-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`Hepatotoxicity, including liver failure, has been observed. Monitor liver
`•
`function tests 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. (5.1)
`
`• Women of childbearing potential should be advised of the potential
`
`hazard to the fetus and to avoid becoming pregnant. (5.2)
`Cardiac toxicity including left ventricular ejection fraction declines to
`below the lower limit of normal and cardiac failure including death
`
`have occurred. Monitor patients for signs and symptoms of congestive
`
`heart failure. (5.3)
`Prolonged QT intervals and Torsade de Pointes have been observed.
`
`Use with caution in patients at higher risk for developing QT interval
`prolongation. When using SUTENT, monitoring with on-treatment
`
`electrocardiograms and electrolytes should be considered. (5.4)
`
`Hypertension may occur. Monitor blood pressure and treat as needed.
`
`
`(5.5)
`Hemorrhagic events including tumor-related hemorrhage have occurred.
`
`Perform serial complete blood counts and physical examinations. (5.6)
`
`Thyroid dysfunction may occur. Patients with signs and/or symptoms
`
`suggestive of hypothyroidism or hyperthyroidism should have laboratory
`monitoring of thyroid function performed and be treated as per standard
`medical practice. (5.7)
`
`Temporary interruption of therapy with SUTENT is recommended in
`patients undergoing major surgical procedures. (5.8)
`
`
`Adrenal hemorrhage was observed in animal studies. Monitor adrenal
`
`function in case of stress such as surgery, trauma or severe infection.
`(5.9)
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`The most common adverse reactions (≥20%) 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. (6)
`
`
`
`•
`
`
`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:
` Consider dose reduction of SUTENT when
`
`•
`
`administered with strong CYP3A4 inhibitors. (7.1)
` Consider dose increase of SUTENT when
`CYP3A4 Inducers:
`
`administered with CYP3A4 inducers. (7.2)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`
`
`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 malate) capsules, oral
`
`Initial U.S. Approval: 2006
`
`
`
`WARNING: HEPATOTOXICITY
`
`
` See full prescribing information for complete boxed warning.
`
`5/2011
`5/2011
`5/2011
`7/2010
`5/2011
`5/2011
`5/2011
`5/2011
`5/2011
`5/2011
`
`
`
`•
`•
`
`
`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)]
`
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Boxed Warning
`7/2010
`Indications and Usage, Advanced Pancreatic Neuroendocrine
` Tumors (1.3)
`Dosage and Administration, Recommended Dose for pNET (2.2)
`Dosage and Administration, Dose Modification (2.3)
`
`Warnings and Precautions, Hepatotoxicity (5.1)
`
`Warnings and Precautions, Pregnancy (5.2)
`Warnings and Precautions, Left Ventricular Dysfunction (5.3)
`Warnings and Precautions, Hypertension (5.5)
`
`Warnings and Precautions, Hemorrhagic Events (5.6)
`Warnings and Precautions, Thyroid Dysfunction (5.7)
`
`Warnings and Precautions, Wound Healing (5.8)
`
`----------------------------INDICATIONS AND USAGE---------------------------
`SUTENT is a kinase inhibitor indicated for the treatment of:
`
`
`Gastrointestinal stromal tumor (GIST) after disease progression on or
`
`•
`intolerance to imatinib mesylate. (1.1)
`Advanced renal cell carcinoma (RCC). (1.2)
`Progressive, well-differentiated pancreatic neuroendocrine tumors
`(pNET) in patients with unresectable locally advanced or metastatic
`
`
`
`disease. (1.3)
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`GIST and RCC:
`
`50 mg orally once daily, with or without food, 4 weeks on treatment
`
`•
`followed by 2 weeks off. (2.1)
`
`pNET:
`
`37.5 mg orally once daily, with or without food, continuously without a
`•
`scheduled off-treatment period. (2.2)
`
`
`Dose Modification:
`
`
`Dose interruptions and/or dose adjustments of 12.5 mg recommended
`•
`based on individual safety and tolerability. (2.3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: HEPATOTOXICITY
`
`1
`INDICATIONS AND USAGE
`1.1 Gastrointestinal stromal tumor
`1.2 Advanced renal cell carcinoma
`
`
`1.3 Advanced pancreatic neuroendocrine tumors
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose for GIST and RCC
`2.2 Recommended Dose for pNET
`
`
`2.3 Dose Modification
`
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Hepatotoxicity
`5.2 Pregnancy
`
`5.3 Left Ventricular Dysfunction
`5.4 QT Interval Prolongation and Torsade de Pointes
`5.5 Hypertension
`5.6 Hemorrhagic Events
`5.7 Thyroid Dysfunction
`
`
`
`
`
`
`
`
`
`
`2
`
`
`
`Reference ID: 2950085
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Capsules: 12.5 mg, 25 mg, 50 mg (3)
`
`
`•
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`None (4)
`•
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`Revised: 5/2011
`
`
`
`
`5.8 Wound Healing
`5.9 Adrenal Function
`
`5.10 Laboratory Tests
`ADVERSE REACTIONS
`6.1 Adverse Reactions in GIST Study A
`
`
`6.2 Adverse Reactions in the Treatment-Naïve RCC Study
`
`6.3 Adverse Reactions in the Phase 3 pNET Study
`
`6.4 Venous Thromboembolic Events
`6.5 Reversible Posterior Leukoencephalopathy Syndrome
`
`6.6 Pancreatic and Hepatic Function
`6.7
` Post-marketing Experience
`DRUG INTERACTIONS
`7.1 CYP3A4 Inhibitors
`7.2 CYP3A4 Inducers
`In Vitro Studies of CYP Inhibition and Induction
`7.3
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`
`
`
`
`
`6
`
`
`7
`
`
`8
`
`Ex. 1090-0001
`
`

`
`14.2 Renal Cell Carcinoma
`14.3 Pancreatic Neuroendocrine Tumors
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Gastrointestinal Disorders
`17.2 Skin Effects
`17.3 Other Common Events
`17.4 Concomitant Medications
`17.5 FDA-Approved Patient Labeling
`* Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`8.6 Hepatic Impairment
`8.7 Renal 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
`_______________________________________________________________________________________________________________________________________
`
`
` FULL PRESCRIBING INFORMATION:
`
`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)]
`
`
`
`
`
`
`
`1 INDICATIONS AND USAGE
`1.1 Gastrointestinal Stromal Tumor (GIST)
`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 (RCC)
`
`SUTENT is indicated for the treatment of advanced renal cell carcinoma.
`1.3 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.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 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.
`2.2 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.
`2.3 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)].
`
`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
`
`Reference ID: 2950085
`
`Ex. 1090-0002
`
`

`
`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.
`
`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.
`
`4 CONTRAINDICATIONS
`None
`
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 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 x ULN or, if due to liver metastases, >5.0 x ULN has not been
`established.
`
` 5.2 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.
`5.3 Left Ventricular Dysfunction
`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, myocardial disorders and cardiomyopathy, some of which
`were fatal, have been reported through post-marketing experience. For GIST and RCC, more patients treated
`with SUTENT 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
`
`
`
`
`Reference ID: 2950085
`
`Ex. 1090-0003
`
`

`
`(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.
`
`5.4 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)].
`5.5 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.
`5.6 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
`
`
`
`Reference ID: 2950085
`
`Ex. 1090-0004
`
`

`
`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. 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. 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.
`
`5.7 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 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.
`
`5.8 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.
`
`
`5.9 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.
`
`Reference ID: 2950085
`
`Ex. 1090-0005
`
`

`
`Laboratory Tests
`5.10
`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
`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.
`6.1 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.
`
`
`Reference ID: 2950085
`
`Ex. 1090-0006
`
`

`
`Adverse Reaction,
`n (%)
`
`SUTENT (n=202)
`All Grades
`Grade 3/4
`Any
`114 (56)
`
`Gastrointestinal
`
`
`9 (4)
`81 (40)
`Diarrhea
`2 (1)
`58 (29)
` Mucositis/stomatitis
`0 (0)
`41 (20)
` Constipation
`Cardiac
`
`
`31 (15)
`9 (4)
`Hypertension
`Dermatology
`
`
`0 (0)
`61 (30)
`Skin discoloration
`2 (1)
`28 (14)
`Rash
`9 (4)
`28 (14)
` Hand-foot syndrome
`Neurology
`
`
`42 (21)
`0 (0)
`Altered taste
`Musculoskeletal
`
`
`28 (14)
`1 (1)
`Myalgia/limb pain
`Metabolism/Nutrition
`
`
`Anorexiaa
`67 (33)
`1 (1)
`45 (22)
`Asthenia
`10 (5)
`
`*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
`a Includes decreased appetite
`
`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.
`
`
`Placebo (n=102)
`All Grades
`Grade 3/4
`52 (51)
`
`
`
`0 (0)
`27 (27)
`2 (2)
`18 (18)
`2 (2)
`14 (14)
`
`
`11 (11)
`0 (0)
`
`
`0 (0)
`23 (23)
`0 (0)
`9 (9)
`3 (3)
`10 (10)
`
`
`12 (12)
`0 (0)
`
`
`9 (9)
`1 (1)
`
`
`30 (29)
`5 (5)
`11 (11)
`3 (3)
`
`Table 1. Adverse Reactions Reported in Study A in at Least 10% of GIST Patients who Received
`SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo*
`GIST
`
`
`
`Reference ID: 2950085
`
`Ex. 1090-0007
`
`

`
`Table 2. Laboratory Abnormalities Reported in Study A in at Least 10% of GIST Patients Who
`Received SUTENT or Placebo in the Double-Blind Treatment Phase*
`GIST
`
`Laboratory Parameter, n (%)
`
`SUTENT (n=202)
`
`Grade 3/4*a
`All Grades*
`
`
`
`68 (34)
`
`
`3 (2)
`78 (39)
`20 (10)
`50 (25)
`7 (4)
`48 (24)
`10 (5)
`35 (17)
`2 (1)
`32 (16)
`0 (0)
`20 (10)
`
`
`22 (11)
`2 (1)
`
`
`25 (12)
`1 (1)
`24 (12)
`1 (1)
`20 (10)
`0 (0)
`
`
`107 (53)
`20 (10)
`76 (38)
`0 (0)
`76 (38)
`10 (5)
`52 (26)
`6 (3)
`
`Any
`Gastrointestinal
` AST / ALT
`Lipase
`Alkaline phosphatase
` Amylase
`Total bilirubin
`Indirect bilirubin
`Cardiac
`
` Decreased LVEF
`Renal/Metabolic
` Creatinine
`
` Potassium decreased
` Sodium increased
`Hematology
`
` Neutrophils
` Lymphocytes
`Platelets
` Hemoglobin
`LVEF=Left ventricular ejection fraction
`*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
`a Grade 4 laboratory abnormalities in patients on SUTENT included alkaline phosphatase (1%), lipase (2%),
`creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%).
`b Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin
`(2%).
`
`Placebo (n=102)
`
`Grade 3/4*b
`All Grades*
`
`
`
`22 (22)
`
`
`1 (1)
`23 (23)
`7 (7)
`17 (17)
`4 (4)
`21 (21)
`3 (3)
`12 (12)
`0 (0)
`8 (8)
`0 (0)
`4 (4)
`
`
`3 (3)
`0 (0)
`
`
`7 (7)
`0 (0)
`4 (4)
`0 (0)
`4 (4)
`1 (1)
`
`
`4 (4)
`0 (0)
`16 (16)
`0 (0)
`4 (4)
`0 (0)
`22 (22)
`2 (2)
`
`
`
`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%).
`6.2 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.
`
`
`
`Reference ID: 2950085
`
`Ex. 1090-0008
`
`

`
`
`
` Table 3 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients
`receiving SUTENT versus IFN-α.
`
`Reference ID: 2950085
`
`
`E