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通用名称：苹果酸舒尼替尼胶囊

  商品名称：苹果酸舒尼替尼胶囊(索坦)

【主要成份】 苹果酸舒尼替尼 化学名：(Z)-N-[2-(二乙胺基)乙基-5-[(5-氟-2-氧代-1，2-二氢-3H-吲哚-3-亚基)甲基]-2，4-二甲基-3-氨甲酰-1H-吡咯苹果酸盐 分子式：C22H27FN4O2 ·C4H6O5 分子量：532.6

【性 状】 本品为胶囊剂，内容物为黄色至橙色的颗粒。

【适应症/功能主治】 1）甲磺酸伊马替尼治疗失败或不能耐受的胃肠间质瘤（GIST） 2）不能手术的晚期肾细胞癌（RCC）

【规格型号】50mg，6片。

【用法用量】本品治疗胃肠间质瘤和晚期肾细胞癌的推荐剂量是50mg，每日一次，口服；服药4周，停药2周(4/2 给药方案)。与食物同服或不同服均可。

【不良反应】尚不明确。

【禁 忌】对本品或药物的非活性成份严重过敏者禁用。

【注意事项】 尚缺乏充分的中国人群临床研究数据，建议在有本品使用经验的医生指导下使用。 左心室功能障碍 若出现充血性心力衰竭(CHF)的临床表现，建议停止使用本品。无充血性心力衰竭临床证据但射血分数小于50% 以及射血分数低于基线20% 的患者也应停止本品治疗和/或减低剂量。 接受舒尼替尼治疗的患者中出现左心室射血分数下降的人数多于安慰剂组或IFN-α组。在胃肠间质瘤（GIST）的研究 A 中， 舒尼替尼组和安慰剂组分别有22/209 例（11%）患者和 3/102 例(3%）患者出现了治疗相关的左心室射血分数 (LVEF)低于正常值下限 (LLN)。舒尼替尼组22 例LVEF 改变的患者中有9 例未经处理自行恢复；5例患者经处理后恢复正常（1例患者减低剂量；4例患者另给予抗高血压药或利尿剂治疗）；6 例患者结束研究但没有恢复情况的记录。此外，舒尼替尼组有3 例（1%）患者出现3 级左心室收缩功能下降至LVEF<40%，其中2 例患者未接受研究药物进一步治疗即死亡。安慰剂组无患者出现3 级LVEF 下降。在胃肠间质瘤（GIST）研究A 中，两组各有1 例患者（舒尼替尼组&

【儿童用药】尚无本品用于儿童患者的安全性和有效性临床研究

【老年患者用药】接受本品治疗的825 例胃肠间质瘤（GIST）和晚期/转移性肾细胞癌（MRCC）患者中有277 例（34%）年龄在65岁或65岁以上。未发现年轻患者与老年患者在安全性或有效性方面存在差异。

【孕妇及哺乳期妇女用药】 妊娠分类D 由于血管形成是胚胎和胎儿发育的关键，舒尼替尼抑制血管形成，可能对妊娠产生不良作用。未在孕妇中对本品进行充分的、严格对照的研究。如果患者妊娠期间使用本品或接受本品治疗期间妊娠，应告知患者药物对胎儿的潜在危害。育龄妇女接受本品治疗时应避孕。 在妊娠大鼠（0.3， 1.5， 3.0， 5.0 mg/kg/日剂量）和妊娠家兔（0.5， 1， 5， 20 mg/kg/日剂量）中评价了舒尼替尼对胚胎的影响。5mg/kg/日剂量时（约为人推荐日剂量[RDD]AUC 的5.5 倍），观察到大鼠的胚胎死亡和发育异常的发生率明显增加。家兔实验中，5mg/kg/日剂量时发现胚胎死亡发生率明显增加，当剂量≥1 mg/kg/日时（约为人推荐日剂量50mg/日时AUC 的0.3 倍）发现发育异常。对发育的影响包括大鼠胎仔的肋骨和椎骨的骨骼畸形发生率增加。家兔实验中，1 mg/kg/日剂量观察到唇裂，5mg/kg/日（约为人推荐日剂量AUC 的2.7 倍）剂量观察到唇裂和腭裂。大鼠实验中，当剂量≤3 mg/kg/日时（约为人推荐日剂量的2.3 倍）未见胎仔流产或畸形。 哺乳妇女

【药物相互作用】CYP3A4 抑制剂：CYP3A4 强抑制剂，如酮康唑，可增加舒尼替尼的血浆浓度。建议选择对此类酶没有或只有最小抑制作用的合并用药。如果必须与CYP3A4 强抑制剂同时应用时，需要考虑降低本品剂量。健康志愿者服用单剂量苹果酸舒尼替尼，同时给予CYP3A4 强抑制剂（酮康唑），可导致总体（舒尼替尼及其主要活性代谢产物）的Cmax 和AUC0-∞分别增加49% 和51% 。舒尼替尼与CYP3A4 酶系强抑制剂（例如：酮康唑、伊曲康唑、克拉霉素、atazanavir 、印地那韦、萘法唑酮、那非那韦、利托那韦、沙奎那韦、泰利霉素、伏立康唑）同时应用时，可增加舒尼替尼浓度，葡萄柚也可增加舒尼替尼的血药浓度。如果必须与CYP3A4 强抑制剂同时应用时，需要考虑降低本品剂量。 CYP3A4 诱导剂：CYP3A4 诱导剂，如利福平，可降低舒尼替尼的血浆浓度。建议选择对此类酶没有或只有最小诱导作用的合并用药。健康志愿者服用单剂舒尼替尼，同时给予CYP3A4 强诱导剂（利福平），可导致总体（舒尼替尼及其主要活性代谢产物）的Cmax 和AUC0-∞分别降低23% 和46% 。舒尼替

【药物过量】处理本品药物过量的方法包括一般的支持性措施。无治疗本品过量的特效解毒剂。如果有临床指征时，应采用催吐或洗胃清除未吸收的药物。已完成的临床研究中未有本品药物过量的报告。非临床研究中在500mg/kg（3000mg/m2）/日，最少给药5 天即观察到大鼠死亡。在此剂量水平，毒性反应征象包括肌肉协调障碍、摇头、活动减退、眼睛分泌物、竖毛和胃肠道不适。在更低剂量水平但更长治疗持续时间时也观察到死亡及相似的毒性反应征象。

【药理毒理】 药理作用 苹果酸舒尼替尼是一种能抑制多个受体酪氨酸激酶（RTK）的小分子，其中某些受体酪氨酸激酶参与肿瘤生长、病理性血管形成和肿瘤转移的过程。通过对舒尼替尼抑制各种激酶（80多种激酶）的活性进行评价，证明舒尼替尼可抑制血小板衍生生长因子受体(PDGFR α和 PDGFRβ)、血管内皮生长因子受体（VEGFR1、VEGFR2 和VEGFR3）、干细胞因子受体（KIT）、Fms 样酪氨酸激酶-3（FLT3）、1型集落刺激因子受体（CSF-1R）和神经胶质细胞系衍生的神经营养因子受体（RET）。生化和细胞测定证实舒尼替尼能抑制这些受体酪氨酸激酶（RTK）的活性，并在细胞增殖测定中证明了舒尼替尼的抑制作用。生化和细胞测定表明主要代谢物与舒尼替尼活性相似。 在表达受体酪氨酸激酶靶点的肿瘤模型的体内试验中，舒尼替尼能抑制多个受体酪氨酸激酶（PDGFR β、VEGFR2 、KIT） 的磷酸化进程；在某些动物肿瘤模型中显示出抑制肿瘤生长或导致肿瘤消退，和/或抑制肿瘤转移的作用。体外实验结果表明苹果酸舒尼替尼能抑制靶向受体酪氨酸激酶（PDGFR、RET 或KIT）表达失调的肿瘤细胞生长，体内试验结果表明其能抑制PDGFRβ-和VEGFR2-依赖的肿瘤血管形成。 毒理研究 重复给药毒性：一项3个月的猴重复给药试验（2，6，12mg/kg/日剂量）研究了药物对雌性生殖系统的影响，12 mg/kg/日剂量（约为推荐人用日剂量[RDD]的AUC 的5.1 倍）观察到卵巢变化（卵泡发育下降）；在≥2 mg/kg/日剂量（约为推荐人用日剂量[RDD] 的AUC 的0.4 倍）观察到子宫变化（子宫内膜萎缩）。在一项9个月的猴重复给药研究中，6mg/kg/日剂量时除阴道萎缩外，还对子宫和卵巢有影响（每日给药0.3， 1.5 和6 mg/kg/日剂量，连续给药28天，停药14天，6 mg/kg/日剂量产生的平均AUC 约为推荐人用日剂量[RDD] AUC 的0.8 倍）。3个月的研究中未明确无毒性效应水平；9个月的研究中无毒性效应剂量水平为1.5mg/kg/日。 生殖毒性：虽然舒尼替尼不影响大鼠的生育能力，但可能损害人的生育能力。雌性大鼠每天给药≤5.0 mg/kg/日剂量未发现生殖毒性(0.5，1.5，5.0 mg/kg/日剂量，给

【药代动力学】 尚缺乏中国人群的药代动力学研究数据，以下均为来自国外的人体药代动力学研究数据。 已在135 例健康志愿者和266 例实体瘤患者中评价了舒尼替尼和苹果酸舒尼替尼的药代动力学。 吸收、分布、代谢和排泄 一般在口服给药后6-1 2小时（Tmax）舒尼替尼达到最大血浆浓度（Cmax）。进食对舒尼替尼生物利用度无影响。与食物同服或不同服均可。 体外实验表明舒尼替尼及其主要活性代谢物的人血浆蛋白结合率分别为95% 和90% ，在100-4000ng/mL 范围内无浓度依赖。舒尼替尼的表观分布容积 (Vd/F)为 2230L. 在25-100mg 的剂量范围内， 血浆药时曲线下面积 (AUC)和最大血浆浓度（Cmax）随剂量成比例增加。 舒尼替尼主要由细胞色素P450 CYP3A4 代谢，产生的主要活性代谢物被CYP3A4 进一步代谢。其主要活性代谢物占总暴露量的23-37%。主要通过粪便排泄。在一项[14C] 标记的舒尼替尼质量平衡的人体试验中，剂量的61% 是通过粪便排出，而肾脏排泄的药物和代谢物约占剂量的16% 。舒尼替尼和主要活性代谢物在血浆、尿和粪便中发现的主要药物相关成分，分别代表了合并标本中的91.5% 、86.4 % 和73.8% 的放射活性。尿和粪便中能检测到次要代谢物，但在血浆中一般未能发现。总口服清除率（CL/F）为34-62 升/小时，患者间的变异系数为40% 。 健康志愿者口服单剂量舒尼替尼后，舒尼替尼和主要活性代谢物的终末半衰期分别为40-60 小时和80-110 小时。每日重复给药后，舒尼替尼蓄积3-4 倍，而其主要代谢物蓄积7-10 倍，在10-14 天内舒尼替尼和主要活性代谢物达稳态浓度。第14 天血浆舒尼替尼和主要活性代谢物的总浓度为62.9-101 ng/mL。每日重复给药或按治疗方案重复周期给药，未发现舒尼替尼和主要活性代谢物的药代动力学有明显的变化。 受试的健康志愿者和实体瘤患者的药代动力学相似，包括胃肠道间质瘤（GIST）和晚期/转移性肾细胞癌（MRCC）患者。 特殊群体 群体药代动力学分析的人口学数据表明年龄、体重、肌酐清除率、人种、性别或ECOG 体力状态评分对舒尼替尼或其活性代谢物的药代动力学没有临床相关性影响

WARNING: HEPATOTOXICITY

Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported. [See Warnings and Precautions (5.1)]

Indications and Usage for Sutent

Gastrointestinal Stromal Tumor (GIST)

Sutent is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.

Advanced Renal Cell Carcinoma (RCC)

Sutent is indicated for the treatment of advanced renal cell carcinoma.

Advanced Pancreatic Neuroendocrine Tumors (pNET)

Sutent is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.

SLIDESHOW

Sutent Dosage and Administration

Recommended Dose for GIST and RCC

The recommended dose of Sutent for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). Sutent may be taken with or without food.

Recommended Dose for pNET

The recommended dose of Sutent for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. Sutent may be taken with or without food.

Dose Modification

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 increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. A dose reduction for Sutent to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily should be considered if Sutent must be co-administered with a strong CYP3A4 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

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. A dose increase for Sutent to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily should be considered if Sutent must be co-administered with a CYP3A4 inducer. If dose is increased, the patient should be monitored carefully for toxicity [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Dosage Forms and Strengths

12.5 mg capsules Hard 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 capsules Hard gelatin capsule with caramel cap and orange body, printed with white ink "Pfizer" on the cap and "STN 25 mg" on the body.

37.5 mg capsules

Hard gelatin capsule with yellow cap and yellow body, printed with black ink "Pfizer" on the cap and "STN 37.5 mg" on the body.

50 mg capsules

Hard gelatin capsule with caramel top and caramel body, printed with white ink "Pfizer" on the cap and "STN 50 mg" on the body.

Contraindications

None

Warnings and Precautions

Hepatotoxicity

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 × ULN or, if due to liver metastases, >5.0 × ULN has not been established.

Pregnancy

Sutent 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 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 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.

Cardiovascular Events

In the presence of clinical manifestations of congestive heart failure (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.

Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported. Use Sutent with caution in patients who are at risk for, or who have a history of, these events. For GIST and RCC, more patients treated with Sutent 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 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 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 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 Sutent and 1 patient on placebo died of diagnosed heart failure; 2 patients on Sutent and 2 patients on placebo died of treatment-emergent cardiac arrest.

In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on Sutent and IFN-α, respectively, had an LVEF value below the LLN. Twenty-six patients on Sutent (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 (<1%) who received Sutent.

In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on Sutent and no patients on placebo.

Patients who presented with cardiac events within 12 months prior to Sutent 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 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.

QT Interval Prolongation and Torsade de Pointes

Sutent 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 Sutent-exposed patients.

Sutent 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, 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 should be considered [see Dosage and Administration (2.2)].

Hypertension

Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of Sutent is recommended until hypertension is controlled.

Of patients receiving Sutent for treatment-naïve RCC, 127/375 patients (34%) receiving Sutent 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 compared to 1/360 patients (<1%) on IFN-α. While all-grade hypertension was similar in GIST patients on Sutent compared to placebo, Grade 3 hypertension was reported in 9/202 GIST patients on Sutent (4%), and none of the GIST patients on placebo. Of patients receiving Sutent in the Phase 3 pNET study, 22/83 patients (27%) on Sutent and 4/82 patients (5%) on placebo experienced hypertension. Grade 3 hypertension was reported in 8/83 pNET patients (10%) on Sutent, and 1/82 patient (1%) on placebo. No Grade 4 hypertension was reported. Sutent dosing was reduced or temporarily delayed for hypertension in 21/375 patients (6%) on the treatment-naive RCC study and 7/83 pNET patients (8%). Four treatment-naïve RCC patients, including one with malignant hypertension, one patient with pNET, and no GIST patients discontinued treatment due to hypertension. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on Sutent (4%), 1/102 GIST patients on placebo (1%), in 32/375 treatment-naïve RCC patients (9%) on Sutent, in 3/360 patients (1%) on IFN-α, and in 8/80 pNET patients (10%) on Sutent 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 Sutent 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 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 in the Phase 3 pNET study, compared to 8/82 patients (10%) receiving placebo. Epistaxis was reported in 17/83 patients (20%) receiving Sutent 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 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 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. 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 Sutent for MRCC, GIST and metastatic lung cancer. Sutent 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 Sutent 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.

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 Sutent. 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.

Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, 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. Discontinue Sutent in patients developing TMA. Reversal of the effects of TMA has been observed after treatment was discontinued.

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 Sutent and dose reduce for 24-hour urine protein ≥ 3 grams. Discontinue Sutent for patients with nephrotic syndrome or repeat episodes of urine protein ≥ 3 grams despite dose reductions. The safety of continued Sutent 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, Sutent treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, Sutent treatment must not be re-started.

Necrotizing fasciitis, including fatal cases, has been reported in patients treated with Sutent, including of the perineum and secondary to fistula formation. Discontinue Sutent in patients who develop necrotizing fasciitis.

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 Sutent treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, on Sutent 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 versus one (1%) on placebo. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on Sutent 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 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.

Hypoglycemia

Sutent has been associated with symptomatic hypoglycemia, which may result in loss of consciousness, or require hospitalization. Hypoglycemia has occurred in clinical trials in 2% of the patients treated with Sutent for RCC and GIST and in approximately 10% of the patients treated with Sutent for pNET. For patients being treated with Sutent for pNET, pre-existing abnormalities in glucose homeostasis were not present in all patients who experienced hypoglycemia. Reductions in blood glucose levels may be worse in diabetic patients. Check blood glucose levels regularly during and after discontinuation of treatment with Sutent. Assess if anti-diabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

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.

Wound Healing

Cases of impaired wound healing have been reported during Sutent therapy. Temporary interruption of Sutent 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 therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.

Adrenal Function

Physicians prescribing Sutent 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 demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of Sutent. 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. 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.

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 Sutent.

Adverse Reactions

The data described below reflect exposure to Sutent in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of GIST [see Clinical Studies (14.1)], an active-controlled trial (n=375) for the treatment of RCC [see Clinical Studies (14.2)] or a placebo-controlled trial (n=83) for the treatment of pNET [see Clinical Studies (14.3)]. 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 Warnings and Precautions (5). 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 Sutent (mean 3.0, range 1–9) and one cycle (mean 1.8, range 1–6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on Sutent and none on placebo. Dose interruptions occurred in 59 patients (29%) on Sutent 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 Sutent 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 Sutent 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 Sutent and reported more commonly in patients receiving Sutent 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 Sutent versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on Sutent versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on Sutent 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 Sutent treatment [see Clinical Studies (14.1)]. For 241 patients randomized to the Sutent arm, including 139 who received Sutent in both the double-blind and open-label treatment phases, the median duration of Sutent treatment was 6 cycles (mean 8.5, range 1 – 44). For the 255 patients who ultimately received open-label Sutent treatment, median duration of study treatment was 6 cycles (mean 7.8, range 1 – 37) from the time of the unblinding. A total of 118 patients (46%) required dosing interruptions, and a total of 72 patients (28%) required dose reductions. The incidence of treatment-emergent adverse reactions resulting in permanent discontinuation was 20%. The most common Grade 3 or 4 treatment-related adverse reactions experienced by patients receiving Sutent in the open-label treatment phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).

Adverse Reactions in the Treatment-Naïve RCC Study

The as-treated patient population for the treatment-naive RCC study included 735 patients, 375 randomized to Sutent and 360 randomized to IFN-α. The median duration of treatment was 11.1 months (range: 0.4 – 46.1) for Sutent treatment and 4.1 months (range: 0.1 – 45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on Sutent and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on Sutent and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for Sutent and 24% for IFN-α. 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 Sutent versus IFN-α, respectively.

Table 3 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving Sutent versus IFN-α.

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 13–532 days) for patients on Sutent and 113 days (range 1–614 days) for patients on placebo. Nineteen patients (23%) on Sutent and 4 patients (5%) on placebo were on study for >1 year. Dose interruptions occurred in 25 patients (30%) on Sutent and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on Sutent and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for Sutent 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 Sutent versus placebo, respectively. Table 5 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving Sutent and reported more commonly in patients receiving Sutent than in patients receiving placebo.

Table 6 provides common (≥10%) treatment-emergent laboratory abnormalities.

Venous Thromboembolic Events

Seven patients (3%) on Sutent 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 Sutent for treatment-naïve 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 Sutent due to pulmonary embolism; dose interruption occurred in two patients with pulmonary embolism and one with DVT. In treatment-naïve RCC patients receiving IFN-α, 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 Sutent for pNET had a venous thromboembolic event reported compared to 5 patients (6%) receiving placebo. The Sutent 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 Sutent 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 Sutent discontinued. Pancreatitis was observed in 5 (1%) patients receiving Sutent for treatment-naïve RCC compared to 1 (<1%) patient receiving IFN-α. Pancreatitis was observed in 1 (1%) patient receiving Sutent for pNET and 1 (1%) patient receiving placebo. Hepatotoxicity was observed in patients receiving Sutent [see Boxed Warning and Warnings and Precautions (5.1)].

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of Sutent. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia1. Suspension of Sutent 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)1. 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 regression1; myopathy and/or rhabdomyolysis with or without acute renal failure1. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.

Renal and urinary disorders: renal impairment and/or failure1.

Respiratory disorders: pulmonary embolism1.

Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive dechallenges.

Vascular disorders: arterial thromboembolic events1. The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction.

1

including some fatalities

Drug Interactions

CYP3A4 Inhibitors

Strong CYP3A4 inhibitors 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 Sutent 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 Sutent in healthy volunteers. Co-administration of Sutent 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 Sutent should be considered when it must be co-administered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)].

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 Sutent 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 Sutent in healthy volunteers. Co-administration of Sutent 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 Sutent should not take St. John's Wort concomitantly. A dose increase for Sutent should be considered when it must be co-administered with CYP3A4 inducers [see Dosage and Administration (2.2)].

In Vitro Studies of CYP Inhibition and Induction

In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitrostudies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.2)].

Sutent 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 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 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 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 [combined AUC of sunitinib + primary active metabolite] in patients administered the recommended daily doses [RDD]). 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).

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 Sutent, 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 Sutent 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.

Geriatric Use

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

Hepatic Impairment

No dose adjustment to the starting dose is required when administering Sutent 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 Sutent were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. Sutent 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.

Renal Impairment

No adjustment to the starting dose is required when administering Sutent to patients with mild, moderate, and severe renal impairment. Subsequent dose modifications should be based on safety and tolerability [see Dosage and Administration (2.3)]. 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.

Overdosage

Treatment of overdose with Sutent should consist of general supportive measures. There is no specific antidote for overdosage with Sutent. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of Sutent, or without adverse reactions. A case of intentional overdose involving the ingestion of 1,500 mg of Sutent 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/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.

Sutent Description

Sutent, an oral multi-kinase inhibitor, is the malate salt of sunitinib. Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-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 strlate 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, 37.5 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 yellow gelatin capsule shells contain titanium dioxide and yellow iron oxide. The white printing ink contains shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide. The black printing ink contains shellac, propylene glycol, potassium hydroxide and black iron oxide.

Sutent - Clinical 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 (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 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 PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.

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. Sutent 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 [14C]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.

Pharmacokinetics in Special Populations

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

Pediatric Use: The pharmacokinetics of Sutent have not been evaluated in pediatric patients.

Renal Insufficiency: Sunitinib systemic exposure after a single dose of Sutent was similar in subjects with severe renal impairment (CLcr<30 mL/min) compared to subjects with normal renal function (CLcr>80 mL/min). Although sunitinib was not eliminated through hemodialysis, the sunitinib systemic exposure was 47% lower in subjects with ESRD on hemodialysis compared to subjects with normal renal function.

Hepatic Insufficiency: Systemic exposures after a single dose of Sutent were similar in subjects with mild exocrine (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment compared to subjects with normal hepatic function.

Cardiac Electrophysiology

See Warnings and Precautions (5.4).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 [AMES Assay], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test.

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, Sutent may impair fertility in humans. In female rats, no fertility effects were observed at doses of ≤5.0 mg/kg/day [(0.5, 1.5, 5.0 mg/kg/day) administered for 21 days up to gestational day 7; the 5.0 mg/kg dose produced an AUC that was ≥5 times the AUC in patients administered the RDD], 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).

Clinical Studies

Gastrointestinal Stromal Tumor

GIST Study A

Study A was a two-arm, international, randomized, double-blind, placebo-controlled trial of Sutent 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 Sutent 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 Sutent 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 Sutent, and patients randomized to Sutent 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 Sutent arm, and 105 patients were randomized to the placebo arm. Demographics were comparable between the Sutent and placebo groups with regard to age (69% vs 72% <65 years for Sutent 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 Sutent 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.

Figure 1. Kaplan-Meier Curve of TTP in GIST Study A 

(Intent-to-Treat Population)

 

The final ITT population enrolled in the double-blind treatment phase of the study included 243 patients randomized to the Sutent 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 Sutent treatment. Ninety-nine of the patients initially randomized to placebo crossed over to receive Sutent in the open-label treatment phase. At the protocol specified final analysis of OS, the median OS was 72.7 weeks for the Sutent arm and 64.9 weeks for the placebo arm [HR= 0.876, 95% CI (0.679, 1.129)].

Study B

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 Sutent on treatment Schedule 4/2. Partial responses were observed in 5 of 55 patients [9.1% PR rate, 95% CI (3.0, 20.0)].

Renal Cell Carcinoma

Treatment-Naïve RCC

A multi-center, international randomized study comparing single-agent Sutent with IFN-α was conducted in patients with treatment-naïve RCC. The objective was to compare Progression-Free Survival (PFS) in patients receiving Sutent versus patients receiving IFN-α. 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 Sutent once daily on Schedule 4/2 or to receive IFN-α 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 Sutent and 375 randomized to IFN-α. Demographics were comparable between the Sutent and IFN-α groups with regard to age (59% vs. 67% <65 years for Sutent vs. IFN-α, 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 Sutent over IFN-α in the endpoint of PFS (see Table 8and 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 Sutent over IFN-α. The ORR was higher in the Sutent arm (see Table 8).

Figure 2. Kaplan-Meier Curve of PFS in Treatment-Naïve RCC Study

 (Intent-to-Treat Population)

At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for the Sutent arm and 94.9 weeks for the IFN-α arm [HR= 0.821, 95% CI (0.673, 1.001)]. The median OS for the IFN-α arm includes 25 patients who discontinued IFN-α treatment because of disease progression and crossed over to treatment with Sutent as well as 121 patients (32%) on the IFN-α arm who received post-study cancer treatment with Sutent.

Cytokine-Refractory RCC

The use of single agent Sutent 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-α, interleukin-2, or IFN-α plus interleukin-2; patients who were treated with IFN-α 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 Sutent 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 86–94% 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 Sutent 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 (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 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 and placebo groups. Additionally, 49% of Sutent 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 patients received prior systemic therapy compared with 72% of placebo patients and 35% of Sutent 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 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 over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring Sutent 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 arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring Sutent over placebo was observed. Efficacy results are summarized in Table 10 and the Kaplan-Meier curve for PFS is in Figure 3.

Table 10. pNET Efficacy Results from the Phase 3 Study
Efficacy Parameter	Sutent (n=86)	Placebo (n=85)	P-value	HR (95% CI)
CI=Confidence interval, HR=Hazard ratio, NA=Not applicable
* 2-sided unstratified log-rank test † Fisher's Exact test
Progression-Free Survival [median, months (95% CI)]	10.2 (7.4, 16.9)	5.4 (3.4, 6.0)	0.000146*	0.427 (0.271, 0.673)
Objective Response Rate [%, (95% CI)]	9.3 (3.2, 15.4)	0	0.0066†	NA

Figure 3. Kaplan-Meier Curve of PFS in the pNET Phase 3 Study                                                                                               

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

37.5 mg Capsules

Hard gelatin capsule with yellow cap and yellow body, printed with black ink "Pfizer" on the cap, "STN 37.5 mg" on the body; available in:
Bottles of 28: NDC 0069-0830-38

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

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

Patient Counseling Information

Advise the patient to read the FDA-Approved Patient Labeling (Medication Guide).

Gastrointestinal Disorders

Gastrointestinal disorders such as diarrhea, nausea, stomatitis, dyspepsia, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received Sutent. 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 Sutent. 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 reactions included fatigue, high blood pressure, bleeding, swelling, mouth pain/irritation and taste disturbance.

Osteonecrosis of the Jaw

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

Hypoglycemia

Patients should be advised of the signs, symptoms, and risks associated with hypoglycemia that may occur during treatment with Sutent. Hypoglycemia may be more severe in patients with diabetes taking anti-diabetic medications. Severe hypoglycemia including loss of consciousness or requiring hospitalization has been reported. Patients should be advised to immediately inform their healthcare provider if severe signs or symptoms of hypoglycemia occur.

Thrombotic Microangiopathy

Thrombotic microangiopathy leading to renal insufficiency and neurologic abnormalities was observed in patients who received Sutent as monotherapy or in combination with bevacizumab. Patients should be advised that signs and symptoms of thrombotic microangiopathy may occur during treatment with Sutent. Patients should be advised to immediately inform their healthcare provider if signs and symptoms of thrombotic microangiopathy occur.

Proteinuria

Proteinuria and nephrotic syndrome has been reported. Patients should be advised that urinalysis will be performed prior to starting as well as during treatment with Sutent. In cases with impact to renal function, treatment with Sutent may be interrupted or discontinued.

Concomitant Medications

Patients should be advised to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements [see Drug Interactions (7)].

This product's label may have been updated. For full prescribing information, please visit www.pfizer.com.                                    

LAB-0317-21.0

MEDICATION GUIDE

Sutent (su TENT)
(sunitinib malate)
capsules

Read the Medication Guide that comes with Sutent before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about Sutent, ask your healthcare provider or pharmacist.

What is the most important information I should know about Sutent?

Sutent can cause serious liver problems, including death.

Tell your healthcare provider right away if you develop any of the following signs and symptoms of liver problems during treatment with Sutent:

o    itching,

o    yellow eyes or skin,

o    dark urine, and

o    pain or discomfort in the right upper stomach area.

Your healthcare provider should do blood tests to check your liver function before you start taking Sutent and during treatment.

What is Sutent?

Sutent is a prescription medicine used to treat people with:

·         a rare cancer of the stomach, bowel, or esophagus called GIST (gastrointestinal stromal tumor) and when:

o    the medicine Gleevec® (imatinib mesylate) did not stop the cancer from growing, or

o    you cannot take Gleevec®.

·         advanced kidney cancer (advanced renal cell carcinoma or RCC).

·         a type of pancreatic cancer known as pancreatic neuroendocrine tumors (pNET), that has progressed and cannot be treated with surgery.

It is not known if Sutent is safe and effective in children.

What should I tell my healthcare provider before taking Sutent?

Before taking Sutent tell your healthcare provider if you:

have any heart problemshave high blood pressurehave thyroid problemshave a history of low blood sugar or diabeteshave kidney function problems (other than cancer)have liver problemshave any bleeding problemhave seizureshave or have had pain in the mouth, teeth or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a toothhave any other medical conditionsare pregnant, could be pregnant or plan to become pregnant. Sutent may harm an unborn baby. You should not become pregnant while taking Sutent. Tell your healthcare provider right away if you become pregnant while taking Sutent.are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take Sutent or breastfeed. You should not do both.

Tell all of your healthcare providers and dentists that you are taking Sutent. They should talk to the healthcare provider who prescribed Sutent for you, before you have any surgery, or medical or dental procedure.

Tell your healthcare provider about all the medicines you take, including prescription medicines and non-prescription medicines, vitamins, and herbal supplements. Using Sutent with certain other medicines can cause serious side effects.

You may have an increased risk of severe jaw bone problems (osteonecrosis) if you take Sutent and a bisphosphonate medicine. Especially tell your healthcare provider if you are taking or have taken Actonel, Aredia, Boniva, Didronel, Fosamax, Reclast, Skelid or Zometa.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Talk with your healthcare provider before starting any new medicines.

How should I take Sutent?

Take Sutent exactly the way your healthcare provider tells you.Take Sutent 1 time each day with or without food.If you take Sutent for GIST or RCC, you will usually take your medicine for 4 weeks (28 days) and then stop for 2 weeks (14 days). This is 1 cycle of treatment. You will repeat this cycle for as long as your healthcare provider tells you to.If you take Sutent for pNET, take it one time each day until your healthcare provider tells you to stop.Do not open the Sutent capsules.Do not drink grapefruit juice or eat grapefruit during your treatment with Sutent. They may cause you to have too much Sutent in your body.Your healthcare provider may do blood tests before each cycle of treatment.If you miss a dose, take it as soon as you remember. Do not take it if it is close to your next dose. Just take the next dose at your regular time. Do not take more than 1 dose of Sutent at a time. Tell your healthcare provider about any missed dose.Call your healthcare provider right away, if you take too much Sutent.

What are possible side effects of Sutent?

Sutent may cause serious side effects including:

See "What is the most important information I should know about Sutent?"Heart problems. Heart problems may include heart failure, heart attack and heart muscle problems (cardiomyopathy) that can lead to death. Tell your healthcare provider if you feel very tired, are short of breath, or have swollen feet and ankles.Abnormal heart rhythm changes. Your healthcare provider may do electrocardiograms and blood tests to watch for these problems during your treatment with Sutent. Tell your healthcare provider if you feel dizzy, faint, or have abnormal heartbeats while taking Sutent.High blood pressure. Your healthcare provider may check your blood pressure during treatment with Sutent. Your healthcare provider may prescribe medicine for you to treat high blood pressure, if needed.Bleeding sometimes leading to death. Tell your healthcare provider right away if you have any of these symptoms or a serious bleeding problem during treatment with Sutent.

o    painful, swollen stomach (abdomen)

o    vomiting blood

o    black, sticky stools

o    bloody urine

o    headache or change in your mental status

Your healthcare provider can tell you other symptoms to watch for.

Jaw-bone problems (osteonecrosis)
Severe jaw bone problems may happen when you take Sutent. Your healthcare provider should examine your mouth before you start Sutent. Your healthcare provider may tell you to see your dentist before you start Sutent.Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells and may lead to death. TLS may cause you to have nausea, shortness of breath, irregular heartbeat, clouding of urine and tiredness associated with abnormal laboratory test results (high potassium, uric acid and phosphorous levels and low calcium levels in the blood) that can lead to changes in kidney function and acute kidney failure. Your healthcare provider may do blood tests to check you for TLS.Damage to the smallest blood vessels. Damage to the smallest blood vessels known as thrombotic microangiopathy (TMA) may occur. TMA is a condition involving injury to the vessels and resulting blood clots and is accompanied by injury to red blood cells leading to a decrease in red cells and a decrease in cells that are involved with clotting. TMA may harm organs such as the brain and kidneys. Symptoms of TMA may include fever, fatigue, tiredness, bruising; you may develop swelling, confusion, vision loss, and seizures. Your healthcare provider may tell you to stop taking Sutent.Protein in your urine. Your healthcare provider will check you for this problem. If there is too much protein in your urine, your healthcare provider may tell you to stop taking Sutent.Serious skin and mouth reactions. Sutent can cause serious skin reactions that can cause death. This can include rash, widespread blistering or peeling of the skin and blistering and peeling on the inside of your mouth. If you develop a rash or these skin symptoms, tell your healthcare provider immediately. Your healthcare provider may tell you to stop taking Sutent.Hormone problems, including thyroid and adrenal gland problems. Your healthcare provider may do tests to check your thyroid and adrenal gland function during Sutent treatment. Tell your healthcare provider if you have any of the following signs and symptoms during treatment with Sutent:

o    tiredness that worsens and does not go away o    loss of appetite o    heat intolerance o    feeling nervous or agitated, tremors o    sweating o    nausea or vomiting

o    diarrhea o    fast heart rate o    weight gain or weight loss o    feeling depressed o    irregular menstrual periods or no menstrual periods o    headache o    hair loss

Low blood sugar (hypoglycemia). Low blood sugar can happen with Sutent, and may cause you to become unconscious, or you may need to be hospitalized. Low blood sugar with Sutent may be worse in people who have diabetes and take anti-diabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with Sutent and may need to adjust the dose of your anti-diabetic medicines. Signs and symptoms of low blood sugar may include:

o    headache o    drowsiness o    weakness o    dizziness o    confusion

o    irritability o    hunger o    fast heart beat o    sweating o    feeling jittery

Common side effects of Sutent include:

·         The medicine in Sutent is yellow, and it may make your skin look yellow. Your skin and hair may get lighter in color. ·         tiredness ·         weakness ·         fever ·         gastrointestinal symptoms, including diarrhea, nausea, vomiting, mouth sores, upset stomach, abdominal pain, and constipation. Talk with your healthcare provider about ways to handle these problems.

·         rash or other skin changes, including drier, thicker, or cracking skin ·         blisters or a rash on the palms of your hands and soles of your feet ·         taste changes ·         loss of appetite ·         pain or swelling in your arms or legs ·         cough ·         shortness of breath ·         bleeding, such as nosebleeds or bleeding from cuts

Call your healthcare provider if you have any swelling or bleeding during treatment with Sutent.

These are not all the possible side effects of Sutent. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store Sutent?

Store Sutent at room temperature, between 59°F to 86°F (15°C to 30°C).

Keep Sutent and all medicines out of the reach of children.

General information about Sutent

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Sutent for a condition for which it was not prescribed. Do not give Sutent to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide gives the most important information about Sutent. For more information about Sutent, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about Sutent that is written for health professionals.

For more information go to www.Sutent.com or call 1-877-5-Sutent.

What are the ingredients in Sutent?

Active ingredient: sunitinib malate

Inactive ingredients: mannitol, croscarmellose sodium, povidone (K-25), magnesium stearate Orange gelatin capsule shell: titanium dioxide, red iron oxide

Caramel gelatin capsule shell: titanium dioxide, red iron oxide, yellow iron oxide, black iron oxide White printing ink: shellac, propylene glycol, sodium hydroxide, povidone, titanium dioxide

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Gleevec® is a registered trademark of Novartis Pharmaceuticals Corp

LAB-0361-9.0
April 2015

PRINCIPAL DISPLAY PANEL - 12.5 mg Capsule Bottle Label

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 0069-0550-38

Pfizer

Sutent®
(sunitinib malate)

12.5 mg*

Capsules

28 Capsules
Rx only

PRINCIPAL DISPLAY PANEL - 25 mg Capsule Bottle Label

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 0069-0770-38

Pfizer

Sutent®
(sunitinib malate)

25 mg*

Capsules

28 Capsules
Rx only

PRINCIPAL DISPLAY PANEL - 50 mg Capsule Bottle Label

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 0069-0980-38

Pfizer

Sutent®
(sunitinib malate)

50 mg*

Capsules

28 Capsules
Rx only

PRINCIPAL DISPLAY PANEL - 37.5 mg Capsule Bottle Label

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 0069-0830-38

Pfizer

Sutent®
(sunitinib malate)

37.5 mg*

Capsules

28 Capsules
Rx only

Sutent sunitinib malate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0069-0550 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUNITINIB MALATE (SUNITINIB) SUNITINIB 12.5 mg

Inactive Ingredients Ingredient Name Strength MANNITOL   CROSCARMELLOSE SODIUM   POVIDONE K25   MAGNESIUM STEARATE   GELATIN, UNSPECIFIED   TITANIUM DIOXIDE   FERRIC OXIDE RED   SHELLAC   PROPYLENE GLYCOL   SODIUM HYDROXIDE   POVIDONE, UNSPECIFIED   POTASSIUM HYDROXIDE

Product Characteristics Color ORANGE Score no score Shape CAPSULE Size 14mm Flavor Imprint Code Pfizer;STN;12;5;mg Contains

Packaging # Item Code Package Description 1 NDC:0069-0550-38 28 CAPSULE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021938 01/26/2006

Sutent sunitinib malate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0069-0770 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUNITINIB MALATE (SUNITINIB) SUNITINIB 25 mg

Inactive Ingredients Ingredient Name Strength MANNITOL   CROSCARMELLOSE SODIUM   POVIDONE K25   MAGNESIUM STEARATE   GELATIN, UNSPECIFIED   TITANIUM DIOXIDE   FERRIC OXIDE RED   FERRIC OXIDE YELLOW   FERROSOFERRIC OXIDE   SHELLAC   PROPYLENE GLYCOL   SODIUM HYDROXIDE   POVIDONE, UNSPECIFIED   POTASSIUM HYDROXIDE

Product Characteristics Color ORANGE, BROWN (caramel) Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Pfizer;STN;25;mg Contains

Packaging # Item Code Package Description 1 NDC:0069-0770-38 28 CAPSULE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021938 01/26/2006

Sutent sunitinib malate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0069-0980 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUNITINIB MALATE (SUNITINIB) SUNITINIB 50 mg

Inactive Ingredients Ingredient Name Strength MANNITOL   CROSCARMELLOSE SODIUM   POVIDONE K25   MAGNESIUM STEARATE   GELATIN, UNSPECIFIED   TITANIUM DIOXIDE   FERRIC OXIDE RED   FERRIC OXIDE YELLOW   FERROSOFERRIC OXIDE   SHELLAC   PROPYLENE GLYCOL   SODIUM HYDROXIDE   POVIDONE, UNSPECIFIED   POTASSIUM HYDROXIDE

Product Characteristics Color BROWN (caramel) Score no score Shape CAPSULE Size 18mm Flavor Imprint Code Pfizer;STN;50;mg Contains

Packaging # Item Code Package Description 1 NDC:0069-0980-38 28 CAPSULE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021938 01/26/2006

Sutent sunitinib malate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0069-0830 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUNITINIB MALATE (SUNITINIB) SUNITINIB 37.5 mg

Inactive Ingredients Ingredient Name Strength MANNITOL   CROSCARMELLOSE SODIUM   POVIDONE K25   MAGNESIUM STEARATE   GELATIN, UNSPECIFIED   TITANIUM DIOXIDE   FERRIC OXIDE RED   FERRIC OXIDE YELLOW   FERROSOFERRIC OXIDE   SHELLAC   PROPYLENE GLYCOL   SODIUM HYDROXIDE   POVIDONE, UNSPECIFIED   POTASSIUM HYDROXIDE

Product Characteristics Color YELLOW Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Pfizer;STN;37;5;mg Contains

Packaging # Item Code Package Description 1 NDC:0069-0830-38 28 CAPSULE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021938 07/12/2014

Labeler - Pfizer Laboratories Div Pfizer Inc (134489525)
Establishment
Name	Address	ID/FEI	Operations
Pfizer Ireland Pharmaceuticals		896090987	API MANUFACTURE(0069-0830, 0069-0980, 0069-0770, 0069-0550)

Establishment
Name	Address	ID/FEI	Operations
Pfizer Italia S.r.l.		458521908	API MANUFACTURE(0069-0550, 0069-0770, 0069-0830, 0069-0980), MANUFACTURE(0069-0550, 0069-0770, 0069-0830, 0069-0980)

Revised: 03/2017

Pfizer Laboratories Div Pfizer Inc