SUTENT (sunitinib)

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Our scientific content is evidence-based, scientifically balanced and non-promotional. It undergoes rigorous internal medical review and is updated regularly to reflect new information.

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Note: the information below includes the Part I: Health Professional Information.

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Health Professional Information

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§ not commercially available in Canada
Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	Hard Gelatin Capsules 12.5 mg; 25 mg; 37.5^§ mg; 50 mg	Not applicable For a complete listing see Dosage Forms, Composition and Packaging section.

Warnings And Precautions

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Serious Warnings and Precautions

Patients receiving therapy with SUTENT (sunitinib malate) should be monitored by a qualified physician experienced in the use of anti-cancer agents.

Tumour Hemorrhage (see WARNINGS AND PRECAUTIONS, Hemorrhage)
Decreases in left ventricular ejection fraction (LVEF), including fatal cases (see WARNINGS AND PRECAUTIONS, Left Ventricular Dysfunction)
Hypertension (see WARNINGS AND PRECAUTIONS, Hypertension)
QT Interval Prolongation, including fatality (see WARNINGS AND PRECAUTIONS, QT Interval Prolongation and DRUG INTERACTIONS).
Cardiomyopathy, including fatal cases (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)
Cases of cerebrovascular and cardiovascular events, including fatal cases (see WARNINGS AND PRECAUTIONS, Arterial Thromboembolic Events)
Pulmonary embolism, including fatal cases (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)
Thrombotic Microangiopathy, including fatal cases (see WARNINGS AND PRECAUTIONS, Thrombotic Microangiopathy)
SUTENT has not been studied in patients with severe hepatic impairment.
Fatal Hepatotoxicity (See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and Thyroid Dysfunction, and ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)
Myopathy and/or rhabdomyolysis, including fatality (see ADVERSE REACTIONS, Post- Market Adverse Drug Reactions)
Renal failure, including fatal cases (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)
Reversible Posterior Leukoencephalopathy Syndrome, including fatal cases (see WARNINGS AND PRECAUTIONS, Seizures and ADVERSE REACTIONS, Post- Market Adverse Drug Reactions)
Pleural Effusion, including fatal cases (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)

Carcinogenesis and Mutagenesis

The carcinogenic potential of sunitinib has been evaluated in rasH2 transgenic mice and in Sprague-Dawley rats.

In rasH2 transgenic mice, gastroduodenal carcinomas, an increased incidence of background hemangiosarcomas, and gastric mucosal hyperplasia have been observed at doses of ≥25 mg/kg/day following 1- or 6-months duration (≥7.3 times the AUC in patients administered the RDD). No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day (≥0.7 times the AUC in patients administered the RDD).

In a 2-year rat carcinogenicity study (0, 0.33, 1, or 3 mg/kg/day), administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in duodenal carcinomas in Brunner’s glands, increases in the incidence of pheochromocytomas and hyperplasia in the adrenal medulla of male rats given 3 mg/kg/day following >1 year of dosing (≥7.8 times the AUC in patients administered the RDD).

The relevance to humans of the neoplastic findings observed in the mouse (rasH2 transgenic) and rat carcinogenicity studies with sunitinib treatment is unclear. (see TOXICOLOGY, Carcinogenicity).

Sunitinib has been tested for genotoxicity in a series of in vitro assays (bacterial mutation [Ames Assay], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test and did not cause genetic damage.

Cardiovascular

Hypertension

Blood pressure was monitored on a routine basis in the clinical studies. Hypertension was a very common adverse reaction reported in clinical trials in subjects with solid tumors, including primarily GIST and cytokine-refractory RCC¹. In the treatment-naïve MRCC study, two patients were discontinued due to treatment-related hypertension, including one with malignant hypertension, and one patient in the pancreatic NET study discontinued due to treatment-related Grade 3 hypertension.

1: From initial clinical trials including primarily patients with GIST and cytokine-refractory MRCC.

In the GIST trial (Study A), hypertension (all grades) was reported as an adverse event in 51/257 (19%) patients on SUTENT and 7/102 (7%) patients on placebo. Severe hypertension (> 200 mmHg systolic or > 110 mmHg diastolic) occurred in 9/237 (4%) patients on SUTENT and no patients on placebo. SUTENT dosing was neither delayed nor reduced due to hypertension in any of the GIST patients in the GIST pivotal trial.

Treatment-related hypertension was reported in approximately 30% of patients receiving SUTENT for treatment-naïve MRCC compared to 2% of patients receiving interferon-alfa (IFN- α). Severe hypertension (> 200 mmHg systolic or > 110 mmHg diastolic) occurred in 9% of treatment-naïve patients on SUTENT and 1% of patients on IFN-α.

In the cytokine-refractory metastatic RCC (MRCC) trials, hypertension (all grades) was reported as an adverse event in 47/169 (28%) patients on SUTENT. Hypertension (>150 mmHg systolic or >100 mmHg diastolic) occurred at least once during the study for 86/165 (52%) patients on SUTENT; severe hypertension (> 200 mmHg systolic or > 110 mmHg diastolic) occurred in 10/165 (6%) patients on SUTENT. SUTENT dosing was delayed or reduced due to hypertension in 8/165 (4%) cytokine-refractory MRCC patients.

Of patients receiving SUTENT in the Phase 3 pancreatic NET study, 19/83 patients (23%) on SUTENT and 3/82 (4%) patients on placebo experienced treatment-related hypertension. Grade 3 treatment-related hypertension was reported in 8/83 (10%) pancreatic NET patients on SUTENT, and 0/82 (0%) patients on placebo. SUTENT dosing was delayed or reduced due to hypertension in 6/83 (7%) of pancreatic NET patients. Severe hypertension (> 200 mmHg systolic or > 110 mmHg diastolic) occurred in 8/80 (10%) of pancreatic NET patients on SUTENT and 2/76 (3%) patients on placebo.

Patients should be monitored for hypertension and treated as appropriate with standard antihypertensive therapy. Temporary suspension of SUTENT is recommended in patients with severe hypertension. Treatment may be resumed once hypertension is controlled.

Patients with hypertension that is not controlled by medications should not be treated with SUTENT.

Serious cases of artery dissection have been reported in patients using VEGFR TKIs, including SUTENT, with or without hypertension.

Left Ventricular Dysfunction

Cardiovascular events, including heart failure, myocardial disorders (See arterial thromboembolic events subsection) and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience.

Decreases in left ventricular ejection fraction (LVEF) of ≥ 20% and below the lower limit of normal (LLN) occurred in approximately 2% of SUTENT-treated GIST patients, 4% of SUTENT-treated cytokine-refractory MRCC patients and 2% of placebo-treated patients.

In the double-blind treatment phase of GIST Study A, 22 patients (11%) on SUTENT and 3 patients (3%) on placebo had treatment-emergent LVEF values below LLN. Nine (9) of 22 GIST patients on SUTENT with LVEF changes recovered without intervention. Five (5) patients had documented LVEF recovery following intervention (dose reduction- 1 patient; addition of antihypertensive or diuretic medications- 4 patients). Six (6) patients went off study without documented recovery. Additionally, 3 patients (1%) on SUTENT had Grade 3 reductions in left ventricular systolic function to LVEF < 40%; 2 of these patients died without receiving further study drug.

In the treatment-naïve MRCC study, 27% and 15% of patients on SUTENT and IFN-α, respectively, had an LVEF value below the LLN. Two (<1%) patients who received SUTENT were diagnosed with congestive heart failure (CHF). One of the two patients with CHF discontinued the study.

In cytokine-refractory MRCC Studies 1 and 2, a total of 24 patients (14%) had treatment- emergent LVEF values below the LLN. Five (5) of 24 patients on SUTENT with LVEF changes recovered without intervention. Five (5) patients had documented LVEF recovery following intervention (dose reduction- 3 patients; addition of antihypertensive or diuretic medications- 2 patients). Eight (8) patients went off study without documented recovery and 6 patients are ongoing on study without recovery.

In the Phase 3 pancreatic NET study, fatal cardiac failure was reported in two patients (2%) on SUTENT and no patients on placebo.

Patients who presented with cardiovascular events such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism within 12 months prior to sunitinib administration, were excluded from SUTENT clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug- related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving SUTENT. Baseline and periodic evaluations of LVEF should also be considered while these patients are receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

In the presence of clinical manifestations of CHF, discontinuation of SUTENT is recommended. The dose of SUTENT should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction < 50% and > 20% below baseline.

QT Interval Prolongation

QT interval prolongation, including fatality, with SUTENT use has been reported in clinical trials. There is clinical evidence that SUTENT prolongs QT interval, PR interval, and decreases the heart rate (See CLINICAL PHARMACOLOGY section). Patients with QTc interval prolongation, atrioventricular (AV) block, and those taking concomitant drugs with dysrhythmic potential were excluded from the pivotal trials, therefore there is no information regarding safety of SUTENT therapy in this group. Because excessive prolongation of the PR interval can result in AV block, caution should be used if SUTENT is prescribed to patients in combination with other drugs that also cause PR interval prolongation, such as beta-blockers, calcium channel blockers, digitalis, or HIV protease inhibitors.

Pre-clinical data (in vitro and in vivo) demonstrate SUTENT causes QT interval prolongation (see DETAILED PHARMACOLOGY).

Particular care should be exercised when administering SUTENT to patients who are at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug, or who are taking concomitant drugs with potential to cause QTc interval prolongation (see DRUG INTERACTIONS section).

Bradycardia and AV block are recognized risk factors for torsade de pointes. For this reason, because SUTENT causes QTc prolongation in association with prolongation of the PR and RR intervals, this raises particular concern with respect to proarrhythmic potential. QT interval prolongation may lead to an increased risk of torsade de pointes. Torsade de pointes has been observed in <0.1% of SUTENT-exposed patients.

SUTENT therapy should be discontinued if symptoms suggestive of arrhythmia occur.

Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) (including cases identified as thrombotic thrombocytopenic purpura [TTP] and haemolytic uraemic syndrome [HUS]), sometimes 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 (see ADVERSE REACTIONS, Post- market Adverse Drug Reactions). Permanently discontinue SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after treatment was discontinued consistent with a role reported for inhibitors of the VEGF pathway in this event. SUTENT is not indicated for use in combination with other agents.

Venous Thromboembolic Events/ Pulmonary Embolism

In the double-blind treatment phase of a Phase 3 GIST study, seven (7) patients (3%) on SUTENT and none on placebo experienced venous thromboembolic events; 5 of the 7 were Grade 3 deep vein thrombosis (DVT), and 2 were Grade 1 or 2. Four (4) of these 7 GIST patients discontinued treatment following first observation of DVT. Four (4) GIST patients receiving SUTENT experienced a Grade 3/4 pulmonary embolism. All 4 GIST patients had a dose interruption or delay, but were able to continue on SUTENT. Two (2) patients receiving placebo experienced pulmonary embolism. No fatalities related to pulmonary embolism were reported.

Thirteen (3%) patients receiving SUTENT for treatment-naïve MRCC and 4 (2%) patients on the 2 cytokine-refractory MRCC studies had treatment-emergent venous thromboembolic events reported. Seven (7) of the treatment-naïve MRCC patients had pulmonary embolism, 1 was Grade 2 and 6 were Grade 4. Six (6) of the treatment-naïve MRCC patients had DVT, including 3 Grade 3. One subject with pulmonary embolism in the cytokine-refractory MRCC study experienced dose interruption. In treatment-naïve MRCC patients receiving IFN-α , 6 (2%) venous thromboembolic events occurred; 1 patient (<1%) experienced a Grade 3 DVT and 5 patients (1%) had pulmonary embolism, all Grade 4.

One patient (1%) receiving SUTENT for pancreatic NET had a venous thromboembolic event reported compared to 5 patients (6%) receiving placebo. The patient receiving SUTENT had Grade 2 thrombosis. Of the 5 patients in the placebo arm who had venous thromboembolic events, two patients had DVT (Grade 3 in one patient and Grade 2 in one patient), two patients had pulmonary embolism (Grade 3 in one patient and Grade 4 in one patient), and one patient had Grade 3 jugular vein thrombosis.

Arterial Thromboembolic Events

Cases of arterial thromboembolic events, sometimes fatal, have been reported in patients treated with sunitinib. The most frequent events included cerebrovascular accident, transient ischemic 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.

Cases of myocardial ischemia and myocardial infarction, some of which were fatal, have been reported through post-marketing experience. Use SUTENT with caution in patients who are at risk for, or who have a history of, these events.

At the time of initial registration, in the clinical trials supporting the indications of GIST and MRCC, there were no cases of myocardial ischemia or myocardial infarction in patients with GIST exposed to either SUTENT or placebo. Two (2) patients with treatment-naïve MRCC experienced treatment-related myocardial infarction (Grade 4), while 2 patients had Grade 3 myocardial ischemia. Two (2) patients with cytokine-refractory MRCC experienced Grade 3 myocardial ischemia, 1 had Grade 2 “cardiovascular toxicity” reported as an adverse event and 1 patient experienced a fatal myocardial infarction while on treatment.

In a pooled analysis of 10 clinical studies of sunitinib in RCC, GIST, and pNET, involving 7115 subjects, the frequency of myocardial ischemia/myocardial infarction events is 2.0%.

Drug Interactions

Sunitinib is metabolized primarily by CYP3A4. Potential interactions may occur with drugs that are inhibitors or inducers of this enzyme system (see DRUG INTERACTIONS).

Endocrine and Metabolism

Adrenal Function Effects

Adrenal toxicity was noted in pre-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 1.1 times the AUC observed in clinical studies. Histological changes of the adrenal gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation. In clinical studies, CT or MRI scanning performed on 336 patients treated with SUTENT demonstrated no evidence of adrenal gland hemorrhage or necrosis. ACTH stimulation testing was conducted in over 400 patients across multiple clinical trials of SUTENT. In the GIST studies, 13 patients with normal baseline testing had abnormalities at post-baseline testing consisting of: peak cortisol levels post-stimulation less than normal (497 nmol/L, or 18 μg/dL); failure of stimulation to increase cortisol level by a normal amount (193 nmol/L, or 7 μg/dL); or failure of ACTH Gel test to detect doubling of cortisol level post-stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency. In the cytokine-refractory MRCC studies, 28 patients with normal baseline testing had abnormalities at post-baseline testing and 3 patients had a treatment-emergent adverse event of adrenal insufficiency, which were not considered by the investigator to be related to SUTENT.

Patients treated with SUTENT should be monitored for adrenal insufficiency when they experience stress such as surgery, trauma, or severe infection.

Hypoglycemia

Decreases in blood glucose, in some cases clinically symptomatic with serious outcomes, have been reported during sunitinib treatment in both diabetic and non-diabetic patients. Blood glucose levels should be checked regularly in all patients. For patients receiving anti-diabetic drugs, drug dosages may needs to be adjusted to minimize the risk of hypoglycemia.

Thyroid dysfunction

Treatment-emergent acquired hypothyroidism was noted in 4% of GIST patients on SUTENT versus 1% on placebo. Although not prospectively studied in clinical trials, treatment-related hypothyroidism was reported as an adverse event in 15% of patients on SUTENT in the treatment-naïve MRCC study and two patients (0.6 %) in the IFN-α arm, and in 4% of patients across the two cytokine-refractory MRCC studies. Additionally, thyroid stimulating hormone (TSH) elevations were reported in 2% of cytokine-refractory MRCC patients. Treatment-related hypothyroidism was reported as an adverse reaction in 5/83 patients (6%) on SUTENT in the Phase 3 pancreatic NET study and in 1/82 patients (1%) in the placebo arm.

Cases of hyperthyroidism, some followed by hypothyroidism, and cases of thyroiditis have been uncommonly reported in clinical trials and through post-marketing experience.

Baseline laboratory measurement of thyroid function is recommended in all patients. During sunitinib treatment, routine monitoring of thyroid function should be performed every 3 months. All patients should be observed closely for signs and symptoms of thyroid dysfunction on sunitinib treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction, such as fatigue, should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice. Thyroid hormone replacement therapy should be initiated and maintained according to the current recommended guidelines. Careful dosage titration of thyroid hormone replacement therapy should be considered to decrease the risk of rapid and unpredictable hepatic failure when used in conjunction with sunitinib therapy. Close observation of liver function tests and thyroid function is required when patients are receiving both SUTENT and thyroid hormone replacement therapy. (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests section)

Gastrointestinal

Esophagitis

Cases of esophagitis have been reported in clinical trials and in the post market setting.

Gastrointestinal Perforation

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, (likely linked to tumour necrosis) have occurred in patients with intra-abdominal malignancies treated with SUTENT.

Gastrointestinal Events

In 6 pooled studies composed primarily of patients with GIST and MRCC, nausea, diarrhea, stomatitis, dyspepsia and vomiting were the most commonly reported treatment-related gastrointestinal events. Supportive care for gastrointestinal adverse events requiring treatment may include anti-emetic or anti-diarrheal medication.

Hemorrhage

Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumour, urinary tract and brain hemorrhages. In the double-blind treatment phase of GIST pivotal trial (Study A), bleeding events occurred in 20% of patients (41/202) receiving SUTENT, compared to 11% (11/102) receiving placebo. In GIST Study A, 14/202 patients (7%) receiving SUTENT and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, 1 patient in Study A taking placebo had a fatal gastrointestinal bleeding event during cycle 2.

In patients receiving SUTENT for treatment-naïve MRCC, 28% of patients had treatment-related bleeding events compared with 3% of patients receiving IFN-α. Eleven (2.1%) patients on SUTENT versus 1 (0.3%) of patients on IFN-α experienced Grade 3 or greater treatment-related bleeding events.

Bleeding events occurred in 50/169 (26%) patients receiving SUTENT for cytokine-refractory MRCC. Most events in cytokine-refractory MRCC patients were Grade 1 or 2; there was one Grade 3 event (bleeding foot wound). Two (2) cytokine-refractory MRCC study patients with pulmonary metastases experienced hemoptysis considered to be related to SUTENT administration.

Epistaxis was the most common hemorrhagic adverse event reported. Treatment-related epistaxis was reported in 16/83 patients (19%) receiving SUTENT for pancreatic NET and in 2/82 patients (2%) receiving placebo. Less common bleeding events in MRCC, GIST and pancreatic NET patients included rectal, gingival, upper GI, genital and wound bleeding.

In the Phase 3 pancreatic NET study, 1/83 patients (1%) receiving SUTENT had Grade 3 epistaxis, and no patients had other Grade 3 or 4 bleeding events. In pancreatic NET patients receiving placebo, no patients had Grade 3 or 4 bleeding events. Treatment-related bleeding events, excluding epistaxis, occurred in 16/83 patients (19%) receiving SUTENT in the Phase 3 pancreatic NET study, compared to 3/82 patients (4%) receiving placebo.

Treatment-related tumour hemorrhage has been observed in patients receiving SUTENT. These events may occur suddenly, and in the case of pulmonary tumours, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Fatal pulmonary hemorrhage occurred in 2 patients receiving SUTENT in a clinical trial of patients with metastatic non-small cell lung cancer (NSCLC). Both patients had squamous cell histology. SUTENT is not approved for use in patients with NSCLC. Treatment-related Grade 3 and 4 tumour hemorrhage occurred in 4/257 (approximately 2%) of GIST patients treated with SUTENT. One (1) patient with tumour hemorrhage had the SUTENT dose temporarily delayed. No patients discontinued treatment due to tumour hemorrhage.

Routine assessment of this event should include serial complete blood counts (CBCs) and physical examination.

Hematologic Events

Decreased absolute neutrophil counts of Grade 3 and 4 severity were reported in 13.1% and 0.9% patients, respectively. One (1) case of febrile neutropenia was reported in a patient receiving SUTENT on the GIST pivotal trial (Study A). Fatal disseminated intravascular coagulation (DIC) secondary to sepsis has also been reported. Decreased platelet counts of grade 3 and 4 severity were reported in 4% and 0.5% of patients respectively. The above events were not cumulative, were typically reversible and generally did not result in treatment discontinuation. Rare cases of fatal pneumonia and sepsis, with or without neutropenia, have been reported. Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT. Supportive care for hematologic events may include colony stimulating factors.

Hepatic/Biliary/Pancreatic

SUTENT has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience. Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.

Safety in patients with ALT or AST >2.5 x ULN or, if due to liver metastases, >5.0 x ULN has not been established.

Pancreatitis has been reported in clinical trials of sunitinib. Grade 3 and 4 increases in serum lipase have been observed in 20 SUTENT patients (10%) versus 7 placebo patients (7%) with GIST. Grade 3 and 4 increases in amylase have been observed in 10 SUTENT patients (5%) versus 3 placebo patients (3%) with GIST. In patients with treatment-naïve MRCC, Grade 3 or 4 increases in amylase and lipase have been observed in 6% and 18% of SUTENT-treated patients and in 3% and 7% of patients receiving IFN-α. In the cytokine-refractory MRCC studies, grade 3 or 4 increases in amylase and lipase have been observed in 4.8% and 16.9% of SUTENT- treated patients, respectively. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects receiving SUTENT for GIST or MRCC. Hepatic failure was observed in <1% of solid tumour patients treated with SUTENT. If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued and be provided with appropriate medical care.

Cases of cholecystitis, including acalculous cholecystitis and emphysematous cholecystitis, have been reported in patients treated with sunitinib (with fatal outcome in some cases).

Metabolism and Nutritional Disorders

Tumour Lysis Syndrome (TLS)

Cases of TLS, some fatal, have been rarely 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.

Neurologic

Seizures

SUTENT has not been studied in patients with known brain metastases. In clinical studies of SUTENT, seizures have been observed in <1% of 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. Discontinuation of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician, although the evidence to support this recommendation (restarting treatment) is extremely limited.

Osteonecrosis of the Jaw (ONJ)

Cases of ONJ have been reported in patients treated with sunitinib. Treatment with sunitinib may be an additional risk factor for the development of osteonecrosis of the jaw. The majority of cases occurred in patients who had received prior or concomitant treatment with IV bisphosphonates, for which ONJ is an identified risk. Caution should therefore be exercised when sunitinib and IV bisphosphonates are used either simultaneously or sequentially.

Invasive dental procedures are also an identified risk factor for ONJ. Prior to treatment with sunitinib, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with sunitinib, who have previously received or are receiving IV bisphosphonates, invasive dental procedures should be avoided, if possible.

Renal

Cases of renal impairment and/or failure, in some cases with fatal outcome, have been reported.

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 sunitinib treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue sunitinib in patients with nephrotic syndrome.

Skin and Tissues

Skin discoloration, possibly due to the active substance color (yellow) is a common treatment- related 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.

The above events were not cumulative, were typically reversible, generally did not result in treatment discontinuation and may include topical therapies for symptomatic relief.

Rare cases of necrotizing fasciitis, including of the perineum, sometimes fatal, have been reported (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). SUTENT therapy should be discontinued in patients who develop necrotizing fasciitis, and appropriate treatment should be promptly initiated.

Cases of pyoderma gangrenosum have been reported (see ADVERSE REACTIONS, Post- Market Adverse Drug Reactions).

Severe cutaneous reactions have been rarely reported, including cases of erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) and cases suggestive of toxic epidermal necrolysis (TEN). Some of these cases were life-threatening and fatal. If signs or symptoms of SJS, TEN, or EM (e.g. progressive skin rash often with blisters or mucosal lesions) are present, SUTENT treatment should be discontinued. If the diagnosis of SJS or TEN is confirmed, treatment must not be restarted. In some cases of suspected EM, patients tolerated the reintroduction of SUTENT therapy at a lower dose after resolution of the reaction. A decision to re-initiate SUTENT after resolution of suspected EM is at the discretion of the treating physician as there is limited evidence to support this recommendation.

Wound Healing/Surgery

No formal clinical studies of the effect of SUTENT on wound healing have been conducted. Impaired wound healing has been reported in patients treated with SUTENT. It is recommended that SUTENT therapy be interrupted in patients undergoing major surgical procedures. Due to limited clinical experience regarding the timing of re-initiation of SUTENT therapy in the post- operative period, the decision to resume SUTENT therapy should be based upon clinical judgment of recovery from surgery.

Special Populations

Pregnant Women:
There are no adequate and well-controlled studies of SUTENT in pregnant women. Repeat- dose studies in animals have shown effects in reproductive organs, as well as embryolethality and fetal structural abnormalities, at maternal systemic exposures less than those achieved in humans at the recommended human dose (see TOXICOLOGY– Reproductive and Developmental Toxicity). SUTENT should not be used during pregnancy or in any woman not employing adequate contraception. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus (see TOXICOLOGY – Reproductive and Developmental Toxicity). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SUTENT.

Nursing Women:
Sunitinib and/or its metabolites are excreted in rat milk. It is not known whether sunitinib or its primary active metabolite are excreted in human milk. Because drugs are commonly excreted in human milk and, because of the potential for serious adverse reactions in nursing infants, women should be advised against breastfeeding while taking SUTENT.

Male Contraception:
Male patients should be surgically sterile or agree to use effective contraception during the period of therapy with SUTENT. SUTENT may cause embryonal and fetal developmental effects should the female partner of a male taking SUTENT become pregnant as the drug may be present in the semen.

Fertility:
In the definitive fertility study in rats, no effects were observed on male or female fertility. However, effects of SUTENT on male and female reproductive systems have been observed in other non-clinical studies so SUTENT treatment may result in adverse effects on reproductive function and fertility in the clinical setting. The safety of SUTENT on reproductive function has not been evaluated in patients.

Pediatrics:
The safety and efficacy of SUTENT in pediatric patients have not been established (see INDICATIONS and TOXICOLOGY). However, physeal dysplasia was observed in Cynomolgus monkeys with open growth plates treated for 3 months with sunitinib at doses that were approximately 0.4 times the recommended human dose (RHD) based on systemic exposure (AUC). The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment.

Hepatic Insufficiency:
A single 50 mg dose of SUTENT was administered to patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, and to control group of patients with normal hepatic function. The pharmacokinetic parameters evaluated demonstrated that dose adjustments might not be necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, SUTENT was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. In addition, repeated administration of SUTENT was not studied in subjects with hepatic impairment.

Renal Insufficiency:
Safety and efficacy of SUTENT have not been established in patients with severe renal impairment or with end-stage renal disease (ESRD) on hemodialysis. Phase 3 studies that were conducted excluded patients with serum creatinine >2.0 x ULN. However, in a small Phase 1 study, systemic exposures after a single 50mg dose of SUTENT were similar in 8 subjects with severe renal impairment (CLcr<30 mL/min) compared to 8 subjects with normal renal function (CLcr>80 mL/min), although the variability was greater in the patients with severe renal impairment. Even though sunitinib and its primary metabolite were not eliminated through hemodialysis in 8 subjects with ESRD, the total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to 8 subjects with normal renal function, most likely due to a lower absorption of sunitinib in subjects with ESRD.

Based on pharmacokinetic data from this Phase 1 study, no adjustment to starting dose is required when administering SUTENT to patients with renal impairment (mild-severe) or with end-stage renal disease (ESRD) on hemodialysis. Subsequent dose modifications should be based on individual safety and tolerability [see DOSAGE AND ADMINISTRATION, Dose Modification]. Repeated administration of SUTENT was not studied in subjects with renal impairment.

Cases of renal impairment and failure, including fatalities, have been reported with SUTENT use. Caution and careful monitoring of patients with severe renal impairment or ESRD on hemodialysis is required while on SUTENT.

Monitoring and Laboratory Tests

CBCs and serum chemistries (including liver function tests, creatinine, electrolytes, magnesium, calcium, phosphate, amylase, and lipase) should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT. In the event of an electrolyte abnormality, there should be prompt correction of the imbalance.

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. In addition, patients should be observed closely for signs and symptoms of thyroid dysfunction during treatment, and patients who develop any signs and/or symptoms suggestive of thyroid dysfunction should have laboratory testing of thyroid function performed as clinically indicated. Patients who develop thyroid dysfunction should be treated as per standard medical practice.

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.

Baseline ECG should be conducted prior to starting SUTENT, and ECGs should be performed periodically during therapy. SUTENT should generally not be prescribed to patients with abnormally long baseline QT/QTc intervals or AV block. If there are symptoms suggestive of arrhythmia or if the QT/QTc interval becomes markedly prolonged while the patient is on SUTENT, the drug should be discontinued.

Blood glucose levels should be checked regularly in all patients. For patients receiving anti- diabetic drugs, drug dosages may need to be adjusted to minimize the risk of hypoglycemia.

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Adverse Reactions

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Overview

The data described below reflect exposure to SUTENT in 660 patients who participated in a placebo-controlled trial (n=202) for the treatment of GIST, an active-controlled trial (n=375) for the treatment of MRCC or a placebo-controlled trial (n=83) for the treatment of pancreatic NET. The GIST and MRCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles, and the pancreatic NET patients received a starting oral dose of 37.5 mg daily without scheduled off-treatment periods. Most adverse events are reversible and do not need to result in discontinuation. If necessary, these events can be managed through dose adjustments or interruptions.

The most common treatment-related adverse reactions (≥20%) in patients with GIST, MRCC or pancreatic NET are fatigue, asthenia, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, anorexia, and bleeding. The potentially serious adverse reactions of left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function are discussed in WARNINGS AND PRECAUTIONS. Other adverse reactions reported in studies of GIST, MRCC and pancreatic NET studies are described below.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions in GIST Placebo-Controlled Study (Study A)

The median duration of blinded study treatment was 2 cycles for patients on the SUTENT arm (mean 3, range 0-9) and one cycle (mean 1.6, range 0-6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on SUTENT and none on placebo. Dose interruptions occurred in 57 patients (28%) on SUTENT and 20 (20%) on placebo. The rate of permanent discontinuation due to treatment-related, non-fatal adverse events was 9% (19/202) vs. 8% (8/102), SUTENT vs. placebo.

Most treatment-related adverse events, reported for both treatment arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-related adverse events were reported in 48% of SUTENT patients and 29% of placebo patients, respectively, in the double-blind treatment phase of the trial. Fatigue was the most common treatment-related adverse event of any maximum severity grade reported for 42% of SUTENT patients and 36% of placebo patients. Diarrhea, nausea, stomatitis, altered taste, skin abnormalities, hypertension and bleeding were all more common in patients receiving SUTENT than in those receiving placebo. Alopecia has been observed in 9 (4.5%) subjects exposed to sunitinib in Study A as compared to 1 (1%) subject exposed to placebo. All events were NCI CTC Grade 1 severity. Hair color changes have been observed in 14 (6.9%) subjects exposed to sunitinib in Study A as compared to 2 (2%) subjects exposed to placebo. Table 1 presents the treatment-emergent adverse events commonly reported (≥ 10% of patients) in Study A.

Table 1: Treatment-Emergent Adverse Events Reported in at Least 10% of GIST Patients Who Received SUTENT or Placebo in Study A in the Double-Blind Treatment Phase of Study A
Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 PPE: Palmar plantar erythrodyaesthesia syndrome NOS: Not otherwise specified
	GIST
	SUTENT (n=202)		Placebo (n=102)
Adverse Event, n (%)	All Grades	Grade 3/4	All Grades	Grade 3/4
Any	190 (94)	97 (48)	99 (97)	30 (29)
Blood and Lymphatic System Disorders	60 (30)	34 (17)	9 (9)	3 (3)
Anemia NOS	39 (19)	16 (8)	7 (7)	2 (2)
Gastrointestinal	171 (85)	40 (20)	75 (74)	19 (19)
Diarrhea NOS	82 (41)	9 (5)	21 (21)	0 (0)
Nausea	66 (33)	2 (1)	23 (23)	3 (3)
Abdominal pain NOS	61 (30)	12 (6)	28 (29)	10 (10)
Vomiting NOS	50 (25)	3 (2)	18 (18)	3 (3)
Constipation	43 (21)	0 (0)	16 (16)	2 (2)
Stomatitis	33 (16)	1 (1)	2 (2)	0 (0)
Dyspepsia	30 (15)	1 (1)	6 (6)	0 (0)
Abdominal pain upper	22 (11)	3 (2)	8 (8)	0 (0)
Metabolism and Nutritional Disorders	81 (40)	15 (8)	26 (26)	1 (1)
Anorexia	62 (31)	1 (1)	19 (19)	1 (1)
Musculoskeletal and Connective Tissue Disorders	90 (45)	11 (5)	35 (34)	5 (5)
Arthralgia	24 (12)	2 (1)	10 (10)	0 (0)
Back pain	21 (10)	1 (1)	13 (13)	3 (3)
General Disorders and Administration Site Conditions	147 (73)	27 (13)	65 (64)	7 (7)
Fatigue	84 (42)	15 (7)	37 (36)	4 (4)
Asthenia	44 (22)	10 (5)	10 (10)	2 (2)
Pyrexia	32 (16)	2 (1)	9 (9)	1(1)
Mucosal inflammation NOS	30 (15)	0 (0)	0 (0)	0 (0)
Nervous System Disorders	89 (44)	8 (4)	29 (28)	3 (3)
Dysgeusia	40 (20)	0 (0)	2 (2)	0 (0)
Headache	38 (19)	2 (1)	17 (17)	0 (0)
Psychiatric Disorders	36 (18)	1 (1)	15 (15)	1 (1)
Insomnia	24 (12)	0 (0)	10 (10)	1 (1)
Skin and Subcutaneous Tissue Disorders	125 (62)	12 (6)	31 (30)	0 (0)
Skin Discoloration	52 (26)	0 (0)	8 (8)	0 (0)
Rash NOS	30 (15)	2 (1)	6 (6)	0 (0)
PPE syndrome	28 (14)	9 (5)	2 (2)	0 (0)
Vascular Disorders	50 (25)	17 (8)	12 (12)	0 (0)
Hypertension NOS	28 (14)	8 (4)	7 (7)	0 (0)

Table 2 depicts common (≥ 10%) treatment-emergent laboratory abnormalities.

Table 2: Treatment-Emergent Laboratory Abnormalities in ≥ 10% of GIST Patients who Received SUTENT or Placebo in the Double-Blind Treatment Phase of Study A
* Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 a Grade 4 AEs in patients on SUTENT included alkaline phosphatase (1%), lipase (2%), creatinine (1%), hypokalemia (1%), neutropenia (2%), anemia (2%), and thrombocytopenia (1%). b Grade 4 AEs in patients on placebo included amylase (1%), lipase (1%), anemia (2%), and thrombocytopenia (1%).
Adverse Event, n (%)	SUTENT (n=202)		Placebo (n=102)
	All Grades	Grade 3/4^a	All Grades	Grade 3/4^b
Any		68 (34)		22 (22)
Gastrointestinal
AST / ALT	78 (39)	3 (2)	23 (23)	1 (1)
Alkaline phosphatase	48 (24)	7 (4)	21 (21)	4 (4)
Total Bilirubin	32 (16)	2 (1)	8 (8)	0 (0)
Indirect Bilirubin	20 (10)	0 (0)	4 (4)	0 (0)
Amylase	35 (17)	10 (5)	12 (12)	3 (3)
Lipase	50 (25)	20 (10)	17 (17)	7 (7)
Cardiac
Decreased LVEF	22 (11)	2 (1)	3 (3)	0 (0)
Renal / Metabolic
Creatinine	25 (12)	1 (1)	7 (7)	0 (0)
Hypokalemia	24 (12)	1 (1)	4 (4)	0 (0)
Hypernatremia	20 (10)	0 (0)	4 (4)	1 (1)
Uric acid	31 (15)	16 (8)	16 (16)	8 (8)
Hematology
Neutropenia	107 (53)	20 (10)	4 (4)	0 (0)
Lymphopenia	76 (38)	0 (0)	16 (16)	0 (0)
Anemia	52 (26)	6 (3)	22 (22)	2 (2)
Thrombocytopenia	76 (38)	10 (5)	4 (4)	0 (0)

Grade 3 or 4 treatment-emergent laboratory abnormalities were seen in 68 SUTENT patients (34%) versus 22 placebo patients (22%). Elevated liver function tests, pancreatic enzymes and creatinine were all more common in SUTENT patients than placebo patients. Decreased LVEF, myelosuppression and electrolyte disturbances were all more common in SUTENT patients than placebo patients. Treatment-emergent acquired hypothyroidism was noted in 4% of GIST patients on SUTENT versus 1% on placebo.

After a positive interim analysis, the study was unblinded, and patients on the placebo arm were given the opportunity to receive open-label SUTENT treatment [see CLINICAL TRIALS]. For 241 patients randomized to the SUTENT arm, including 139 who received SUTENT in both the double-blind and open-label treatment phases, the median duration of SUTENT treatment was 6 cycles (mean 8.5, range 1 – 44). For the 255 patients who ultimately received open-label SUTENT treatment, median duration of study treatment was 6 cycles (mean 7.8, range 1 – 37) from the time of the unblinding. A total of 118 patients (46%) required dosing interruptions, and a total of 72 patients (28%) required dose reductions during the open-label treatment phase. The incidence of treatment-emergent adverse reactions resulting in permanent discontinuation was 20%. The most common Grade 3 or 4 treatment-related adverse reactions experienced by patients receiving SUTENT in the open-label treatment phase were neutropenia (11%), fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).

Adverse Reactions in MRCC Patient Population

Treatment-Naive
The as-treated patient population for the interim safety analysis of the Phase 3 MRCC study included 735 patients, 375 randomized to SUTENT and 360 randomized to IFN-a. The median duration of treatment was 11.1 months (range: 0.4 – 46.1) for SUTENT treatment and 4.1 months (range: 0.1 – 45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on SUTENT and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on SUTENT and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for SUTENT and 23% for IFN-α. Most treatment-related adverse events in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-related adverse events were reported in 69% and 38% of patients on SUTENT versus IFN-α, respectively. Common treatment-related adverse events of any grade for patients receiving SUTENT are fatigue, diarrhea, nausea, stomatitis, hypertension, hand-foot syndrome, ejection fraction decline. Table 3 compares the incidence of common (≥10%) treatment-related adverse events for patients receiving SUTENT versus those on IFN-α.

Table 3: Treatment-Related Adverse Events Reported in at Least 10% of Patients with Treatment-Naïve MRCC Who Received SUTENT or IFN-α
* The following terms have been combined: abdominal pain and abdominal pain upper. ** The following terms have been combined: rash, rash erythematous, exfoliative rash, rash follicular,rash macular, rash papular, rash pruritic, rash maculo-papular, rash psoriaform, and rash generalised.
Adverse Event, n (%)	SUTENT (n =375)		IFN-α (n =360)
	All Grades n (%)	Grade 3/4 n (%)	All Grades n (%)	Grade 3/4 n (%)
Any adverse event	358 (95.5%)	258 (68.8%)	331 (91.9%)	139 ( 38.6%)
Blood and lymphatic system disorders
Thrombocytopenia	69 (18.4%)	33 (8.8%)	11 (3.1%)	2 (0.6 %)
Neutropenia	70 (18.7%)	40 (10.7%)	31 (8.6%)	12 (3.3%)
Anemia	51 (13.6%)	19 (5.1%)	31 (8.6%)	7 (1.9%)
Leukopenia	40 (10.7%)	12 (3.2%)	14 (3.9%)	3 (0.8%)
Metabolism and nutrition disorders
Anorexia	129 (34.4%)	7 (1.9%)	101 (28.1%)	6 (1.7%)
Decreased appetite	37 (9.9%)	1 (0.3%)	38 (10.6%)	0 (0%)
Nervous system disorders
Dysgeusia	175 (46.7%)	1 (0.3%)	52 (13.9%)	0 (0%)
Headache	53 (14.1%)	2 (0.5%)	55 (15.3%)	0 (0%)
Vascular disorders
Hypertension	113 (30.1%)	46 (12.3%)	6 (1.7%)	1 (0. 3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	67 (17.9%)	3 (0.8%)	5 (1.4%)	0 (0%)
Gastrointestinal disorders
Diarrhea	229 (61.1%)	33 (8.8%)	49 (13.6%)	1 (0.3%)
Nausea	195 (52.0%)	17 (4.5%)	124 (34.4%)	4 (1.1%)
Dyspepsia	118 (31.5%)	7 (1.9%)	13 (3.6%)	0 (0%)
Stomatitis	110 (29.3%)	5 (1.3%)	10 (2.8%)	1 (0.3%)
Vomiting	117 (31.2%)	14 (3.7%)	41 (11.4%)	2 (0.6%)
Abdominal pain*	70 (18.7%)	7 (1.9%)	15 (4.2%)	0 (0%)
Dry mouth	45 (12.0%)	0 (0%)	24 (6.7%)	1 (0.3%)
Constipation	44 (11.7%)	1 (0.3%)	14 (3.9%)	0 (0.0%)
Flatulence	43 (11.5%)	0 (0.0%)	6 (1.6%)	0 (0.0%)
Skin and subcutaneous tissue disorders
Rash**	115 (30.7%)	4 (1.1%)	33 (9.2%)	3 (0.8%)
Palmar-plantar erythrodysesthesia	108 (30.0%)	32 (8.5%)	2 (0.6%)	0 (0%)
syndrome
Dry skin	79 (21.1%)	1 (0.3%)	19 (5.3%)	0 (0%)
Skin discoloration	89 (23.7%)	1 (0.3%)	0 (0%)	0 (0%)
Hair color changes	75 (20.0%)	0 (0%)	1 (0.3%)	0 (0%)
Erythema	39 (10.4%)	2 (0.5%)	3 (0.8%)	0 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	66 (17.6%)	5 (1.3%)	11 (3.1%)	0 (0%)
Arthralgia	43 (11.5%)	1 (0.3%)	49 (13.6%)	0 (0%)
Myalgia	32 (8.5%)	1 (0.3%)	60 (16.7%)	2 (0.6%)
General disorders and administration site conditions
Fatigue	206 (54.9%)	43 (11.5%)	186 (51.7%)	48 (13.3%)
Mucosal inflammation	98 (26.1%)	7 (1.9%)	6 (1.7%)	1 (0.3%)
Asthenia	76 (20.3%)	28 (7.5%)	67 (18.6%)	14 (3.9%)
Pyrexia	31 (8.3%)	3 (0.8%)	125 (34.7%)	1 (0.3%)
Chills	28 (7.5%)	2 (0.5%)	105 (29.2%)	0 (0%)
Investigations
Ejection fraction decreased	51 (13.6%)	10 (2.7%)	11 (3.1%)	3 (0.8%)
Weight decreased	46 (12.3%)	1 (0.3%)	50 (13.9%)	1 (0.3%)

In the treatment-naive MRCC study, 75 (20%) versus 37 (10%) patients experienced treatment- emergent Grade 4 chemistry laboratory abnormalities on SUTENT versus IFN-a, respectively. The most common Grade 4 chemistry abnormalities were hyperuricemia (14% on SUTENT, 8% on IFN-α) and increased lipase (3% on SUTENT, 1% on IFN-α). The most common Grade 3 chemistry abnormalities observed on both arms were increased lipase (15% on SUTENT, 7% on IFN-α) and hypophosphatemia (6% on SUTENT, 6% on IFN-α). Other common Grade 3 laboratory abnormalities on SUTENT were hyponatremia (8%) and increased amylase (5%), and on IFN-α was hyperglycemia (6%). Hematologic laboratory abnormalities in the treatment-naïve MRCC patient population are presented in Table 4.

Grade 4 hematology laboratory abnormalities in the Phase 3 MRCC study include neutropenia (2% on SUTENT, 1% on IFN-α) and anemia (2% on SUTENT, <1% on IFN-α). Grade 3 hematology laboratory abnormalities included neutropenia (15% on SUTENT, 8% on IFN-α), lymphopenia (16% on SUTENT, 24% on IFN-α), thrombocytopenia (8% on SUTENT, 1% on IFN-α), leukopenia (8% on SUTENT, 2% on IFN-α) and anemia (6% on SUTENT, 5% on IFN-α).

Table 4. Treatment-Emergent Laboratory Abnormalities Reported in at Least 10% of Treatment-Naïve MRCC Patients Who Received SUTENT or IFN-α
* Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 a Grade 4 laboratory abnormalities in patients on SUTENT included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), glucose increased (<1%), calcium decreased (<1%), phosphorous (<1%), potassium increased (<1%), and sodium decreased (<1%). b Grade 4 laboratory abnormalities in patients on IFN-α included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%) and hemoglobin (<1%).
Laboratory Parameter, n (%)	Treatment-Naïve RCC
	SUTENT (n=375)		IFN-α (n=360)
	All Grades*	Grade 3/4*^a	All Grades*	Grade 3/4*^b
Gastrointestinal
AST	211 (56)	6 (2)	136 (38)	8 (2)
ALT	192 (51)	10 (3)	144 (40)	9 (2)
Lipase	211 (56)	69 (18)	165 (46)	29 (8)
Alkaline phosphatase	171 (46)	7 (2)	132 (37)	6 (2)
Amylase	130 (35)	22 (6)	114 (32)	12 (3)
Total bilirubin	75 (20)	3 (1)	8 (2)	0 (0)
Indirect bilirubin	49 (13)	4 (1)	3 (1)	0 (0)
Renal/Metabolic
Creatinine	262 (70)	2 (<1)	183 (51)	1 (<1)
Creatine kinase	183 (49)	9 (2)	40 (11)	4 (1)
Uric acid	173 (46)	54 (14)	119 (33)	29 (8)
Calcium decreased	156 (42)	4 (1)	145 (40)	4 (1)
Phosphorus	116 (31)	22 (6)	87 (24)	23 (6)
Albumin	106 (28)	4 (1)	72 (20)	0 (0)
Glucose increased	86 (23)	21 (6)	55 (15)	22 (6)
Sodium decreased	75 (20)	31 (8)	55 (15)	13 (4)
Glucose decreased	65 (17)	0 (0)	43 (12)	1 (<1)
Potassium increased	61 (16)	13 (3)	61 (17)	15 (4)
Calcium increased	50 (13)	2 (<1)	35 (10)	5 (1)
Potassium decreased	49 (13)	3 (1)	7 (2)	1 (<1)
Sodium increased	48 (13)	0 (0)	38 (10)	0 (0)
Hematology
Neutrophils	289 (77)	65 (17)	178 (49)	31 (9)
Hemoglobin	298 (79)	29 (8)	250 (69)	18 (5)
Platelets	255 (68)	35 (9)	85 (24)	2 (1)
Lymphocytes	256 (68)	66 (18)	245 (68)	93 (26)
Leukocytes	293 (78)	29 (8)	202 (56)	8 (2)

Cytokine-Refractory MRCC
The data described below reflect exposure to SUTENT in 169 patients with cytokine-refractory MRCC enrolled in Studies 1 and 2. The median duration of treatment was 5.5 months (range: 23 days to 11.2 months) for Study 1 and 7.9 months (range: 6 days to 1.3 years) for Study 2. Dose interruptions occurred in 48 patients (45%) on Study 1 and 45 patients (71%) on Study 2; one or more dose reductions occurred in 23 patients (22%) on Study 1 and 22 patients (35%) on Study 2. Permanent discontinuation from the study due to treatment-related adverse events occurred in 7 patients (8%) on Study 1 and 6 patients (10%) on Study 2. Treatment-related Adverse events are presented by maximum severity grade for at least 10% of the MRCC patient population in Table 5. Treatment-related Adverse events were experienced by nearly all of the patients with MRCC. Fatigue; gastrointestinal disorders, such as nausea, diarrhea, stomatitis, dyspepsia, vomiting and constipation; dysgeusia; skin discoloration; anorexia and rash were the most common treatment-related adverse events (experienced by at least 20% of the patients). The relative frequency of the most common all-causality adverse events was similar to that of these treatment-related adverse events.

Table 5: Treatment-Related Adverse Events Reported in at Least 10% of Patients Treated with SUTENT in the Two Cytokine-Refractory MRCC Studies
Severity grading was consistent with Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 *1 patient (0.6%) was missing. Abbreviations: n=number of subjects, MRCC=metastatic renal cell carcinoma
Adverse Event	All Grades n (%)	Grade 3/4 n (%)
Any Treatment-Related AE Experienced by ≥10% Patients	166 ( 98.2)	91 ( 53.9)
Blood and Lymphatic System Disorders	57 ( 33.7)	30 ( 15.8)
Anemia	21 ( 12.4)	6 ( 3.6)
Leukopenia	24 ( 14.2)	10 ( 5.9)
Neutropenia	24 ( 14.2)	14 ( 8.3)
Thrombocytopenia	23 ( 13.6)	11 ( 6.5)
Eye disorders	17 (10.1)	0 (0.0)
Gastrointestinal disorders	156 ( 92.3)	15 (8.9)
Constipation	34 ( 20.1)	0 ( 0.0)
Diarrhoea	83 ( 49.1)	5 ( 3.0)
Dyspepsia	69 ( 40.8)	1 ( 0.6)
Glossodynia	25 ( 14.8)	0 ( 0.0)
Nausea	84 ( 49.7)	2 ( 1.2)
Stomatitis	70 ( 41.4)	6 ( 3.6)
Vomiting	52 ( 30.8)	2 ( 1.2)
General disorders and administration site conditions	118 ( 69.8)	19 ( 11.2)
Fatigue	102 ( 60.4)	18 ( 10.7)
Mucosal inflammation	30 ( 17.8)	1 ( 0.6)
Infections and infestations	21 ( 12.4)	4 ( 2.4)
Investigations*	65 ( 38.5)	31 ( 20.1)
Ejection fraction decreased	24 ( 14.2)	4 ( 2.4)
Lipase increased	17 ( 10.1)	15 ( 8.9)
Metabolism and nutrition disorders Anorexia	68 ( 40.2) 47 ( 27.8)	9 ( 5.3) 1 ( 0.6)
Musculoskeletal and connective tissue disorders Pain in extremity	45 ( 26.6) 21 ( 12.4)	3 ( 1.8) 1 ( 0.6)
Nervous system disorders	101 ( 59.8)	6 ( 3.6)
Dysgeusia	71 ( 42.0)	0 ( 0.0)
Headache	25 ( 14.8)	1 ( 0.6)
Psychiatric disorders	17 ( 10.1)	2 ( 1.2)
Respiratory, thoracic and mediastinal disorders	40 ( 23.7)	3 ( 1.8)
Skin and subcutaneous tissue disorders	122 ( 72.2)	12 ( 7.1)
Dry skin	22 ( 13.0)	0 ( 0.0)
Erythema	20 ( 11.8)	0 ( 0.0)
Hair color changes	24 ( 14.2)	0 ( 0.0)
Palmar-plantar erythrodysesthesia syndrome	21 ( 12.4)	6 ( 3.6)
Rash	44 ( 26.0)	1 ( 0.6)
Skin discoloration	54 ( 32.0)	0 ( 0.0)
Vascular disorders	40 ( 23.7)	11 ( 6.5)
Hypertension	28 ( 16.6)	7 ( 4.1)

Treatment-emergent laboratory abnormalities are presented by maximum severity grade for at least 10% of the MRCC patient population in Table 6. Hematologic laboratory abnormalities in the MRCC patient population were comparable to that observed in the overall solid tumour patient population.

Table 6. Abnormal Post-Baseline Laboratory Tests Occurring in at Least 10% of Cytokine-Refractory MRCC Patients (As-Treated Population)
Grading is based on Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 criteria; the grading criteria are not available for all lab tests performed on study; if applicable, a subject was summarized only once for each test under the maximum post-baseline grade. Abbreviations: n=number of subjects, MRCC=metastatic renal cell carcinoma
	Total 50 mg QD, Schedule 4/2 (N=169)
Laboratory Test	Grade 1-4 n (%)	Grade 3/4 n (%)
Any		105 (62.1%)
Gastrointestinal
Albumin(Hypoalbuminemia)	47 ( 27.8)	0 ( 0.0)
Alkaline Phosphatase	93 ( 55.0)	3 ( 1.8)
Amylase	47 ( 27.8)	8 ( 4.7)
AST/ALT	97 ( 57.4)	6 ( 3.6)
Lipase	84 ( 49.7)	28 ( 16.6)
Total Bilirubin	20 ( 11.8)	1 ( 0.6)
Renal/Metabolic
Calcium (Hypercalcemia)	19 ( 11.2)	1 ( 0.6)
Calcium (Hypocalcemia)	72 ( 42.6)	1 ( 0.6)
Creatine Kinase	65 ( 38.5)	2 ( 1.2)
Creatinine	100 ( 59.2)	2 ( 1.2)
Glucose (Hyperglycemia)	30 ( 17.8)	6 ( 3.6)
Glucose (Hypoglycemia)	34 ( 20.1)	0 ( 0.0)
Hypophosphatemia	37 ( 21.9)	15 ( 8.9)
Potassium (Hyperkalemia)	23 ( 13.6)	7 ( 4.1)
Sodium (Hypernatremia)	22 ( 13.0)	1 ( 0.6)
Sodium (Hyponatremia)	17 ( 10.1)	6 ( 3.6)
Uric Acid	83 ( 49.1)	25 ( 14.8)
Hematology
Anemia	125 ( 74.0)	12 ( 7.1)
Neutropenia	116 ( 68.6)	22 ( 13.0)
Lymphopenia	99 ( 58.6)	33 ( 19.5)
Thrombocytopenia	99 ( 58.6)	5 ( 3.0)

Adverse Reactions in the Phase 3 pancreatic NET Study

The median number of days on treatment was 139 days (range 13-532 days) for patients on SUTENT and 113 days (range 1-614 days) for patients on placebo. Nineteen patients (23%) on SUTENT and 3 patients (4%) on placebo were on study for >1 year. Dose interruptions occurred in 25 patients (30%) on SUTENT and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on SUTENT and 9 patients (11%) on placebo. Discontinuation rates due to treatment-related adverse reactions were 12% for SUTENT and 2% for placebo.

Most treatment-related adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-related adverse reactions were reported in 43% versus 20% of patients on SUTENT versus placebo, respectively. Table 7 compares the incidence of common (≥10%) treatment-related adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.

Table 7 – Treatment-Related Adverse Reactions Reported in the Phase 3 pancreatic NET Study in at Least 10% of Patients who Received SUTENT and More Commonly Than in Patients Given Placebo
Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0
Adverse reactions	Pancreatic NET
	SUTENT (n=83)		Placebo (n=82)
	All Grades n (%)	Grade 3/4 n (%)	All Grades n (%)	Grade 3/4 n (%)
Any	81 (97.6%)	36 (43.4%)	64 (78.0%)	16 (19.5)
Blood and lymphatic system disorders
Neutropoenia	24 (28.9%)	10 (12.0%)	3 (3.7%)	0 (0.0%)
Thrombocytopoenia	14 (16.9%)	3 (3.6%)	4 (4.9%)	0 (0.0%)
Metabolism and nutrition disorders
Anorexia	17 (20.5%)	2 (2.4%)	11 (13.4%)	0 (0.0%)
Nervous system disorders
Dysgeusia	16 (19.3%)	0 (0.0%)	3 (3.7%)	0 (0.0%)
Headeache	10 (12.0%)	0 (0.0%)	5 (6.1%)	1 (1.2%)
Vascular disorders
Hypertension	19 (22.9%)	8 (9.6%)	3 (3.7%)	0 (0.0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	16 (19.3%)	1 (1.2%)	2 (2.4%)	0 (0.0%)
Gastrointestinal disorders
Diarrhoea	44 (53.0%)	4 (4.8%)	25 (30.5%)	1 (1.2%)
Nausea	32 (38.6%)	1 (1.2%)	18 (22.0%)	0 (0.0%)
Vomiting	21 (25.3%)	0 (0.0%)	14 (17.1%)	0 (0.0%)
Stomatitis	18 (21.7%)	3 (3.6%)	2 (2.4%)	0 (0.0%)
Abdominal pain	12 (14.5%)	1 (1.2%)	10 (12.2%)	3 (3.7%)
Dyspepsia	12 (14.5%)	0 (0.0%)	1 (1.2%)	0 (0.0%)
Skin and subcutaneous tissue disorders
Hair colour changes	24 (28.9%)	1 (1.2%)	1 (1.2%)	0 (0.0%)
Palmar-plantar erythrodysaesthesia	19 (22.9%)	5 (6.0%)	2 (2.4%)	0 (0.0%)
syndrome
Rash	13 (15.7%)	0 (0.0%)	4 (4.9%)	0 (0.0%)
Dry skin	11 (13.3%)	0 (0.0%)	9 (11.0%)	0 (0.0%)
General disorders and administration site conditions
Asthenia	26 (31.3%)	3 (3.6%)	18 (22.0%)	2 (2.4%)
Fatigue	24 (28.9%)	4 (4.8%)	14 (17.1%)	3 (3.7%)
Mucosal Inflammation	13 (15.7%)	1 (1.2%)	6 (7.3%)	0 (0.0%)
Investigations
Weight decreased	11 (13.3%)	1 (1.2%)	6 (7.3%)	0 (0.0%)

Table 8 provides common (≥10%) treatment-emergent laboratory abnormalities.

Table 8. Laboratory Abnormalities Reported in the Phase 3 pancreatic NET Study in at Least 10% of Patients Who Received SUTENT
* Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 a Grade 4 laboratory abnormalities in patients on SUTENT included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%) and total bilirubin (1%). b Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%) and lipase (1%).
Laboratory Parameter, n (%)	Pancreatic NET
	SUTENT			Placebo
	N	All Grades*	Grade 3/4*^a	N	All Grades*	Grade 3/4*^b
Gastrointestinal
AST	82	59 (72)	4 (5)	80	56 (70)	2 (3)
ALT	82	50 (61)	3 (4)	80	44 (55)	2 (3)
Alkaline phosphatase	82	52 (63)	8 (10)	80	56 (70)	9 (11)
Total bilirubin	82	30 (37)	1 (1)	80	22 (28)	3 (4)
Amylase	74	15 (20)	3 (4)	74	7 (10)	1 (1)
Lipase	75	13 (17)	4 (5)	72	8 (11)	3 (4)
Renal/Metabolic
Glucose increased	82	58 (71)	10 (12)	80	62 (78)	14 (18)
Albumin	81	33 (41)	1 (1)	79	29 (37)	1 (1)
Phosphorus	81	29 (36)	6 (7)	77	17 (22)	4 (5)
Calcium decreased	82	28 (34)	0 (0)	80	15 (19)	0 (0)
Sodium decreased	82	24 (29)	2 (2)	80	27 (34)	2 (3)
Creatinine	82	22 (27)	4 (5)	80	22 (28)	4 (5)
Glucose decreased	82	18 (22)	2 (2)	80	12 (15)	3 (4)
Potassium decreased	82	17 (21)	3 (4)	80	11 (14)	0 (0)
Magnesium decreased	52	10 (19)	0 (0)	39	4 (10)	0 (0)
Potassium increased	82	15 (18)	1 (1)	80	9 (11)	1 (1)
Hematology
Neutrophils	82	58 (71)	13 (16)	80	13 (16)	0 (0)
Hemoglobin	82	53 (65)	0 (0)	80	44 (55)	1 (1)
Platelets	82	49 (60)	4 (5)	80	12 (15)	0 (0)
Lymphocytes	82	46 (56)	6 (7)	80	28 (35)	3 (4)

Other Adverse Reactions

Musculoskeletal

Rhabdomyolysis has been reported in some cases from non-pivotal clinical trials (see See WARNINGS AND PRECAUTIONS section and ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Cardiovascular

See WARNINGS AND PRECAUTIONS section.

Investigations

Increase in blood uric acid.

Pulmonary Embolism

See WARNINGS AND PRECAUTIONS section.

Pancreatic and Hepatic Function

If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued. Pancreatitis was observed in 5 (1%) patients receiving SUTENT for treatment-naïve RCC compared to 1 (<1%) patient receiving IFN-α. Hepatotoxicity was observed in patients receiving SUTENT (See WARNINGS AND PRECAUTIONS section).

Seizures

See WARNINGS AND PRECAUTIONS section.

Skin and subcutaneous tissue disorders

Rare cases of Stevens-Johnson syndrome.

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during post approval use of SUTENT. 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.

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.

Cases of myocardial ischemia and myocardial infarction, some of which were fatal, have been reported.

Blood and lymphatic system disorders:

Cases of DIC, ITP, hemolytic anemia, and microangiopathic hemolytic anemia have been reported. Suspension of sunitinib is recommended. There are no data to support re-initiation of treatment following resolution. Physician discretion is recommended.

Cardiovascular:

Cases of left ventricular failure, cardiac failure, cardiovascular ischemia-related events (See Post- Market Adverse Drug Reactions- Arterial Thromboembolic Events) and rhythm disorder events have been reported in patients with pre-existing disease and/or cardiovascular risk factors, but a causal association with sunitinib could not be ruled out.

Cases of cardiomyopathy, in some cases with fatal outcome attributed to SUTENT, have been reported.

Endocrine disorders:

Cases of thyroiditis and hypothyroidism, as well as hyperthyroidism, with some cases followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience (See WARNINGS AND PRECAUTIONS, Thyroid Dysfunction).

Decreases in blood glucose, in some cases clinically symptomatic with serious outcomes, have been reported during sunitinib treatment in both diabetic and non-diabetic patients.

Hemorrhage:

Epistaxis is one of the most common hemorrhagic adverse events reported with sunitinib (see WARNINGS AND PRECAUTIONS, Hemorrhage). Although most cases are mild and self- limited, serious cases have been reported through post-marketing experience.

Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumour, urinary tract and brain hemorrhages. In addition, cases of fatal hemorrhage associated with thrombocytopenia have been reported.

Cases of pulmonary, gastrointestinal, tumour, urinary tract, and brain hemorrhage, some fatal, have been reported in patients treated with SUTENT.

Hepatic and Biliary Function

Hepatotoxicity has been observed in clinical trials and post-marketing experience

Cases of cholecystitis, including acalculous cholecystitis and emphysematous cholecystitis, have been reported in patients treated with sunitinib (with fatal outcome in some cases).

Immune system disorders:

Hypersensitivity reactions, including angioedema, have been reported.

Infections and infestations:

Cases of serious infection (with or without neutropenia), in some cases with fatal outcome, have been reported. The infections observed most commonly with sunitinib treatment are respiratory infections (e.g. pneumonia, bronchitis), urinary tract infections, skin infections (e.g. cellulitis), sepsis/septic shock, and abscess (e.g. genital, anorectal, skin, limb, visceral), viral (e.g. nasopharyngitis, oral herpes), or fungal (e.g. candidiasis: oral, esophageal). Cases of necrotizing fasciitis, including of the perineum, sometimes fatal, have been reported.

Musculoskeletal and connective tissue disorders:

Cases of myopathy and/or rhabdomyolysis, some with acute renal failure and including fatality, have been reported. Most of these patients had pre-existing risk factors and/or were receiving concomitant medications known to be associated with these adverse reactions. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice. (See WARNINGS AND PRECAUTIONS section)

Cases of osteonecrosis of the jaw (ONJ) have been reported in patients treated with sunitinib, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to i.v. bisphosphonates and/or a history of dental disease requiring invasive dental procedures (See WARNINGS AND PRECAUTIONS section).

Nervous system disorders:

Taste disturbance, including ageusia, has been reported.

Renal and urinary disorders:

Cases of renal impairment and/or failure, in some cases with fatal outcome, have been reported.

Cases of proteinuria and nephrotic syndrome have been reported (See WARNINGS AND PRECAUTIONS section). Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. The safety of continued sunitinib treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue sunitinib in patients with nephrotic syndrome.

Respiratory disorders:

Cases of pulmonary embolism, in some cases with fatal outcome attributed to SUTENT, have been reported. Cases of Pleural effusion, in some cases with fatal outcome, have been reported.

Vascular disorders:

Artery dissection and artery aneurysm (including rupture) have been reported in association with VEGFR TKIs, including SUTENT.

Gastrointestinal disorders:

Esophagitis.

Neurologic

Cases of reversible posterior leukoencephalopathy syndrome, in some cases with fatal outcome have been reported.

Other:

Fistula formation: Cases of fistula formation (including anal, enterocutaneous, gastrointestinal, tracheo-esophageal, and pleural fistulae), sometimes associated with tumour necrosis and/or regression, in some cases with fatal outcome, have been reported.

Skin and subcutaneous tissue disorders: Radiation interaction skin reaction has been reported when SUTENT was given concurrently with radiotherapy.

Cases of pyoderma gangrenosum, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including life-threatening and fatal cases, as well as erythema multiforme have been reported.

Tumour Lysis Syndrome: Cases of tumour lysis syndrome, some fatal and some occurring soon after initiation of SUTENT have been reported.

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Drug Interactions

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Overview

Sunitinib is metabolized primarily by CYP3A4. Potential interactions may occur with drugs/foods/herbs that are inhibitors or inducers of this enzyme system.

Drug-Drug Interactions

CYP3A4 Inhibitors: Co-administration of SUTENT (sunitinib malate) with inhibitors of the CYP3A4 family may increase SUTENT concentrations (see ACTION AND CLINICAL PHARMACOLOGY). Concomitant administration of SUTENT with CYP3A4 inhibitors should be avoided. These include, but are not limited to: non-dihydropyridine calcium channel blockers (e.g. diltiazem, verapamil); antifungals (e.g. ketoconazole, fluconazole, itraconazole, voriconazole); macrolide antibiotics (e.g. erythromycin, clarithromycin, telithromycin); fluoroquinolone antibiotics (e.g. ciprofloxacin, norfloxacin); and some HIV antivirals (e.g. ritonavir, indinavir).

CYP3A4 Inducers: Co-administration of SUTENT with inducers of the CYP3A4 family may decrease SUTENT concentrations (see ACTION AND CLINICAL PHARMACOLOGY). Concomitant administration of SUTENT with CYP3A4 inducers should be avoided. CYP3A4 inducers include, but are not limited to: barbiturates (e.g. phenobarbital); anticonvulsants (e.g. carbamazepine, phenytoin); rifampin; glucocorticoids; pioglitazone; and some HIV antivirals (e.g. efavirenz, nevirapine).

Drugs Which Prolong the QT/QTc Interval: The concomitant use of SUTENT with another QT/QTc-prolonging drug is discouraged. However, if it is necessary, particular care should be used. Drugs that have been associated with QT/QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QT/QTc prolongation and/or torsade de pointes:

Antiarrhythmics (Class IA, e.g., quinidine, procainamide, disopyramide; Class III, e.g. amiodarone, sotalol, ibutilide; Class IC, e.g. flecainide, propafenone)
Antipsychotics (e.g. thioridazine, chlorpromazine, pimozide, haloperidol, droperidol)
Antidepressants (e.g. amitriptyline, imipramine, maprotiline, fluoxetine, venlafaxine)
Opioids (e.g. methadone)
Macrolide antibiotics (e.g. erythromycin, clarithromycin, telithromycin)
Quinolone antibiotics (e.g. moxifloxacin, gatifloxacin, ciprofloxacin)
Antimalarials (e.g. quinine)
Pentamidine
Azole antifungals (e.g. ketoconazole, fluconazole, voriconazole)
Gastrointestinal drugs (e.g. domperidone, 5HT3 antagonists, such as granisetron, ondansetron, dolasetron)
Βeta 2-adrenoreceptor agonists (e.g. salmeterol, formoterol)
Tacrolimus

Drugs Which Prolong the PR Interval: Caution should be used if SUTENT is prescribed to patients in combination with other drugs that also cause PR interval prolongation, such as beta blockers, calcium channel blockers, digitalis, or HIV protease inhibitors (See WARNINGS AND PRECAUTIONS, Cardiovascular, QT Interval Prolongation).

The above list of potentially interacting drugs is not comprehensive. Current scientific literature should be consulted for more information.

Drug-Food Interactions

Grapefruit juice has CYP3A4 inhibitory activity. Therefore, ingestion of grapefruit juice while on SUTENT therapy may lead to decreased SUTENT metabolism and increased SUTENT plasma concentrations (see Drug-Drug Interactions). Concomitant administration of SUTENT with grapefruit juice should be avoided.

Drug-Herb Interactions

St. John’s Wort is a potent CYP3A4 inducer. Co-administration with SUTENT may lead to increased SUTENT metabolism and decreased SUTENT plasma concentrations (see Drug-Drug Interactions). Patients receiving SUTENT should not take St. John’s Wort concomitantly.

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Dosage And Administration

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Recommended Dose for GIST and MRCC
The recommended dose of SUTENT (sunitinib malate) is one 50-mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off.

Recommended Dose for pancreatic NET
The recommended dose of SUTENT for pancreatic neuroendocrine tumours (pancreatic NET) is 37.5 mg taken orally once daily without a scheduled off-treatment period.

SUTENT may be taken with or without food.

Dose Modification

Daily doses should not exceed 50 mg nor be decreased below 25 mg. Dose modification of 12.5- mg is recommended based on individual safety and tolerability.

CYP3A4 Inhibitors: Concurrent administration of sunitinib malate with the CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in combined (sunitinib + active metabolite) C_max and AUC_0-∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Doses of SUTENT may need to be reduced to a minimum of 25 mg daily, and clinical response and tolerability should be carefully monitored, in patients receiving a potent CYP3A4 inhibitor such as ketoconazole (see DRUG INTERACTIONS and ACTION AND CLINICAL PHARMACOLOGY). Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential should be considered. NOTE: This recommendation is based on pharmacokinetic data from healthy volunteers. In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inhibitors has not been established. In the 2 cytokine-refractory MRCC studies, 14 of the 169 patients used a potent CYP 3A4 inhibitor concomitantly with SUTENT with no modification of the starting dose of SUTENT.

CYP3A4 Inducers: Concurrent administration of sunitinib malate with the potent CYP3A4 inducer, rifampin, resulted in a more than 23% and 46% reduction in combined (sunitinib + active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. The dose of SUTENT may need to be increased (maximum 50mg), and clinical response and tolerability should be carefully monitored, in patients receiving SUTENT with a potent CYP3A4 inducer, such as rifampin (See DRUG INTERACTIONS and ACTION AND CLINICAL PHARMACOLOGY). Selection of an alternate concomitant medication with no or minimal enzyme induction potential should be considered. NOTE: This recommendation is based on pharmacokinetic data from healthy volunteers. In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inducers has not been established. In the two cytokine-refractory MRCC studies, 33 of the 169 patients received a potent CYP3A4 inducer concomitantly with SUTENT with no modification of the starting dose of SUTENT.

Special Populations: No dose adjustment is required on the basis of patient age, body weight, creatinine clearance, race, gender or ECOG score. (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations).

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Overdosage

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Action And Clinical Pharmacology

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SUTENT (sunitinib malate) is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumour growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as a potent inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Inhibition of the activity of these RTKs by sunitinib has been demonstrated in biochemical and/or cellular assays, and inhibition of function has been demonstrated in cell proliferation or viability assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. (see DETAILED PHARMACOLOGY).

Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumour xenografts expressing RTK targets in vivo and demonstrated inhibition of tumour growth or tumour regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumour cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumour angiogenesis in vivo.

Pharmacokinetics

The pharmacokinetics of sunitinib and its primary active metabolite have been evaluated in 135 healthy volunteers and in 266 patients with solid tumours.

Absorption and Distribution
Maximum plasma concentrations (C_max) of sunitinib are generally observed from 6 to 12 hours (T_max) post-dose. Food has no effect on the bioavailability of sunitinib. Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. After repeated daily administration, in the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and C_max for sunitinib and total drug increases proportionally with dose. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite, are achieved within 10 to 14 days. By Day 14, combined trough plasma concentrations of sunitinib and its active metabolite are 62.9-101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite are observed with repeated daily administration or with repeated cycles in the dosing regimens tested. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L.

The pharmacokinetics were similar in healthy volunteers and in the solid tumour patient populations tested, including patients with GIST, MRCC, and pancreatic NET (See CLINICAL TRIALS).

Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no apparent concentration dependence.

Metabolism and Elimination
Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23 to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of [¹⁴C] sunitinib, 61% of the radioactive dose was eliminated in feces, with renal elimination of drug and metabolites accounting for 16% of the administered radioactive dose. Sunitinib and its primary active metabolite are the major drug-related compounds identified in plasma, urine and feces, representing 91.5 %, 86.4 % and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces, but were generally not found in plasma. Total oral clearance (CL/F) was 34 - 62 L/hr with an inter-patient variability of 40%.

Special Populations

Population pharmacokinetic analyses of demographic data suggest that there are no clinically relevant effects of age, body weight, creatinine clearance, race, gender or ECOG score on the pharmacokinetics of sunitinib or the active metabolite.

There are no pharmacokinetic data available in pediatric patients.

Hepatic Insufficiency
A single 50 mg dose of SUTENT was administered to patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, and to control group of patients with normal hepatic function. The pharmacokinetic parameters evaluated demonstrated that dose adjustments to starting dose might not be necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, SUTENT was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. In addition, repeated administration of SUTENT was not studied in subjects with hepatic impairment.

Renal Insufficiency
Safety and efficacy of SUTENT have not been established in patients with severe renal impairment or with end-stage renal disease (ESRD) on hemodialysis. Phase 3 studies that were conducted excluded patients with serum creatinine >2.0 x ULN. However, in a small Phase 1 study, systemic exposures after a single 50mg dose of SUTENT were similar in 8 subjects with severe renal impairment (CLcr<30 mL/min) compared to 8 subjects with normal renal function (CLcr>80 mL/min), although the variability was greater in the patients with severe renal impairment. Even though sunitinib and its primary metabolite were not eliminated through hemodialysis in 8 subjects with ESRD, the total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to 8 subjects with normal renal function, most likely due to a lower absorption of sunitinib in subjects with ESRD.

Based on pharmacokinetic data from this Phase 1 study, no adjustment to starting dose is required when administering SUTENT to patients with renal impairment (mild-severe) or with end-stage renal disease (ESRD) on hemodialysis. Subsequent dose modifications should be based on individual safety and tolerability [see DOSAGE AND ADMINISTRATION, Dose Modification]. Repeated administration of SUTENT was not studied in subjects with renal impairment.

Cases of renal impairment and failure, including fatalities, have been reported with SUTENT use. Caution and careful monitoring of patients with severe renal impairment or ESRD on hemodialysis is required while on SUTENT.

In a population pharmacokinetic analysis, no relationship was observed between renal function (as measured by calculated creatinine clearance, range 42-347 mL/min) and sunitinib pharmacokinetics.

Pharmacodynamics

QT/QTc Interval Prolongation
In a phase I clinical QT study, patients with advanced solid tumours received SUTENT 150 mg on Days 3 and 9, and SUTENT 50 mg daily Days 4 to 8 (positive control given Day 1 and placebo given Day 2). Manual serial ECG readings were conducted in accordance with current guidelines. At approximately twice therapeutic concentrations, SUTENT was associated with QTc prolongation. On both Day 3 and Day 9, SUTENT was associated with a progressive increase in the QTc interval that continued throughout the 24-hour observation period, without reaching any obvious peak, plateau, or offset. Because of this, the peak effect could not be characterized with confidence. At the last observation (24 h), the maximum mean placebo-adjusted increase from baseline was 9.6 (90% CI 4.1, 15.1) msec for Day 3 and 15.4 (90% CI 8.4, 22.4) msec for Day 9 using a time-matched baseline and Fridericia’s heart rate correction. The magnitude of these increases is considered to justify cause for concern. However, no subjects experienced an effect on the QTc interval greater than grade 2 (CTCAE version 3.0). No patient presented with a cardiac arrhythmia (see WARNINGS AND PRECAUTIONS section).

T wave Morphology
At baseline, the incidence of patients with T wave abnormalities and the proportion of ECGs with abnormal T waves was high in this population of cancer patients. After 7 days of SUTENT therapy, however, these incidences had increased.

QTc prolongation in association with changes in T wave morphology has been suggested to merit intensified concern with respect to proarrhythmic potential.

PR Interval and Heart Rate
Mean placebo-adjusted changes in the PR interval were positive at all time points, with the maximum increase occurring 7 to 12 hours post-dosing, followed by a decline at 24 hours. Outlier analyses for the PR interval (>200 msec) were consistent with a shift toward a higher proportion of outliers in patients treated with SUTENT. Excessive PR interval prolongation can result in AV block. Progressive levels of AV block are associated with increasing morbidity and mortality.

On Days 3 and 9, heart rate decreased progressively over the 24 hours period following SUTENT dosing, but was not affected by the positive control. During the study, an event of bradycardia occurred that was considered treatment-related, and dizziness was experienced by 7 of 48 patients.

Bradycardia and AV block are recognized risk factors for torsade de pointes. For this reason, a drug that causes QTc prolongation in associated with prolongation of the PR and RR intervals raises particular concerns with respect to proarrhythmic potential.

Drug-Drug Interactions

In vitro studies indicate that sunitinib does not induce or inhibit major CYP enzymes.

In vitro Studies of CYP Inhibition and Induction: The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

CYP3A4 Inhibitors: Concurrent administration of SUTENT with the potent CYP3A4 inhibitor, ketoconazole, resulted in a 49% and 51% increase in the combined (sunitinib + active metabolite) C_max and AUC_0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers.

Administration of SUTENT with potent inhibitors of the CYP3A4 family may increase SUTENT concentrations. Concomitant administration of SUTENT with inhibitors should 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 dose of SUTENT may need to be reduced (see DOSAGE AND ADMINISTRATION). NOTE: In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inhibitors has not been established.

CYP3A4 Inducers: Concurrent administration of SUTENT with the potent CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + active metabolite) C_max and AUC_0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers.

Administration of SUTENT with potent inducers of CYP3A4 may decrease SUTENT concentrations. Concomitant administration of SUTENT should be avoided or selection of an alternate concomitant medication 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 (see DOSAGE AND ADMINISTRATION). NOTE: In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inducers have not been established.

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Storage And Stability

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Special Handling Instructions

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Dosage Forms, Composition And Packaging

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Report Adverse Event

Pfizer Safety

Contact Pfizer Safety to report an adverse event, side effect or concern about the quality of a Pfizer product: 1 866 723-7111.

To report an adverse event related to the Pfizer-BioNTech COVID-19 Vaccine, and you are not part of a clinical trial* for this product, click the link below to submit your information:

Pfizer Safety Reporting Site

*If you are involved in a clinical trial for this product, adverse events should be reported to your coordinating study site.

Canada Vigilance Program

You may also contact the Canada Vigilance Program directly to report adverse events or product quality concerns at 1-866-234-2345 or www.healthcanada.gc.ca/medeffect.

SUTENT Quick Finder

Health Professional Information

SUMMARY PRODUCT INFORMATION

Indications And Clinical Use

Contraindications

Warnings And Precautions

Carcinogenesis and Mutagenesis

Cardiovascular

Hypertension

Left Ventricular Dysfunction

QT Interval Prolongation

Thrombotic Microangiopathy

Venous Thromboembolic Events/ Pulmonary Embolism

Arterial Thromboembolic Events

Drug Interactions

Endocrine and Metabolism

Adrenal Function Effects

Hypoglycemia

Thyroid dysfunction

Gastrointestinal

Esophagitis

Gastrointestinal Perforation

Gastrointestinal Events

Hemorrhage

Hematologic Events

Hepatic/Biliary/Pancreatic

Metabolism and Nutritional Disorders

Tumour Lysis Syndrome (TLS)

Neurologic

Seizures

Osteonecrosis of the Jaw (ONJ)

Renal

Skin and Tissues

Wound Healing/Surgery

Special Populations

Monitoring and Laboratory Tests

Adverse Reactions

Overview

Adverse Reactions in GIST Placebo-Controlled Study (Study A)

Adverse Reactions in MRCC Patient Population

Adverse Reactions in the Phase 3 pancreatic NET Study

Other Adverse Reactions

Musculoskeletal

Cardiovascular

Investigations

Pulmonary Embolism

Pancreatic and Hepatic Function

Seizures

Skin and subcutaneous tissue disorders

Post-Market Adverse Drug Reactions

Arterial Thromboembolic Events:

Blood and lymphatic system disorders:

Cardiovascular:

Endocrine disorders:

Hemorrhage:

Hepatic and Biliary Function

Immune system disorders:

Infections and infestations:

Musculoskeletal and connective tissue disorders:

Nervous system disorders:

Renal and urinary disorders:

Respiratory disorders:

Vascular disorders:

Gastrointestinal disorders:

Neurologic

Other:

Drug Interactions

Overview

Drug-Drug Interactions

Drug-Food Interactions

Drug-Herb Interactions

Dosage And Administration

Dose Modification

Overdosage

Action And Clinical Pharmacology

Pharmacokinetics

Special Populations

Pharmacodynamics

Drug-Drug Interactions