Sunitinib

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# Black Box Warning

# Overview
Sunitinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate, advanced renal cell carcinoma (RCC) and Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, palmar plantar erythrodysesthesia, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia and bleeding.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Gastrointestinal Stromal Tumor (GIST)
- Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.
- Dosage: one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2).
- Sunitinib malate may be taken with or without food

### Advanced Renal Cell Carcinoma (RCC)
- Sunitinib malate is indicated for the treatment of advanced renal cell carcinoma.
- Dosage: one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2).
- Sunitinib malate may be taken with or without food

### Advanced Pancreatic Neuroendocrine Tumors (pNET)
- Sunitinib malate is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.
- Dosage: 37.5 mg taken orally once daily continuously without a scheduled off-treatment period.
- Sunitinib malate may be taken with or without food.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sunitinib in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Sunitinib in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sunitinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sunitinib in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Sunitinib in pediatric patients.

# Contraindications
None

# Warnings

### Hepatotoxicity
Sunitinib malate has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 ) 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. Sunitinib malate should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart sunitinib malate 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  ULN or, if due to liver metastases, >5.0  ULN has not been established.

### Pregnancy
Sunitinib malate can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of sunitinib malate should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of sunitinib malate in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with sunitinib malate.

### Left Ventricular Dysfunction
In the presence of clinical manifestations of congestive heart failure (CHF), discontinuation of sunitinib malate is recommended. The dose of sunitinib malate should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction 20% below baseline.
Cardiovascular events, including heart failure, myocardial disorders and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience. For GIST and RCC, more patients treated with sunitinib malate experienced decline in left ventricular ejection fraction (LVEF) than patients receiving either placebo or interferon- (IFN-). In the double-blind treatment phase of GIST Study A, 22/209 patients (11%) on sunitinib malate and 3/102 patients (3%) on placebo had treatment-emergent LVEF values below the lower limit of normal (LLN). Nine of 22 GIST patients on sunitinib malate with LVEF changes recovered without intervention. Five patients had documented LVEF recovery following intervention (dose reduction: one patient; addition of antihypertensive or diuretic medications: four patients). Six patients went off study without documented recovery. Additionally, three patients on sunitinib malate had Grade 3 reductions in left ventricular systolic function to LVEF <40%; two of these patients died without receiving further study drug. No GIST patients on placebo had Grade 3 decreased LVEF. In the double-blind treatment phase of GIST Study A, 1 patient on sunitinib malate and 1 patient on placebo died of diagnosed heart failure; 2 patients on sunitinib malate and 2 patients on placebo died of treatment-emergent cardiac arrest.
In the treatment-naive RCC study, 103/375 (27%) and 54/360 (15%) patients on sunitinib malate and IFN-, respectively, had an LVEF value below the LLN. Twenty-six patients on sunitinib malate (7%) and seven on IFN- (2%) experienced declines in LVEF to >20% below baseline and to below 50%. Left ventricular dysfunction was reported in four patients (1%) and CHF in two patients (<1%) who received sunitinib malate.
In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on sunitinib malate and no patients on placebo.
Patients who presented with cardiac events within 12 months prior to sunitinib malate administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from sunitinib malate 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 sunitinib malate. Baseline and periodic evaluations of LVEF should also be considered while these patients are receiving sunitinib malate. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

### QT Interval Prolongation and Torsade de Pointes
Sunitinib malate has been shown to prolong the QT interval in a dose dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes has been observed in <0.1% of sunitinib malate-exposed patients.
Sunitinib malate should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using sunitinib malate, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and dose reduction of sunitinib malate should be considered.

### Hypertension
Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of sunitinib malate is recommended until hypertension is controlled.
Of patients receiving sunitinib malate for treatment-naive RCC, 127/375 patients (34%) receiving sunitinib malate compared with 13/360 patients (4%) on IFN- experienced hypertension. Grade 3 hypertension was observed in 50/375 treatment-naive RCC patients (13%) on sunitinib malate compared to 1/360 patients (200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on sunitinib malate (4%), 1/102 GIST patients on placebo (1%), in 32/375 treatment-naive RCC patients (9%) on sunitinib malate, in 3/360 patients (1%) on IFN-, and in 8/80 pNET patients (10%) on sunitinib malate and 2/76 pNET patients (3%) on placebo.

### Hemorrhagic Events
Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumor, urinary tract and brain hemorrhages. In patients receiving sunitinib malate in a clinical trial for treatment-naive RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%) receiving IFN-. Bleeding events occurred in 37/202 patients (18%) receiving sunitinib malate in the double-blind treatment phase of GIST Study A, compared to 17/102 patients (17%) receiving placebo. Epistaxis was the most common hemorrhagic adverse event reported. Bleeding events, excluding epistaxis, occurred in 18/83 patients (22%) receiving sunitinib malate in the Phase 3 pNET study, compared to 8/82 patients (10%) receiving placebo. Epistaxis was reported in 17/83 patients (20%) receiving sunitinib malate for pNET and 4 patients (5%) receiving placebo. Less common bleeding events in GIST, RCC and pNET patients included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In the double-blind treatment phase of GIST Study A, 14/202 patients (7%) receiving sunitinib malate and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, one patient in GIST Study A taking placebo had a fatal gastrointestinal bleeding event during Cycle 2. Most events in RCC patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a treatment-naive patient. In the pNET study, 1/83 patients (1%) receiving sunitinib malate had Grade 3 epistaxis, and no patients had other Grade 3 or 4 bleeding events. In pNET patients receiving placebo, 3/82 patients (4%) had Grade 3 or 4 bleeding events.
Tumor-related hemorrhage has been observed in patients treated with sunitinib malate. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib malate for MRCC, GIST and metastatic lung cancer. Sunitinib malate is not approved for use in patients with lung cancer. Treatment-emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving sunitinib malate on Study A. Tumor hemorrhages were observed as early as Cycle 1 and as late as Cycle 6. One of these five patients received no further drug following tumor hemorrhage. None of the other four patients discontinued treatment or experienced dose delay due to tumor hemorrhage. No patients with GIST in the Study A placebo arm were observed to undergo intratumoral hemorrhage. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations.
Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred rarely in patients with intra-abdominal malignancies treated with sunitinib malate.

### Osteonecrosis of the Jaw (ONJ)
ONJ has been observed in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease, may increase the risk of osteonecrosis of the jaw.

### Tumor Lysis Syndrome (TLS)
Cases of TLS, some fatal, have been observed in clinical trials and have been reported in post-marketing experience, primarily in patients with RCC or GIST treated with sunitinib malate. Patients generally at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as clinically indicated.

### Thyroid Dysfunction
Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of sunitinib malate treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, on sunitinib malate treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.
Treatment-emergent acquired hypothyroidism was noted in eight GIST patients (4%) on sunitinib malate versus one (1%) on placebo. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on sunitinib malate in the treatment-naive RCC study and in three patients (1%) in the IFN- arm. Hypothyroidism was reported as an adverse reaction in 6/83 patients (7%) on sunitinib malate in the Phase 3 pNET study and in 1/82 patients (1%) in the placebo arm.
Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.

### Wound Healing
Cases of impaired wound healing have been reported during sunitinib malate therapy. Temporary interruption of sunitinib malate therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sunitinib malate therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.

### Proteinuria
Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt sunitinib malate and dose reduce for 24-hour urine protein  3 grams. Discontinue sunitinib malate for patients with nephrotic syndrome or repeat episodes of urine protein  3 grams despite dose reductions. The safety of continued sunitinib malate treatment in patients with moderate to severe proteinuria has not been systematically evaluated.

### Dermatologic Toxicities
Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of SJS, TEN, or EM (e.g., progressive skin rash often with blisters or mucosal lesions) are present, sunitinib malate treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, sunitinib malate treatment must not be re-started.
Necrotizing fasciitis, including fatal cases, has been reported in patients treated with sunitinib malate, including of the perineum and secondary to fistula formation. Discontinue sunitinib malate in patients who develop necrotizing fasciitis.

### Adrenal Function
Physicians prescribing sunitinib malate are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection.
Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 0.7 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/MRI obtained in 336 patients after exposure to one or more cycles of sunitinib malate demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of sunitinib malate. Among patients with normal baseline ACTH stimulation testing, one patient developed consistently abnormal test results during treatment that are unexplained and may be related to treatment with sunitinib malate. Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 1216.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency.

### Laboratory Tests
CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with sunitinib malate.

# Adverse Reactions

## Clinical Trials Experience
The data described below reflect exposure to sunitinib malate in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of GIST, an active-controlled trial (n=375) for the treatment of RCC or a placebo-controlled trial (n=83) for the treatment of pNET. The GIST and RCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles, and the pNET patients received a starting oral dose of 37.5 mg daily without scheduled off-treatment periods.
The most common adverse reactions (20%) in patients with GIST, RCC or pNET are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, palmar-plantar erythrodysesthesia, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia and bleeding. The potentially serious adverse reactions are hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function. Other adverse reactions occurring in GIST, RCC and pNET 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 practice.

### Adverse Reactions in GIST Study A
Median duration of blinded study treatment was two cycles for patients on sunitinib malate (mean 3.0, range 19) and one cycle (mean 1.8, range 16) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on sunitinib malate and none on placebo. Dose interruptions occurred in 59 patients (29%) on sunitinib malate and 31 patients (30%) on placebo. The rates of treatment-emergent, non-fatal adverse reactions resulting in permanent discontinuation were 7% and 6% in the sunitinib malate and placebo groups, respectively.
Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56% versus 51% of patients on sunitinib malate versus placebo, respectively, in the double-blind treatment phase of the trial. Table 1 compares the incidence of common (10%) treatment-emergent adverse reactions for patients receiving sunitinib malate and reported more commonly in patients receiving sunitinib malate than in patients receiving placebo.
In the double-blind treatment phase of GIST Study A, oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on sunitinib malate versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on sunitinib malate versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on sunitinib malate versus 2 (2%) on placebo.
Table 2 provides common (10%) treatment-emergent laboratory abnormalities.
After an interim analysis, the study was unblinded, and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate treatment. For 241 patients randomized to the sunitinib malate arm, including 139 who received sunitinib malate in both the double-blind and open-label treatment phases, the median duration of sunitinib malate treatment was 6 cycles (mean 8.5, range 1  44). For the 255 patients who ultimately received open-label sunitinib malate 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. 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 sunitinib malate in the open-label treatment phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), palmar-plantar erythrodysesthesia (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).

### Adverse Reactions in the Treatment-Naive RCC Study
The as-treated patient population for the treatment-naive RCC study included 735 patients, 375 randomized to sunitinib malate and 360 randomized to IFN-. The median duration of treatment was 11.1 months (range: 0.4  46.1) for sunitinib malate treatment and 4.1 months (range: 0.1  45.6) for IFN- treatment. Dose interruptions occurred in 202 patients (54%) on sunitinib malate and 141 patients (39%) on IFN-. Dose reductions occurred in 194 patients (52%) on sunitinib malate and 98 patients (27%) on IFN-. Discontinuation rates due to adverse reactions were 20% for sunitinib malate and 24% for IFN-. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on sunitinib malate versus IFN-, respectively.
Table 3 compares the incidence of common (10%) treatment-emergent adverse reactions for patients receiving sunitinib malate versus IFN-.
Treatment-emergent Grade 3/4 laboratory abnormalities are presented in Table 4.

### Adverse Reactions in the Phase 3 pNET Study
The median number of days on treatment was 139 days (range 13532 days) for patients on sunitinib malate and 113 days (range 1614 days) for patients on placebo. Nineteen patients (23%) on sunitinib malate and 4 patients (5%) on placebo were on study for >1 year. Dose interruptions occurred in 25 patients (30%) on sunitinib malate and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on sunitinib malate and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for sunitinib malate and 17% for placebo.
Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 54% versus 50% of patients on sunitinib malate versus placebo, respectively. Table 5 compares the incidence of common (10%) treatment-emergent adverse reactions for patients receiving sunitinib malate and reported more commonly in patients receiving sunitinib malate than in patients receiving placebo.
Table 6 provides common (10%) treatment-emergent laboratory abnormalities.

### Venous Thromboembolic Events
Seven patients (3%) on sunitinib malate and none on placebo in the double-blind treatment phase of GIST Study A experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT.
Thirteen (3%) patients receiving sunitinib malate for |treatment-naive RCC]] had venous thromboembolic events reported. Seven (2%) of these patients had pulmonary embolism, one was Grade 2 and six were Grade 4, and six (2%) patients had DVT, including three Grade 3. One patient was permanently withdrawn from sunitinib malate due to pulmonary embolism; dose interruption occurred in two patients with pulmonary embolism and one with DVT. In treatment-naive RCC patients receiving IFN-, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all Grade 4. One patient (1%) receiving sunitinib malate for pNET had a venous thromboembolic events reported compared to 5 patients (6%) receiving placebo. The sunitinib malate patient had Grade 2 thrombosis. Two placebo patients had DVT, one was Grade 3, two placebo patients had pulmonary embolism, one was Grade 3 and one was Grade 4, and one placebo patient had Grade 3 jugular thrombosis.

### Reversible Posterior Leukoencephalopathy Syndrome
There have been reports (<1%), some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness should be controlled with medical management including control of hypertension. Temporary suspension of sunitinib malate is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

### Pancreatic and Hepatic Function
If symptoms of pancreatitis or hepatic failure are present, patients should have sunitinib malate discontinued. Pancreatitis was observed in 5 (1%) patients receiving sunitinib malate for treatment-naive RCC compared to 1 (<1%) patient receiving IFN-. Pancreatitis was observed in 1 (1%) patient receiving sunitinib malate for pNET and 1 (1%) patient receiving placebo. Hepatotoxicity was observed in patients receiving sunitinib malate.

## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of sunitinib malate. 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.

### Blood and lymphatic system disorders
- Thrombotic microangiopathy; hemorrhage associated with thrombocytopenia.
- Suspension of sunitinib malate is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

### Gastrointestinal disorders
- Esophagitis

### Hepatobiliary disorders
- Cholecystitis, particularly acalculous cholecystitis.

### Immune system disorders
- Hypersensitivity reactions, including angioedema.

### Infections and infestations
- Serious infection (with or without neutropenia)
- The infections most commonly observed with sunitinib treatment include respiratory, urinary tract, skin infections, sepsis/septic shock.

### Musculoskeletal and connective tissue disorders
- Fistula formation, sometimes associated with tumor necrosis and/or regression; myopathy and/or rhabdomyolysis with or without acute renal failure.
- Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.

### Renal and urinary disorders
- Renal impairment and/or failure

### Respiratory disorders
- Pulmonary embolism

### Skin and subcutaneous tissue disorders
- Pyoderma gangrenosum, including positive dechallenges.

### Vascular disorders
- Arterial thromboembolic events.
- The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction.

# Drug Interactions

### CYP3A4 Inhibitors
strong CYP3A4 inhibitor such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of sunitinib malate with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0 values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of sunitinib malate with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for sunitinib malate should be considered when it must be co-administered with strong CYP3A4 inhibitors.

### CYP3A4 Inducers
CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of sunitinib malate with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0 values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of sunitinib malate with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving sunitinib malate should not take St. John's Wort concomitantly. A dose increase for sunitinib malate should be considered when it must be co-administered with CYP3A4 inducers.

### In Vitro Studies of CYP Inhibition and Induction
In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. 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 enzyme.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
Sunitinib malate can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of sunitinib malate should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of sunitinib malate in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with sunitinib malate.
Sunitinib was evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) for effects on the embryo. Significant increases in the incidence of embryolethality and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5 times the systemic exposure  in patients administered the recommended daily doses ). Significantly increased embryolethality was observed in rabbits at 5 mg/kg/day while developmental effects were observed at 1 mg/kg/day (approximately 0.3 times the AUC in patients administered the RDD of 50 mg/day). Developmental effects consisted of fetal skeletal malformations of the ribs and vertebrae in rats. In rabbits, cleft lip was observed at 1 mg/kg/day and cleft lip and cleft palate were observed at 5 mg/kg/day (approximately 2.7 times the AUC in patients administered the RDD). Neither fetal loss nor malformations were observed in rats dosed at 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD).
Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses 1 mg/kg/day but no maternal reproductive toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). At the high dose of 3 mg/kg/day, reduced body weights were observed at birth and persisted for offspring of both sexes during the pre-weaning period and in males during post-weaning period. No other developmental toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sunitinib in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Sunitinib during labor and delivery.

### Nursing Mothers
Sunitinib and its metabolites are excreted in rat milk. In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were extensively excreted in milk at concentrations up to 12-fold higher than in plasma. It is not known whether this drug or its primary active metabolite are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from sunitinib malate, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

### Pediatric Use
The safety and efficacy of sunitinib malate in pediatric patients have not been established.
Physeal dysplasia was observed in cynomolgus monkeys with open growth plates treated for 3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) with sunitinib at doses that were >0.4 times the RDD based on systemic exposure (AUC). In developing rats treated continuously for 3 months (1.5, 5.0 and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses 5 mg/kg (approximately 10 times the RDD based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment; however, findings in the teeth were not. A no effect level was not observed in monkeys treated continuously for 3 months, but was 1.5 mg/kg/day when treated intermittently for 8 cycles. In rats the no effect level in bones was 2 mg/kg/day.

### Geriatic Use
Of 825 GIST and RCC patients who received sunitinib malate on clinical studies, 277 (34%) were 65 and over. In the Phase 3 pNET study, 22 (27%) patients who received sunitinib malate were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients.

### Gender
There is no FDA guidance on the use of Sunitinib with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Sunitinib with respect to specific racial populations.

### Renal Impairment
No adjustment to the starting dose is required when administering sunitinib malate to patients with mild, moderate, and severe renal impairment. Subsequent dose modifications should be based on safety and tolerability. In patients with end-stage renal disease (ESRD) on hemodialysis, no adjustment to the starting dose is required. However, compared to subjects with normal renal function, the sunitinib exposure is 47% lower in subjects with ESRD on hemodialysis. Therefore, the subsequent doses may be increased gradually up to 2 fold based on safety and tolerability.

### Hepatic Impairment
No dose adjustment to the starting dose is required when administering sunitinib malate to patients with Child-Pugh Class A or B hepatic impairment. Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of sunitinib malate were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. sunitinib malate was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. Studies in cancer patients have excluded patients with ALT or AST >2.5  ULN or, if due to liver metastases, >5.0  ULN.

### Females of Reproductive Potential and Males
Effects on the female reproductive system were identified in a 3-month repeat dose monkey study (2, 6, 12 mg/kg/day), where ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (5.1 times the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at 2 mg/kg/day (0.4 times the AUC in patients administered the RDD). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day in the 9-month monkey study (0.3, 1.5 and 6 mg/kg/day administered daily for 28 days followed by a 14 day respite; the 6 mg/kg dose produced a mean AUC that was 0.8 times the AUC in patients administered the RDD). A no effect level was not identified in the 3 month study; 1.5 mg/kg/day represents a no effect level in monkeys administered sunitinib for 9 months.
Although fertility was not affected in rats, sunitinib malate may impair fertility in humans. In female rats, no fertility effects were observed at doses of 5.0 mg/kg/day , however significant embryolethality was observed at the 5.0 mg/kg dose. No reproductive effects were observed in male rats dosed (1, 3 or 10 mg/kg/day) for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses 10 mg/kg/day (the 10 mg/kg/day dose produced a mean AUC that was 25.8 times the AUC in patients administered the RDD).

### Immunocompromised Patients
There is no FDA guidance one the use of Sunitinib in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Oral

### Monitoring
There is limited information regarding Sunitinib Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Sunitinib and IV administrations.

# Overdosage
Treatment of overdose with sunitinib malate should consist of general supportive measures. There is no specific antidote for overdosage with sunitinib malate. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. A few cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of sunitinib malate, or without adverse reactions. A case of intentional overdose involving the ingestion of 1,400 mg of sunitinib malate in an attempted suicide was reported without adverse reaction. In non-clinical studies mortality was observed following as few as 5 daily doses of 400 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

# Pharmacology

## Mechanism of Action
Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor 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 an inhibitor of platelet-derived growth factor receptors (PDGFR and PDGFR), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.
Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFR, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFR- and VEGFR2-dependent tumor angiogenesis in vivo.

## Structure
Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with N--5--2,4-dimethyl-1H-pyrrole-3-carboxamide (1:1). The molecular formula is C22H27FN4O2 - C4H6O5 and the molecular weight is 532.6 Daltons.
The chemical structure of sunitinib malate is:

## Pharmacodynamics
There is limited information regarding Sunitinib Pharmacodynamics in the drug label.

## Pharmacokinetics
The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors.
Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. sunitinib malate may be taken with or without food.
Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no concentration dependence in the range of 100  4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25  100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionately with dose.
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 sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were 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 generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hr with an inter-patient variability of 40%.
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. 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 plasma concentrations of sunitinib and its active metabolite ranged from 62.9  101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles in the dosing regimens tested.
The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC.

## Nonclinical Toxicology

### Carcinogenesis and Mutagenesis
The carcinogenic potential of sunitinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at doses of 25 mg/kg/day following daily dose administration of sunitinib in studies of 1 or 6 months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day (approximately 0.9 times the AUC in patients given the RDD of 50 mg/day).At the high dose of 3 mg/kg/day (approximately 7.8 times the AUC in patients at the RDD of 50 mg/day) the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal. Sunitinib did not cause genetic damage when tested in in vitro assays (bacterial mutation ]], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test.

# Clinical Studies

### Gastrointestinal Stromal Tumor
Study A was a two-arm, international, randomized, double-blind, placebo-controlled trial of sunitinib malate in patients with GIST who had disease progression during prior imatinib mesylate (imatinib) treatment or who were intolerant of imatinib. The objective was to compare Time-to-Tumor Progression (TTP) in patients receiving sunitinib malate plus best supportive care versus patients receiving placebo plus best supportive care. Other objectives included Progression-Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS). Patients were randomized (2:1) to receive either 50 mg sunitinib malate or placebo orally, once daily, on Schedule 4/2 until disease progression or withdrawal from the study for another reason. Treatment was unblinded at the time of disease progression. Patients randomized to placebo were then offered crossover to open-label sunitinib malate, and patients randomized to sunitinib malate were permitted to continue treatment per investigator judgment.
At the time of a pre-specified interim analysis, the intent-to-treat (ITT) population included 312 patients. Two-hundred seven (207) patients were randomized to the sunitinib malate arm, and 105 patients were randomized to the placebo arm. Demographics were comparable between the sunitinib malate and placebo groups with regard to age (69% vs 72% <65 years for sunitinib malate vs. placebo, respectively), gender (Male: 64% vs. 61%), race (White: (88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and Performance Status (ECOG 0: 44% vs. 46%, ECOG 1: 55% vs. 52%, and ECOG 2: 1 vs. 2%). Prior treatment included surgery (94% vs. 93%) and radiotherapy (8% vs. 15%). Outcome of prior imatinib treatment was also comparable between arms with intolerance (4% vs. 4%), progression within 6 months of starting treatment (17% vs. 16%), or progression beyond 6 months (78% vs. 80%) balanced.
The planned interim efficacy and safety analysis was performed after 149 TTP events had occurred. There was a statistically significant advantage for sunitinib malate over placebo in TTP, meeting the primary endpoint. Efficacy results are summarized in Table 7 and the Kaplan-Meier curve for TTP is in Figure 1.
The final ITT population enrolled in the double-blind treatment phase of the study included 243 patients randomized to the sunitinib malate arm and 118 patients randomized to the placebo arm. After the primary endpoint was met at the interim analysis, the study was unblinded, and patients on the placebo arm were offered open-label sunitinib malate treatment. Ninety-nine of the patients initially randomized to placebo crossed over to receive sunitinib malate in the open-label treatment phase. At the protocol specified final analysis of OS, the median OS was 72.7 weeks for the sunitinib malate arm and 64.9 weeks for the placebo arm .
Study B was an open-label, multi-center, single-arm, dose-escalation study conducted in patients with GIST following progression on or intolerance to imatinib. Following identification of the recommended Phase 2 regimen (50 mg once daily on Schedule 4/2), 55 patients in this study received the 50 mg dose of sunitinib malate on treatment Schedule 4/2. Partial responses were observed in 5 of 55 patients .

### Renal Cell Carcinoma
A multi-center, international randomized study comparing single-agent sunitinib malate with IFN- was conducted in patients with treatment-naive RCC. The objective was to compare Progression-Free Survival (PFS) in patients receiving sunitinib malate versus patients receiving IFN-. Other endpoints included Objective Response Rate (ORR), Overall Survival (OS) and safety. Seven hundred fifty (750) patients were randomized (1:1) to receive either 50 mg sunitinib malate once daily on Schedule 4/2 or to receive IFN- administered subcutaneously at 9 MIU three times a week. Patients were treated until disease progression or withdrawal from the study.
The ITT population included 750 patients, 375 randomized to sunitinib malate and 375 randomized to IFN-. Demographics were comparable between the sunitinib malate and IFN- groups with regard to age (59% vs. 67% <65 years for sunitinib malate vs. IFN-, respectively), gender (Male: 71% vs. 72%), race (White: 94% vs. 91%, Asian: 2% vs. 3%, Black: 1% vs. 2%, remainder not reported), and Performance Status (ECOG 0: 62% vs. 61%, ECOG 1: 38% each arm, ECOG 2: 0 vs. 1%). Prior treatment included nephrectomy (91% vs. 89%) and radiotherapy (14% each arm). The most common site of metastases present at screening was the lung (78% vs. 80%, respectively), followed by the lymph nodes (58% vs. 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% vs. 77%, respectively).
There was a statistically significant advantage for sunitinib malate over IFN- in the endpoint of PFS (see TABLE 8 and FIGURE 2). In the pre-specified stratification factors of LDH (>1.5 ULN vs. 1.5 ULN), ECOG performance status (0 vs. 1), and prior nephrectomy (yes vs. no), the hazard ratio favored sunitinib malate over IFN-. The ORR was higher in the sunitinib malate arm (see TABLE 8).
At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for the sunitinib malate arm and 94.9 weeks for the IFN- arm . The median OS for the IFN- arm includes 25 patients who discontinued IFN- treatment because of disease progression and crossed over to treatment with sunitinib malate as well as 121 patients (32%) on the IFN- arm who received post-study cancer treatment with sunitinib malate.
The use of single agent sunitinib malate in the treatment of cytokine-refractory RCC was investigated in two single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokine-based therapy. In Study 1, failure of prior cytokine therapy was based on radiographic evidence of disease progression defined by RECIST or World Health Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy treatment (IFN-, interleukin-2, or IFN- plus interleukin-2; patients who were treated with IFN- alone must have received treatment for at least 28 days). In Study 2, failure of prior cytokine therapy was defined as disease progression or unacceptable treatment-related toxicity. The endpoint for both studies was ORR. Duration of Response (DR) was also evaluated.
One hundred six patients (106) were enrolled into Study 1, and 63 patients were enrolled into Study 2. Patients received 50 mg sunitinib malate on Schedule 4/2. Therapy was continued until the patients met withdrawal criteria or had progressive disease. The baseline age, gender, race and ECOG performance statuses of the patients were comparable between Studies 1 and 2. Approximately 8694% of patients in the two studies were White. Men comprised 65% of the pooled population. The median age was 57 years and ranged from 24 to 87 years in the studies. All patients had an ECOG performance status <2 at the screening visit.
The baseline malignancy and prior treatment history of the patients were comparable between Studies 1 and 2. Across the two studies, 95% of the pooled population of patients had at least some component of clear-cell histology. All patients in Study 1 were required to have a histological clear-cell component. Most patients enrolled in the studies (97% of the pooled population) had undergone nephrectomy; prior nephrectomy was required for patients enrolled in Study 1. All patients had received one previous cytokine regimen. Metastatic disease present at the time of study entry included lung metastases in 81% of patients. Liver metastases were more common in Study 1 (27% vs. 16% in Study 2) and bone metastases were more common in Study 2 (51% vs. 25% in Study 1); 52% of patients in the pooled population had at least 3 metastatic sites. Patients with known brain metastases or leptomeningeal disease were excluded from both studies.
The ORR and DR data from Studies 1 and 2 are provided in Table 9. There were 36 PRs in Study 1 as assessed by a core radiology laboratory for an ORR of 34.0% (95% CI 25.0, 43.8). There were 23 PRs in Study 2 as assessed by the investigators for an ORR of 36.5% (95% CI 24.7, 49.6). The majority (>90%) of objective disease responses were observed during the first four cycles; the latest reported response was observed in Cycle 10. DR data from Study 1 is premature as only 9 of 36 patients (25%) responding to treatment had experienced disease progression or died at the time of the data cutoff.

### Pancreatic Neuroendocrine Tumors
The Phase 3 study was a multi-center, international, randomized, double-blind placebo-controlled study of single-agent sunitinib malate conducted in patients with unresectable pNET. Patients were required to have documented RECIST-defined disease progression within the prior 12 months and were randomized (1:1) to receive either 37.5 mg sunitinib malate (n=86) or placebo (n=85) once daily without a scheduled off-treatment period. The primary objective was to compare Progression-Free Survival (PFS) in patients receiving sunitinib malate versus patients receiving placebo. Other endpoints included Overall Survival (OS), Objective Response Rate (ORR), and safety. Use of somatostatin analogs was allowed in the study.
Demographics were comparable between the sunitinib malate and placebo groups. Additionally, 49% of sunitinib malate patients had non-functioning tumors vs 52% of placebo patients, and 92% patients in both arms had liver metastases. A total of 66% of sunitinib malate patients received prior systemic therapy compared with 72% of placebo patients and 35% of sunitinib malate patients had received somatostatin analogs compared with 38% of placebo patients. Patients were treated until disease progression or withdrawal from the study. Upon disease progression, or study closure, patients were offered access to sunitinib malate in a separate extension study.
As recommended by the Independent Data Monitoring Committee, the study was terminated prematurely prior to the pre-specified interim analysis. This may have led to an overestimate of the magnitude of PFS effect. A clinically significant improvement for sunitinib malate over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring sunitinib malate was observed in all subgroups of baseline characteristics evaluated. OS data were not mature at the time of the analysis. There were 9 deaths in the sunitinib malate arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring sunitinib malate over placebo was observed. Efficacy results are summarized in Table 10 and the Kaplan-Meier curve for PFS is in Figure 3.

# How Supplied
- 12.5 mg Capsules
- Bottles of 28
- NDC 0069-0550-38
- 25 mg Capsules
- Bottles of 28
- NDC 0069-0770-38
- 37.5 mg Capsules
- Bottles of 28
- NDC 0069-0830-38
- 50 mg Capsules
- Bottles of 28
- NDC 0069-0980-38

## Storage
Store at 25C (77F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

### Gastrointestinal Disorders
Gastrointestinal disorders such as diarrhea, nausea, stomatitis, dyspepsia, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received sunitinib malate. Supportive care for gastrointestinal adverse events requiring treatment may include anti-emetic or anti-diarrheal medication.

### Skin Effects
Skin discoloration possibly due to the drug color (yellow) occurred in approximately one third of patients. Patients should be advised that depigmentation of the hair or skin may occur during treatment with sunitinib malate. Other possible dermatologic effects may include dryness, thickness or cracking of skin, blister or rash on the palms of the hands and soles of the feet. Severe dermatologic toxicities including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported. Patients should be advised to immediately inform their healthcare provider if severe dermatologic reactions occur.

### Other Common Events
Other commonly reported adverse events included fatigue, high blood pressure, bleeding, swelling, mouth pain/irritation and taste disturbance.

### Musculoskeletal Disorders
Prior to treatment with sunitinib malate, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with sunitinib malate, who have previously received or are receiving bisphosphonates, invasive dental procedures should be avoided, if possible.

### Concomitant Medications
Patients should be advised to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements

# Precautions with Alcohol
Alcohol-Sunitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Sutent 

# Look-Alike Drug Names
There is limited information regarding Sunitinib Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price