Sutent Information
Sutent (Sunitinib malate)
Sutent (Sunitinib malate) Indications And Usage
Sutent (Sunitinib malate) is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.
Sutent (Sunitinib malate) Dosage And Administration
The recommended dose of Sutent (Sunitinib malate) for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. Sutent (Sunitinib malate) may be taken with or without food.
Dose interruption and/or dose modification in 12.5 mg increments or decrements is recommended based on individual safety and tolerability. The maximum dose administered in the Phase 3 pNET study was 50 mg daily.
Strong CYP3A4 inhibitors such as ketoconazole may sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. A dose reduction for Sutent (Sunitinib malate) to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily should be considered if Sutent (Sunitinib malate) must be co-administered with a strong CYP3A4 inhibitor
CYP3A4 inducers such as rifampin may sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. A dose increase for Sutent (Sunitinib malate) to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily should be considered if Sutent (Sunitinib malate) must be co-administered with a CYP3A4 inducer. If dose is increased, the patient should be monitored carefully for toxicity .
Sutent (Sunitinib malate) Dosage Forms And Strengths
12.5 mg capsulesHard gelatin capsule with orange cap and orange body, printed with white ink "Pfizer" on the cap and "STN 12.5 mg" on the body.
25 mg capsulesHard gelatin capsule with caramel cap and orange body, printed with white ink "Pfizer" on the cap and "STN 25 mg" on the body.
50 mg capsulesHard gelatin capsule with caramel top and caramel body, printed with white ink "Pfizer" on the cap and "STN 50 mg" on the body.
Sutent (Sunitinib malate) Contraindications
Sutent (Sunitinib malate) Warnings And Precautions
Sutent (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 [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 (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 Sutent (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.
Sutent (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 Sutent (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 Sutent (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 Sutent (Sunitinib malate) .
In the presence of clinical manifestations of congestive heart failure (CHF), discontinuation of Sutent (Sunitinib malate) is recommended.
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 Sutent (Sunitinib malate) experienced decline in left ventricular ejection fraction (LVEF) than patients receiving either placebo or interferon-α (IFN-α). In the double-blind treatment phase of GIST Study A, 22/209 patients (11%) on Sutent (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 Sutent (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 Sutent (Sunitinib malate) had Grade 3 reductions in left ventricular systolic function to LVEF
In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on Sutent (Sunitinib malate) and IFN-α, respectively, had an LVEF value below the LLN. Twenty-six patients on Sutent (Sunitinib malate) (7%) and seven on IFN-α (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 (
In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on Sutent (Sunitinib malate) and no patients on placebo.
Patients who presented with cardiac events within 12 months prior to Sutent (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 Sutent (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.
Sutent (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
Sutent (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 Sutent (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 Sutent (Sunitinib malate) should be considered .
Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of Sutent (Sunitinib malate) is recommended until hypertension is controlled.
Of patients receiving Sutent (Sunitinib malate) for treatment-naïve RCC, 127/375 patients (34%) receiving Sutent (Sunitinib malate) compared with 13/360 patients (4%) on IFN-α experienced hypertension. Grade 3 hypertension was observed in 50/375 treatment-naïve RCC patients (13%) on Sutent (Sunitinib malate) compared to 1/360 patients (200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on Sutent (Sunitinib malate) (4%), 1/102 GIST patients on placebo (1%), in 32/375 treatment-naïve RCC patients (9%) on Sutent (Sunitinib malate) , in 3/360 patients (1%) on IFN-α, and in 8/80 pNET patients (10%) on Sutent (Sunitinib malate) and 2/76 pNET patients (3%) on placebo.
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 Sutent (Sunitinib malate) in a clinical trial for treatment-naïve RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%) receiving IFN-α. Bleeding events occurred in 37/202 patients (18%) receiving Sutent (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 Sutent (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 Sutent (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 Sutent (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-naïve patient. In the pNET study, 1/83 patients (1%) receiving Sutent (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 Sutent (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. Fatal pulmonary hemorrhage occurred in 2 patients receiving Sutent (Sunitinib malate) on a clinical trial of patients with metastatic non-small cell lung cancer (NSCLC). Both patients had squamous cell histology. Sutent (Sunitinib malate) is not approved for use in patients with NSCLC. Treatment-emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving Sutent (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 Sutent (Sunitinib malate) .
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 Sutent (Sunitinib malate) treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on Sutent (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 Sutent (Sunitinib malate) versus one (1%) on placebo. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on Sutent (Sunitinib malate) in the treatment-naïve RCC study and in three patients (1%) in the IFN-α arm. Hypothyroidism was reported as an adverse reaction in 6/83 patients (7%) on Sutent (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.
Cases of impaired wound healing have been reported during Sutent (Sunitinib malate) therapy. Temporary interruption of Sutent (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 Sutent (Sunitinib malate) therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.
Physicians prescribing Sutent (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 Sutent (Sunitinib malate) demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of Sutent (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 Sutent (Sunitinib malate) . Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 12–16.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency.
Sutent (Sunitinib malate) Adverse Reactions
The data described below reflect exposure to Sutent (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, hand-foot syndrome, 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 of hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function are discussed in . 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.
Sutent (Sunitinib malate) Use In Specific Populations
The safety and efficacy of Sutent (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.
Sutent (Sunitinib malate) Overdosage
Treatment of overdose with Sutent (Sunitinib malate) should consist of general supportive measures. There is no specific antidote for overdosage with Sutent (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 Sutent (Sunitinib malate) , or without adverse reactions. A case of intentional overdose involving the ingestion of 1,500 mg of Sutent (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 500 mg/kg (3000 mg/m) 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.
Sutent (Sunitinib malate) Description
Sutent (Sunitinib malate) , an oral multi-kinase inhibitor, is the malate salt of sunitinib. Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with -[2-(diethylamino)ethyl]-5-[()-(5-fluoro-1,2-dihydro-2-oxo--indol-3-ylidine)methyl]-2,4-dimethyl--pyrrole-3-carboxamide (1:1). The molecular formula is CHFNO ∙ CHO and the molecular weight is 532.6 Daltons.
The chemical structure of sunitinib malate is:
Sunitinib malate is a yellow to orange powder with a pKa of 8.95. The solubility of sunitinib malate in aqueous media over the range pH 1.2 to pH 6.8 is in excess of 25 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7 is 5.2.
Sutent (Sunitinib malate) capsules are supplied as printed hard shell capsules containing sunitinib malate equivalent to 12.5 mg, 25 mg or 50 mg of sunitinib together with mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate as inactive ingredients.
The orange gelatin capsule shells contain titanium dioxide, and red iron oxide. The caramel gelatin capsule shells contain titanium dioxide, red iron oxide, yellow iron oxide and black iron oxide. The white printing ink contains shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide.
Sutent (Sunitinib malate) Clinical Pharmacology
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 (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor 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 (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets 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) and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis .
The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors.
Maximum plasma concentrations (C) of sunitinib are generally observed between 6 and 12 hours (T) following oral administration. Food has no effect on the bioavailability of sunitinib. Sutent (Sunitinib malate) may be taken with or without food.
Binding of sunitinib and its primary active metabolite to human plasma protein 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 C 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 [C]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.
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Sutent (Sunitinib malate) Clinical Studies
The Phase 3 study was a multi-center, international, randomized, double-blind placebo-controlled study of single-agent Sutent (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 Sutent (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 Sutent (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 Sutent (Sunitinib malate) and placebo groups. Additionally, 49% of Sutent (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 Sutent (Sunitinib malate) patients received prior systemic therapy compared with 72% of placebo patients and 35% of Sutent (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 Sutent (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 Sutent (Sunitinib malate) over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring Sutent (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 Sutent (Sunitinib malate) arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring Sutent (Sunitinib malate) over placebo was observed. Efficacy results are summarized in Table 10 and the Kaplan-Meier curve for PFS is in Figure 3.
Figure 3. Kaplan-Meier Curve of PFS in the pNET Phase 3 Study
Sutent (Sunitinib malate) How Supplied/storage And Handling
12.5 mg Capsules
Hard gelatin capsule with orange cap and orange body, printed with white ink "Pfizer" on the cap, "STN 12.5 mg" on the body; available in:
Bottles of 28: NDC 0069-0550-38
25 mg Capsules
Hard gelatin capsule with caramel cap and orange body, printed with white ink "Pfizer" on the cap, "STN 25 mg" on the body; available in:
Bottles of 28: NDC 0069-0770-38
50 mg Capsules
Hard gelatin capsule with caramel cap and caramel body, printed with white ink "Pfizer" on the cap, "STN 50 mg" on the body; available in:
Bottles of 28: NDC 0069-0980-38
Sutent (Sunitinib malate) Patient Counseling Information
Sutent (Sunitinib malate)
Sutent (Sunitinib malate)
Sutent (Sunitinib malate)
Sutent (Sunitinib malate)
