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SUTENT®Adverse Reactions (sunitinib malate)

6 ADVERSE REACTIONS

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

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 1 summarizes the adverse reactions for Study 1.

Table 1. 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 ReactionGIST
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 Reaction94569751
Gastrointestinal
  Diarrhea404270
  Mucositis/stomatitis291182
  Constipation200142
Metabolism/Nutrition
  Anorexia331295
  Asthenia225113
Dermatology
  Skin discoloration300230
  Rash14190
  Hand-foot syndrome144103
Neurology
  Altered taste210120
Cardiac
  Hypertension154110
Musculoskeletal
  Myalgia/limb pain14191

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 2 summarizes the laboratory abnormalities in Study 1.

Table 2. Laboratory Abnormalities Reported in ≥10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase* in Study 1
Laboratory ParameterGIST
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%).
Any3422
Hematology
  Neutrophils531040
  Lymphocytes380160
  Platelets38540
  Hemoglobin263222
Gastrointestinal
  AST/ALT392231
  Lipase2510177
  Alkaline phosphatase244214
  Amylase175123
  Total bilirubin16180
  Indirect bilirubin10040
Renal/Metabolic
  Creatinine12170
  Potassium decreased12140
  Sodium increased10041
Cardiac
  Decreased LVEF11130

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 3 summarizes the adverse reactions for Study 3.

Table 3. Adverse Reactions Reported in ≥10% of Patients With RCC Who Received SUTENT or Interferon Alfa* in Study 3
Adverse ReactionTreatment-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 Reaction99779955
Gastrointestinal
  Diarrhea661021<1
  Nausea586412
  Mucositis/stomatitis4735<1
  Vomiting395171
  Dyspepsia34240
  Abdominal pain§305121
  Constipation23114<1
  Dry mouth1307<1
  Oral pain14<110
  Flatulence14020
  GERD/reflux esophagitis12<110
  Glossodynia11010
  Hemorrhoids10020
Constitutional
  Fatigue62155615
  Asthenia2611226
  Fever22137<1
  Weight decreased16<1171
  Chills141310
  Chest Pain13271
  Influenza like illness5015<1
Metabolism/Nutrition
  Anorexia483422
Neurology
  Altered taste#47<1150
  Headache231190
  Dizziness11<1141
Hemorrhage/Bleeding
  Bleeding, all sites374Þ101
Cardiac
  Hypertension34134<1
  Edema peripheral24251
  Ejection fraction decreased16352
Dermatology
  Rash29211<1
  Hand-foot syndrome29810
  Skin discoloration/yellow skin25<100
  Dry skin23<170
  Hair color changes200<10
  Alopecia14090
  Erythema12<110
  Pruritus12<17<1
Musculoskeletal
  Pain in extremity/limb discomfort405302
  Arthralgia303191
  Back pain285142
Respiratory
  Cough27114<1
  Dyspnea266204
  Nasopharyngitis14020
  Oropharyngeal pain14<120
  Upper respiratory tract infection11<120
Endocrine
  Hypothyroidism16210
Psychiatric
  Insomnia15<1100
  Depressionß110141

Table 4 summarizes the laboratory abnormalities in Study 3.

Table 4. Laboratory Abnormalities Reported in ≥10% of RCC Patients Who Received SUTENT or Interferon Alfa in Study 3
Laboratory ParameterTreatment-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
  Hemoglobin798695
  Neutrophils7717499
  Platelets689241
  Lymphocytes68186826
Renal/Metabolic
  Creatinine70<151<1
  Creatine kinase492111
  Uric acid4614338
  Calcium decreased421401
  Phosphorus316246
  Albumin281200
  Glucose increased236156
  Sodium decreased208154
  Glucose decreased17012<1
  Potassium increased163174
  Calcium increased13<1101
  Potassium decreased1312<1
  Sodium increased130100
Gastrointestinal
  AST562382
  Lipase5618468
  ALT513402
  Alkaline phosphatase462372
  Amylase356323
  Total bilirubin20120
  Indirect bilirubin13110

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 5 summarizes the adverse reactions in S-TRAC.

Table 5. Adverse Reactions Reported in ≥10% of Patients With RCC Who Received SUTENT and More Commonly Than in Patients Given Placebo* in S-TRAC
Adverse ReactionAdjuvant 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 Reaction99608815
Gastrointestinal
  Mucositis/Stomatitis616150
  Diarrhea57422<1
  Nausea342150
  Dyspepsia27170
  Abdominal pain2529<1
  Vomiting19270
  Constipation120110
Constitutional
  Fatigue/Asthenia578342
  Localized edema§18<1<10
  Pyrexia12<160
Dermatology
  Hand-foot syndrome501610<1
  Rash242120
  Hair color changes22020
  Skin discoloration/Yellow skin18010
  Dry skin14060
Cardiac
  Hypertension#398141
  Edema/Peripheral edema10<170
Neurology
  Altered tasteÞ38<160
  Headache19<1120
Endocrine
  Hypothyroidism/TSH increased24<140
Hemorrhage/Bleeding
  Bleeding events, all sitesß24<15<1
Metabolism/Nutrition
  Anorexia/Decreased appetite19<150
Musculoskeletal
  Pain in extremity15<170
  Arthralgia11<1100

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 6 summarizes the adverse reactions in Study 6.

Table 6. Adverse Reactions Reported in ≥10% of Patients With pNET Who Received SUTENT and More Commonly Than in Patients Given Placebo* in Study 6
Adverse ReactionpNET
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 Reaction99549550
Gastrointestinal
  Diarrhea595392
  Stomatitis/oral syndromes486180
  Nausea451291
  Abdominal pain§3953410
  Vomiting340312
  Dyspepsia15060
Constitutional
  Asthenia345274
  Fatigue335279
  Weight decreased161110
Dermatology
  Hair color changes29110
  Hand-foot syndrome23620
  Rash18050
  Dry skin150110
Cardiac
  Hypertension271051
Hemorrhage/Bleeding
  Bleeding events220104
  Epistaxis21150
Neurology
  Dysgeusia21050
  Headache180131
Psychiatric
  Insomnia180120
Musculoskeletal
  Arthralgia15060

Table 7 summarizes the laboratory abnormalities in Study 6.

Table 7. Laboratory Abnormalities Reported in ≥10% of Patients With pNET Who Received SUTENT in Study 6
Laboratory ParameterpNET
SUTENTPlacebo
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 increased725703
  Alkaline phosphatase increased63107011
  ALT increased614553
  Total bilirubin increased371284
  Amylase increased204101
  Lipase increased175114
Hematology
  Neutrophils decreased7116160
  Hemoglobin decreased650551
  Platelets decreased605150
  Lymphocytes decreased567354
Renal/Metabolic
  Glucose increased71127818
  Albumin decreased411371
  Phosphorus decreased367225
  Calcium decreased340190
  Sodium decreased292343
  Creatinine increased275285
  Glucose decreased222154
  Potassium decreased214140
  Magnesium decreased190100
  Potassium increased181111

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 5 patients (1%) receiving SUTENT for treatment-naïve RCC compared to 1 patient (<1%) receiving interferon alfa. 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.

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
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