SUTENT SIDE EFFECTS

Last updated on MDtodate: 10/12/2022

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling.

• Hepatotoxicity
• Cardiovascular Events
• QT Interval Prolongation and Torsade de Pointes
• Hypertension ]
• Hemorrhagic Events
• Tumor Lysis Syndrome (TLS)
• Thrombotic Microangiopathy
• Proteinuria
• Dermatologic Toxicities
• Thyroid Dysfunction
• Hypoglycemia
• Osteonecrosis of the Jaw (ONJ)
• Wound Healing

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 data described in the Warnings and Precautions reflect exposure to SUTENT (N = 7527) in GIST, advanced RCC, adjuvant treatment of RCC, and pNET. In this database, the most common adverse reactions (≥25%) are fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia.

The data below reflect exposure to SUTENT in 966 patients who participated in the treatment phase of randomized trials of GIST (n=202), advanced RCC (n=375), adjuvant treatment of RCC (n=306), and pNET (n=83).

Gastrointestinal Stromal Tumor (GIST)

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. 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, nonfatal 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.

Table 1. Adverse Reactions Reported in Study 1 in ≥10% of GIST Patients Who Received SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo*

Adverse Reaction	GIST
	SUTENT (N=202)		Placebo (N=102)
	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
Any Adverse Reaction	94	56	97	51
Gastrointestinal
Diarrhea	40	4	27	0
Mucositis/stomatitis	29	1	18	2
Constipation	20	0	14	2
Cardiac
Hypertension	15	4	11	0
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
Musculoskeletal
Myalgia/limb pain	14	1	9	1
Metabolism/Nutrition
Anorexiaa	33	1	29	5
Asthenia	22	5	11	3
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients. a Includes decreased appetite.

 

In the double-blind treatment phase of GIST Study 1, 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.

Table 2. Laboratory Abnormalities Reported in Study 1 in ≥10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase*

Laboratory Parameter	GIST
	SUTENT (N=202)		Placebo (N=102)
	All Grades* %	Grade 3-4*,a %	All Grades* %	Grade 3-4*,b %
Any		68 (34)		22 (22)
Gastrointestinal
AST/ALT	39	2	23	1
Lipase	25	10	17	7
Alkaline phosphatase	24	4	21	4
Amylase	17	5	12	3
Total bilirubin	16	1	8	0
Indirect bilirubin	10	0	4	0
Cardiac
Decreased LVEF	11	1	3	0
Renal/Metabolic
Creatinine	12	1	7	0
Potassium decreased	12	1	4	0
Sodium increased	10	0	4	1
Hematology
Neutrophils	53	10	4	0
Lymphocytes	38	0	16	0
Platelets	38	5	4	0
Hemoglobin	26	3	22	2
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; GIST=gastrointestinal stromal tumor; LVEF=left ventricular ejection fraction; N=number of patients. 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%).

 

After an interim analysis, the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label SUTENT treatment. 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%).

Advanced Renal Cell Carcinoma (RCC)

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 IFN-α 9 million International Units (MIU) (n=360). The median duration of treatment was 11.1 months (range: 0.4-46.1) for SUTENT treatment and 4.1 months (range: 0.1–45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on SUTENT and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on SUTENT and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for SUTENT and 24% for IFN-α. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on SUTENT versus IFN-α, respectively.

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

Table 3. Adverse Reactions Reported in Study 3 in ≥10% of Patients With RCC Who Received SUTENT or IFN-α*

Adverse Reaction	Treatment-Naive RCC
	SUTENT (N=375)		IFN-α (N=360)
	All Grades %	Grade 3-4a %	All Grades %	Grade 3-4b %
Any Adverse Reaction	99	77	99	55
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
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 painc	30	51	12	1
Constipation	23	1	14	<1
Dry mouth	13	0	7	<1
GERD/reflux esophagitis	12	<1	1	0
Flatulence	14	0	2	0
Oral pain	14	<1	1	0
Glossodynia	11	0	1	0
Hemorrhoids	10	0	2	0
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
Neurology
Altered tasted	47	<1	15	0
Headache	23	1	19	0
Dizziness	11	<1	14	1
Musculoskeletal
Back pain	28	5	14	2
Arthralgia	30	3	19	1
Pain in extremity/limb discomfort	40	5	30	2
Endocrine
Hypothyroidism	16	2	1	0
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
Metabolism/Nutrition
Anorexiae	48	3	42	2
Hemorrhage/Bleeding
Bleeding, all sites	37	4f	10	1
Psychiatric
Insomnia	15	<1	10	0
Depressiong	11	0	14	1
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ARs=adverse reactions; IFN=interferon-α; N=number of patients; RCC=renal cell carcinoma. a 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%). b Grade 4 ARs in patients on IFN-α included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%). c Includes flank pain. d Includes ageusia, hypogeusia, and dysgeusia. e Includes decreased appetite. f Includes 1 patient with Grade 5 gastric hemorrhage. g Includes depressed mood.

 

Treatment-emergent Grade 3-4 laboratory abnormalities are presented in Table 4.

Table 4. Laboratory Abnormalities Reported in Study 3 in ≥10% of Treatment-Naive RCC Patients Who Received SUTENT or IFN-α

Laboratory Parameter	Treatment-Naive RCC
	SUTENT (N=375)		IFN-α (N=360)
	All Grades* %	Grade 3-4*,a %	All Grades* %	Grade 3-4*,b %
Gastrointestinal
AST	56	2	38	2
ALT	51	3	40	2
Lipase	56	18	46	8
Alkaline phosphatase	46	2	37	2
Amylase	35	6	32	3
Total bilirubin	20	1	2	0
Indirect bilirubin	13	1	1	0
Renal/Metabolic
Creatinine	70	<1	51	<1
Creatine kinase	49	2	11	1
Uric acid	46	14	33	8
Calcium decreased	42	1	40	1
Phosphorus	31	6	24	6
Albumin	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
Hematology
Neutrophils	77	17	49	9
Hemoglobin	79	8	69	5
Platelets	68	9	24	1
Lymphocytes	68	18	68	26
Leukocytes	78	8	56	2
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; IFN=interferon-α; N=number of patients; RCC=renal cell carcinoma. a 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%). b Grade 4 laboratory abnormalities in patients on IFN-α included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%).

 

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 (n=306) on Schedule 4/2 or placebo (n=304). The median duration of treatment was 12.4 months (range: 0.13-14.9) for SUTENT and 12.4 months (range: 0.03-13.7) for placebo. Permanent discontinuation due to an adverse reaction occurred in 28% of patients on SUTENT and 6% on placebo. Adverse reactions leading to permanent discontinuation in >2% of patients include hand-foot syndrome and fatigue/asthenia. Dosing interruptions or delays occurred in 166 (54%) and 84 (28%) patients on SUTENT and placebo, respectively. One hundred forty patients (45.8%) out of 306 patients in the SUTENT arm and 15 patients (5%) out of 304 patients in the placebo arm had dose reductions.

Table 5 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT versus placebo.

Table 5. Adverse Reactions Reported in S-TRAC in ≥10% of Patients With RCC Who Received SUTENT and More Commonly Than in Patients Given Placebo*

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

 

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

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 daily continuous dosing (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. Dose interruptions occurred in 25 patients (30%) on SUTENT and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on SUTENT and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for SUTENT and 17% for placebo.

Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 54% versus 50% of patients on SUTENT versus placebo, respectively. Table 6 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.

Table 6. Adverse Reactions Reported in the pNET Study 6 in ≥10% of Patients Who Received SUTENT and More Commonly Than in Patients Given Placebo*

Adverse Reaction	pNET
	SUTENT (N=83)		Placebo (N=82)
	All Grades %	Grade 3-4a %	All Grades %	Grade 3-4b %
Any Adverse Reaction	99	54	95	50
Constitutional
Asthenia	34	5	27	4
Fatigue	33	5	27	9
Weight decreased	16	1	11	0
Gastrointestinal
Diarrhea	59	5	39	2
Stomatitis/oral syndromesb	48	6	18	0
Nausea	45	1	29	1
Abdominal painc	39	5	34	10
Vomiting	34	0	31	2
Dyspepsia	15	0	6	0
Cardiac
Hypertension	27	10	5	1
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
Neurology
Dysgeusia	21	0	5	0
Headache	18	0	13	1
Musculoskeletal
Arthralgia	15	0	6	0
Psychiatric
Insomnia	18	0	12	0
Hemorrhage/Bleeding
Bleeding eventsd	22	0	10	4
Epistaxis	21	1	5	0
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: N=number of patients; pNET=pancreatic neuroendocrine tumors. a Grade 4 adverse reactions in patients on SUTENT included fatigue (1%). b Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth. c Includes abdominal discomfort, abdominal pain, and abdominal pain upper. d Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia.

 

Table 7 provides common (≥10%) treatment-emergent laboratory abnormalities.

Table 7. Laboratory Abnormalities Reported in the pNET Study 6 in ≥10% of Patients Who Received SUTENT

Laboratory Parameter	pNET
	SUTENT			Placebo
	N	All Grades* %	Grade 3-4*,a %	N	All Grades* %	Grade 3-4*,b %
AST increased	82	72	5	80	70	3
ALT increased	82	61	4	80	55	3
Alkaline phosphatase increased	82	63	10	80	70	11
Total bilirubin increased	82	37	1	80	28	4
Amylase increased	74	20	4	74	10	1
Lipase increased	75	17	5	72	11	4
Renal/Metabolic
Glucose increased	82	71	12	80	78	18
Albumin decreased	81	41	1	79	37	1
Phosphorus decreased	81	36	7	77	22	5
Calcium decreased	82	34	0	80	19	0
Sodium decreased	82	29	2	80	34	3
Creatinine increased	82	27	5	80	28	5
Glucose decreased	82	22	2	80	15	4
Potassium decreased	82	21	4	80	14	0
Magnesium decreased	52	19	0	39	10	0
Potassium increased	82	18	1	80	11	1
Hematology
Neutrophils decreased	82	71	16	80	16	0
Hemoglobin decreased	82	65	0	80	55	1
Platelets decreased	82	60	5	80	15	0
Lymphocytes decreased	82	56	7	80	35	4
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; N=number of patients; pNET=pancreatic neuroendocrine tumors. a 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%). b Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%).

 

Venous Thromboembolic Events

In patients treated with SUTENT (N=7527) for GIST, advanced RCC, adjuvant treatment of RCC and pNET, 3.5% of patients experienced a venous thromboembolic event; 2.2% Grade 3-4.

Reversible Posterior Leukoencephalopathy Syndrome

There have been reports (<1%), some fatal, of patients presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness, should be controlled with medical management including control of hypertension. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating healthcare provider.

Pancreatic Function

Pancreatitis was observed in 5 patients (1%) receiving SUTENT for treatment-naive RCC compared to 1 patient (<1%) receiving IFN-α. In a trial of patients receiving adjuvant treatment for RCC, 1 patient (<1%) on SUTENT and none on placebo experienced pancreatitis. Pancreatitis was observed in 1 patient (1%) receiving SUTENT for pNET and 1 patient (1%) receiving placebo.

Postmarketing Experience

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

Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia*. Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating healthcare provider.

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)*. The infections most commonly observed with SUTENT treatment include respiratory, urinary tract, skin infections, and sepsis/septic shock.

Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression*; myopathy and/or rhabdomyolysis with or without acute renal failure*. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.

Renal and urinary disorders: renal impairment and/or failure*.

Respiratory disorders: pulmonary embolism*, pleural effusion*.

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

Vascular disorders: arterial (including aortic) aneurysms, dissections*, and rupture*; arterial thromboembolic events*. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction.

*including some fatalities