Tinsuneb 12,5; 25 or 50 mg Hard gelatin capsules

Gastrointestinal stromal tumour (GIST)
TINSUNEB is indicated for the treatment of gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance.

Metastatic renal cell carcinoma (MRCC)
TINSUNEB is indicated for the treatment of treatment-nau00efve advanced and/or metastatic renal cell carcinoma. TINSUNEB is also indicated for the treatment of metastatic renal cell carcinoma (MRCC) after failure of cytokine-based therapy (interferon u03b1, interleukin -2). Efficacy is based on time to tumour progression and an increase in survival in GIST and on objective response rates for MRCC. Efficacy and safety has not been reported for more than 12 months.

Pancreatic neuroendocrine tumours (pNET)
TINSUNEB is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours with disease progression in adults.

Therapy should be initiated by a medical practitioner experienced in the treatment of renal cell carcinoma, GIST or pNET. Posology
For GIST and MRCC, the recommended dose of TINSUNEB is one 50 mg dose orally, taken daily for 4 consecutive weeks, followed by a 2 week rest period (Schedule 4/2) to comprise a complete cycle of 6 weeks. For pNET, the recommended dose of TINSUNEB is 37,5 mg taken orally once daily without a scheduled rest period.

Dose modifications
Safety and tolerability
For GIST and MRCC, dose modifications in 12,5 mg increments may be applied based on individual safety and tolerability. Daily dose should not exceed 75 mg nor be decreased below 25 mg. For pNET, dose modification in 12,5 mg steps may be applied based on individual safety and tolerability. The reported maximum dose administered in the Phase 3 pNET study was 50 mg daily. Dose interruptions may be required based on individual safety and tolerability.

CYP3A4 inhibitors/inducers
In patients receiving TINSUNEB with a potent CYP3A4 inducer such as rifampicin, its use should be avoided (see section 4.5). If this is not possible, the dosage of TINSUNEB may need to be increased in 12,5 mg increments (up to 87,5 mg per day for GIST and MRCC or 62,5 mg per day for pNET). Clinical response and tolerability should be carefully monitored. In patients receiving TINSUNEB with a CYP3A4 inhibitor such as ketoconazole, its use should be avoided (see section 4.5). If this is not possible, the doses of TINSUNEB may need to be reduced to a minimum of 37,5 mg daily for GIST and MRCC or 25 mg daily for pNET, based on tolerability and/or clinical response. Selection of an alternate concomitant medication with no, or minimal potential to induce or inhibit CYP34 should be considered.

Population pharmacokinetic analyses of demographic data indicate that no dose adjustments are necessary for age, body weight, creatinine clearance, race, gender or ECOG (Eastern Cooperative Oncology Group) score.

Special populations
Elderly patients
No significant differences in safety or efficacy has been reported between younger and older patients.
Hepatic insufficiency
No dosage adjustment is necessary when administering TINSUNEB to patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Sunitinib as contained in TINSUNEB was not studied in patients with severe (Child-Pugh Class C) hepatic impairment (see section 5.2).

Renal insufficiency
No starting dose adjustment is required when administering TINSUNEB to patients with renal impairment (mild-severe) or with end-stage renal disease (ESRD) on haemodialysis. Subsequent dose adjustments should be based on individual safety and tolerability.

Paediatric population
The safety and efficacy of TINSUNEB in paediatric patients have not been established.

Method of administration
For oral use. TINSUNEB may be taken with or without food. If a dose is missed, the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day.

• TINSUNEB is contraindicated in patients with hypersensitivity to sunitinib malate or to any of the other excipients of TINSUNEB (listed in section 6.1).
• Pregnancy and lactation (see section 4.6).

Cerebrovascular adverse events identified as class related adverse events have occurred in patients treated with TKI (Tyrosine Kinase Inhibitor) containing medicines such as TINSUNEB. These adverse events include cerebrovascular accident (CA), transient ischaemic attack (TIA), ischaemic stroke (IS), and cerebral infarct (CI). These events may occur in patients on treatment, with or without risk factors and may occur at any time during treatment. Patients on treatment should be carefully monitored and relevant risk factors managed to reduce the risk of these cerebrovascular adverse events. Treatment with TINSUNEB should be discontinued, and alternative treatment options be considered in patients who develop these class related adverse events.

Co-administration with potent CYP3A4 inducers should be avoided because it may decrease sunitinib plasma concentration. Co-administration with potent CYP3A4 inhibitors should be avoided because it may increase the plasma concentration of sunitinib.

Skin and tissues
Skin discolouration due to the active substance colour (yellow) has been reported to be a very common adverse event occurring in approximately 30 % of patients. Patients should be advised that depigmentation of the hair or skin may also occur during treatment with TINSUNEB. Other possible dermatologic effects may include dryness, thickness or cracking of the skin, blisters or occasional rash on the palms of the hands and soles of the feet.

Mouth pain/irritation has been reported in approximately 14 % of patients. Dysgeusia (taste disturbance) has been reported in approximately 28 % of patients. The above events were not cumulative, were typically reversible and generally did not result in treatment discontinuation.

Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM) and cases suggestive of Stevens-Johnson syndrome (SJS), some of which were fatal. If signs or symptoms of SJS or EM (e.g., progressive skin rash often with blisters or mucosal lesions) are present, TINSUNEB should be discontinued. If the diagnosis of SJS is confirmed, treatment must not be re-started. In some cases of suspected EM, patients tolerated the reintroduction of TINSUNEB at a lower dose after resolution of the reaction; some of these patients also received concomitant treatment with corticosteroids or antihistamines.

Haemorrhage
Haemorrhagic events reported through post-marketing experience, some of which were fatal, have included gastrointestinal (GI), respiratory, tumour, urinary tract and brain haemorrhage. In clinical trials, tumour haemorrhage reported in approximately 2 % of patients with GIST. These events may occur suddenly, and in the case of pulmonary tumours, may present as severe or life-threatening haemoptysis or pulmonary haemorrhage. Tumour haemorrhage has not been reported in patients with MRCC or other solid tumours. Cases of pulmonary haemorrhage some with a fatal outcome, have been reported in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib for MRCC, GIST, and metastatic non-small cell lung cancer (NSCLC). TINSUNEB is not approved for use in patients with NSCLC.

In patients receiving sunitinib as contained in TINSUNEB for treatment-nau00efve MRCC, 39 % had bleeding events. Of patients receiving sunitinib as contained in TINSUNEB for cytokine-refractory MRCC, 26 % reported to have experienced bleeding. Bleeding events, excluding epistaxis, reported in 21,7 % of patients receiving sunitinib as contained in TINSUNEB in a Phase 3 pNET study compared to 9,85 % of subjects receiving placebo. Routine assessment of these events should include complete blood counts and physical examination. Patients receiving concomitant treatment with anticoagulants (e.g., warfarin, acenocoumarole) may be periodically monitored by complete blood counts (platelets), coagulation factors (PT/INR), and physical examination.

Treatment-related epistaxis was reported in 8 % of patients with solid tumours. Epistaxis was the most common treatment related haemorrhagic adverse event, having been reported for approximately half of the patients with solid tumours who experienced haemorrhagic events.

Gastrointestinal events
Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation have been reported in patients with intra-abdominal malignancies treated with sunitinib as contained in TINSUNEB. Nausea, diarrhoea, stomatitis, dyspepsia and vomiting were the most commonly reported treatment related gastrointestinal events. Supportive care for gastrointestinal adverse events requiring treatment may include medication with an anti-emetic, anti-diarrhoeal, or antacid properties medication.

Pancreatitis
Pancreatitis has been reported in clinical trials of sunitinib as contained in TINSUNEB. Increases in serum lipase and amylase has been reported in patients with various solid tumours who received sunitinib as contained in TINSUNEB. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with various solid tumours. If symptoms of pancreatitis are present, patients should have proper medical follow-up.

Hepatotoxicity
Hepatotoxicity has been reported in patients treated with sunitinib as contained in TINSUNEB. Cases of hepatic failure, some with a fatal outcome, were reported in < 1 % of solid tumour patients treated with sunitinib as contained in TINSUNEB. Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) should be monitored before initiation of treatment, during each cycle of treatment, and additionally as clinically indicated. TINSUNEB treatment should be interrupted for Grade 3 or 4 hepatic-related adverse events and discontinued if there is no resolution of the adverse events.

Haematological
Decreased absolute neutrophil counts reported commonly and decreased platelet counts were reported less commonly. Such events were not cumulative, were typically reversible and generally did not result in treatment discontinuation. In addition, some cases of fatal haemorrhage associated with thrombocytopenia were reported through post-marketing experience. Anaemia has been reported to occur early as well as late during treatment with sunitinib as contained in TINSUNEB. Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with TINSUNEB.

Cardiovascular
Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischaemia, angina pectoris and myocardial infarction, some of which were fatal, have been reported in clinical trials and through reported post-marketing experience. Decreases in left ventricular ejection fraction (LVEF) of u2265 20 % and below the lower limit of normal reported in approximately 2 % of GIST patients treated with sunitinib as contained in TINSUNEB, 4 % of MRCC patients and 2 % of placebo-treated patients. In the reported treatment-nau00efve MRCC study, 27 % patients on sunitinib as contained in TINSUNEB, had an LVEF value below the lower limit of normal. Less than 1 % of the study patients who received sunitinib as contained in TINSUNEB were diagnosed with congestive heart failure. Cardiac failure, congestive cardiac failure or left ventricular failure were reported in 0,8 % of patients with solid tumours and 1 % of patients treated with placebo. In a reported Phase 3 pNET study, 1,2 % patient who received sunitinib as contained in TINSUNEB had treatment-related fatal cardiac failure. The relationship between receptor tyrosinase kinase (RTK) inhibition and cardiac function remains unclear but seems to be a class effect. Reported data from non-clinical (in vitro and in vivo) studies, at doses higher than the recommended human dose, indicate that sunitinib as contained in TINSUNEB has the potential to inhibit the cardiac action potential repolarisation process (e.g., prolongation of QT interval). Increases in the QTc interval to over 500 msec reported in 0,5 % and changes from baseline in excess of 60 msec reported in 1,1 % of the solid tumour patients in the study; both these parameters are reported as potentially significant changes.

QT interval prolongation
At approximately twice the therapeutic concentrations, sunitinib as contained in TINSUNEB has been reported to prolong the QTcF (Fredericiau2019s correction) interval. QT interval prolongation may lead to an increased risk for ventricular dysrhythmias including torsade de pointes. Torsade de pointes has been reported in < 0,1 % of patients exposed to sunitinib as contained in TINSUNEB. TINSUNEB should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antidysrhythmics or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Concomitant treatment with strong CYP3A4 inhibitors, which may increase plasma concentrations of sunitinib as contained in TINSUNEB, should be used with caution and the dose of TINSUNEB reduced (see section 4.2 and 4.5).

Hypertension
Patients treated with TINSUNEB should have regular blood pressure assessments. Hypertension was a very common adverse event reported in clinical trials in patients with solid tumours, including primarily GIST and cytokine-refractory RCC. Dosing of sunitinib as contained in TINSUNEB, was reduced or temporarily delayed in approximately 2,7 % of this patient population. None of these patients were discontinued from treatment with sunitinib as contained in TINSUNEB. Severe hypertension (> 200 mmHg systolic or 110 mmHg diastolic) reported in 4,7 % of this patient population. Hypertension has been reported in approximately 33,9 % of patients receiving sunitinib as contained in TINSUNEB for treatment-nau00efve MRCC. Severe hypertension reported in 12 % of treatment-nau00efve patients on sunitinib as contained in TINSUNEB. Hypertension has been reported in 26,5 % of patients receiving sunitinib as contained in TINSUNEB, in a Phase 3 pNET study, compared to 4,9 % of patients receiving placebo. Severe hypertension reported in 10 % of pNET patients on sunitinib as contained in TINSUNEB and 3 % of patients on placebo. Patients should be screened for hypertension and controlled as appropriate. Temporary suspension of TINSUNEB therapy is recommended in patients with severe hypertension that is not controlled with medical management. Treatment may be resumed once hypertension is appropriately controlled.

Aneurysms and artery dissections
The use of vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating TINSUNEB, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Thyroid dysfunction
Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical treatment prior to the start of TINSUNEB treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction whilst on TINSUNEB treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice. Acquired hypothyroidism has been reported in 6,2 % of GIST patients. Hypothyroidism has been reported as an adverse event in 16 % of patients on sunitinib as contained in TINSUNEB, in the treatment-nau00efve MRCC study and in 4 % of subjects across 2 cytokine-refractory MRCC studies. Overall 7 % of the cytokine-refractory MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism. In a Phase 3 pNET study, hypothyroidism has been reported in 7,2 % of the study patients receiving sunitinib as contained in TINSUNEB and in 1,2 % patients on placebo. Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through reported post-marketing experience.

Seizures
In reported clinical studies of sunitinib as contained in TINSUNEB, seizures have been reported in subjects with radiological evidence of brain metastases. In addition, there have been rare (< 1 %) reports, some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness, should be controlled with medical management including control of hypertension. Temporary suspension of TINSUNEB therapy is recommended in patients with seizures or RPLS. Following resolution, treatment may be resumed at the discretion of the treating medical practitioner.

Surgical procedures
Cases of impaired wound healing have been reported during therapy with sunitinib as contained in TINSUNEB. Temporary interruption of TINSUNEB therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of re-initiation of therapy following major surgical intervention. Therefore, the decision to resume TINSUNEB therapy following a major surgical intervention should be based upon clinical judgement of recovery from surgery.

Osteonecrosis of the Jaw (ONJ)
ONJ has been uncommonly reported in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib as contained in TINSUNEB. The majority of cases reported in patients who had received prior or concomitant treatment with intravenous (IV) bisphosphonates, for which ONJ is an identified risk. Caution should therefore exercised when TINSUNEB and IV bisphosphonates are used either simultaneously or sequentially. Invasive dental procedures are also an identified risk factor for ONJ. Prior to treatment with TINSUNEB, a dental examination and appropriate preventative dentistry should be considered. In patients being treated with TINSUNEB, who have previously received or are receiving IV bisphosphonates, invasive dental procedures should be avoided, if possible.

Venous thromboembolic events
In a reported GIST study, 3 % of patients on sunitinib as contained in TINSUNEB, experienced venous thromboembolic events; 72 % were Grade 3 deep vein thrombosis (DVT). 3 % of patients receiving sunitinib as contained in TINSUNEB for treatment-nau00efve MRCC had venous thrombolic events reported such as pulmonary embolism. Pulmonary embolism
Pulmonary embolism has been reported in approximately 2,2 % of patients with solid tumours who received sunitinib as contained in TINSUNEB. None of these events reported in a patient discontinuing treatment with sunitinib as contained in TINSUNEB; however a dose reduction or temporary delay in treatment occurred in a few cases. There were no further occurrences of pulmonary embolism in these patients after treatment was resumed.

Tumour Lysis Syndrome (TLS)
Cases of TLS, some fatal, have been reported in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib as contained in TINSUNEB. Patients generally at risk of TLS are those with high tumour burden prior to treatment. These patients should be monitored closely and treated as clinically indicated.

Necrotising fasciitis
Cases of necrotising fasciitis, including of the perineum, sometimes fatal, have been reported. TINSUNEB therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.

Thrombotic microangiopathy
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS), frequently leading to renal failure or a fatal outcome, has been reported in clinical trials and in post-marketing experience of sunitinib as contained in TINSUNEB as monotherapy and in combination with bevacizumab. Discontinue TINSUNEB in patients developing TMA.

Proteinuria
Cases of proteinuria and nephrotic syndrome have been reported. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. The safety of continued TINSUNEB treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue TINSUNEB in patients with nephrotic syndrome.

Hypoglycaemia
Decreases in blood glucose, in some cases clinically symptomatic, have been reported during treatment with sunitinib as contained in TINSUNEB. Blood glucose levels in diabetic patients should be checked regularly in order to assess if anti-diabetic medicine dosage needs to be adjusted to minimise the risk of hypoglycaemia.

Renal function
Cases of renal impairment, renal failure and/or acute renal failure, in some cases with fatal outcome, have been reported (see section 4.8). Risk factors associated with renal impairment/failure in patients receiving sunitinib included, in addition to underlying RCC (Renal cell carcinoma), older age, diabetes mellitus, underlying renal impairment, cardiac failure, hypertension, sepsis, dehydration/hypovolaemia, and rhabdomyolysis.

Fistula
If fistula formation occurs, sunitinib treatment should be interrupted. Limited information has been reported on the continued use of sunitinib in patients with fistulae (see section 4.8).

Hypersensitivity/angioedema
If angioedema due to hypersensitivity occurs, TINSUNEB treatment should be interrupted and standard medical care provided (see section 4.8).

Infections
Serious infections, with or without neutropenia, including some with a fatal outcome, have been reported. Sunitinib therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.

Viral reactivation
Hepatitis B reactivation, including fatal outcomes have reported in patients treated with sunitinib as contained in TINSUNEB. Hepatitis B virus (HBV) status should be established before initiating treatment with TINSUNEB. Patients should be monitored for signs and symptoms (fever, chills, weakness, confusion, vomiting and jaundice) and appropriate therapy should be instituted as indicated. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.

Class effects of Tyrosine Kinase Inhibitors (TKIs) such as contained in TINSUNEB
Although TKIs may have different kinase inhibition profiles and/or off target binding profiles, there is some evidence that the TKIs share to a variable degree, class related cerebrovascular adverse events (e.g. cerebrovascular accident, transient ischaemic attack, ischaemic stroke, and cerebral infarction). These cerebrovascular adverse events may occur in patients on treatment with TKIs with or without risk factors for these events and may occur at any time during treatment with TKIs. Patients on treatment with TINSUNEB should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events. Treatment with TINSUNEB should be discontinued, and alternative treatment options be considered in patients who developed these class related cerebrovascular adverse events.

Excipient
TINSUNEB contains mannitol and may have a laxative effect. This medicinal product contains less than 1 mmol (23 mg) sodium per capsule, that is to say essentially 'sodium-free'.

When TINSUNEB is co-administered with other medicines, there is a potential for medicine interaction. Reported in vitro studies indicate that sunitinib as contained TINSUNEB neither induces nor inhibits major CYP enzymes, including CYP3A4. The dose of TINSUNEB may need to be reduced based on tolerability when co-administered with CYP3A4 inhibitors. The dose of TINSUNEB may need to be increased when it is co-administered with potent CYP3A4 inducers.

Medicines that may increase TINSUNEB plasma concentrations
Concurrent administration of sunitinib as contained in TINSUNEB with the CYP3A4 inhibitor, ketoconazole, reported in 49 % and 51 % increase in sunitinib C max and AUC 0- u221e values, respectively, after a single dose of sunitinib as contained in TINSUNEB in healthy volunteers. Administration of TINSUNEB with other inhibitors of the CYP3A4 family (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) may increase TINSUNEB concentrations. Concomitant administration with inhibitors should therefore be avoided, or the selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4, should be considered. If this is not possible, the dosage of TINSUNEB may need to be reduced (see section 4.2, Dose modifications).

Medicines that may decrease TINSUNEB plasma concentrations
Concomitant use of sunitinib as contained in TINSUNEB, with the CYP3A4 inducer, rifampicin, have been reported to result in a more than 23 % and 46 % reduction in sunitinib C max and AUC 0- u221e values, respectively, after a single dose of TINSUNEB in healthy volunteers. Administration of TINSUNEB with strong inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbitone or Hypericum perforatum known also as St. Johnu2019s Wort) may decrease TINSUNEB concentrations. To maintain TINSUNEB target concentrations, dose adjustment of TINSUNEB, or selection of co-medications with less enzyme induction potential, should be considered.

Effect of Breast Cancer Resistance Protein (BCRP) inhibitors
Limited reported clinical data are available on the interaction between sunitinib as contained in TINSUNEB and BCRP inhibitors and the possibility of an interaction between sunitinib and other BCRP inhibitors cannot be excluded.

Women of childbearing potential / Contraception in males and females
Teratogenicity has been reported in animal studies. Female patients and female sexual partners of male patients receiving genotoxic anticancer medicines, should be advised to use highly effective contraception, until the end of relevant systemic exposure to the genotoxic compound including potential genotoxic metabolites (i.e. five half-lives after the last dose) plus 6 months (which covers the growth and maturation phase of folliculogenesis). Due to the genotoxic potential of sunitinib, women of childbearing age must use effective contraception during treatment with sunitinib and for 6 months after treatment discontinuation. Male patients should be advised to use highly effective contraception, until the end of relevant systemic exposure to the genotoxic compound including potential genotoxic metabolites (i.e. five half-lives after the last dose) plus 90 days (i.e., 60-75 days for sperm production plus 10-14 days for the transport to epididymis). Men must be advised to use effective methods of contraception and not to father a child during treatment with sunitinib and in the 3 months following its discontinuation.

Pregnancy
TINSUNEB is contraindicated in pregnancy as safety has not been reported.

Breastfeeding
TINSUNEB is secreted in breast milk. Women using TINSUNEB should not breastfeed their infants, because of the potential for serious adverse reactions in nursing infants.

Fertility
Based on the findings of reported pre-clinical studies, fertility in males and females may be compromised by treatment with TINSUNEB.

TINSUNEB has minor influence on the ability to drive and use machines. Patients should be advised that they may experience dizziness during treatment with TINSUNEB.

Summary of the safety profile
The most important serious adverse events associated with TINSUNEB treatment of solid tumour patients were reported to be pulmonary embolism, thrombocytopenia, tumour haemorrhage, febrile neutropenia, and hypertension. The most very common adverse events of any grade included: fatigue; gastrointestinal disorders, such as diarrhoea, nausea, stomatitis, dyspepsia and vomiting; skin discolouration; rash; hand-foot syndrome (palmar-plantar erythrodysaesthesia); dry skin; hair colour changes; mucosal inflammation; asthenia; dysgeusia; anorexia and hypertension. Fatigue, hypertension and neutropenia were the most common adverse events of Grade 3 maximum severity; and increased lipase was the most frequently reported adverse event of Grade 4 maximum severity in patients with solid tumours.

Tabulated summary of adverse reactions
The treatment-emergent, all causality frequency of adverse events reported in patients who received sunitinib as contained in TINSUNEB in single-medicine studies in advanced RCC, GIST and pNET and from reported post-marketing experience are listed below, by system organ class, frequency category and grade of severity.

There is no specific antidote for over dosage with TINSUNEB. Treatment of overdose is symptomatic and supportive. Cases of overdose have been reported; some cases were associated with adverse reactions consistent with the known adverse effects profile of sunitinib (see section 4.8).