6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling.

Hepatotoxicity [see Warnings and Precautions (5.1)]
Cardiovascular Events [see Warnings and Precautions (5.2)]
QT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Hemorrhagic Events [see Warnings and Precautions (5.5)]
Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]
Proteinuria [see Warnings and Precautions (5.8)]
Dermatologic Toxicities [see Warnings and Precautions (5.9)]
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10)]
Thyroid Dysfunction [see Warnings and Precautions (5.11)]
Hypoglycemia [see Warnings and Precautions (5.12)]
Osteonecrosis of the Jaw [see Warnings and Precautions (5.13)]
Impaired Wound Healing [see Warnings and Precautions (5.14)]

6.1 Clinical Trials Experience

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.

The pooled safety population described in the Warnings and Precautions reflect exposure to SUTENT in 7527 patients with GIST, RCC (advanced and adjuvant), or pNET. In this pooled safety population, the most common adverse reactions (≥25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia.

Gastrointestinal Stromal Tumor

The safety of SUTENT was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received SUTENT 50 mg daily on Schedule 4/2 (n=202) or placebo (n=102). Median duration of blinded study treatment was 2 cycles for patients on SUTENT (mean: 3.0; range: 1–9) and 1 cycle (mean; 1.8; range: 1–6) for patients on placebo at the time of the interim analysis.

Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the SUTENT arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received SUTENT.

Table 3 summarizes the adverse reactions for Study 1.

Table 3. Adverse Reactions Reported in ≥10% of GIST Patients Who Received SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo* in Study 1
Adverse Reaction	GIST
	SUTENT (N=202)		Placebo (N=102)
	All Grades %	Grade 3–4 %	All Grades %	Grade 3–4 %
Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients.
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Includes decreased appetite.
Any Adverse Reaction	94	56	97	51
Gastrointestinal
Diarrhea	40	4	27	0
Mucositis/stomatitis	29	1	18	2
Constipation	20	0	14	2
Metabolism/Nutrition
Anorexia†	33	1	29	5
Asthenia	22	5	11	3
Dermatology
Skin discoloration	30	0	23	0
Rash	14	1	9	0
Hand-foot syndrome	14	4	10	3
Neurology
Altered taste	21	0	12	0
Cardiac
Hypertension	15	4	11	0
Musculoskeletal
Myalgia/limb pain	14	1	9	1

Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received SUTENT.

Table 4 summarizes the laboratory abnormalities in Study 1.

Table 4. Laboratory Abnormalities Reported in ≥10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase* in Study 1
Laboratory Abnormality	GIST
	SUTENT (N=202)		Placebo (N=102)
	All Grades* %	Grade 3–4*,† %	All Grades* %	Grade 3–4*,‡ %
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; GIST=gastrointestinal stromal tumor; LVEF=left ventricular ejection fraction; N=number of patients.
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † 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%). ‡ Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%).
Any Laboratory Abnormality		34		22
Hematology
Neutrophils decreased	53	10	4	0
Lymphocytes decreased	38	0	16	0
Platelets decreased	38	5	4	0
Hemoglobin decreased	26	3	22	2
Gastrointestinal
AST/ALT increased	39	2	23	1
Lipase increased	25	10	17	7
Alkaline phosphatase increased	24	4	21	4
Amylase increased	17	5	12	3
Total bilirubin increased	16	1	8	0
Indirect bilirubin increased	10	0	4	0
Renal/Metabolic
Creatinine increased	12	1	7	0
Potassium decreased	12	1	4	0
Sodium increased	10	0	4	1
Cardiac
Decreased LVEF	11	1	3	0

After an interim analysis, the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label SUTENT [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 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 treatment was 6 cycles (mean: 7.8; range: 1–37) from the time of the unblinding.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received SUTENT. Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received SUTENT.

The most common Grade 3 or 4 adverse reactions in patients who received SUTENT in the open-label 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%).

Advanced Renal Cell Carcinoma

The safety of SUTENT was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received SUTENT 50 mg daily on Schedule 4/2 (n=375) or interferon alfa 9 million International Units (MIU) (n=360). The median duration of treatment was 11.1 months (range: 0.4 to 46.1) for SUTENT treatment and 4.1 months (range: 0.1 to 45.6) for interferon alfa treatment.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients in the SUTENT arm. Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received SUTENT.

Table 5 summarizes the adverse reactions for Study 3.

Table 5. Adverse Reactions Reported in ≥10% of Patients With RCC Who Received SUTENT or Interferon Alfa* in Study 3
Adverse Reaction	Treatment-Naïve RCC
	SUTENT (N=375)		Interferon Alfa (N=360)
	All Grades %	Grade 3–4† %	All Grades %	Grade 3–4‡ %
Abbreviations: ARs=adverse reactions; N=number of patients; RCC=renal cell carcinoma.
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Grade 4 ARs in patients on SUTENT included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%). ‡ Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%). § Includes flank pain. ¶ Includes decreased appetite. # Includes ageusia, hypogeusia, and dysgeusia. Þ Includes 1 patient with Grade 5 gastric hemorrhage. ß Includes depressed mood.
Any Adverse Reaction	99	77	99	55
Gastrointestinal
Diarrhea	66	10	21	<1
Nausea	58	6	41	2
Mucositis/stomatitis	47	3	5	<1
Vomiting	39	5	17	1
Dyspepsia	34	2	4	0
Abdominal pain§	30	5	12	1
Constipation	23	1	14	<1
Dry mouth	13	0	7	<1
Oral pain	14	<1	1	0
Flatulence	14	0	2	0
GERD/reflux esophagitis	12	<1	1	0
Glossodynia	11	0	1	0
Hemorrhoids	10	0	2	0
Constitutional
Fatigue	62	15	56	15
Asthenia	26	11	22	6
Fever	22	1	37	<1
Weight decreased	16	<1	17	1
Chills	14	1	31	0
Chest Pain	13	2	7	1
Influenza like illness	5	0	15	<1
Metabolism/Nutrition
Anorexia¶	48	3	42	2
Neurology
Altered taste#	47	<1	15	0
Headache	23	1	19	0
Dizziness	11	<1	14	1
Hemorrhage/Bleeding
Bleeding, all sites	37	4Þ	10	1
Cardiac
Hypertension	34	13	4	<1
Edema peripheral	24	2	5	1
Ejection fraction decreased	16	3	5	2
Dermatology
Rash	29	2	11	<1
Hand-foot syndrome	29	8	1	0
Skin discoloration/yellow skin	25	<1	0	0
Dry skin	23	<1	7	0
Hair color changes	20	0	<1	0
Alopecia	14	0	9	0
Erythema	12	<1	1	0
Pruritus	12	<1	7	<1
Musculoskeletal
Pain in extremity/limb discomfort	40	5	30	2
Arthralgia	30	3	19	1
Back pain	28	5	14	2
Respiratory
Cough	27	1	14	<1
Dyspnea	26	6	20	4
Nasopharyngitis	14	0	2	0
Oropharyngeal pain	14	<1	2	0
Upper respiratory tract infection	11	<1	2	0
Endocrine
Hypothyroidism	16	2	1	0
Psychiatric
Insomnia	15	<1	10	0
Depressionß	11	0	14	1

Table 6 summarizes the laboratory abnormalities in Study 3.

Table 6. Laboratory Abnormalities Reported in ≥10% of RCC Patients Who Received SUTENT or Interferon Alfa in Study 3
Laboratory Abnormality	Treatment-Naïve RCC
	SUTENT (N=375)		Interferon Alfa (N=360)
	All Grades* %	Grade 3–4*,† %	All Grades* %	Grade 3–4*,‡ %
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; N=number of patients; RCC=renal cell carcinoma.
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Grade 4 laboratory abnormalities in patients on SUTENT included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), glucose increased (<1%), calcium decreased (<1%), phosphorous (<1%), potassium increased (<1%), and sodium decreased (<1%). ‡ Grade 4 laboratory abnormalities in patients on interferon alfa included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%).
Hematology
Hemoglobin decreased	79	8	69	5
Neutrophils decreased	77	17	49	9
Platelets decreased	68	9	24	1
Lymphocytes decreased	68	18	68	26
Renal/Metabolic
Creatinine increased	70	<1	51	<1
Creatine kinase increased	49	2	11	1
Uric acid increased	46	14	33	8
Calcium decreased	42	1	40	1
Phosphorus decreased	31	6	24	6
Albumin decreased	28	1	20	0
Glucose increased	23	6	15	6
Sodium decreased	20	8	15	4
Glucose decreased	17	0	12	<1
Potassium increased	16	3	17	4
Calcium increased	13	<1	10	1
Potassium decreased	13	1	2	<1
Sodium increased	13	0	10	0
Gastrointestinal
AST increased	56	2	38	2
Lipase increased	56	18	46	8
ALT increased	51	3	40	2
Alkaline phosphatase increased	46	2	37	2
Amylase increased	35	6	32	3
Total bilirubin increased	20	1	2	0
Indirect bilirubin increased	13	1	1	0

Long-Term Safety in RCC

The long-term safety of SUTENT in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings. The analysis included 5739 patients, of whom 807 (14%) were treated for at least 2 years and 365 (6%) for at least 3 years. Prolonged treatment with SUTENT did not appear to be associated with new types of adverse reactions. There appeared to be no increase in the yearly incidence of adverse reactions at later time points. Hypothyroidism increased during the second year of treatment with new cases reported up to year 4.

Adjuvant Treatment of RCC

The safety of SUTENT was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received SUTENT 50 mg daily on Schedule 4/2 (n=306) or placebo (n=304). The median duration of treatment was 12.4 months (range: 0.13 to 14.9) for SUTENT and 12.4 months (range: 0.03 to 13.7) for placebo.

Permanent discontinuation due to an adverse reaction occurred in 28% of patients in the SUTENT arm. Adverse reactions leading to permanent discontinuation in >2% of patients include hand-foot syndrome and fatigue/asthenia. Dosing interruptions occurred in 54% and dose reductions occurred in 46% of patients who received SUTENT.

Table 7 summarizes the adverse reactions in S-TRAC.

Table 7. Adverse Reactions Reported in ≥10% of Patients With RCC Who Received SUTENT and More Commonly Than in Patients Given Placebo* in S-TRAC
Adverse Reaction	Adjuvant Treatment of RCC
	SUTENT (N=306)		Placebo (N=304)
	All Grades %	Grade 3–4 %	All Grades %	Grade 3–4 %
Abbreviations: ARs=adverse reactions; N=number of patients; RCC=renal cell carcinoma.
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Includes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain. ‡ Includes abdominal pain, abdominal pain lower, and abdominal pain upper. § Includes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema. ¶ Includes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic. # Includes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis. Þ Includes ageusia, hypogeusia, and dysgeusia. ß Includes epistaxis, gingival bleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria.
Any Adverse Reaction	99	60	88	15
Gastrointestinal
Mucositis/Stomatitis†	61	6	15	0
Diarrhea	57	4	22	<1
Nausea	34	2	15	0
Dyspepsia	27	1	7	0
Abdominal pain‡	25	2	9	<1
Vomiting	19	2	7	0
Constipation	12	0	11	0
Constitutional
Fatigue/Asthenia	57	8	34	2
Localized edema§	18	<1	<1	0
Pyrexia	12	<1	6	0
Dermatology
Hand-foot syndrome	50	16	10	<1
Rash¶	24	2	12	0
Hair color changes	22	0	2	0
Skin discoloration/Yellow skin	18	0	1	0
Dry skin	14	0	6	0
Cardiac
Hypertension#	39	8	14	1
Edema/Peripheral edema	10	<1	7	0
Neurology
Altered tasteÞ	38	<1	6	0
Headache	19	<1	12	0
Endocrine
Hypothyroidism/TSH increased	24	<1	4	0
Hemorrhage/Bleeding
Bleeding events, all sitesß	24	<1	5	<1
Metabolism/Nutrition
Anorexia/Decreased appetite	19	<1	5	0
Musculoskeletal
Pain in extremity	15	<1	7	0
Arthralgia	11	<1	10	0

Grade 4 adverse reactions in patients on SUTENT included hand-foot syndrome (1%), fatigue (<1%), abdominal pain (< 1%), stomatitis (<1%), and pyrexia (< 1%).

Grade 3–4 laboratory abnormalities that occurred in ≥2% of patients receiving SUTENT include neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).

Advanced Pancreatic Neuroendocrine Tumors

The safety of SUTENT was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received SUTENT 37.5 mg once daily (n=83) or placebo (n=82). The median number of days on treatment was 139 days (range: 13–532 days) for patients on SUTENT and 113 days (range: 1–614 days) for patients on placebo. Nineteen patients (23%) on SUTENT and 4 patients (5%) on placebo were on study for >1 year.

Permanent discontinuation due to an adverse reaction occurred in 22% in the SUTENT arm. Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received SUTENT.

Table 8 summarizes the adverse reactions in Study 6.

Table 8. Adverse Reactions Reported in ≥10% of Patients With pNET Who Received SUTENT and More Commonly Than in Patients Given Placebo* in Study 6
Adverse Reaction	pNET
	SUTENT (N=83)		Placebo (N=82)
	All Grades %	Grade 3–4† %	All Grades %	Grade 3–4 %
Abbreviations: N=number of patients; pNET=pancreatic neuroendocrine tumors.
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Grade 4 adverse reactions in patients on SUTENT included fatigue (1%). ‡ Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth. § Includes abdominal discomfort, abdominal pain, and abdominal pain upper. ¶ Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia.
Any Adverse Reaction	99	54	95	50
Gastrointestinal
Diarrhea	59	5	39	2
Stomatitis/oral syndromes‡	48	6	18	0
Nausea	45	1	29	1
Abdominal pain§	39	5	34	10
Vomiting	34	0	31	2
Dyspepsia	15	0	6	0
Constitutional
Asthenia	34	5	27	4
Fatigue	33	5	27	9
Weight decreased	16	1	11	0
Dermatology
Hair color changes	29	1	1	0
Hand-foot syndrome	23	6	2	0
Rash	18	0	5	0
Dry skin	15	0	11	0
Cardiac
Hypertension	27	10	5	1
Hemorrhage/Bleeding
Bleeding events¶	22	0	10	4
Epistaxis	21	1	5	0
Neurology
Dysgeusia	21	0	5	0
Headache	18	0	13	1
Psychiatric
Insomnia	18	0	12	0
Musculoskeletal
Arthralgia	15	0	6	0

Table 9 summarizes the laboratory abnormalities in Study 6.

Table 9. Laboratory Abnormalities Reported in ≥10% of Patients With pNET Who Received SUTENT in Study 6
Laboratory Abnormality	pNET
	SUTENT			Placebo
		All Grades* %	Grade 3–4*,† %		All Grades* %	Grade 3–4*,‡ %
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; N=number of patients; pNET=pancreatic neuroendocrine tumors.
* The denominator used to calculate the rate varied from 52 to 82 for SUTENT and 39 to 80 for Placebo based on the number of patients with a baseline value and at least one post-treatment value. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Grade 4 laboratory abnormalities in patients on SUTENT included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%), and total bilirubin (1%). ‡ Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%).
Gastrointestinal
AST increased		72	5		70	3
Alkaline phosphatase increased		63	10		70	11
ALT increased		61	4		55	3
Total bilirubin increased		37	1		28	4
Amylase increased		20	4		10	1
Lipase increased		17	5		11	4
Hematology
Neutrophils decreased		71	16		16	0
Hemoglobin decreased		65	0		55	1
Platelets decreased		60	5		15	0
Lymphocytes decreased		56	7		35	4
Renal/Metabolic
Glucose increased		71	12		78	18
Albumin decreased		41	1		37	1
Phosphorus decreased		36	7		22	5
Calcium decreased		34	0		19	0
Sodium decreased		29	2		34	3
Creatinine increased		27	5		28	5
Glucose decreased		22	2		15	4
Potassium decreased		21	4		14	0
Magnesium decreased		19	0		10	0
Potassium increased		18	1		11	1

Venous Thromboembolic Events

In pooled safety population, 3.5% of patients experienced a venous thromboembolic event, including Grade 3–4 in 2.2% of patients.

Pancreatic Function

Pancreatitis was observed in 1 patient (1%) in the pNET study, 5 patients (1%) in the treatment-naïve RCC study, and 1 patient (<1%) in the adjuvant treatment for RCC study on SUTENT.

6.2 Postmarketing Experience

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

Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia1.
Gastrointestinal disorders: esophagitis.
Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis.
Immune system disorders: hypersensitivity reactions, including angioedema.
Infections and infestations: serious infection (with or without neutropenia)1. The infections most commonly observed with SUTENT include respiratory, urinary tract, skin infections, and sepsis/septic shock.
Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression1; myopathy and/or rhabdomyolysis with or without acute renal failure1.
Renal and urinary disorders: renal impairment and/or failure1.
Respiratory disorders: pulmonary embolism1, pleural effusion1.
Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive de-challenges.
Vascular disorders: arterial (including aortic) aneurysms, dissections1, and rupture1; arterial thromboembolic events1. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction.
General disorders and administration site conditions: impaired wound healing.

1: including some fatalities