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SUTENT (sunitinib capsules) Warnings And Precautions

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Warnings And Precautions

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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