Cases of fistula formation, sometimes associated with tumor necrosis and regression, occasionally fatal, have been reported (see section "Special precautions for use").

Cases of osteonecrosis of the jaw (ONJ) have been reported in patients receiving sunitinib, mostly in patients with identified risk factors for ONJ, such as intravenous bisphosphonate administration and/or history of dental disease requiring invasive dental procedures (see section "Special precautions for use").

Investigations

Preclinical (in vitro and in vivo) studies using doses higher than recommended for humans suggest that sunitinib may inhibit the repolarization phase of the cardiac action potential (i.e., cause QT interval prolongation).

QTc prolongation to over 500 ms and changes exceeding 60 ms from baseline were reported in 0.5% and 1.1% of 450 patients with solid tumors, respectively. Both values are considered potentially significant changes. At concentrations approximately twice the therapeutic level, sunitinib caused QTcF (Fridericia-corrected) prolongation.

QTc prolongation was studied in a trial involving 24 patients aged 20–87 years with advanced malignancies. Results showed sunitinib affects the QTc interval (defined as mean change, placebo-adjusted, >10 ms with upper bound of 90% confidence interval (CI) >15 ms) at therapeutic concentrations (day 3) using baseline correction method, and at concentrations above therapeutic (day 9) using both baseline correction methods. No patient had QTc >500 ms. Although QTcF effect was observed on day 3, 24 hours after dose (i.e., at therapeutic plasma concentration expected after recommended initial dose of 50 mg), clinical significance using daily baseline correction method is not fully established.

Based on comprehensive assessment of serial ECGs during periods corresponding to therapeutic or higher-than-therapeutic drug concentrations, no patient in the evaluable population or randomized patients had QTc prolongation considered "severe" (i.e., ≥ grade 3 by CTCAE v3.0).

At therapeutic plasma concentrations, maximum mean difference from baseline QTcF was 9 ms (90% CI: 15.1 ms). At concentrations approximately twice therapeutic, maximum mean difference from baseline QTcF was 15.4 ms (90% CI: 22.4 ms). Moxifloxacin (400 mg), used as positive control, showed maximum mean difference from baseline QTcF of 5.6 ms. No patient experienced QTc effect greater than grade 2 (CTCAE v3.0) (see section "Special precautions for use").

Long-term safety in mRCC treatment

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

Pediatric population

The safety profile of sunitinib described below is based on results from a phase 1 dose-escalation study, an open-label phase 2 study, a non-comparative phase 1/2 study, and published literature data.

A phase 1 dose-escalation study with oral sunitinib was conducted in 35 patients, 30 of whom were pediatric (aged 3–17 years) and 5 were young adults (18–21 years) with refractory solid tumors, most with primary brain tumor diagnosis.

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 exposed to cardiac irradiation and/or anthracyclines compared to those not receiving such treatment. The maximum tolerated dose was established for the group not previously exposed to anthracyclines or cardiac irradiation (see section "Pharmacological properties").

An open-label phase 2 study was conducted in 29 patients, 27 of whom were pediatric (3–16 years) and 2 were young adults (18–19 years) with recurrent/progressive/refractory high-grade glioma or ependymoma. No grade 5 adverse reactions were observed in either group. The most common (≥10%) treatment-related adverse events were decreased neutrophil count (6 [20.7%] patients) and intracranial hemorrhage (3 [10.3%] patients).

A non-comparative phase 1/2 study was conducted in 6 children (aged 13–16 years) with advanced unresectable GIST. The most common drug-related adverse reactions were diarrhea, nausea, decreased white blood cell count, neutropenia, and headache, each observed in 3 (50.0%) patients and mostly of grade 1 or 2 severity.

Adverse events of grade 3–4 related to treatment occurred in 4 of 6 patients (66.7%) (grade 3 hypophosphatemia, neutropenia, and thrombocytopenia, each in one patient, and grade 4 neutropenia in one patient). No serious adverse events or grade 5 adverse reactions were reported in this study. Based on clinical trial results and literature analysis, the safety profile corresponded to the known safety profile in adults.

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging to protect from moisture at temperatures not exceeding 30°C. Keep out of reach of children.

Packaging. 7 hard capsules per blister; 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Industries Ltd.

Manufacturer's address and location of operations. 18 Eli Hurvitz Street, Industrial Zone, Kfar Saba, Israel.