Judgia-sunitinib
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUGIA-SUNITINIB
Composition:
Active substance: sunitinib;
1 capsule contains sunitinib malate equivalent to sunitinib 12.5 mg, 50 mg;
Excipients:
12.5 mg capsules: mannitol (E 421), sodium croscarmellose, povidone, magnesium stearate, hard gelatin capsule No. 4: titanium dioxide (E 171), iron oxide red (E 172), gelatin;
50 mg capsules: mannitol (E 421), sodium croscarmellose, povidone, magnesium stearate, hard gelatin capsule No. 2: titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172), FD&C Blue 2 dye, gelatin.
Pharmaceutical form. Capsules.
Main physicochemical properties:
12.5 mg: hard gelatin capsules No. 4 with an opaque red body printed with "S12.5" in white ink and an opaque red cap without printing, containing yellow to orange granules;
50 mg: hard gelatin capsules No. 2 with an opaque olive-green body printed with "S50" in black ink and an opaque olive-green cap without printing, containing yellow to orange granules.
Pharmacotherapeutic group. Antineoplastic agents, 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 associated with tumor growth, pathological angiogenesis, and metastatic progression of cancer. Sunitinib has been evaluated for its inhibitory activity against various kinases (>80 kinases) and has been identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor-1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (RET). Inhibition of these RTKs by sunitinib has been demonstrated in biochemical and cellular assays, and functional inhibition has been shown in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.
Sunitinib inhibited phosphorylation of several RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing these target RTKs in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibition of metastases in certain experimental cancer models. Sunitinib demonstrated the ability to inhibit tumor cell growth expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro, and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.
Exposure-response relationship
Based on population pharmacokinetic/pharmacodynamic analysis, a relationship was established between changes over time in various pharmacodynamic endpoints (i.e., safety and efficacy endpoints) and plasma exposure to sunitinib.
Cardiac electrophysiology
Sunitinib may cause dose-dependent QT interval prolongation, which may increase the risk of ventricular arrhythmias, including torsade de pointes (see section "Special precautions").
Pharmacokinetics
The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy volunteers and in patients with solid tumors.
Maximum plasma concentration (Cmax) of sunitinib is generally observed within 6–12 hours (time to maximum plasma concentration [Tmax]) after oral administration. Food does not affect the bioavailability of sunitinib. Sunitinib can be administered independently of food intake.
Protein binding of sunitinib and its primary active metabolite to human plasma proteins in vitro was 95% and 90%, respectively, without concentration dependence within the range of 100–4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dose range of 25–100 mg, the area under the concentration-time curve (AUC) and Cmax increase proportionally with dose (0.5 to 2 times higher than corresponding values following the approved recommended daily dose of 50 mg).
Sunitinib is primarily metabolized by CYP3A4 to a primary active metabolite, which is subsequently metabolized by CYP3A4. The primary active metabolite accounts for 23–37% of total exposure. Elimination occurs primarily via feces. In a human mass balance study with [14C]sunitinib, 61% of the dose was excreted in feces and renal excretion accounted for 16% of the administered dose. Sunitinib and its primary active metabolite were the main compounds detected in plasma, urine, and feces, representing 91.5%, 86.4%, and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were detected in urine and feces but generally not in plasma. Total oral clearance (C/F) ranged from 34 to 62 L/h, with inter-individual variability of 40%.
After administration of a single oral dose in healthy volunteers, the terminal half-life of sunitinib and its primary active metabolite is approximately 40–60 hours and 80–110 hours, respectively. With repeated daily dosing of sunitinib, 3–4-fold accumulation of sunitinib and 7–10-fold accumulation of the primary metabolite are observed. Steady-state concentrations of sunitinib and its primary active metabolite are reached within 10–14 days. By day 14, the combined plasma concentration of sunitinib and its active metabolite ranged from 62.9 to 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or its primary active metabolite were observed with repeated daily dosing or repeated cycles in dosing regimens.
Pharmacokinetics were similar in healthy volunteers and in patient populations with solid tumors included in the study, including patients with gastrointestinal stromal tumor (GIST) and renal cell carcinoma (RCC).
Pharmacokinetics in special patient populations
Population pharmacokinetic analysis of demographic data indicates no clinically significant effect of age, body weight, creatinine clearance, race, gender, or Eastern Cooperative Oncology Group (ECOG) performance status on the pharmacokinetics of sunitinib or its primary active metabolite.
Patients with renal impairment
No clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite were predicted or observed in patients with mild (CLcr 50–80 mL/min), moderate (CLcr 30–50 mL/min), or severe (CLcr < 30 mL/min) renal impairment not on dialysis, compared to patients with normal renal function (CLcr > 80 mL/min). Although sunitinib is not removed by hemodialysis, systemic exposure to sunitinib was 47% lower in patients with end-stage renal disease (ESRD) on hemodialysis compared to patients with normal renal function.
Hepatic impairment
Sunitinib and its primary metabolite are predominantly metabolized in the liver. Systemic exposures after a single dose of sunitinib were similar in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment compared to patients with normal hepatic function. The use of sunitinib in patients with severe (Child-Pugh class C) hepatic impairment has not been studied.
Clinical Characteristics
Indications
Gastrointestinal stromal tumor (GIST)
Sunitinib is indicated for the treatment of gastrointestinal stromal tumor following disease progression or intolerance to imatinib mesylate.
Advanced renal cell carcinoma (RCC)
Sunitinib is indicated for the treatment of advanced renal cell carcinoma.
Adjuvant treatment of renal cell carcinoma (RCC)
Sunitinib is indicated for adjuvant treatment of adult patients at high risk for recurrent RCC following nephrectomy.
Advanced pancreatic neuroendocrine tumors (pNET)
Sunitinib is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease.
Contraindications
Hypersensitivity to sunitinib malate or to any of the excipients.
Interactions with other medicinal products and other forms of interactions
Strong CYP3A4 inhibitors
Strong CYP3A4 inhibitors, such as ketoconazole, may increase plasma concentrations of sunitinib. It is recommended to select an alternative concomitant medication with no or minimal enzyme inhibition potential. Concomitant administration of sunitinib with the strong CYP3A4 inhibitor ketoconazole resulted in a 49% and 51% increase in combined (sunitinib + primary active metabolite) Cmax and AUC0-∞, respectively, after a single dose of sunitinib in healthy volunteers. Concomitant use of sunitinib with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir) may increase sunitinib concentrations. Grapefruit juice may also increase sunitinib plasma concentrations. Dose reduction should be considered when sunitinib is co-administered with strong CYP3A4 inhibitors (see section "Dosage and administration").
Strong CYP3A4 inducers
CYP3A4 inducers, such as rifampicin, may decrease sunitinib plasma concentrations. It is recommended to select an alternative concomitant medication with no or minimal enzyme induction potential. Concomitant administration of sunitinib with the strong CYP3A4 inducer rifampicin resulted in a 23% and 46% decrease in combined (sunitinib + primary active metabolite) Cmax and AUC0-∞, respectively, after a single dose of sunitinib in healthy volunteers. Concomitant use of sunitinib with CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, St. John’s wort) may reduce sunitinib concentrations. Dose escalation should be considered when sunitinib is co-administered with CYP3A4 inducers (see section "Dosage and administration").
In vitro studies of CYP inhibition and induction
In vitro studies have shown that sunitinib does not induce or inhibit major CYP enzymes. In vitro studies in liver microsomes and hepatocytes assessing the activity of CYP isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 showed that sunitinib and its primary active metabolite are not expected to cause any clinically significant drug interactions with agents metabolized by these enzymes.
Drugs that prolong the QT interval
Sunitinib may prolong the QT interval. In patients requiring treatment with drugs known to prolong the QT interval, QT interval monitoring via ECG should be performed more frequently.
Special precautions for use
Hepatotoxicity
Sunitinib may cause severe hepatotoxicity leading to liver failure or fatal outcome. Liver failure has been observed in < 1 % of patients in the overall safety cohort in clinical trials. Liver failure includes jaundice, elevated transaminases and/or hyperbilirubinemia in combination with encephalopathy, coagulopathy and/or renal failure.
Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) should be monitored at the beginning of treatment, during each treatment cycle, and as clinically indicated. Treatment should be interrupted for Grade 3 hepatotoxicity until improvement to Grade ≤ 1 or baseline levels, and then resumed at a reduced dose.
Treatment should be discontinued in patients with Grade 4 hepatotoxicity, in patients who do not recover from Grade 3 hepatotoxicity, in patients with serious abnormalities in liver function tests, and in patients who have 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 with levels > 5 times ULN in the presence of liver metastases, has not been established.
Pancreatitis
Elevated serum lipase and amylase activity have been observed in patients with various solid tumours receiving sunitinib. Increases in lipase activity were transient and generally not associated with symptoms of pancreatitis in patients with various solid tumours (see section "Adverse reactions").
Serious adverse reactions involving the pancreas have been reported, some of which resulted in fatal outcomes. Sunitinib should be discontinued in patients with symptoms suggestive of pancreatitis, and appropriate supportive treatment should be initiated.
Gastrointestinal disorders
Diarrhoea, nausea/vomiting, abdominal pain, dyspepsia, and stomatitis/oral pain were the most commonly reported gastrointestinal adverse reactions; cases of oesophagitis have also been reported (see section "Adverse reactions").
Supportive therapy for gastrointestinal adverse reactions requiring treatment may include medications with antiemetic, antidiarrheal, or antacid properties.
Serious, sometimes fatal, gastrointestinal complications, including gastrointestinal perforation, have been reported in patients with intra-abdominal malignancies receiving sunitinib.
Cardiovascular disorders
Cases of cardiovascular disorders, including heart failure, cardiomyopathy, myocardial ischaemia, and myocardial infarction, some of which were fatal, have been reported.
Heart failure was observed in 3 % of patients in the overall safety cohort, with recovery reported in 71 % of these patients. Fatal heart failure was observed in < 1 % of patients.
In the adjuvant renal cell carcinoma (RCC) study, left ventricular ejection fraction (LVEF) decline Grade 2 (LVEF 40–50 %, decrease of 10–19 % from baseline) was observed in eleven patients. No patient experienced LVEF decline Grade 3–4. LVEF did not return to ≥ 50 % or baseline levels in three of these eleven patients at the time of last measurement. No patient receiving sunitinib was diagnosed with congestive heart failure (CHF).
Patients with cardiovascular disorders within 12 months prior to sunitinib administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass grafting, symptomatic CHF, acute cerebrovascular accident or transient ischaemic attack, or pulmonary artery thromboembolism, were excluded from sunitinib clinical trials. Patients with a history of anthracycline therapy or radiation therapy to the heart were also excluded from some studies. It is unknown whether patients with these comorbidities may be at increased risk of left ventricular dysfunction.
Assessment of LVEF at the beginning of treatment and periodically thereafter should be considered as clinically indicated. Patients should be closely monitored for clinical signs and symptoms of CHF. Sunitinib should be discontinued in patients who develop clinical manifestations of CHF. Treatment should be interrupted and/or dose reduced in patients without clinical signs of CHF who experience a decline in LVEF of more than 20 % but less than 50 % from baseline or below the lower limit of normal, if baseline LVEF value is not available.
QT interval prolongation and torsades de pointes
Sunitinib may cause dose-dependent QT interval prolongation, which may increase the risk of ventricular arrhythmias, including torsades de pointes. Torsades de pointes has been observed in < 0.1 % of patients.
Patients at increased risk of QT interval prolongation, including those with a history of QT prolongation, those taking antiarrhythmic drugs, or those with relevant pre-existing cardiac failure, bradycardia, or electrolyte imbalances, should be monitored. Periodic monitoring of ECG and electrolytes (e.g., magnesium, potassium) during treatment should be considered. More frequent monitoring of QT interval is recommended when sunitinib is used concomitantly with strong CYP3A4 inhibitors or with drugs known to prolong the QT interval. Dose reduction of sunitinib should be considered (see sections "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration").
Arterial hypertension
Arterial hypertension was observed in 29 % of patients in the overall safety cohort. Grade 3 arterial hypertension was observed in 7 % of patients and Grade 4 in 0.2 %.
Blood pressure should be monitored at the beginning of treatment and periodically thereafter as clinically indicated. Antihypertensive therapy should be initiated and/or adjusted as necessary. In case of Grade 3 arterial hypertension, sunitinib should be temporarily withheld until improvement to Grade ≤ 1 or baseline levels, and then resumed at a reduced dose. Sunitinib should be discontinued in patients who develop Grade 4 arterial hypertension.
Haematological disorders
Decreases in absolute neutrophil and platelet counts have been reported with sunitinib use (see section "Adverse reactions"). These events were not cumulative, were usually reversible, and generally did not lead to treatment discontinuation. None of these events were fatal in Phase 3 studies, but rare fatal haematological events, including bleeding associated with thrombocytopenia and neutropenic infections, have been reported during post-marketing surveillance.
Anaemia occurred both early and late during sunitinib treatment.
A complete blood count should be performed at the beginning of each treatment cycle in patients receiving sunitinib (see section "Adverse reactions").
Venous thromboembolic events
Cases of treatment-related venous thromboembolic events, including deep vein thrombosis and pulmonary embolism, have been reported in patients receiving sunitinib (see section "Adverse reactions"). Fatal pulmonary embolism has been reported during post-marketing surveillance.
Arterial thromboembolic events
Cases of arterial thromboembolic events (ATE), sometimes fatal, have been reported in patients receiving sunitinib. The most common events were cerebrovascular accidents, transient ischaemic attacks, and cerebral infarction. Risk factors associated with ATE, in addition to underlying malignancy and age ≥ 65 years, included arterial hypertension, diabetes mellitus, and prior thromboembolic disease.
Hypersensitivity / angioedema
If angioedema occurs due to hypersensitivity, sunitinib treatment should be interrupted and standard medical management provided (see section "Adverse reactions").
Seizures
Seizures have been reported in clinical trials of sunitinib and during post-marketing use. Patients who experience seizures or symptoms of reversible posterior leukoencephalopathy syndrome (RPLS), such as arterial hypertension, headache, decreased alertness, impaired thinking, or visual disturbances including cortical blindness, require monitoring and medical management, including control of arterial hypertension. Temporary discontinuation of sunitinib is recommended; after resolution of the event, treatment with sunitinib may be resumed at the physician's discretion (see section "Adverse reactions").
Bleeding events and organ perforation
Bleeding events, some of which were fatal, included gastrointestinal, respiratory tract, tumour, urinary tract, and intracranial haemorrhage. Bleeding events were observed in 30 % of patients in the overall safety cohort, including Grade 3 or 4 events in 4.2 % of patients. The most common bleeding adverse reaction was epistaxis, while gastrointestinal bleeding was the most common Grade 3–5 event.
Bleeding events related to tumours have been observed in patients receiving sunitinib. These events may occur suddenly and, in the case of lung tumours, may present as severe and life-threatening haemoptysis or pulmonary haemorrhage. Pulmonary haemorrhage, some fatal, has been observed in clinical trials in patients receiving sunitinib for metastatic RCC, GIST, and metastatic lung cancer. Sunitinib is not approved for use in patients with lung cancer.
Serious, sometimes fatal, gastrointestinal complications, including gastrointestinal perforation, have been reported in patients with intra-abdominal malignancies receiving sunitinib.
A series of clinical blood tests and physical examinations should be included in the clinical evaluation of bleeding events. Sunitinib should be interrupted for Grade 3 or 4 bleeding events until improvement to Grade ≤ 1 or baseline levels, then resumed at a reduced dose.
Sunitinib treatment should be discontinued in patients with persistent Grade 3 or 4 bleeding events.
Tumour lysis syndrome (TLS)
Cases of TLS, sometimes fatal, have been observed in clinical trials and during post-marketing use, primarily in patients with RCC or GIST. The overall risk of TLS exists for patients with high tumour burden prior to the start of treatment. These patients should be monitored for TLS and appropriate treatment initiated.
Aneurysms and arterial dissection
Use of vascular endothelial growth factor pathway inhibitors in patients with or without arterial hypertension may lead to the development of aneurysms and/or arterial dissections. This risk should be carefully considered before initiating treatment in patients with risk factors such as arterial hypertension or history of aneurysm.
Thrombotic microangiopathy
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, sometimes leading to renal failure or fatal outcome, has been observed in clinical studies and during post-marketing use of sunitinib as monotherapy and in combination with bevacizumab. Sunitinib is not approved for use in combination with bevacizumab. Sunitinib should be discontinued in patients who develop TMA. Resolution of TMA effects has been observed after discontinuation of sunitinib.
Proteinuria
Proteinuria and nephrotic syndrome have been observed. Some of these cases led to renal failure and fatal outcomes. Patients should be monitored for the development or worsening of proteinuria. Baseline and periodic urinalysis should be performed during treatment, with subsequent measurement of 24-hour urine protein as clinically indicated. Sunitinib should be interrupted and the dose reduced if 24-hour urine protein reaches 3 g or more. Sunitinib should be discontinued in patients with nephrotic syndrome or recurrent episodes of 24-hour urine protein ≥ 3 g despite dose reduction. The safety of continuing sunitinib therapy in patients with moderate to severe proteinuria has not been evaluated.
Skin toxicity
Serious skin adverse reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, some of which were fatal, have been reported. Sunitinib should be permanently discontinued in patients experiencing these serious skin reactions.
Necrotising fasciitis, including fatal cases, has been reported in patients receiving sunitinib, including perineal area involvement and fistula formation. Sunitinib should be discontinued in patients who develop necrotising fasciitis.
Reversible posterior leukoencephalopathy syndrome (RPLS)
Cases of RPLS have been reported in < 1 % of patients, some of which were fatal. Patients may present with arterial hypertension, headache, decreased alertness, impaired thinking, and visual disturbances, including cortical blindness. Diagnosis should be confirmed by magnetic resonance imaging. Sunitinib should be discontinued in patients who develop RPLS.
Thyroid dysfunction
Cases of hyperthyroidism, sometimes followed by hypothyroidism, have been reported in clinical trials and post-marketing experience with sunitinib.
Thyroid function should be monitored at the beginning of treatment, periodically during treatment, and as clinically indicated. All patients should be closely monitored for symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, during sunitinib treatment. Thyroid dysfunction therapy should be initiated and/or adjusted as necessary.
Hypoglycaemia
Sunitinib may cause symptomatic hypoglycaemia, which may lead to loss of consciousness or require hospitalisation. Hypoglycaemia occurred in 2 % of patients in the combined safety population receiving sunitinib. Hypoglycaemia occurred in 2 % of patients receiving sunitinib for advanced RCC (Study 3) and GIST (Study 1) (N = 577), and in approximately 10 % of patients receiving sunitinib for pNET (Study 6) (N = 83). Not all patients who experienced hypoglycaemia while receiving sunitinib for pNET had pre-existing glucose homeostasis disorders. Blood glucose reduction may be more pronounced in patients with diabetes mellitus.
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 mellitus should have their antidiabetic therapy evaluated for potential adjustment to minimise the risk of hypoglycaemia.
Osteonecrosis of the jaw (ONJ)
Osteonecrosis of the jaw has been observed in patients receiving sunitinib. Concurrent exposure to other risk factors, such as bisphosphonate use or dental disease/invasive dental procedures, may increase the risk of ONJ. An oral examination should be performed before starting treatment and periodically during therapy. Patients should be advised on proper oral hygiene. Treatment with sunitinib should be interrupted, if possible, at least 3 weeks prior to planned dental surgery or invasive dental procedures. Sunitinib treatment should be discontinued in patients who develop ONJ until complete healing. The safety of resuming sunitinib after healing of jaw osteonecrosis has not been established.
Impaired wound healing
Impaired wound healing has been observed in patients receiving sunitinib treatment (see section "Adverse reactions"). Treatment with sunitinib should be interrupted at least 3 weeks prior to planned surgical intervention. Sunitinib should not be administered for at least 2 weeks after major surgery and until adequate wound healing has occurred. The safety of resuming sunitinib treatment after resolution of wound healing complications has not been established.
Embryo-fetal toxicity
Based on animal studies and mechanism of action, sunitinib may cause fetal harm when administered to pregnant women. Administration of sunitinib to pregnant rats and rabbits during organogenesis resulted in teratogenicity, approximately 5.5 and 0.3 times greater than that observed with combined systemic exposure [AUC of sunitinib and its active metabolite] in patients receiving the recommended daily dose of 50 mg.
Pregnant women should be informed of the potential risk to the fetus. Women of reproductive potential should be advised to use effective contraception during sunitinib treatment and for 4 weeks after the last dose (see section "Pregnancy or lactation").
Hyperammonaemic encephalopathy
Hyperammonaemic encephalopathy has been observed with sunitinib use (see section "Adverse reactions"). In patients who develop unexplained lethargy or altered mental status, ammonia levels should be measured and appropriate supportive treatment initiated.
Paediatric use
The safety and efficacy of sunitinib in children have not been established.
Use in elderly patients
Among 7,527 patients with GIST, RCC (metastatic and adjuvant therapy) or pNET who received sunitinib, 32 % were aged 65 years and older, and 7 % were aged 75 years and older. In patients aged ≥ 65 years, the incidence of Grade 3 or 4 adverse reactions was higher (67 %) compared to younger patients (60 %).
In the GIST study, 73 patients (30 %) receiving sunitinib were aged ≥ 65 years. In the RCC study, 152 patients (41 %) receiving sunitinib were aged ≥ 65 years. Overall, no differences in safety or efficacy were observed between these patients and younger patients.
In the pNET study, 22 patients (27 %) receiving sunitinib were aged ≥ 65 years. Clinical trials of sunitinib did not include a sufficient number of pNET patients to determine whether patients aged ≥ 65 years respond differently than younger patients.
Hepatic impairment
No dose adjustment is required when sunitinib is administered to patients with mild or moderate hepatic impairment (Child-Pugh class A or B) (see section "Pharmacokinetics"). The use of sunitinib in patients with severe (Child-Pugh class C) hepatic impairment has not been studied.
Renal impairment
No dose adjustment is required when sunitinib is administered to patients without dialysis and with mild (CLcr 50–80 mL/min), moderate (CLcr 30–< 50 mL/min), or severe (CLcr < 30 mL/min) renal impairment (see section "Pharmacokinetics"). No dose adjustment is required for patients with end-stage renal disease (ESRD) on haemodialysis (see section "Pharmacokinetics").
Cases of renal function impairment, renal failure, and/or acute renal failure, sometimes fatal, have been reported (see section "Adverse reactions").
Risk factors associated with renal function impairment/failure in patients receiving sunitinib, in addition to the underlying renal cell carcinoma, include advanced age, diabetes mellitus, pre-existing renal dysfunction, heart failure, arterial hypertension, sepsis, dehydration/hypovolemia, and rhabdomyolysis.
The safety of continuing sunitinib treatment in patients with moderate to severe proteinuria has not been systematically evaluated.
Cases of proteinuria and rare cases of nephrotic syndrome have been reported. A baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. Sunitinib should be discontinued in patients with nephrotic syndrome.
Use during pregnancy or lactation
Pregnancy
Summary of risk information
Based on reproductive toxicity studies in animals and the mechanism of action of sunitinib, the medicinal product may cause fetal harm when administered to pregnant women (see section "Pharmacodynamics"). There are no data in pregnant women to inform a drug-associated risk. In animal studies of developmental and reproductive toxicity, oral administration of sunitinib to pregnant rats and rabbits during organogenesis resulted in teratogenic effects (embryonic, craniofacial, and skeletal malformations) at exposures approximately 5.5 and 0.3 times greater than the combined AUC (combined systemic exposure of sunitinib plus its active metabolite) in patients receiving the recommended daily dose of 50 mg. Women of reproductive potential should be advised of the potential risk to the fetus.
The expected background risk of major congenital malformations and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of congenital malformations, miscarriage, or other adverse outcomes. In the general US population, the estimated background risk of major congenital malformations and miscarriage in clinically recognised pregnancies is 2–4 % and 15–20 %, respectively.
Lactation
There is no information on the presence of sunitinib and its metabolites in human breast milk. Sunitinib and its metabolites were excreted into rat milk at concentrations up to 12 times higher than in plasma. Due to the potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment with sunitinib and for at least 4 weeks after the last dose.
Men and women of reproductive potential
Sunitinib may cause fetal harm when administered to pregnant women (see section "Pregnancy").
Pregnancy testing
Women of reproductive potential should be tested for pregnancy before starting treatment with the medicinal product.
Contraception
Women. Women of reproductive potential should be advised to use effective contraception during treatment with the medicinal product and for at least 4 weeks after the last dose.
Men. Based on reproductive toxicity studies in animals, male patients and their female partners of reproductive potential should be advised to use effective contraception during treatment with the medicinal product and for 7 weeks after the last dose.
Infertility
Based on reproductive toxicity studies in animals, sunitinib may impair fertility in men and women.
Ability to drive and use machines
The medicinal product has a minor influence on the ability to drive and use machines. Patients should be warned about the possible occurrence of dizziness during treatment with the medicinal product.
Administration and Dosage
Recommended Dose of Sunitinib in GIST and Advanced RCC
The recommended dose of sunitinib in GIST and advanced RCC is 50 mg orally once daily on a schedule of 4 weeks on treatment followed by 2 weeks off (schedule 4/2) until disease progression or unacceptable toxicity occurs. Sunitinib can be taken regardless of food intake.
Recommended Dose for Adjuvant Therapy in RCC
The recommended dose of sunitinib for adjuvant therapy in RCC is 50 mg orally once daily on a schedule of 4 weeks on treatment followed by 2 weeks off (schedule 4/2) for nine 6-week cycles. Sunitinib can be taken regardless of food intake.
Recommended Dose in PNET
The recommended dose of sunitinib in PNET is 37.5 mg orally once daily until disease progression or unacceptable toxicity occurs. Sunitinib can be taken regardless of food intake.
Dose Modifications in the Event of Adverse Reactions
Recommended dose reductions of sunitinib in the event of adverse reactions are provided in Table 1. Table 2 provides recommended dose modifications of sunitinib in the event of adverse reactions.
| Table 1 Recommended sunitinib dose reductions in the event of adverse reactions |
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| Indication |
RCC |
GIST |
NET |
|
| Advanced GIST |
Adjuvant GIST therapy |
|||
| First dose reduction |
37.5 mg once daily |
37.5 mg once daily |
37.5 mg once daily |
25 mg once daily |
| Second dose reduction |
25 mg once daily |
25 mg once daily |
NR |
NR |
| Table 2 Recommended dose modifications of sunitinib in the event of adverse reactions |
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| Adverse reaction |
Severity |
Sunitinib dose modifications |
|
| Hepatotoxicity (see section "Special warnings and precautions for use") |
Grade 3 |
|
|
| Grade 4 |
|
||
| Cardiovascular disorders (see section "Special warnings and precautions for use") |
Asymptomatic left ventricular dysfunction (LVEF decrease >20% but <50% from baseline or below lower limit of normal if baseline values are unavailable) |
|
|
| Clinically symptomatic congestive heart failure (CHF) |
|
||
| Arterial hypertension (see section "Special warnings and precautions for use") |
Grade 3 |
|
|
| Grade 4 |
|
||
| Bleeding events (see section "Special warnings and precautions for use") |
Grade 3 or 4 |
|
|
| Thrombotic microangiopathy (see section "Special warnings and precautions for use") |
Any grade |
|
|
| Proteinuria or nephrotic syndrome (see section "Special warnings and precautions for use") |
Proteinuria ≥3 grams in 24 hours without nephrotic syndrome |
|
|
| Nephrotic syndrome or recurrent proteinuria ≥3 grams in 24 hours despite dose reduction |
|
||
| Dermatologic toxicity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrotizing fasciitis (see section "Special warnings and precautions for use") |
Any grade |
|
|
| Reversible posterior leukoencephalopathy syndrome (see section "Special warnings and precautions for use") |
Any grade |
|
|
| Osteonecrosis of the jaw (see section "Special warnings and precautions for use") |
Any grade |
|
|
| Impaired wound healing (see section "Special warnings and precautions for use") |
Any grade |
|
|
Dose modification due to drug interactions
Strong CYP3A4 inhibitors
An alternative concomitant medication with no or minimal enzyme inhibition potential should be selected. If concomitant use of sunitinib with a strong CYP3A4 inhibitor cannot be avoided, consideration should be given to reducing the sunitinib dose to the minimum (see section "Interaction with other medicinal products and other forms of interaction"): 37.5 mg orally once daily on a 4-weeks-on/2-weeks-off schedule (Schedule 4/2) for GIST and RCC, or 25 mg orally once daily for PNET.
Strong CYP3A4 inducers
An alternative concomitant medication with no or minimal enzyme induction potential should be selected. If concomitant use of sunitinib with a strong CYP3A4 inducer cannot be avoided, consideration should be given to increasing the sunitinib dose to the maximum: 87.5 mg orally once daily on a 4-weeks-on/2-weeks-off schedule (Schedule 4/2) for GIST and RCC, or 62.5 mg once daily for PNET. If the dose is increased, patients should be closely monitored for signs of adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").
Dose modification in patients with end-stage renal disease on haemodialysis
No initial dose adjustment is required in patients with ESRD on haemodialysis. However, due to decreased drug exposure in patients with ESRD compared to those with normal renal function, subsequent doses may be gradually increased by up to two-fold based on safety and tolerability data (see section "Pharmacodynamics").
Paediatric population
The safety and efficacy of sunitinib in children have not been established.
Overdose
Management of overdose should consist of general supportive measures. There is no specific antidote for sunitinib overdose. If indicated, elimination of unabsorbed drug should be achieved by inducing emesis or gastric lavage. Cases of accidental overdose have been reported; these were associated with adverse reactions consistent with the known safety profile of sunitinib or no adverse reactions. In preclinical studies, mortality was observed at doses of 500 mg/kg (3000 mg/m²), which is five times the daily dose, in rats. Toxicity signs at this dose included impaired muscle coordination, head tremors, hypoactivity, ocular discharge, piloerection, and gastrointestinal disturbances. Mortality and similar toxicity signs were observed at lower doses when administered over a longer period.
Adverse Reactions
The most important serious adverse reactions (including fatal outcomes) associated with sunitinib use are renal failure, heart failure, pulmonary embolism, gastrointestinal perforation, and hemorrhages (e.g., gastrointestinal bleeding, respiratory tract hemorrhage, tumor hemorrhage, urinary tract hemorrhage, or intracranial bleeding). The most common adverse reactions of any grade observed in clinical trials involving patients with RCC, GIST, and progressive pancreatic neuroendocrine tumors include decreased appetite, taste alterations, hypertension, fatigue, gastrointestinal disorders (diarrhea, nausea, stomatitis, dyspepsia, and vomiting), skin discoloration, and hand-foot syndrome. The intensity of these symptoms may decrease over time with continued treatment. Hypothyroidism may develop during treatment. Common adverse drug reactions include hematologic disorders (e.g., neutropenia, thrombocytopenia, and anemia).
Fatal outcomes considered possibly related to sunitinib include multi-organ failure, disseminated intravascular coagulation, peritoneal hemorrhage, adrenal insufficiency, pneumothorax, shock, and sudden death.
Below is a list of adverse reactions reported in patients with gastrointestinal stromal tumors (GIST), metastatic renal cell carcinoma (mRCC), and progressive pancreatic neuroendocrine tumors. This information is derived from pooled data of 7115 patients. Adverse reactions are categorized by system organ class, frequency, and severity (according to NCI-CTCAE criteria). The list also includes adverse reactions observed in post-marketing clinical studies. Within each frequency group, adverse reactions are listed in descending order of severity. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and not known (cannot be estimated from available data).
Adverse reactions observed in clinical trials
Infections and infestations
Common: viral infectionsa, respiratory tract infectionsb*, abscessc*, fungal infectionsd, urinary tract infections, skin infectionse (and phlegmon), sepsisf*.
Uncommon: necrotizing fasciitis*, bacterial infectionsg.
Blood and lymphatic system disorders
Very common: neutropenia, thrombocytopenia, anemia, leukopenia.
Common: lymphopenia.
Uncommon: pancytopenia.
Rare: thrombotic microangiopathyh*.
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 disturbancej.
Common: peripheral neuropathy, paresthesia, hypoesthesia, hyperesthesia.
Uncommon: intracranial hemorrhage*, stroke*, transient ischemic attack.
Rare: reversible posterior leukoencephalopathy syndrome*.
Not known: hyperammonemia encephalopathy.
Eye disorders
Common: periorbital edema, eyelid edema, increased lacrimation.
Cardiac disorders
Common: myocardial ischemiak*, decreased ejection fractionl.
Uncommon: congestive heart failure, myocardial infarctionm*, heart failure*, cardiomyopathy*, pericardial effusion, QT interval prolongation on ECG.
Rare: left ventricular dysfunction*, torsades de pointes.
Vascular disorders
Very common: arterial hypertension.
Common: deep vein thrombosis, flushing, hyperemia.
Uncommon: tumor hemorrhage*.
Not known: aneurysms and arterial dissection*.
Respiratory, thoracic and mediastinal disorders
Very common: dyspnea, epistaxis, cough.
Common: pulmonary embolism*, pleural effusion*, hemoptysis, exertional dyspnea, mouth and throat painn (also throat and larynx), nasal congestion, dryness of nasal mucosa.
Uncommon: pulmonary hemorrhage*, respiratory failure*.
Gastrointestinal disorders
Very common: stomatitiso, abdominal painp, vomiting, diarrhea, dyspepsia, nausea, constipation.
Common: gastroesophageal reflux disease, dysphagia, gastrointestinal hemorrhage*, esophagitis*, abdominal distension, abdominal discomfort, rectal hemorrhage, gingival bleeding, oral ulcers, proctalgia, cheilitis, hemorrhoids, glossodynia, mouth pain, dry mouth, flatulence, oral discomfort, belching.
Uncommon: gastrointestinal (and intestinal) perforationq*, pancreatitis, anal fistula, colitisr.
Hepatobiliary disorders
Uncommon: liver failure*, cholecystitiss*, hepatic function abnormalities.
Rare: hepatitis.
Skin and subcutaneous tissue disorders
Very common: skin color changest, hand-foot skin reaction, rashu, hair color changes, dry skin.
Common: skin desquamation, skin reactionsv, eczema, blisters, erythema, alopecia, acne, pruritus, skin hyperpigmentation, skin disorders, hyperkeratosis, dermatitis, nail disordersw.
Rare: erythema multiforme*, Stevens-Johnson syndrome*, pyoderma gangrenosum, toxic epidermal necrolysis*.
Musculoskeletal and connective tissue disorders
Very common: limb pain, arthralgia, back pain.
Common: musculoskeletal pain, muscle spasms, myalgia, muscle weakness.
Uncommon: osteonecrosis of the jaw, fistula*.
Rare: rhabdomyolysis*, myopathy.
Renal and urinary disorders
Common: renal failure*, acute renal failure*, hematuria, proteinuria.
Uncommon: hemorrhage from urinary tract.
Rare: nephrotic syndrome.
General disorders and administration site conditions
Very common: mucositis, fatiguex (and general weakness), edemay (facial edema, edema, and peripheral edema), pyrexia.
Common: chest pain, pain, influenza-like illness, chills.
Uncommon: impaired healing.
Investigations
Common: weight decreased, white blood cell count decreased, lipase increased, platelet count decreased, hemoglobin decreased, amylase increasedz, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased, blood pressure increased, blood uric acid increased.
Uncommon: creatine phosphokinase increased in blood, thyroid-stimulating hormone increased in blood.
*Includes fatal cases.
Combined terms:
a Pharyngitis, nasopharyngitis, and oral herpes.
b Bronchitis, lower respiratory tract infections, pneumonia, and respiratory tract infections.
c Abscess, limb abscess, anal abscess, gingival abscess, liver abscess, pancreatic abscess, perineal abscess, perirectal abscess, rectal abscess, subcutaneous abscess, and dental abscess.
d Esophageal candidiasis and oral candidiasis.
e Cellulitis and skin infections.
f Sepsis and septic shock.
g Abdominal abscess, abdominal sepsis, diverticulitis, and osteomyelitis.
h Thrombotic microangiopathy, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome.
i Decreased appetite and anorexia.
j Taste alteration, taste loss, and taste disturbance.
k Acute coronary syndrome, angina, unstable angina, coronary artery occlusion, and myocardial ischemia.
l Decreased/abnormal ejection fraction.
m Acute myocardial infarction, myocardial infarction, and asymptomatic myocardial infarction.
n Mouth and throat pain, throat and larynx pain.
o Stomatitis and aphthous stomatitis.
p Abdominal pain, lower and upper abdominal pain.
q Gastrointestinal perforation and intestinal perforation.
r Colitis and ischemic colitis.
s Cholecystitis and acalculous cholecystitis.
t Jaundice, skin color change, and pigmentation disorder.
u Psoriasiform dermatitis, exfoliative rash, rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, papular rash, and pruritic rash.
v Skin reactions and skin disorders.
w Nail disorders and nail color change.
x Fatigue and asthenia.
y Facial edema, edema, and peripheral edema.
z Increased amylase.
Description of selected adverse reactions
Infections and infestations. Serious infections (with or without neutropenia), including fatal cases, have been reported. Cases of necrotizing fasciitis, including peritonitis, have been documented, some resulting in death (see section "Special precautions").
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, in 16% and 1.6% of patients in the phase 3 RCC study, and in 13% and 2.4% of patients in the phase 3 pNET study. Grade 3 and 4 thrombocytopenia was observed in 3.7% and 0.4% of patients in the phase 3 GIST study, in 8.2% and 1.1% of patients in the phase 3 mRCC study, and in 3.7% and 1.2% of patients in the phase 3 pNET study (see section "Special precautions").
Bleeding events were reported in 18% of patients receiving sunitinib in the phase 3 GIST study compared to 17% of placebo recipients. In 39% of patients receiving sunitinib for previously untreated RCC, bleeding occurred compared to 11% of interferon-α (IFN-α) recipients. Grade 3 or higher bleeding occurred in 17 (4.5%) sunitinib recipients compared to 5 (1.7%) IFN-α recipients. Bleeding occurred in 26% of patients receiving sunitinib for cytokine-refractory RCC. Bleeding events (excluding epistaxis) were reported in 21.7% of sunitinib recipients in the phase 3 pNET study compared to 9.85% of placebo recipients (see section "Special precautions").
Tumor hemorrhage occurred in approximately 2% of GIST patients in clinical trials.
Immune system disorders. Hypersensitivity reactions, including angioedema, have been reported (see section "Special precautions").
Endocrine disorders. Hypothyroidism was reported in 7 (4%) patients receiving sunitinib in two cytokine-refractory RCC studies; in 61 (16%) patients receiving sunitinib and 3 (<1%) patients in the IFN-α group in the previously untreated RCC study.
Additionally, increased thyroid-stimulating hormone (TSH) levels were recorded in 4 cytokine-refractory RCC patients (2%). Overall, 7% of RCC patients developed clinical or laboratory evidence of hypothyroidism during treatment. Acquired hypothyroidism occurred in 6.2% of GIST patients receiving sunitinib compared to 1% in the placebo group. In the phase 3 pNET study, hypothyroidism was recorded in 6 (7.2%) patients receiving sunitinib and 1 (1.2%) patient receiving placebo.
In two studies of breast cancer patients, prospective thyroid function monitoring was conducted; sunitinib is not approved for breast cancer treatment. In one study, hypothyroidism occurred in 15 (13.6%) sunitinib recipients and 3 (2.9%) standard therapy recipients. Increased TSH levels were recorded in 1 (0.9%) sunitinib recipient and not observed in standard therapy recipients. Hyperthyroidism was not reported in sunitinib recipients and occurred in 1 (1.0%) standard therapy recipient. In another study, hypothyroidism occurred in 31 (13%) sunitinib recipients and 2 (0.8%) capecitabine recipients. Increased TSH levels were recorded in 12 (5%) sunitinib recipients and not observed in capecitabine recipients.
Hyperthyroidism occurred in 4 (1.7%) sunitinib recipients and not in capecitabine recipients. Decreased TSH levels were observed in 3 (1.3%) sunitinib recipients and not in capecitabine recipients. Elevated T4 levels occurred in 2 (0.8%) sunitinib recipients and 1 (0.4%) capecitabine recipient. Elevated T3 levels occurred in 1 (0.8%) sunitinib recipient and not in capecitabine recipients. All thyroid-related reactions were grade 1–2 severity (see section "Special precautions").
Metabolism and nutrition disorders. Hypoglycemia occurred more frequently in pNET patients compared to metastatic RCC and GIST patients. However, most of these adverse reactions observed in clinical trials were considered unrelated to the investigational treatment.
Nervous system disorders. Rare reports (<1%), some fatal, of seizures and radiological findings consistent with reversible posterior leukoencephalopathy syndrome have been received during sunitinib clinical trials and post-marketing use. Seizures occurred in patients with or without radiological evidence of brain metastases (see section "Special precautions").
Cardiac function disorders. In clinical trials, a decrease in LVEF of ≥20% below the lower limit of normal was reported in approximately 2% of GIST patients receiving sunitinib, 4% of cytokine-refractory RCC patients, and 2% of GIST patients receiving placebo. These LVEF abnormalities are not progressive and often improve with continued treatment. In the previously untreated RCC study, a decrease in LVEF below the lower limit of normal occurred in 27% of sunitinib recipients and 15% of IFN-α recipients. Two patients (<1%) receiving sunitinib were diagnosed with CHF.
Heart failure, CHF, or left ventricular dysfunction were reported in 1.2% of GIST patients in the sunitinib group and 1% in the placebo group. In the main phase 3 GIST study (N=312), fatal cardiac events related to the drug occurred in 1% of patients in each study group (sunitinib and placebo). In a phase 2 study of cytokine-refractory RCC patients, 0.9% had fatal myocardial infarction related to the drug. In a phase 3 study of previously untreated RCC patients, 0.6% in the IFN-α group and 0% in the sunitinib group had fatal cardiac events. In the phase 3 pNET study, 1 (1%) patient receiving sunitinib had fatal heart failure related to the drug.
Vascular disorders
Arterial hypertension
Arterial hypertension was very commonly reported in clinical trials. Dose reduction or temporary discontinuation of sunitinib occurred in approximately 2.7% of patients due to arterial hypertension. No patient permanently discontinued sunitinib due to hypertension. Severe arterial hypertension (systolic pressure >200 mm Hg or diastolic pressure 110 mm Hg) occurred in 4.7% of patients with solid tumors. Arterial hypertension occurred in approximately 33.9% of patients receiving sunitinib for previously untreated RCC compared to 3.6% of IFN-α recipients. Severe arterial hypertension occurred in 12% of previously untreated patients and <1% of IFN-α recipients. Arterial hypertension was recorded in 26.5% of sunitinib recipients in the phase 3 pNET study compared to 4.9% of placebo recipients. Severe arterial hypertension was reported in 10% of pNET patients receiving sunitinib and 3% of placebo recipients.
Thromboembolic events
Venous thromboembolic events related to the drug were reported in approximately 1.0% of patients with solid tumors receiving sunitinib in GIST and RCC clinical trials.
In the phase 3 GIST study, venous thromboembolic events occurred in 7 (3%) sunitinib recipients and none in the placebo group; 5 of 7 had grade 3 deep vein thrombosis (DVT) and 2 had grade 1 or 2. Four of these 7 GIST patients discontinued treatment after the first DVT event.
Thirteen (3%) sunitinib recipients in the phase 3 previously untreated RCC study and 4 patients (2%) from 2 cytokine-refractory RCC studies reported venous thromboembolism. Nine of these patients had pulmonary embolism grade 1–2 and 8 had grade 4. Eight of these patients had DVT: 1 grade 1, 2 grade 2, 4 grade 3, and 1 grade 4. One patient with pulmonary embolism in the cytokine-refractory RCC study discontinued therapy.
In previously untreated RCC patients receiving IFN-α, 6 (2%) venous thromboembolic events were recorded; 1 patient (<1%) had grade 3 DVT and 5 patients (1%) had grade 4 pulmonary embolism.
Venous thromboembolism was reported in 1 (1.2%) sunitinib group patient and 5 (6.1%) placebo group patients in the phase 3 pNET study. Two placebo group patients had DVT: 1 grade 2 and 1 grade 3.
No fatal cases were reported in registration studies of GIST, RCC, and pNET. Fatal cases occurred during post-marketing use.
Pulmonary embolism occurred in approximately 3.1% of GIST patients and 1.2% of RCC patients receiving sunitinib in phase 3 studies. No pulmonary embolism was reported in pNET patients receiving sunitinib in the phase 3 study. Rare fatal cases occurred during post-marketing use.
Patients with pulmonary embolism within the previous 12 months were excluded from sunitinib clinical trials.
In patients receiving sunitinib in phase 3 registration studies, lung disorders (dyspnea, pleural effusion, pulmonary embolism, or pulmonary edema) were recorded in approximately 17.8% of GIST patients, 26.7% of RCC patients, and 12% of pNET patients.
Approximately 22.2% of patients with solid tumors, including GIST and RCC, receiving sunitinib in clinical trials experienced lung disorders.
Gastrointestinal disorders. Pancreatitis occurred uncommonly (<1%) in patients receiving sunitinib for GIST or RCC. No pancreatitis related to the drug was reported in the phase 3 pNET study (see section "Special precautions").
Gastrointestinal bleeding with fatal outcome was reported in 0.98% of placebo recipients in the phase 3 GIST study.
Hepatobiliary disorders. Cases of hepatic dysfunction, including abnormal liver function tests, hepatitis, or liver failure, have been reported (see section "Special precautions").
Skin and subcutaneous tissue disorders. Cases of pyoderma gangrenosum, usually reversible upon discontinuation of sunitinib, have been documented (see section "Special precautions").
Musculoskeletal and connective tissue disorders. Cases of myopathy and/or rhabdomyolysis, some associated with acute renal failure, have been reported. Patients with symptoms of muscle toxicity should be managed according to current medical standards.
Cases of fistula formation, sometimes associated with tumor necrosis and regression, occasionally leading to death, have been reported.
Osteonecrosis of the jaw has been described in patients receiving sunitinib, primarily in the presence of risk factors (e.g., intravenous bisphosphonates and/or history of dental disease requiring invasive dental procedures) (see section "Special precautions").
Investigations. Data from preclinical studies (in vitro and in vivo) at doses exceeding the recommended human dose indicate that sunitinib may inhibit cardiac repolarization (e.g., QT interval prolongation).
QTc interval prolongation to >500 msec was observed in 0.5%, and changes from baseline >60 msec in 1.1% of 450 patients with solid tumors; both parameters considered potentially significant. Sunitinib at concentrations approximately twice the therapeutic level prolonged QTcF (QT interval corrected by Frederica's formula).
QTc prolongation was studied in a trial involving 24 patients aged 20–87 years with advanced malignancies. Results showed sunitinib affected QTc (defined as mean change, placebo-corrected, >10 msec with 90% confidence interval [CI] upper limit >15 msec) at therapeutic concentration (day 3) using baseline correction over 24 hours and at supratherapeutic concentration (day 9) using both baseline correction methods. No patient had QTc >500 msec. Although QTcF prolongation was observed on day 3, 24 hours after dosing (i.e., at plasma concentration expected after recommended initial dose of 50 mg) using the 24-hour baseline correction method, the clinical significance of this finding is unclear.
Based on comprehensive assessment of serial ECGs at times corresponding to therapeutic or supratherapeutic drug concentrations, no patient in the evaluable population or ITT population had QTc prolongation considered "severe" (i.e., ≥ grade 3 according to Common Terminology Criteria for Adverse Events [CTCAE] version 3.0).
At therapeutic plasma concentrations, the maximum mean difference from baseline in QTcF (corrected by Frederica's formula) was 9 msec (90% CI: 15.1 msec). At concentrations approximately twice therapeutic, the maximum mean difference from baseline in QTcF was 15.4 msec (90% CI: 22.4 msec). Moxifloxacin (400 mg), used as positive control, showed a maximum mean difference from baseline in QTcF of 5.6 msec. No subject experienced QTc effect greater than grade 2 (CTCAE version 3.0) (see section "Special precautions").
Long-term safety in RCC treatment
Long-term safety of sunitinib in RCC patients was analyzed in 9 completed clinical trials conducted in first-line, bevacizumab-refractory, and cytokine-refractory settings involving 5739 patients, of whom 807 (14%) received treatment for 2–6 years. In these 807 patients receiving long-term sunitinib therapy, most drug-related adverse reactions initially developed within the first 6 months to 1 year and then remained stable or decreased in frequency over time, except for hypothyroidism, which progressively increased over time with new cases occurring throughout the 6-year period. Long-term sunitinib treatment was not associated with new types of drug-related adverse reactions.
Pediatric population
A phase I dose-escalation study of oral sunitinib was conducted in 35 patients, including 30 pediatric patients (aged 3–17 years) and 5 young adults (aged 18–21 years), with refractory solid tumors, most 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, fatigue, and elevated ALT levels. The risk of cardiac adverse drug 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 patients not previously treated with anthracyclines or cardiac irradiation.
Adjuvant therapy in RCC
The safety of sunitinib was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who underwent nephrectomy for RCC received sunitinib 50 mg daily on a 4-weeks-on/2-weeks-off schedule (N=306) or placebo (N=304). Mean treatment duration was 12.4 months (range: 0.13–14.9) for sunitinib and 12.4 months (range: 0.03–13.7) for placebo. Drug discontinuation due to adverse reactions occurred in 28% of sunitinib recipients. Adverse reactions leading to drug discontinuation in >2% of patients included hand-foot syndrome and fatigue/asthenia. Treatment interruption occurred in 54% and dose reduction in 46% of sunitinib recipients. Table 3 summarizes adverse reactions in the S-TRAC trial.
| Table 3 Adverse reactions reported in ≥ 10 % of patients with RCC receiving sunitinib and more frequently than in patients receiving placebo in S-TRAC* |
||||
| Adjuvant therapy of RCC |
||||
| Adverse reaction |
Sunitinib (N = 306) |
Placebo (N = 304) |
||
| All grades, % |
Grade 3–4, % |
All grades, % |
Grade 3–4, % |
|
| Any adverse reaction |
99 |
60 |
88 |
15 |
| Gastrointestinal disorders: mucositis/stomatitis, diarrhea, nausea, dyspepsia, abdominal painb, vomiting, constipation |
61 57 34 27 25 19 12 |
6 4 2 1 2 2 0 |
15 22 15 7 9 7 11 |
0 <1 0 0 <1 0 0 |
| Systemic: fatigue/asthenia, localized edema, fever |
57 18 12 |
8 < 1 < 1 |
34 < 1 6 |
2 0 0 |
| Dermatological: hand-foot syndrome, rashd, hair color changes, skin discoloration/yellowing of skin, dry skin |
50 24 22 18 14 |
16 2 0 0 0 |
10 12 2 1 6 |
< 1 0 0 0 0 |
| Cardiac: hypertensione, edema/peripheral edema |
39 10 |
8 < 1 |
14 7 |
1 0 |
| Neurological: taste alterationf, headache |
38 19 |
< 1 < 1 |
6 12 |
0 0 |
| Endocrine system: hypothyroidism/elevated TSH |
24 |
< 1 |
4 |
0 |
| Bleeding/hemorrhage: bleeding events, all sites g |
24 |
< 1 |
5 |
< 1 |
| Metabolism/nutrition: anorexia/decreased appetite |
19 |
< 1 |
5 |
0 |
| Musculoskeletal disorders: limb pain, arthralgia |
15 11 |
< 1 < 1 |
7 10 |
0 0 |
| * National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: AE – adverse events, N – number of patients, RCC – renal cell carcinoma. a Includes mucosal inflammation, aphthous stomatitis, oral mucosal ulceration, tongue ulcer, oropharyngeal pain, and mouth pain. b Includes abdominal pain, lower abdominal pain, and upper abdominal pain. c Includes localized edema, facial edema, eyelid edema, periorbital edema, facial swelling, and eye swelling. d Includes dermatitis, psoriasiform dermatitis, rash desquamative, genital rash, rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, abnormal rash, and pruritic rash. e Includes hypertension, increased blood pressure, increased systolic blood pressure, increased diastolic blood pressure, and hypertensive crisis. f Includes ageusia, hypogeusia, and dysgeusia. g Includes epistaxis, gingival bleeding, rectal bleeding, hemoptysis, anal bleeding, upper gastrointestinal hemorrhage, and hematuria. |
||||
| Grade 4 adverse reactions in patients receiving sunitinib included hand-foot syndrome (1 %), fatigue (< 1 %), abdominal pain (< 1 %), stomatitis (< 1 %), and pyrexia (< 1 %). Grade 3–4 laboratory abnormalities occurring in ≥ 2 % of patients receiving sunitinib included neutropenia (13 %), thrombocytopenia (5 %), leukopenia (3 %), lymphopenia (3 %), elevated ALT (2 %), elevated AST (2 %), hyperglycemia (2 %), and hyperkalemia (2 %). |
||||
Post-marketing experience
The following adverse reactions have been identified during post-marketing use of sunitinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: bleeding associated with thrombocytopenia*.
Gastrointestinal disorders: esophagitis.
Hepatobiliary disorders: cholecystitis, including acalculous cholecystitis.
Immune system disorders: hypersensitivity reactions, including angioneurotic edema.
Infections and infestations: serious infection (with or without neutropenia)*. The most commonly observed infections during sunitinib use include respiratory tract infections, urinary tract infections, skin infections, and sepsis/septic shock.
Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression*; myopathy and/or rhabdomyolysis with or without acute renal failure*.
Renal and urinary disorders: impaired renal function and/or renal failure*.
Respiratory disorders: pulmonary embolism*, pleural effusion*.
Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including cases with positive dechallenge.
Vascular disorders: arterial (including aortic) aneurysms, dissections* and ruptures*; arterial thromboembolic events*. The most common events included stroke, transient ischemic attack, and ischemic stroke.
General disorders and administration site conditions: impaired wound healing.
*Including some fatal cases.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach and sight of children.
Packaging
28 capsules in a plastic container. One plastic container in a cardboard box.
Prescription status. Prescription only.
Manufacturer
Yugia Pharma Specialities Limited.
Manufacturer's address and place of business
Unit-1, Survey No 550, 551 and 552, Koltur Village, Shamirpet Mandal, Medchal – Malkajgiri, Medchal District, Telangana 500101 – India.