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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` SUTENT safely and effectively. See full prescribing information for
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` SUTENT.
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`SUTENT® (sunitinib malate) capsules, oral
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`Initial U.S. Approval: 2006
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`WARNING: HEPATOTOXICITY
`See full prescribing information for complete boxed warning.
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`Hepatotoxicity has been observed in clinical trials and post-marketing
`experience. This hepatotoxicity may be severe, and deaths have been
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`reported. [See Warnings and Precautions (5.1)]
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`----------------------------RECENT MAJOR CHANGES-------------------------­
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`Warnings and Precautions, Cardiovascular Events (5.3)
`X/2015
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`Warnings and Precautions, Thrombotic Microangiopathy (5.8)
`X/2015
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`Warnings and Precautions, Proteinuria (5.9)
`6/2014
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`Warnings and Precautions, Dermatologic Toxicities (5.10)
`6/2014
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`Warnings and Precautions, Hypoglycemia (5.12)
`12/2014
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`----------------------------INDICATIONS AND USAGE--------------------------­
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`SUTENT is a kinase inhibitor indicated for the treatment of:
`
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`Gastrointestinal stromal tumor (GIST) after disease progression on or
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`intolerance to imatinib mesylate. (1.1)
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`Advanced renal cell carcinoma (RCC). (1.2)
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`tumors
`Progressive, well-differentiated pancreatic neuroendocrine
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`(pNET) in patients with unresectable locally advanced or metastatic
`disease. (1.3)
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`----------------------DOSAGE AND ADMINISTRATION----------------------­
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`GIST and RCC:
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`50 mg orally once daily, with or without food, 4 weeks on treatment
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`followed by 2 weeks off. (2.1)
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`pNET:
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`37.5 mg orally once daily, with or without food, continuously without a
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`scheduled off-treatment period. (2.2)
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`Dose Modification:
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`Dose interruptions and/or dose adjustments of 12.5 mg recommended
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`based on individual safety and tolerability. (2.3)
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`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
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`Capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg (3)
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`-------------------------------CONTRAINDICATIONS-----------------------------­
`
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`None (4)
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`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
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`Hepatotoxicity, including liver failure, has been observed. Monitor liver
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`function tests before initiation of treatment, during each cycle of
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`treatment, and as clinically indicated. SUTENT should be interrupted
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`for Grade 3 or 4 drug-related hepatic adverse events and discontinued if
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`there is no resolution. Do not restart SUTENT if patients subsequently
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`experience severe changes in liver function tests or have other signs and
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`symptoms of liver failure. (5.1)
` Women of childbearing potential should be advised of the potential
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`hazard to the fetus and to avoid becoming pregnant. (5.2)
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`Cardiovascular events
`including myocardial ischemia, myocardial
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`infarction, left ventricular ejection fraction declines to below the lower
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`limit of normal and cardiac failure including death have occurred.
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`See 17 for PATIENT COUNSELING INFORMATION and FDA-
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`approved patient labeling.
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`_______________________________________________________________________________________________________________________________________
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`Monitor patients for signs and symptoms of congestive heart failure.
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`(5.3)
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`Prolonged QT intervals and Torsade de Pointes have been observed.
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`Use with caution in patients at higher risk for developing QT interval
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`prolongation. When using SUTENT, monitoring with on-treatment
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`electrocardiograms and electrolytes should be considered. (5.4)
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`ypertension may occur. Monitor blood pressure and treat as needed.
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`5.5)
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`emorrhagic events including tumor-related hemorrhage have occurred.
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`erform serial complete blood counts and physical examinations. (5.6)
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`ases of Tumor Lysis Syndrome (TLS) have been reported primarily in
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`atients with RCC and GIST with high tumor burden. Monitor these
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`atients closely and treat as clinically indicated. (5.7)
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`hrombotic microangiopathy, including thrombotic thrombocytopenic
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`urpura and hemolytic uremic syndrome, sometimes leading to renal
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`ilure or a fatal outcome, has been reported in clinical trials and in post-
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`arketing experience of SUTENT. (5.8)
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`roteinuria: Monitor urine protein. Interrupt treatment for 24-hour urine
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`rotein ≥3 grams. Discontinue for repeat episodes of protein ≥3 grams
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`espite dose reductions or nephrotic syndrome. (5.9)
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`iscontinue SUTENT if necrotizing fasciitis, erythema multiforme,
`D
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`Stevens-Johnson Syndrome or toxic epidermal necrolysis occurs. (5.10).
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`Thyroid dysfunction may occur. Patients with signs and/or symptoms
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`suggestive of hypothyroidism or hyperthyroidism should have laboratory
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`monitoring of thyroid function performed and be treated as per standard
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`medical practice. (5.11)
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`Hypoglycemia may occur. Check blood glucose levels regularly and
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`assess if anti-diabetic drug dose modifications are required. (5.12)
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`Osteonecrosis of the jaw has been reported. Consider preventive
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`dentistry prior to treatment with SUTENT. If possible, avoid invasive
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`dental procedures, particularly
`in patients receiving
`intravenous
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`bisphosphonate therapy. (5.13)
` Wound Healing: Impaired wound healing has occurred with SUTENT.
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`Temporary interruption of therapy with SUTENT is recommended in
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`patients undergoing major surgical procedures. (5.14)
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`Adrenal hemorrhage was observed in animal studies. Monitor adrenal
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`function in case of stress such as surgery, trauma or severe infection.
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`(5.15)
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`H (
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`H P
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`C p p
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`T p f
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`a m
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`P p d
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`------------------------------ADVERSE REACTIONS------------------------------­
`
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`The most common adverse reactions (≥20%) are fatigue, asthenia, fever,
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`diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal
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`pain, constipation, hypertension, peripheral edema, rash, hand-foot
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`syndrome, skin discoloration, dry skin, hair color changes, altered taste,
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`headache, back pain, arthralgia, extremity pain, cough, dyspnea,
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`anorexia, and bleeding. (6)
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`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at
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`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS------------------------------­
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`
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`CYP3A4 Inhibitors: Consider dose reduction of SUTENT when
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`administered with strong CYP3A4 inhibitors. (7.1)
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`CYP3A4 Inducers: Consider dose
`increase of SUTENT when
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`administered with CYP3A4 inducers. (7.2)
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`
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`Revised: X/2015
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`WARNING: HEPATOTOXICITY
`
`
`1
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`INDICATIONS AND USAGE
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`1.1 Gastrointestinal Stromal Tumor
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`1.2 Advanced Renal Cell Carcinoma
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`1.3 Advanced Pancreatic Neuroendocrine Tumors
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`DOSAGE AND ADMINISTRATION
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`2.1 Recommended Dose for GIST and RCC
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`2.2 Recommended Dose for pNET
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`2.3 Dose Modification
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`2
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`Reference ID: 3739774
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`
`DOSAGE FORMS AND STRENGTHS
`3
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`CONTRAINDICATIONS
`4
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Hepatotoxicity
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`5.2 Pregnancy
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`5.3 Cardiovascular Events
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`5.4 QT Interval Prolongation and Torsade de Pointes
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`5.5 Hypertension
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`5.6 Hemorrhagic Events
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`5.7 Tumor Lysis Syndrome
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`5.8 Thrombotic Microangiopathy
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`Ex. 1114-0001
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`

`

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`6
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`7
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`8
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` 8.7 Renal Impairment
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` 5.9 Proteinuria
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` 5.10 Dermatologic Toxicities
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` 10 OVERDOSAGE
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` 5.11 Thyroid Dysfunction
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` 11 DESCRIPTION
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` 5.12 Hypoglycemia
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` 12 CLINICAL PHARMACOLOGY
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` 12.1 Mechanism of Action
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` 5.13 Osteonecrosis of the Jaw
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` 12.3 Pharmacokinetics
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` 5.14 Wound Healing
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` 12.4 Cardiac Electrophysiology
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` 5.15 Adrenal Function
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` 5.16 Laboratory Tests
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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` ADVERSE REACTIONS
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` 6.1 Adverse Reactions in GIST Study A
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`14 CLINICAL STUDIES
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`14.1 Gastrointestinal Stromal Tumor
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` 6.2 Adverse Reactions in the Treatment-Naïve RCC Study
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`14.2 Renal Cell Carcinoma
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` 6.3 Adverse Reactions in the Phase 3 pNET Study
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`14.3 Pancreatic Neuroendocrine Tumors
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` 6.4 Venous Thromboembolic Events
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` 6.5 Reversible Posterior Leukoencephalopathy Syndrome
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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` 6.6 Pancreatic and Hepatic Function
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`17 PATIENT COUNSELING INFORMATION
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`17.1 Gastrointestinal Disorders
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` 6.7 Post-marketing Experience
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`17.2 Skin Effects
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` DRUG INTERACTIONS
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`17.3 Other Common Events
` 7.1 CYP3A4 Inhibitors
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`17.4 Osteonecrosis of the Jaw
` 7.2 CYP3A4 Inducers
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`17.5 Hypoglycemia
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`7.3
` In Vitro Studies of CYP Inhibition and Induction
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`17.6 Thrombotic Microangiopathy
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` USE IN SPECIFIC POPULATIONS
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`17.7 Proteinuria
` 8.1 Pregnancy
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`17.8 Concomitant Medications
` 8.3 Nursing Mothers
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` 8.4 Pediatric Use
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`* Sections or subsections omitted from the full prescribing information are not
` 8.5 Geriatric Use
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`listed.
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` 8.6 Hepatic Impairment
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`_______________________________________________________________________________________________________________________________________
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` 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)
`
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`SUTENT is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or
`
`intolerance to imatinib mesylate.
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`1.2 Advanced Renal Cell Carcinoma (RCC)
`
`SUTENT is indicated for the treatment of advanced renal cell carcinoma.
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`1.3 Advanced Pancreatic Neuroendocrine Tumors (pNET)
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`SUTENT is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors
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`in patients with unresectable locally advanced or metastatic disease.
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`
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`2 DOSAGE AND ADMINISTRATION
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`2.1 Recommended Dose for GIST and RCC
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`The recommended dose of SUTENT for gastrointestinal stromal tumor (GIST) and advanced renal cell
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`carcinoma (RCC) is one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by
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`2 weeks off (Schedule 4/2). SUTENT may be taken with or without food.
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`2.2 Recommended Dose for pNET
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`The recommended dose of SUTENT for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally
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`once daily continuously without a scheduled off-treatment period. SUTENT may be taken with or without
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`food.
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`2.3 Dose Modification
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`Dose interruption and/or dose modification in 12.5 mg increments or decrements is recommended based on
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`individual safety and tolerability. The maximum dose administered in the Phase 3 pNET study was 50 mg
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`daily.
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`Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. Selection of
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`an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. A dose
`
`
`
`Reference ID: 3739774
`
`Ex. 1114-0002
`
`

`

`
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`reduction for SUTENT to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily should be considered
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`if SUTENT must be co-administered with a strong CYP3A4 inhibitor [see Drug Interactions (7.1) and Clinical
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`Pharmacology (12.3)].
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`CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate
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`concomitant medication with no or minimal enzyme induction potential is recommended. A dose increase for
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`SUTENT to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily should be considered if
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`SUTENT must be co-administered with a CYP3A4 inducer.
`If dose is increased, the patient should be
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`monitored carefully for toxicity [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`12.5 mg capsules
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`Hard gelatin capsule with orange cap and orange body, printed with white ink “Pfizer” on the cap and
`
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`“STN 12.5 mg” on the body.
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`25 mg capsules
`Hard gelatin capsule with caramel cap and orange body, printed with white ink “Pfizer” on the cap and
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`“STN 25 mg” on the body.
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`37.5 mg capsules
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`Hard gelatin capsule with yellow cap and yellow body, printed with black ink “Pfizer” on the cap and
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`“STN 37.5 mg” on the body.
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`50 mg capsules
`Hard gelatin capsule with caramel top and caramel body, printed with white ink “Pfizer” on the cap and
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`“STN 50 mg” on the body.
`
`
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`4 CONTRAINDICATIONS
`
`None
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`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
`
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`jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy,
`
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`
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`and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during
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`
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`
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`
`
`
`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.
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`5.2 Pregnancy
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`SUTENT can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical
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`component of embryonic and fetal development, inhibition of angiogenesis following administration of
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`SUTENT should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats
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`and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled
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`studies of SUTENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes
`
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`pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of
`
`
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`
`
`
`
`childbearing potential should be advised to avoid becoming pregnant while receiving treatment with
`
`SUTENT.
`
`
`
`Reference ID: 3739774
`
`Ex. 1114-0003
`
`

`

`
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` 5.3 Cardiovascular Events
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`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
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`clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.
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`Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial
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`infarction, some of which were fatal, have been reported. Use SUTENT with caution in patients who are at risk
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`for, or who have a history of, these events. For GIST and RCC, more patients treated with SUTENT
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`experienced decline in left ventricular ejection fraction (LVEF) than patients receiving either placebo or
`interferon- (IFN-).
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`In the double-blind treatment phase of GIST Study A, 22/209 patients (11%) on
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`SUTENT and 3/102 patients (3%) on placebo had treatment-emergent LVEF values below the lower limit of
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`normal (LLN). Nine of 22 GIST patients on SUTENT with LVEF changes recovered without intervention.
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`Five patients had documented LVEF recovery following intervention (dose reduction: one patient; addition of
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`antihypertensive or diuretic medications: four patients). Six patients went off study without documented
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`recovery. Additionally, three patients on SUTENT had Grade 3 reductions in left ventricular systolic function
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`to LVEF <40%; two of these patients died without receiving further study drug. No GIST patients on placebo
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`had Grade 3 decreased LVEF. In the double-blind treatment phase of GIST Study A, 1 patient on SUTENT and
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`1 patient on placebo died of diagnosed heart failure; 2 patients on SUTENT and 2 patients on placebo died of
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`treatment-emergent cardiac arrest.
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`In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on SUTENT and IFN-,
`respectively, had an LVEF value below the LLN. Twenty-six patients on SUTENT (7%) and seven on IFN-
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`(2%) experienced declines in LVEF to >20% below baseline and to below 50%. Left ventricular dysfunction
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`was reported in four patients (1%) and CHF in two patients (<1%) who received SUTENT.
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`In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on SUTENT
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`and no patients on placebo.
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`Patients who presented with cardiac events within 12 months prior to SUTENT administration, such as
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`myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic
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`CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from
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`SUTENT clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher
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`risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against
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`the potential benefits of the drug. These patients should be carefully monitored for clinical signs and
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`symptoms of CHF while receiving SUTENT. Baseline and periodic evaluations of LVEF should also be
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`considered while these patients are receiving SUTENT. In patients without cardiac risk factors, a
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`baseline evaluation of ejection fraction should be considered.
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`5.4 QT Interval Prolongation and Torsade de Pointes
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`SUTENT has been shown to prolong the QT interval in a dose dependent manner, which may lead to an
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`increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes has been observed
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`in <0.1% of SUTENT-exposed patients.
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`SUTENT should be used with caution in patients with a history of QT interval prolongation, patients who are
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`taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte
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`disturbances. When using SUTENT, periodic monitoring with on-treatment electrocardiograms and electrolytes
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`(magnesium, potassium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which
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`may increase sunitinib plasma concentrations, should be used with caution and dose reduction of SUTENT
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`should be considered [see Dosage and Administration (2.2)].
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`5.5 Hypertension
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`Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy.
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`In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is
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`controlled.
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`Of patients receiving SUTENT for treatment-naïve RCC, 127/375 patients (34%) receiving SUTENT
`compared with 13/360 patients (4%) on IFN- experienced hypertension. Grade 3 hypertension was observed
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`in 50/375 treatment-naïve RCC patients (13%) on SUTENT compared to 1/360 patients (<1%) on IFN-.
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`Reference ID: 3739774
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`Ex. 1114-0004
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`

`

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` While all-grade hypertension was similar in GIST patients on SUTENT compared to placebo, Grade 3
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` hypertension was reported in 9/202 GIST patients on SUTENT (4%), and none of the GIST patients on placebo.
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` Of patients receiving SUTENT in the Phase 3 pNET study, 22/83 patients (27%) on SUTENT and 4/82 patients
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` (5%) on placebo experienced hypertension. Grade 3 hypertension was reported in 8/83 pNET patients (10%) on
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` SUTENT, and 1/82 patient (1%) on placebo. No Grade 4 hypertension was reported. SUTENT dosing was
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` reduced or temporarily delayed for hypertension in 21/375 patients (6%) on the treatment-naive RCC study and
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` 7/83 pNET patients (8%). Four treatment-naïve RCC patients, including one with malignant hypertension, one
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` patient with pNET, and no GIST patients discontinued treatment due to hypertension. Severe hypertension
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` (>200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on SUTENT (4%), 1/102 GIST
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` patients on placebo (1%), in 32/375 treatment-naïve RCC patients (9%) on SUTENT, in 3/360 patients (1%) on
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` IFN-, and in 8/80 pNET patients (10%) on SUTENT and 2/76 pNET patients (3%) on placebo.
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` 5.6 Hemorrhagic Events
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` Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included
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` GI, respiratory, tumor, urinary tract and brain hemorrhages. In patients receiving SUTENT in a clinical trial for
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` treatment-naïve RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%)
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` receiving IFN-. Bleeding events occurred in 37/202 patients (18%) receiving SUTENT in the double-blind
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` treatment phase of GIST Study A, compared to 17/102 patients (17%) receiving placebo. Epistaxis was the
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` most common hemorrhagic adverse event reported. Bleeding events, excluding epistaxis, occurred in
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` 18/83 patients (22%) receiving SUTENT in the Phase 3 pNET study, compared to 8/82 patients (10%) receiving
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` placebo. Epistaxis was reported in 17/83 patients (20%) receiving SUTENT for pNET and 4 patients (5%)
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` receiving placebo. Less common bleeding events in GIST, RCC and pNET patients included rectal, gingival,
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` upper gastrointestinal, genital, and wound bleeding. In the double-blind treatment phase of GIST Study A,
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` 14/202 patients (7%) receiving SUTENT and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events.
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` In addition, one patient in GIST Study A taking placebo had a fatal gastrointestinal bleeding event during
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` Cycle 2. Most events in RCC patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a
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` treatment-naïve patient. In the pNET study, 1/83 patients (1%) receiving SUTENT had Grade 3 epistaxis, and
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` no patients had other Grade 3 or 4 bleeding events. In pNET patients receiving placebo, 3/82 patients (4%) had
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` Grade 3 or 4 bleeding events.
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` Tumor-related hemorrhage has been observed in patients treated with SUTENT. These events may occur
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` suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or
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` pulmonary hemorrhage. Cases of pulmonary hemorrhage, some with a fatal outcome, have been observed in
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` clinical trials and have been reported in post-marketing experience in patients treated with SUTENT for MRCC,
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` GIST and metastatic lung cancer. SUTENT is not approved for use in patients with lung cancer. Treatment-
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` emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving SUTENT on
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` Study A. Tumor hemorrhages were observed as early as Cycle 1 and as late as Cycle 6. One of these five
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` patients received no further drug following tumor hemorrhage. None of the other four patients discontinued
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` treatment or experienced dose delay due to tumor hemorrhage. No patients with GIST in the Study A placebo
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` arm were observed to undergo intratumoral hemorrhage. Clinical assessment of these events should include
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` serial complete blood counts (CBCs) and physical examinations.
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` Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred
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` rarely in patients with intra-abdominal malignancies treated with SUTENT.
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` 5.7 Tumor Lysis Syndrome (TLS)
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` Cases of TLS, some fatal, have been observed in clinical trials and have been reported in post-marketing
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` experience, primarily in patients with RCC or GIST treated with SUTENT. Patients generally at risk of TLS
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` are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as
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` clinically indicated.
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` 5.8 Thrombotic Microangiopathy
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`Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic
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`syndrome, sometimes leading to renal failure or a fatal outcome, has been reported in clinical trials and in post-
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`marketing experience of SUTENT as monotherapy and in combination with bevacizumab. Discontinue
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`Reference ID: 3739774
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`Ex. 1114-0005
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` SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after treatment was
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`discontinued.
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`5.9 Proteinuria
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`Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure
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`and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and
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`periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically
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`indicated. Interrupt SUTENT and dose reduce for 24-hour urine protein ≥ 3 grams. Discontinue SUTENT for
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`patients with nephrotic syndrome or repeat episodes of urine protein ≥ 3 grams despite dose reductions. The
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`safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been
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`systematically evaluated.
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`5.10 Dermatologic Toxicities
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`Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), Stevens-
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`Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal.
`If signs or
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`symptoms of SJS, TEN, or EM (e.g., progressive skin rash often with blisters or mucosal lesions) are present,
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`SUTENT treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, SUTENT treatment
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`must not be re-started.
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`Necrotizing fasciitis, including fatal cases, has been reported in patients treated with Sutent, including of the
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`perineum and secondary to fistula formation. Discontinue Sutent in patients who develop necrotizing fasciitis.
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`5.11 Thyroid Dysfunction
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`Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or
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`hyperthyroidism should be treated as per standard medical practice prior to the start of SUTENT treatment. All
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`patients should be observed closely for signs and symptoms of thyroid dysfunction, including hypothyroidism,
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`hyperthyroidism, and thyroiditis, on SUTENT treatment. Patients with signs and/or symptoms suggestive of
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`thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per
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`Treatment-emergent acquired hypothyroidism was noted in eight GIST patients (4%) on SUTENT versus
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`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- arm. Hypothyroidism was
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`reported as an adverse reaction in 6/83 patients (7%) on SUTENT in the Phase 3 pNET study and in
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`1/82 patients (1%) in the placebo arm.
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`Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and
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`5.12 Hypoglycemia
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`SUTENT has been associated with symptomatic hypoglycemia, which may result in loss of consciousness, or
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`require hospitalization. Hypoglycemia has occurred in clinical trials in 2% of the patients treated with
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`SUTENT for RCC and GIST and in approximately 10% of the patients treated with SUTENT for pNET. For
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`patients being treated with SUTENT for pNET, pre-existing abnormalities in glucose homeostasis were not
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`present in all patients who experienced hypoglycemia. Reductions in blood glucose levels may be worse in
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`diabetic patients. Check blood glucose levels regularly during and after discontinuation of treatment with
`SUTENT. Assess if anti-diabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.
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`5.13 Osteonecrosis of the Jaw (ONJ)
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`ONJ has been observed in clinical trials and has been reported in post-marketing experience in patients
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`treated with sunitinib. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease,
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`may increase the risk of osteonecrosis of the jaw.
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`5.14 Wound Healing
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`Cases of impaired wound healing have been reported during SUTENT therapy. Temporary interruption of
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`SUTENT therapy is recommended for precautionary reasons in patients undergoing major surgical procedures.
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`There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical
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`intervention. Therefore, the decision to resume SUTENT therapy following a major surgical intervention
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`should be based upon clinical judgment of recovery from surgery.
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`Reference ID: 3739774
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`Ex. 1114-0006
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`5.15 Adrenal Function
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`Physicians prescribing SUTENT are advised to monitor for adrenal insufficiency in patients who experience
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`Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at
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`plasma exposures as low as 0.7 times the AUC observed in clinical studies. Histological changes of the adrenal
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`gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation.
`In clinical
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`studies, CT/MRI obtained in 336 patients after exposure to one or more cycles of SUTENT demonstrated no
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`evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately
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`400 patients across multiple clinical trials of SUTENT. Among patients with normal baseline ACTH
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`stimulation testing, one patient developed consistently abnormal test results during treatment that are
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`unex