Sutent 12,5 mg, 25 mg and 50 mg Hard capsules

Gastrointestinal stromal tumour (GIST)
SUTENT 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)
SUTENT is indicated for the treatment of treatment-nau00efve advanced and/or metastatic renal cell carcinoma. SUTENT 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 have not been demonstrated for more than 12 months.

Pancreatic neuroendocrine tumours (pNET)
SUTENT 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 SUTENT 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 SUTENT 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 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 SUTENT 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 SUTENT 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 SUTENT with a CYP3A4 inhibitor such as ketoconazole, its use should be avoided (see section 4.5). If this is not possible, the doses of SUTENT 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 were observed between younger and older patients.

Hepatic insufficiency
No dosage adjustment is necessary when administering SUTENT to patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SUTENT 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 SUTENT 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 SUTENT in paediatric patients have not been established.

Method of administration
For oral use. SUTENT 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.

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

Skin and tissues
Skin discolouration due to the active substance colour (yellow) was 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 SUTENT. 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 was reported in approximately 14 % of patients. Dysgeusia (taste disturbance) was 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, SUTENT 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 SUTENT 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 occurred 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 observed in patients with MRCC or other solid tumours. Cases of pulmonary haemorrhage some with a fatal outcome, have been observed in clinical trials and have been reported in post-marketing experience in patients treated with SUTENT for MRCC, GIST, and metastatic non-small cell lung cancer (NSCLC). SUTENT is not approved for use in patients with NSCLC.

In patients receiving SUTENT for treatment-nau00efve MRCC, 39 % had bleeding events. Of patients receiving SUTENT for cytokine-refractory MRCC, 26 % experienced bleeding. Bleeding events, excluding epistaxis, occurred in 21,7 % of patients receiving SUTENT 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.

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 occurred in patients with intra-abdominal malignancies treated with SUTENT. 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 or anti-diarrhoeal medication.

Pancreatitis
Pancreatitis has been reported in clinical trials of SUTENT. Increases in serum lipase and amylase were observed in patients with various solid tumours who received SUTENT. 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 observed in patients treated with SUTENT. Cases of hepatic failure, some with a fatal outcome, were observed in < 1 % of solid tumour patients treated with SUTENT. 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. SUTENT 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 occurred commonly and decreased platelet counts were reported less commonly in clinical trials. 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. Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.

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 post-marketing experience. Decreases in left ventricular ejection fraction (LVEF) of u2265 20 % and below the lower limit of normal occurred in approximately 2 % of SUTENT-treated GIST patients, 4 % of MRCC patients and 2 % of placebo-treated patients. In the treatment-nau00efve MRCC study, 27 % patients on SUTENT had an LVEF value below the lower limit of normal. Two patients (< 1 %) who received SUTENT 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 the Phase 3 pNET study, one (1,2 %) patient who received SUTENT 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. Data from non-clinical (in vitro and in vivo) studies, at doses higher than the recommended human dose, indicate that SUTENT 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 occurred in 0,5 % and changes from baseline in excess of 60 msec occurred in 1,1 % of the 450 solid tumour patients; both these parameters are recognised as potentially significant changes.

QT interval prolongation
At approximately twice the therapeutic concentrations, SUTENT has been shown 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 observed in < 0,1 % of SUTENT-exposed patients. SUTENT 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 SUTENT plasma concentrations, should be used with caution and the dose of SUTENT reduced (see section 4.2 and 4.5).

Hypertension
Patients treated with SUTENT 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. SUTENT dosing was reduced or temporarily delayed in approximately 2,7 % of this patient population. None of these patients were discontinued from treatment with SUTENT. Severe hypertension (> 200 mmHg systolic or 110 mmHg diastolic) occurred in 4,7 % of this patient population. Hypertension was reported in approximately 33,9 % of patients receiving SUTENT for treatment-nau00efve MRCC. Severe hypertension occurred in 12 % of treatment-nau00efve patients on SUTENT. Hypertension was reported in 26,5 % of patients receiving SUTENT in a Phase 3 pNET study, compared to 4,9 % of patients receiving placebo. Severe hypertension occurred in 10 % of pNET patients on SUTENT and 3 % of patients on placebo. Patients should be screened for hypertension and controlled as appropriate. Temporary suspension of SUTENT 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 SUTENT, 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 SUTENT treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction whilst on SUTENT 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 was noted in 6,2 % of GIST patients. Hypothyroidism was reported as an adverse event in 16 % of patients on SUTENT 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 was reported in six patients (7,2 %) receiving SUTENT and in one (1,2 %) patient on placebo. Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.

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

Venous thromboembolic events
Seven patients (3 %) on SUTENT in a GIST study experienced venous thromboembolic events; five of the seven were Grade 3 deep vein thrombosis (DVT). Thirteen patients (3 %) receiving SUTENT for treatment-nau00efve MRCC had venous thrombolic events reported such as pulmonary embolism.

Pulmonary embolism
Pulmonary embolism was reported in approximately 2,2 % of patients with solid tumours who received SUTENT. None of these events resulted in a patient discontinuing treatment with SUTENT; 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 observed in clinical trials and have been reported in post-marketing experience in patients treated with SUTENT. 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. SUTENT 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 SUTENT as monotherapy and in combination with bevacizumab. Discontinue SUTENT 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 SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue SUTENT in patients with nephrotic syndrome.

Hypoglycaemia
Decreases in blood glucose, in some cases clinically symptomatic, have been reported during SUTENT treatment. 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.

Viral reactivation
Hepatitis B reactivation, including fatal outcomes have occurred in patients treated with SUTENT. Hepatitis B virus (HBV) status should be established before initiating treatment with SUTENT. 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 SUTENT
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 SUTENT should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events. Treatment with SUTENT should be discontinued, and alternative treatment options be considered in patients who developed these class related cerebrovascular adverse events.

Hyperammonaemic encephalopathy
Hyperammonaemic encephalopathy has been observed with SUTENT (see section 4.8). In patients who develop unexplained lethargy or changes in mental status, ammonia level should be measured, and appropriate clinical management should be initiated.

Mannitol
SUTENT contains mannitol and may have a laxative effect.

When SUTENT is co-administered with other medicines, there is a potential for medicine interaction. In vitro studies indicate that SUTENT neither induces nor inhibits major CYP enzymes, including CYP3A4.

The dose of SUTENT may need to be reduced based on tolerability when co-administered with CYP3A4 inhibitors. The dose of SUTENT may need to be increased when it is co-administered with potent CYP3A4 inducers.

Medicines that may increase SUTENT plasma concentrations
Concurrent administration of SUTENT with the CYP3A4 inhibitor, ketoconazole, resulted in 49 % and 51 % increases in sunitinib C max and AUC 0-u221e values, respectively, after a single dose of SUTENT in healthy volunteers. Administration of SUTENT with other inhibitors of the CYP3A4 family (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) may increase SUTENT 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 SUTENT may need to be reduced (see section 4.2, Dose modifications).

Medicines that may decrease SUTENT plasma concentrations
Concomitant use of SUTENT with the CYP3A4 inducer, rifampicin, resulted in a more than 23 % and 46 % reduction in sunitinib C max and AUC 0-u221e values, respectively, after a single dose of SUTENT in healthy volunteers. Administration of SUTENT 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 SUTENT concentrations. To maintain SUTENT target concentrations, dose adjustment of SUTENT, or selection of co-medications with less enzyme induction potential, should be considered.

Women of childbearing potential / Contraception in males and females
Teratogenicity has been observed in animal studies. Women of childbearing potential should use effective contraceptive measures during SUTENT treatment and 4 weeks after the last dose of SUTENT.

Pregnancy
SUTENT is contraindicated in pregnancy as safety has not been demonstrated.

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

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

No studies on the effects on the ability to drive or operate machinery have been performed. Patients should be advised that they may experience dizziness during treatment with SUTENT.

Summary of the safety profile
The most important serious adverse events associated with SUTENT treatment of solid tumour patients were 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 occurring 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 SUTENT in single-medicine studies in advanced RCC, GIST and pNET and from post-marketing experience are listed below, by system organ class, frequency category and grade of severity. Frequencies are defined as: very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 1/10 000 to < 1/1 000), very rare (< 1/10 000).

There is no specific antidote for overdosage with SUTENT. 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).