SUTENT® (sunitinib malate) capsules, oral
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use sutent safely and effectively. See full prescribing information for sutent.
sutent (sunitinib malatecapsule for oral use
Initial U.S. Approval: 2006

RECENT MAJOR CHANGES

Indications and Usage ( 1.2) 7/2006
Warnings and Precautions, Left Ventricular Function ( 5.2) 7/2006
Warnings and Precautions, QT Interval Prolongation ( 5.3) 7/2006
Warnings and Precautions, Hemorrhagic Events ( 5.4) 7/2006
Warnings and Precautions, Hypertension ( 5.5) 7/2006

INDICATIONS AND USAGE

SUTENT is a multi-kinase inhibitor indicated for

  • the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.
  • the treatment of advanced renal cell carcinoma (RCC).

DOSAGE AND ADMINISTRATION

  • One 50-mg oral capsule 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. Dose increase or reduction of 12.5-mg increments is recommended based on individual safety and tolerability.

DOSAGE FORMS AND STRENGTHS

  • 12.5-mg capsules
  • 25-mg capsules
  • 50-mg capsules

CONTRAINDICATIONS

  • None

WARNINGS AND PRECAUTIONS

  • Pregnancy Category D: There are no adequate and well-controlled studies of SUTENT in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SUTENT.
  • Left Ventricular Dysfunction: Left ventricular ejection fraction (LVEF) declines have been observed below the lower limit of normal in both GIST and MRCC patients. It is unknown whether patients with concomitant cardiac 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 the patient is receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered. In the presence of clinical manifestations of CHF, discontinuation of SUTENT is recommended. The dose of SUTENT should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.
  • QT Interval Prolongation: At approximately twice therapeutic concentrations, SUTENT has been shown to prolong the QTcF interval. Torsade de pointe has been observed in <0.1% of SUTENT-exposed patients. SUTENT should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. 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.
  • Hemorrhagic Events: Tumor-related hemorrhage has been observed in patients treated with SUTENT as early as cycle 1 and as late as cycle 6. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations.
  • Hypertension: Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 4% of GIST patients on SUTENT and 1% of GIST patients on placebo, 5% of treatment-naïve MRCC patients on SUTENT and 1% on interferon-α (IFN-α), and 6% of cytokine-refractory MRCC patients. Patients should be monitored for hypertension and treated as needed with standard antihypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.

ADVERSE REACTIONS

  • Most common all-causality adverse reactions (≥ 20%) are Constitutional (fatigue), Gastrointestinal (diarrhea, nausea, mucositis/stomatitis, vomiting, constipation, and abdominal pain), Cardiac (hypertension), Dermatology (rash, skin discoloration), Neurology (altered taste, headache), Musculoskeletal (arthralgia, myalgia/limb pain), Metabolism/Nutrition (anorexia, asthenia), Hemorrhage/bleeding (bleeding, all sites).
  • Elevated liver function tests, pancreatic enzymes, creatinine, and myelosuppression were more common in GIST patients treated with SUTENT than placebo. Acquired hypothyroidism was noted in 8 patients (4%) on SUTENT versus 1 (1%) on placebo. Common treatment emergent laboratory abnormalities also observed in the MRCC studies included hypophosphatemia, hyperuricemia and increased lipase.


To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS

  • CYP3A4 Inhibitors: Concurrent administration of sunitinib malate with the strong CYP3A4 inhibitor, ketoconazole, resulted in an increase in exposure after a single dose of sunitinib malate. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors.
  • CYP3A4 Inducers: Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a reduction in exposure after a single dose of SUTENT. A dose increase for SUTENT should be considered when it must be co-administered with CYP3A4 inducers.

USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: It is not known whether sunitinib or its primary active metabolite is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, women should be advised against breastfeeding while taking SUTENT.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.



Revised: 02/2007

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1 INDICATIONS AND USAGE

1.1 Gastrointestinal Stromal Tumor

1.2 Advanced Renal Cell Carcinoma

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

2.2 Dose Modification

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Pregnancy Category D

5.2 Left Ventricular Dysfunction

5.3 QT Interval Prolongation

5.4 Hemorrhagic Events

5.5 Hypertension

5.6 Adrenal Function

5.7 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Overview

6.2 Adverse Events in GIST Study A

6.3 Adverse Events in MRCC Studies

6.4 Cardiovascular Events

6.5 Venous Thromboembolic Events

6.6 Seizures

6.7 Laboratory Abnormalities/Testing

7 DRUG INTERACTIONS

7.1 In Vitro Studies of CYP Inhibition and Induction

7.2 CYP3A4 Inhibitors

7.3 CYP3A4 Inducers

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism Of Action

12.3 Pharmacokinetics

12.4 Cardiac Electrophysiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Gastrointestinal Stromal Tumor

14.2 Renal Cell Carcinoma

15 REFERENCE

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 12.5-mg Capsules

16.2 25-mg Capsules

16.3 50-mg Capsules

16.4 Storage

17 PATIENT COUNSELING INFORMATION

17.1 Gastrointestinal Disorders

17.2 Skin Effects

17.3 Other Common Events

17.4 Concomitant Medications


FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Gastrointestinal Stromal Tumor

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

1.2 Advanced Renal Cell Carcinoma

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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dose of SUTENT for 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. SUTENT may be taken with or without food.

2.2 Dose Modification

Dose increase or reduction of 12.5-mg increments is recommended based on individual safety and tolerability.

Strong CYP3A4 inhibitors such as ketoconazole may increase SUTENT plasma concentrations (see 7 DRUG INTERACTIONS). 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 daily should be considered if SUTENT must be co-administered with a strong CYP3A4 inhibitor.

CYP3A4 inducers such as rifampin may decrease SUTENT plasma concentrations (see 7 DRUG INTERACTIONS). 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 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. St. John's Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. John's Wort concomitantly.

3 DOSAGE FORMS AND STRENGTHS

12.5-mg capsules

25-mg capsules

50-mg capsules

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Pregnancy Category D

Sunitinib was evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) for effects on the embryo. Significant increases in the incidence of embryolethality and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5 times the systemic exposure in patients administered the recommended daily doses [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).

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. There are no adequate and well-controlled studies of SUTENT in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SUTENT.

5.2 Left Ventricular Dysfunction

In GIST Study A, 22/209 patients (11%) on SUTENT and 3/102 patients (3%) on placebo had treatment-emergent left ventricular ejection fraction (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 (1%) 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 GIST Study A, 1 patient (<1%) on SUTENT and 1 patient (1%) on placebo died of diagnosed heart failure; 2 patients (1%) on SUTENT and 2 patients (2%) on placebo died of treatment-emergent cardiac arrest.  In the treatment-naïve MRCC study, 78 (21%) and 44 (12%) patients on SUTENT and IFN-α, respectively, had an LVEF value below the LLN. One (<1%) patient who received SUTENT was diagnosed with congestive heart failure (CHF). In the two cytokine-refractory MRCC studies, 25 patients (15%) had decreases in LVEF to below the LLN.

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 the patient is receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

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

5.3 QT Interval Prolongation

 At approximately twice therapeutic concentrations, SUTENT has been shown to prolong the QTcF interval (see 12.4 Cardiac Electrophysiology). There were no patients on this study with greater than Grade 2 (CTCAE v3.0) QT/QTc interval prolongation. QT interval prolongation may lead to an increased risk for ventricular arrhythmias including torsade de pointes. Torsade de pointe has been observed in <0.1% of SUTENT-exposed patients. SUTENT should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. 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 2.2 Dose Modification).

5.4 Hemorrhagic Events

Bleeding events occurred in 37/202 patients (18%) receiving SUTENT in GIST Study A, compared to 17/102 patients (17%) receiving placebo.  In patients receiving SUTENT for treatment-naïve MRCC, 104/375 patients (28%) had bleeding events compared with 25/360 patients (7%) receiving IFN-α; 44/169 patients (26%) receiving SUTENT for cytokine-refractory MRCC experienced bleeding. Epistaxis was the most common hemorrhagic adverse event reported. Less common bleeding events in GIST or MRCC patients included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In GIST Study A, 14/202 patients (7%) receiving SUTENT and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, one patient in Study A taking placebo had a fatal gastrointestinal bleeding event during cycle 2. Most events in MRCC patients were Grade 1 or 2; there was one Grade 3 event (bleeding foot wound) in a cytokine-refractory patient  and one Grade 5 event of gastric bleed, unrelated to SUTENT treatment, in a treatment-naïve patient.

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. Fatal pulmonary hemorrhage occurred in 2 patients receiving SUTENT on a clinical trial of patients with metastatic non-small cell lung cancer (NSCLC). Both patients had squamous cell histology. SUTENT is not approved for use in patients with NSCLC. Treatment-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. Tumor hemorrhage has not been observed in patients with MRCC. 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.

5.5 Hypertension

Hypertension (all grades) was reported in 31/202 GIST patients on SUTENT (15%) and 11/102 GIST patients on placebo (11%); Grade 3 hypertension was reported in 9/202 GIST patients on SUTENT (4%), none of the GIST patients on placebo.  Of patients receiving SUTENT for treatment-naïve MRCC, 101/375 patients (27%) receiving SUTENT compared with 13/360 patients (4%) on IFN-α experienced hypertension, as did 48/169 cytokine-refractory MRCC patients (28%). Grade 3 hypertension was observed in  34/375 treatment-naïve MRCC patients (9%) on SUTENT compared to 1/360 patient (<1%) on IFN-α, and 10/169 cytokine-refractory MRCC patients (6%). No Grade 4 hypertension was reported. SUTENT dosing was reduced or temporarily delayed for hypertension in none of the patients in GIST Study A and 6/169 cytokine-refractory MRCC patients (4%). No patients were discontinued from treatment with SUTENT due to systemic 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%),  20/375 treatment-naïve patients (5%) on SUTENT and 2/360 patients (1%) on IFN-α, and 10/169 cytokine-refractory MRCC patients (6%).

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.

5.6 Adrenal Function

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.

Physicians prescribing SUTENT are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection.

5.7 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.

6 ADVERSE REACTIONS

6.1 Overview

One thousand nine hundred twenty-four (1924) patients with solid tumors including 808 patients (42%) with GIST and 816 patients (42%) with MRCC have been treated with SUTENT in 20 completed and ongoing clinical trials. Most patients received SUTENT once daily as a 50-mg oral capsule on Schedule 4/2. One hundred two (102) patients received placebo in the randomized, double-blind, placebo-controlled clinical trial conducted in patients with GIST. Three hundred sixty (360) patients received IFN-α in the randomized clinical trial in patients with treatment-naïve MRCC.

The potentially serious adverse events relating to left ventricular dysfunction, hemorrhage, hypertension, and adrenal function are discussed in Section 5 WARNINGS AND PRECAUTIONS. Other all-causality adverse events occurring in GIST and MRCC studies are described below.

6.2 Adverse Events 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. Dose reductions occurred in 23 patients (11%) on SUTENTand 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 events resulting in permanent discontinuation were 7% and 6% in the SUTENT and placebo groups, respectively.

Most treatment-emergent adverse events in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse events were reported in 56% vs. 51% of patients on SUTENT versus placebo, respectively. Diarrhea, hypertension, bleeding, mucositis, skin abnormalities, and altered taste were more common in patients receiving SUTENT. Table 1 compares the incidence of common (>10%) treatment-emergent adverse events for patients receiving SUTENT versus those on placebo.

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 1. Treatment-Emergent Adverse Events Reported in at Least 10% of GIST Patients Who Received SUTENT or Placebo in Study A*
GIST
SUTENT (n=202) Placebo (n=102)
Adverse Event, n (%) All Grades Grade 3/4 All Grades Grade 3/4
*
Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0
Grade 4 AEs in patients on SUTENT included abdominal pain (2%) and bleeding (2%).
Grade 4 AEs in patients on placebo included fatigue (3%), mucositis (1%), vomiting (1%), abdominal pain (3%), back pain (1%), and bone pain (1%).
§
Includes abdominal quadrant, gastric, hypochondrial, abdominal, flank, and cancer-related pain
Includes decreased appetite
Any 114 (56) 52 (51)
Constitutional
  Fatigue 84 (42) 17 (8) 48 (47) 8 (8)
  Fever 36 (18) 3 (2) 17 (17) 1 (1)
Gastrointestinal
  Diarrhea 81 (40) 9 (4) 27 (27) 0 (0)
  Nausea 63 (31) 3 (2) 33 (32) 5 (5)
  Mucositis/stomatitis 58 (29) 2 (1) 18 (18) 2 (2)
  Vomiting 49 (24) 4 (2) 24 (24) 3 (3)
  Constipation 41 (20) 0 (0) 14 (14) 2 (2)
  Abdominal pain§ 67 (33) 22 (11) 39 (38) 12 (12)
Cardiac
  Hypertension 31 (15) 9 (4) 11 (11) 0 (0)
Dermatology
  Rash 28 (14) 2 (1) 9 (9) 0 (0)
  Skin discoloration 61 (30) 0 (0) 23 (23) 0 (0)
  Hand-foot syndrome 28 (14) 9 (4) 10 (10) 3 (3)
Neurology
  Altered taste 42 (21) 0 (0) 12 (12) 0 (0)
  Headache 26 (13) 3 (2) 23 (23) 0 (0)
Musculoskeletal
  Arthralgia 24 (12) 2 (1) 16 (16) 0 (0)
  Back pain 23 (11) 2 (1) 16 (16) 4 (4)
  Myalgia/limb pain 28 (14) 1 (1) 9 (9) 1 (1)
Respiratory
  Dyspnea 20 (10) 0 (0) 19 (19) 3 (3)
  Cough 17 (8) 0 (0) 13 (13) 0 (0)
Metabolism/Nutrition
  Anorexia 67 (33) 1 (1) 30 (29) 5 (5)
  Asthenia 45 (22) 10 (5) 11 (11) 3 (3)
Hemorrhage/Bleeding
  Bleeding, all sites 37 (18) 14 (7) 17 (17) 9 (9)

Table 2 provides common (≥10%) treatment-emergent laboratory abnormalities. Grade 3 or 4 treatment-emergent laboratory abnormalities were observed in 68 (34%) versus 22 (22%) patients on SUTENT and placebo, respectively. Elevated liver function tests, pancreatic enzymes, and creatinine were more common in patients treated with SUTENT than placebo. Decreased LVEF and myelosuppression were also more common with SUTENT treatment. Treatment-emergent electrolyte disturbances of all types were more common in patients on SUTENT than on placebo, including hyperkalemia (6% vs. 4%), hypokalemia (12% vs. 4%), hypernatremia (10% vs. 4%), hyponatremia (6% vs. 1%), and hypophosphatemia (9% vs. 0%). Three SUTENT patients (1.5%) had Grade 3 hypophosphatemia. Acquired hypothyroidism was noted in 8 patients (4%) on SUTENT versus 1 (1%) on placebo.

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

6.3 Adverse Events in MRCC Studies

The as-treated patient population for the interim safety analysis of the treatment-naive MRCC study included 735 patients, 375 randomized to SUTENT and 360 randomized to IFN-α. The median duration of treatment was 5.6 months (range: 0.4–15.6) for SUTENT treatment and 4.1 months (range: 0.1–13.7) on IFN-α treatment. Dose reductions occurred in 121 patients (32%) on SUTENTand 77 patients (21%) on IFN-α. Dose interruptions occurred in 142 patients (38%) on SUTENT and 115 patients (32%) on IFN-α. The rates of treatment-emergent, non-fatal adverse events resulting in permanent discontinuation were 8% and 13% in the SUTENT and IFN-α groups, respectively. Most treatment-emergent adverse events in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse events were reported in 63% versus 48% of patients on SUTENT versus IFN-α, respectively. Diarrhea, mucositis/ stomatitis, dyspepsia, hypertension, bleeding, skin abnormalities, and altered taste were more common in patients receiving SUTENT. Table 3 compares the incidence of common (≥10%) treatment-emergent adverse events for patients receiving SUTENT versus IFN-α.

Data on SUTENT treatment in 169 patients with cytokine-refractory MRCC enrolled in Studies 1 and 2 are also included in Table 3. Dose interruptions occurred in 48 patients (45%) on Study 1 and 45 patients (71%) on Study 2; one or more dose reductions occurred in 23 patients (22%) on Study 1 and 22 patients (35%) on Study 2.

Other significant adverse events occurring in cytokine-refractory MRCC patients receiving SUTENT included peripheral neuropathy (10%), appetite disturbance (9%), blistering of the skin (7%), periorbital edema (7%) and increased lacrimation (6%).

In the treatment-naive MRCC study, 20 (17%) versus 14 patients (10%) experienced treatment-emergent Grade 4 chemistry laboratory abnormalities on SUTENT versus IFN-α, respectively. The most common Grade 4 chemistry abnormalities were hyperuricemia (12% on SUTENT, 8% on IFN-α) and increased lipase (3% on SUTENT, 1% on IFN-α). The most common Grade 3 chemistry abnormalities observed on both arms were increased lipase (13% on SUTENT, 5% on IFN-α) and hypophosphatemia (4% on SUTENT, 6% on IFN-α). Other common Grade 3 laboratory abnormalities on SUTENT were hyponatremia (5%) and increased amylase (4%), and on IFN-α was hyperglycemia (6%).

Common treatment-emergent Grade 3 and 4 chemistry laboratory abnormalities in patients on SUTENT in the cytokine-refractory MRCC studies included increased lipase (16%), increased amylase (5%), hypophosphatemia (10%), and hyperuricemia (10%).

Table 3. Treatment-Emergent Adverse Events Reported in at Least 10% of Patients with MRCC Who Received SUTENT or IFN-α*
Treatment-Naïve MRCC Cytokine-Refractory MRCC
SUTENT
(n=375)
IFN-α
(n=360)
SUTENT
(N=169)
Adverse Event, n (%) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4§
*
Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0
Grade 4 AEs in patients on SUTENT included arthralgia (<1%), asthenia (<1%), back pain (1%), dehydration (<1%), fatigue (<1%), limb pain (<1%) and rash (<1%).
Grade 4 AEs in patients on IFN-α included dyspnea (1%), depression (<1%) and fatigue (1%).
§
There were no Grade 4 adverse events among the events reported with a ≥10% incidence in the cytokine-refractory MRCC population.
Includes flank pain
#
Includes ageusia, hypogeusia and dysgeusia
Þ
Includes decreased appetite
ß
Includes one patient with non-treatment-related Grade 5 gastric hemorrhage
Any 370 (99) 235 (63) 354 (98) 172 (48) 169 (100) 123 (73)
Constitutional
  Fatigue 215 (57) 35 (9) 199 (55) 47 (13) 125 (74) 19 (11)
  Asthenia 78 (21) 26 (7) 85 (24) 20 (6) 16 (9) 4 (2)
  Fever 61 (16) 3 (1) 129 (36) 0 (0) 26 (15) 2 (1)
  Weight decreased 43 (12) 0 (0) 52 (14) 2 (1) 19 (11) 1 (1)
  Chills 41 (11) 3 (1) 108 (30) 0 (0) 18 (11) 0 (0)
Gastrointestinal
  Diarrhea 218 (58) 22 (6) 71 (20) 0 (0) 93 (55) 8 (5)
  Nausea 182 (49) 14 (4) 134 (37) 5 (1) 92 (54) 4 (2)
  Mucositis/stomatitis 153 (41) 10 (3) 13 (4) 2 (<1) 90 (53) 7 (4)
  Vomiting 104 (28) 15 (4) 49 (14) 3 (1) 63 (37) 7 (4)
  Dyspepsia 104 (28) 3 (1) 14 (4) 0 (0) 77 (46) 1 (1)
  Abdominal pain 74 (20) 9 (2) 39 (11) 5 (1) 34 (20) 5 (3)
  Constipation 59 (16) 0 (0) 44 (12) 1 (<1) 57 (34) 1 (1)
  Dry mouth 44 (12) 0 (0) 26 (7) 1 (<1) 10 (6) 0 (0)
  Flatulence 36 (10) 0 (0) 8 (2) 0 (0) 24 (14) 0 (0)
  Glossodynia 37 (10) 0 (0) 2 (1) 0 (0) 25 (15) 0 (0)
Cardiac
  Hypertension 101 (27) 34 (9) 13 (4) 1 (<1) 48 (28) 10 (6)
  Edema, peripheral 42 (11) 2 (1) 15 (4) 2 (1) 28 (17) 1 (1)
Dermatology
  Dry skin 64 (17) 1 (<1) 23 (6) 0 (0) 29 (17) 0 (0)
  Rash 85 (23) 3 (1) 31 (9) 2 (1) 64 (38) 1 (1)
  Hair color changes 54 (14) 0 (0) 1 (<1) 0 (0) 29 (17) 0 (0)
  Hand-foot syndrome 77 (21) 19 (5) 3 (1) 0 (0) 21 (12) 5 (3)
  Skin discoloration 60 (16) 0 (0) 0 (0) 0 (0) 55 (33) 0 (0)
  Alopecia 30 (8) 0 (0) 30 (8) 0 (0) 20 (12) 0 (0)
Neurology
  Altered taste# 166 (44) 1 (<1) 51 (14) 0 (0) 73 (43) 0 (0)
  Headache 68 (18) 3 (1) 61 (17) 0 (0) 43 (25) 2 (1)
  Dizziness 28 (8) 1 (<1) 39 (11) 1 (<1) 27 (16) 3 (2)
Musculoskeletal
  Back pain 68 (18) 11 (3) 43 (12) 6 (2) 29 (17) 1 (1)
  Myalgia/limb pain 84 (22) 6 (2) 91 (25) 6 (2) 60 (36) 2 (2)
  Arthralgia 66 (18) 4 (1) 60 (17) 1 (<1) 48 (28) 2 (1)
Respiratory
  Cough 62 (17) 2 (1) 43 (12) 0 (0) 29 (17) 1 (1)
  Dyspnea 57 (15) 15 (4) 64 (18) 14 (4) 47 (28) 8 (5)
Metabolism/Nutrition
  AnorexiaÞ 139 (37) 6 (2) 145 (40) 6 (2) 53 (31) 1 (1)
  Dehydration 30 (8) 8 (2) 17 (5) 2 (1) 19 (11) 5 (3)
Hemorrhage/Bleeding
  Bleeding, all sites 104 (28) 10 (3)ß 25 (7) 2 (1) 44 (26) 1 (1)
Psychiatric
  Insomnia 42 (11) 1 (<1) 31 (9) 0 (0) 22 (13) 1 (1)
  Depression 28 (8) 0 (0) 42 (12) 4 (1) 14 (8) 1 (1)

Grade 4 hematology laboratory abnormalities in the Phase 3 MRCC study include neutropenia (1% on SUTENT, 0% on IFN-α) and anemia (<1% each arm). Grade 3 hematology laboratory abnormalities included neutropenia (11% on SUTENT, 7% on IFN-α), lymphopenia (12% on SUTENT, 22% on IFN-α), thrombocytopenia (8% on SUTENT, 0% on IFN-α), leukopenia (5% on SUTENT, 2% on IFN-α) and anemia (3% on SUTENT, 4% on IFN-α).

In the SUTENT-treated cytokine-refractory MRCC patients, Grade 4 hematology abnormalities included anemia (2%), neutropenia (1%) and lymphopenia (1%). Grade 3 abnormalities were lymphopenia (20%) neutropenia (12%), leukopenia (7%), anemia (5%) and thrombocytopenia (3%).

6.4 Cardiovascular Events

See 5 WARNINGS AND PRECAUTIONS for information on left ventricular dysfunction and QTc interval prolongation.

Two patients with cytokine-refractory MRCC experienced Grade 3 myocardial ischemia, one had Grade 2 "cardiovascular toxicity" reported as an adverse event and one patient experienced a fatal myocardial infarction while on treatment.

6.5 Venous Thromboembolic Events

Seven patients (3%) on SUTENT and none on placebo in 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. Seven (2%) patients receiving SUTENT for treatment-naïve MRCC and four patients (2%) on the two cytokine-refractory MRCC studies had venous thromboembolic events reported. Six of these patients had pulmonary embolism, one was Grade 3 and five were Grade 4, and five patients had DVT, one each with Grade 1 and 4, and three with Grade 3. Dose interruption occurred in one of these cases. In treatment-naïve MRCC 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, one Grade 1 and four with Grade 4.

6.6 Seizures

In clinical studies of SUTENT, seizures have been observed in subjects with radiological evidence of brain metastases. In addition, there have been rare (<1%) reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None of these subjects had a fatal outcome to the event. 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.

6.7 Laboratory Abnormalities/Testing

Hematologic Events

Grade 3 and 4 neutropenia were reported in 19 (9%) and 3 (2%) patients with GIST on SUTENT. Grade 4 neutropenia was reported in 3 (1%) and 1 (1%) patients receiving SUTENT for treatment-naïve and cytokine-refractory MRCC, respectively. Grade 3 neutropenia was reported in 41 (11%) and 21 (12%) patients receiving SUTENT for treatment-naïve and cytokine-refractory MRCC, respectively. Twenty-four (7%) and 0 patients treated with IFN-α for treatment-naïve MRCC had Grade 3 and 4 neutropenia, respectively. In Study A, one GIST patient each in the SUTENT and placebo groups had febrile neutropenia. Grade 3 and 4 thrombocytopenia was reported in 7 (4%) and 1 (1%) patients with GIST on SUTENT and 35 (11%) and 0 patients with MRCC, respectively. No GIST patients receiving placebo experienced either Grade 3 or 4 neutropenia or thrombocytopenia. The rates of dose reductions and delays for hematologic abnormalities were 2% and 4% for neutropenia, 0% and 2% for anemia, and 1% and 1% for thrombocytopenia for GIST and cytokine-refractory MRCC patients, respectively. One cytokine-refractory MRCC patient with an adverse event report of Grade 4 thrombocytopenia discontinued treatment.

Patients receiving SUTENT should be monitored regularly for myelosuppression.

Hypothyroidism

Treatment-emergent acquired hypothyroidism was noted in 8 GIST patients (4%) on SUTENT versus 1 (1%) on placebo. Hypothyroidism was reported as an adverse event in nine patients (2%) on SUTENT in the treatment-naïve MRCC study and one patient (<1%) in the IFN-α arm, and in 7 patients (4%) across the two cytokine-refractory MRCC studies. Additionally, TSH elevations were reported in 4 cytokine-refractory MRCC patients (2%). Overall, 7% of the cytokine-refractory MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism.

Patients with symptoms suggestive of hypothyroidism should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.

Gastrointestinal Function

Grade 3 and 4 increases in serum lipase were observed in 23 (14%) and 4 (2%), respectively, of 169 patients receiving SUTENT for cytokine-refractory MRCC and in 49 (13%) and 11 (3%), respectively, of patients receiving SUTENT for treatment-naïve MRCC. Grade 3 and 4 increases in serum amylase were observed in 8 (5%) and 1 (1%) cytokine-refractory MRCC patients, respectively and in 16 (4%) and 3 (1%), respectively, of patients receiving SUTENT for treatment-naïve MRCC. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with either GIST or MRCC. Pancreatitis has been observed rarely (<1%) in patients receiving SUTENT for GIST or MRCC. Hepatic failure was observed in <1% of solid tumor patients treated with SUTENT. If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued and be provided with appropriate supportive care.

7 DRUG INTERACTIONS

7.1 In Vitro Studies of CYP Inhibition and Induction

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

7.2 CYP3A4 Inhibitors

Concurrent administration of sunitinib malate with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors (see 2.2 Dose Modification).

7.3 CYP3A4 Inducers

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 SUTENT 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 2.2 Dose Modification).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

See 5 WARNINGS AND PRECAUTIONS.

8.3 Nursing Mothers

Sunitinib and/or 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 SUTENT or its primary active metabolite are excreted in human milk. Because drugs are commonly excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breastfeeding while taking SUTENT.

8.4 Pediatric Use

The safety and efficacy of SUTENT in pediatric patients have not been studied in clinical trials.

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.

8.5 Geriatric Use

Of the 825 GIST and MRCC patients who received SUTENT on pivotal clinical studies, 277 (34%) were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients.

8.7 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. No dose adjustment is required when administering SUTENT to patients with Child Pugh Class A or B hepatic impairment.

10 OVERDOSAGE

No overdose of SUTENT was reported in completed clinical studies. 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. 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.

11 DESCRIPTION

SUTENT, an oral multi-kinase inhibitor targeting several receptor tyrosine kinases (RTK), 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 structure of sunitinib malate is:

Image from Drug Label Content

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 also contain yellow iron oxide and black iron oxide. The printing ink contains shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism Of Action

Sunitinib malate is a small molecule that inhibits multiple 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.

12.3 Pharmacokinetics

The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors.

Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. Sunitinib 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 MRCC.

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 sunitinib have not been evaluated in pediatric patients.

Renal Insufficiency: No clinical studies were conducted in patients with impaired renal function. Studies that were conducted excluded patients with serum creatinine > 2.0 × ULN. Population pharmacokinetic analyses have shown that sunitinib pharmacokinetics were unaltered in patients with calculated creatinine clearances in the range of 42 –347 mL/min.

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

12.4 Cardiac Electrophysiology

QT interval prolongation was investigated in a trial with 24 evaluable patients, aged 20–87 years, with advanced malignancies. At therapeutic plasma concentrations, the maximum QTcF (Fridericia's Correction) mean change from baseline was 9.6 msec (90% CI 15.1 msec). At approximately twice therapeutic concentrations, the maximum QTcF mean change from baseline was 15.4 msec (90% CI 22.4 msec). Moxifloxacin (400 mg) used as a positive control showed a 5.6 msec maximum mean QTcF change from baseline. No subjects experienced an effect on the QTc interval greater than Grade 2 (CTCAE v.3.0). No patient on this study presented with a cardiac arrhythmia (see 5 WARNINGS AND PRECAUTIONS).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with sunitinib have not been performed.

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 (approximately 5.1 times the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day (approximately 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 approximately 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 approximately 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 approximately 25.8 times the AUC in patients administered the RDD).

14 CLINICAL STUDIES

The clinical safety and efficacy of SUTENT have been studied in patients with gastrointestinal stromal tumor (GIST) after progression on or intolerance to imatinib mesylate, and in patients with metastatic renal cell carcinoma (MRCC).

14.1 Gastrointestinal Stromal Tumor

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 primary 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. Secondary 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 a schedule of 4 weeks on treatment followed by 2 weeks off (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.

The intent-to-treat (ITT) population included 312 patients. Two-hundred seven patients were randomized to the SUTENT arm, and 105 patients were randomized to the placebo arm. Baseline age, gender, race and ECOG performance status were comparable between the placebo and SUTENT groups. Prior exposure to imatinib was similar between the two study arms. Demographics and patient characteristics are shown in Table 4.

Table 4. Baseline Demographics in Study A
GIST
SUTENT (n=207) Placebo (n=105)
Gender [N (%)]
  Male 132 (64) 64 (61)
  Female 75 (36) 41 (39)
Self-identified Race [N (%)]
  White 183 (88) 92 (88)
  Asian 10 (5) 5 (5)
  Black 8 (4) 4 (4)
  Not reported 6 (3) 4 (4)
Age Group [N (%)]
  < 65 years 143 (69) 76 (72)
  ≥ 65 years 64 (31) 29 (28)
Performance Status [N (%)]
  0 92 (44) 48 (46)
  1 113 (55) 55 (52)
  2 2 (1) 2 (2)
Prior Treatment [N (%)]
  Surgery (other than biopsy) 194 (94) 98 (93)
  Radiotherapy 16 (8) 16 (15)
Imatinib outcome [N (%)]
  Intolerance 9 (4) 4 (4)
  Progression within 6 months 36 (17) 17 (16)
  Progression beyond 6 months 162 (78) 84 (80)

A 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 the primary endpoint of TTP, as well as in the secondary endpoint of progression-free survival. Data were not mature enough to determine the overall survival benefit. Efficacy results are summarized in Table 5 and the Kaplan-Meyer curve for TTP is in Figure 1.

Table 5. GIST Efficacy Results from Study A (interim analysis)
Efficacy Parameter SUTENT
(N = 207)
Placebo
(N = 105)
P-value (log-rank test) HR
(95% CI)
CI=Confidence interval, HR=Hazard ratio, PR=Partial response
*
Time from randomization to progression; deaths prior to documented progression were censored at time of last radiographic evaluation
A comparison is considered statistically significant if the p-value is < 0.0042 (O'Brien Fleming stopping boundary)
Time from randomization to progression or death due to any cause
§
Pearson chi-square test
Time to Tumor Progression*
[median, weeks (95% CI)]
27.3
(16.0, 32.1)
6.4
(4.4, 10.0)
<0.0001 0.33
(0.23, 0.47)
Progression-free Survival
[median, weeks (95% CI)]
24.1
(11.1, 28.3)
6.0
(4.4, 9.9)
<0.0001 0.33
(0.24, 0.47)
Objective Response Rate
(PR) [%, (95% CI)]
6.8
(3.7, 11.1)
0 0.006§

Figure 1. Kaplan-Meier Curve of TTP in Study A (Intent-to-Treat Population)

Image from Drug Label Content

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)].

14.2 Renal Cell Carcinoma

Treatment-Naïve MRCC

A Phase 3 randomized study comparing single-agent SUTENT with IFN-α was conducted in patients with treatment-naïve MRCC. The primary objective was to compare PFS in patients receiving SUTENT versus patients receiving IFN-α. Secondary objectives included TTP, ORR, OS safety and patient reported outcomes (PRO). 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 are treated until disease progression or withdrawal from the study for another reason.

The ITT population for this interim analysis included 750 patients, 375 randomized to SUTENT and 375 randomized to IFN-α. Baseline age, gender, race and ECOG performance status were comparable and balanced between the SUTENT and IFN-α groups. Demographics and patient characteristics are shown in Table 6. The most common site of metastases present at screening was the lung (78% versus 80%, respectively), followed by the lymph nodes (58% versus 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% versus 77%, respectively).

Table 6. Baseline Demographics in Treatment-Naïve MRCC Study
Treatment-Naïve MRCC
SUTENT (n=375) IFN-α (n=375)
*
Patients had ECOG performance status of 1 at screening which changed to 2 at baseline
Gender [n (%)]
  Male 267 (71) 269 (72)
  Female 108 (29) 106 (28)
Self-identified Race [n (%)]
  White 354 (94) 340 (91)
  Asian 7 (2) 12 (3)
  Black 4 (1) 9 (2)
  Not reported 10 (3) 14 (4)
Age Group [n (%)]
  < 65 years 223 (59) 252 (67)
  ≥ 65 years 152 (41) 123 (33)
Performance Status [n (%)]
  0 231 (62) 229 (61)
  1 144 (38) 142 (38)
  2 0 (0) 4 (1)*
Prior Treatment [n (%)]
  Nephrectomy 340 (91) 335 (89)
  Radiotherapy 53 (14) 54 (14)

A planned interim analysis showed a statistically significant advantage for SUTENT over IFN-α in the primary endpoint of PFS, with PFS for SUTENT more than double that of IFN-α (47.3 and 22.0 weeks, respectively). The secondary endpoint of ORR was more than four times higher for SUTENT than IFN-α (27.5% and 5.3%, respectively). Data were not mature enough to determine the overall survival benefit; at the time of this analysis, 374 of 750 patients enrolled (50%) continued on study, 248/375 (66%) on the SUTENT arm and 126/375 (34%) on the IFN-α arm. Efficacy results are summarized in Table 7 and the Kaplan-Meier curve for PFS is in Figure 2. The results were similar in the supportive analyses and they were robust when controlling for demographic (age, gender, race and performance status) and known risk factors. For 264 of 750 patients (35%) with no MSKCC risk factors,1 median PFS was not yet reached in the SUTENT arm and was 34.3 weeks on the IFN-α arm (HR 0.371, 95% CI [0.214 – 0.643]); for the 421 patients (56%) with 1 or 2 risk factors, median PFS was 47.3 weeks on the SUTENT arm and 16.0 weeks on the IFN-α arm (HR 0.388, 95% CI [0.281 – 0.537]); and for the 48 patients (6%) with ≥3 risk factors, median PFS was 18.0 weeks on the SUTENT arm and 5.7 weeks on the IFN-α arm (HR 0.534 95% CI [0.231 – 1.234]).

Table 7. MRCC Efficacy Results
CI=Confidence interval, NA=Not applicable
*
Assessed by blinded core radiology laboratory; 90 patients' scans had not been read at time of analysis
Assessed by investigators
Median DR has not yet been reached
§
Data not mature enough to determine upper confidence limit
Treatment-Naive MRCC
Efficacy Parameter SUTENT
(n=375)
IFN-α
(n=375)
P-value (log-rank test) HR
(95% CI)
Progression-Free Survival*
[median, weeks (95% CI)]
47.3
(42.6, 50.7)
22.0
(16.4, 24.0)
<0.000001 0.415
(0.320, 0.539)
Time to Tumor Progression*
[median, weeks (95% CI)]
47.9
(45.9, 50.7)
22.3
(17.3, 31.3)
<0.0001 0.416
(0.318, 0.545)
Objective Response Rate*
[%, (95% CI)]
27.5
(23.0, 32.3)
5.3
(3.3, 8.1)
<0.0001 NA
Efficacy Parameter Cytokine-Refractory MRCC
Study 1
(N = 106)
Study 2
(N = 63)
Objective Response Rate
[%, (95% CI)]
34.0*
(25.0, 43.8)
36.5
(24.7, 49.6)
Duration of Response
[median, weeks (95% CI)]

(42.0, §)
54
(34.3, 70.1)

Figure 2. Kaplan-Meier Curve of PFS in Treatment-Naïve MRCC Study (Intent-to-Treat Population)

Image from Drug Label Content

The FKSI-DRS (Disease Related Symptom Scale of the Functional Assessment of Cancer Therapy - Advanced Kidney Cancer Symptom Index) was used to assess patient-reported kidney cancer related symptoms (lack of energy/fatigue, pain/bone pain, weight loss, shortness of breath, cough, fever, and hematuria) in 719 patients. Patients treated with SUTENT reported statistically significant (p<0.0001) better FKSI-DRS index scores than patients treated with IFN-α in all post-baseline assessment time points up to nine cycles of treatment.

Cytokine-Refractory MRCC

The use of single agent SUTENT in the treatment of cytokine-refractory MRCC 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 primary endpoint for both studies was ORR. DR was also evaluated.

One hundred six patients 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 7. 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.

15 REFERENCE

1 Motzer RJ, Bacik J, Murphy BA, et al. Interferon-Alfa as a Comparative Treatment for Clinical Trials of New Therapies Against Advanced Renal Cell Carcinoma. J Clin Oncol 20:289–296, 2001.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 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
Bottles of 30:     NDC 0069-0550-30

16.2 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
Bottles of 30:     NDC 0069-0770-30

16.3 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
Bottles of 30:     NDC 0069-0980-30

16.4 Storage

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

17 PATIENT COUNSELING INFORMATION

17.1 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.

17.2 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.

17.3 Other Common Events

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

17.4 Concomitant Medications

Patients should be advised to inform their health care providers of all concomitant medications, including over-the-counter medications and dietary supplements (see 7 DRUG INTERACTIONS).

Rev: [July/2006]


Sutent (sunitinib malate)
PRODUCT INFO
Product Code 0069-0550 Dosage Form CAPSULE
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
sunitinib malate (sunitinib) Active 12.5 MILLIGRAM  In 1 CAPSULE
mannitol Inactive  
croscarmellose sodium Inactive  
povidone (K-25) Inactive  
magnesium stearate Inactive  
gelatin Inactive  
titanium dioxide Inactive  
red iron oxide Inactive  
shellac Inactive  
propylene glycol Inactive  
sodium hydroxide Inactive  
povidone Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color ORANGE Score 1
Shape CAPSULE Symbol false
Imprint Code Pfizer;STN;12.5;mg Coating false
Size 14mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0069-0550-38 28 CAPSULE In 1 BOTTLE None
2 0069-0550-30 30 CAPSULE In 1 BOTTLE None

Sutent (sunitinib malate)
PRODUCT INFO
Product Code 0069-0770 Dosage Form CAPSULE
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
sunitinib malate (sunitinib) Active 25 MILLIGRAM  In 1 CAPSULE
mannitol Inactive  
croscarmellose sodium Inactive  
povidone (K-25) Inactive  
magnesium stearate Inactive  
gelatin Inactive  
titanium dioxide Inactive  
red iron oxide Inactive  
yellow iron oxide Inactive  
black iron oxide Inactive  
shellac Inactive  
propylene glycol Inactive  
sodium hydroxide Inactive  
povidone Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color ORANGE, BROWN (caramel) Score 1
Shape CAPSULE Symbol false
Imprint Code Pfizer;STN;25;mg Coating false
Size 16mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0069-0770-38 28 CAPSULE In 1 BOTTLE None
2 0069-0770-30 30 CAPSULE In 1 BOTTLE None

Sutent (sunitinib malate)
PRODUCT INFO
Product Code 0069-0980 Dosage Form CAPSULE
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
sunitinib malate (sunitinib) Active 50 MILLIGRAM  In 1 CAPSULE
mannitol Inactive  
croscarmellose sodium Inactive  
povidone (K-25) Inactive  
magnesium stearate Inactive  
gelatin Inactive  
titanium dioxide Inactive  
red iron oxide Inactive  
yellow iron oxide Inactive  
black iron oxide Inactive  
shellac Inactive  
propylene glycol Inactive  
sodium hydroxide Inactive  
povidone Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color BROWN (caramel) Score 1
Shape CAPSULE Symbol false
Imprint Code Pfizer;STN;50;mg Coating false
Size 18mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0069-0980-38 28 CAPSULE In 1 BOTTLE None
2 0069-0980-30 30 CAPSULE In 1 BOTTLE None

Revised: 02/2007