Sutent

/ Pfizer

Dosage: For GIST and MRCC, the recommended dose of Sunitinib is 50 mg taken orally once 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 Sunitinib is 37.5 mg taken orally once daily without a scheduled rest period.
Dose adjustments
Safety and tolerability: For GIST and MRCC, dose modifications in 12.5 mg steps 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: Co-administration of sunitinib with potent CYP3A4 inducers, such as rifampicin, should be avoided. If this is not possible, the dose of sunitinib may need to be increased in 12.5 mg steps (up to 87.5 mg per day for GIST and MRCC or 62.5 mg per day for pNET) based on careful monitoring of tolerability. Co-administration of sunitinib with potent CYP3A4 inhibitors, such as ketoconazole, should be avoided. If this is not possible, the dose of sunitinib 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 careful monitoring of tolerability. Selection of an alternative concomitant medicinal product with no or minimal potential to induce or inhibit CYP3A4 should be considered.
Special populations
Paediatric population: The safety and efficacy of sunitinib in patients below 18 years of age have not been established.
Elderly patients: Approximately one-third of the patients in clinical studies who received sunitinib were 65-years of age or over. No significant differences in safety or efficacy were observed between younger and older patients
Hepatic impairment: No starting dose adjustment is recommended when administering sunitinib to patients with mild or moderate (Child-Pugh class A and B) hepatic impairment. Sunitinib has not been studied in subjects with severe (Child-Pugh class C) hepatic impairment and therefore its use in patients with severe hepatic impairment cannot be recommended.
Renal impairment: No starting dose adjustment is required when administering sunitinib 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. Approximately one-third of the patients in clinical studies who received sunitinib were 65 years of age or over. No significant differences in safety or efficacy were observed between younger and older patients.
Method of administration: Sunitinib is for oral administration. It 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.                       

Gastrointestinal Stromal Tumor: Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.
Advanced Renal Cell Carcinoma: Sunitinib is indicated for the treatment of advanced renal cell carcinoma.
Pancreatic Neuroendocrine Tumors (pNET): Treatment of unresectable or metastatic, well differentiated pancreatic neuroendocrine tumours (pNET) with disease progression.   

Hypersensitivity to the active substance or to any of the excipients.

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 tissue disorders: Patients should be advised that depigmentation of the hair or skin may occur during treatment with sunitinib. Other possible dermatological effects may include dryness, thickness or cracking of the skin, blisters, or rash on the palms of the hands and soles of the feet.
Haemorrhage and tumour bleeding: Haemorrhagic events, some of which were fatal, reported in clinical studies with sunitinib and during postmarketing surveillance have included gastrointestinal, respiratory, urinary tract, and brain
haemorrhages.
Gastrointestinal disorders: Diarrhoea, nausea/vomiting, abdominal pain, dyspepsia and stomatitis/oral pain were the most commonly reported gastrointestinal adverse reactions; oesophagitis events have been also reported.
Haematological disorders:Decreased absolute neutrophil counts and decreased platelet counts were reported in association with sunitinib. The above events were not cumulative, were typically reversible, and generally did not result in treatment discontinuation. None of these events in the Phase 3 studies were fatal, but rare fatal haematological events, including haemorrhage associated with thrombocytopenia and neutropenic infections, have been reported during postmarketing surveillance. Anaemia has been observed to occur early as well as late during treatment with sunitinib.
Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with sunitinib.
Cardiac disorders: Cardiovascular events, including heart failure, cardiomyopathy, left ventricular ejection fraction decline to below the lower limit of normal, myocarditis, myocardial ischaemia and myocardial infarction, some of which were fatal, have been reported in patients treated with sunitinib. These data suggest that sunitinib increases the risk of cardiomyopathy. No specific additional risk factors for sunitinib-induced cardiomyopathy apart from the drug-specific effect have been identified in the treated patients. Use sunitinib with caution in patients who are at risk for, or who have a history of,
these events.
QT interval prolongation: Prolongation of QT interval and Torsade de pointes have been observed in sunitinib-exposed patients.
Venous thromboembolic events: Treatment-related venous thromboembolic events were reported in patients who received sunitinib including deep venous thrombosis and pulmonary embolism. Cases of pulmonary embolism with fatal outcome have been observed in postmarketing surveillance.
Arterial thromboembolic events: Cases of arterial thromboembolic events (ATE), sometimes fatal, have been reported in patients treated with sunitinib. The most frequent events included cerebrovascular accident, transient ischaemic attack, and cerebral infarction. Risk factors associated with ATE, in addition to the underlying malignant disease and age ≥ 65 years, included hypertension, diabetes mellitus, and prior thromboembolic disease.
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 sunitinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
Thrombotic microangiopathy (TMA): The diagnosis of TMA, including thrombotic thrombocytopaenic purpura (TTP) and haemolytic uraemic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, should be considered in the occurrence of haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological manifestation, renal impairment, and fever. Sunitinib therapy should be discontinued in patients who develop TMA and prompt treatment is required. Reversal of the effects of TMA has been observed after treatment discontinuation
Thyroid dysfunction: Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of sunitinib treatment. During sunitinib treatment, routine monitoring of thyroid function should be performed every 3 months.
Pancreatitis: Increases in serum lipase and amylase activities were observed in patients with various solid tumours who received sunitinib. If symptoms of pancreatitis are present, patients should have sunitinib discontinued and be provided with appropriate supportive care.
Hepatotoxicity: Monitor liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) before initiation of treatment, during each cycle of treatment, and as clinically indicated.
Renal function: Risk factors associated with renal impairment/failure in patients receiving sunitinib included, in addition to underlying RCC, older age, diabetes mellitus, underlying renal impairment, cardiac failure, hypertension, sepsis, dehydration/hypovolaemia, and rhabdomyolysis. Cases of proteinuria and rare cases of nephrotic syndrome have been reported. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. Discontinue sunitinib in patients with nephrotic syndrome.
Hypersensitivity/angioedema: If angioedema due to hypersensitivity occurs, sunitinib treatment should be interrupted and standard medical care provided.
Seizures: In clinical studies of sunitinib and from postmarketing surveillance, seizures have been reported. Patients with seizures and signs/symptoms consistent with posterior reversible leukoencephalopathy syndrome (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 sunitinib is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.
Tumour lysis syndrome (TLS): Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension, and acidic urine. These patients should be monitored closely and treated as clinically indicated, and prophylactic hydration should be considered.
Infections: Sunitinib therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.
Hypoglycaemia: Decreases in blood glucose, in some cases clinically symptomatic and requiring hospitalisation due to loss of consciousness, have been reported during sunitinib treatment. In case of symptomatic hypoglycaemia, sunitinib should be temporarily interrupted. Blood glucose levels in diabetic patients should be checked regularly in order to assess if antidiabetic medicinal product’s dosage needs to be adjusted to minimise the risk of hypoglycaemia
Hyperammonaemic encephalopathy: Hyperammonaemic encephalopathy has been observed with sunitinib. In patients who develop unexplained lethargy or changes in mental status, ammonia level should be measured and appropriate clinical management should be initiated.
See prescribing information for full details.

The most serious adverse reactions associated with sunitinib, some fatal, are renal failure, heart failure, pulmonary embolism, gastrointestinal perforation, and haemorrhages (e.g., respiratory tract, gastrointestinal, tumour, urinary tract, and brain haemorrhages). The most common adverse reactions of any grade (experienced by patients in RCC, GIST, and pNET registrational trials) included
decreased appetite, taste disturbance, hypertension, fatigue, gastrointestinal disorders (i.e. diarrhoea, nausea, stomatitis, dyspepsia, and vomiting), skin discolouration, and palmar-plantar erythrodysaesthesia syndrome. These symptoms may diminish as treatment continues.
Hypothyroidism may develop during treatment. Haematological disorders (e.g., neutropenia, thrombocytopenia, and anaemia) are amongst the most common adverse drug reactions.
Fatal events other than those mentioned that were considered possibly related to sunitinib included multi-system organ failure, disseminated intravascular
coagulation, peritoneal haemorrhage, adrenal insufficiency, pneumothorax, shock, and sudden death.
See prescribing information for full details.

Medicinal products that may increase sunitinib plasma concentrations
Effect of CYP3A4 inhibitors: Administration of sunitinib with potent CYP3A4 inhibitors (e.g. ritonavir, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole , grapefruit juice) may increase sunitinib concentrations. Combination with CYP3A4 inhibitors should therefore be avoided, or the selection of an alternate concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If this is not possible, the dose 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 careful monitoring of tolerability.
Effect of Breast Cancer Resistance Protein (BCRP) inhibitors: Limited clinical data are available on the interaction between sunitinib and BCRP inhibitors and the possibility of an interaction between sunitinib and other BCRP inhibitors cannot be excluded.
Medicinal products that may decrease sunitinib plasma concentrations
Effect of CYP3A4 inducers: Administration of sunitinib with potent CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin , phenobarbital or herbal preparations containing St. John’s Wort/Hypericum perforatum) may decrease sunitinib concentrations. Combination with CYP3A4 inducers should therefore be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. If this is not possible, the dose 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), based on careful monitoring of tolerability.
See prescribing information for full details.

Pregnancy: There are no studies in pregnant women using sunitinib. Studies in animals have shown reproductive toxicity including foetal malformations. Sutent should not be used during pregnancy or in women not using effective contraception, unless the potential benefit justifies the potential risk to the foetus. If Sutent is used during pregnancy or if the patient becomes pregnant while on treatment with Sutent, the patient should be apprised of the potential hazard to the foetus.
Lactation: Sunitinib and/or its metabolites are excreted in rat milk. It is not known whether sunitinib or its primary active metabolite is excreted in human milk. Because active substances are commonly excreted in human milk and because of the potential for serious adverse reactions in breast-feeding infants, women should not breast-feed while taking Sutent.

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

Storage: Store below 30ºC.