6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. 14 )] 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.
gov/medwatch. 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 sunitinib malate in 7,527 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 sunitinib malate was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib malate 50 mg daily on Schedule 4/2 (n = 202) or placebo (n = 102).
8; range: 1 to 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 sunitinib malate arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib malate.
Table 3 summarizes the adverse reactions for Study 1. Table 3. 0.
Abbreviations:
GIST = gastrointestinal stromal tumor; N = number of patients. a Includes decreased appetite. 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 sunitinib malate.
Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. 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 sunitinib malate 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%). 1 )] . 5; range: 1 to 44). 8; range: 1 to 37) from the time of the unblinding. Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received sunitinib malate.
Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received sunitinib malate. The most common Grade 3 or 4 adverse reactions in patients who received sunitinib malate 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 sunitinib malate was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received sunitinib malate 50 mg daily on Schedule 4/2 (n = 375) or interferon alfa 9 million International Units (MIU) (n = 360).
6) for interferon alfa treatment. Permanent discontinuation due to an adverse reaction occurred in 20% of patients in the sunitinib malate arm. Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received sunitinib malate.
Table 5 summarizes the adverse reactions for Study 3. Table 5. 0.
Abbreviations:
ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. a Grade 4 ARs in patients on sunitinib malate 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 interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%). c Includes flank pain. d Includes decreased appetite. e Includes ageusia, hypogeusia, and dysgeusia. f Includes 1 patient with Grade 5 gastric hemorrhage.
g Includes depressed mood. Table 6 summarizes the laboratory abnormalities in Study 3. Table 6. 0.
Abbreviations:
ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; RCC = renal cell carcinoma. a Grade 4 laboratory abnormalities in patients on sunitinib malate 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 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%).
Long-Term Safety in RCC The long-term safety of sunitinib malate 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 5,739 patients, of whom 807 (14%) were treated for at least 2 years and 365 (6%) for at least 3 years. Prolonged treatment with sunitinib malate 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 sunitinib malate was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received sunitinib malate 50 mg daily on Schedule 4/2 (n = 306) or placebo (n = 304).
7) for placebo. Permanent discontinuation due to an adverse reaction occurred in 28% of patients in the sunitinib malate 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 sunitinib malate. Table 7 summarizes the adverse reactions in S-TRAC. Table 7. 0.
Abbreviations:
ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. a Includes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain. b Includes abdominal pain, abdominal pain lower, and abdominal pain upper.
c Includes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema. d Includes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic.
e Includes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis. f Includes ageusia, hypogeusia, and dysgeusia. g Includes epistaxis, gingival bleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria.
Grade 4 adverse reactions in patients on sunitinib malate included hand-foot syndrome (1%), fatigue (<1%), abdominal pain (< 1%), stomatitis (<1%), and pyrexia (< 1%). Grade 3 to 4 laboratory abnormalities that occurred in ≥2% of patients receiving sunitinib malate include neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).
5 mg once daily (n = 83) or placebo (n = 82). The median number of days on treatment was 139 days (range: 13 days to 532 days) for patients on sunitinib malate and 113 days (range: 1 day to 614 days) for patients on placebo. Nineteen patients (23%) on sunitinib malate and 4 patients (5%) on placebo were on study for >1 year.
Permanent discontinuation due to an adverse reaction occurred in 22% in the sunitinib malate arm. Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received sunitinib malate. Table 8 summarizes the adverse reactions in Study 6.
Table 8. 0.
Abbreviations:
N = number of patients; pNET = pancreatic neuroendocrine tumors. a Grade 4 adverse reactions in patients on sunitinib malate 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 9 summarizes the laboratory abnormalities in Study 6. Table 9.
Laboratory Abnormalities Reported in ≥10% of Patients with pNET Who Received Sunitinib Malate in Study 6 Laboratory Abnormality pNET Sunitinib Malate Placebo All Grades* % Grade 3 to 4* ,a % All Grades* % Grade 3 to 4* ,b % 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 * The denominator used to calculate the rate varied from 52 to 82 for sunitinib malate and 39 to 80 for Placebo based on the number of patients with a baseline value and at least one post-treatment value.
0.
Abbreviations:
ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; pNET = pancreatic neuroendocrine tumors. a Grade 4 laboratory abnormalities in patients on sunitinib malate 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%). 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 sunitinib malate.
2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sunitinib malate. 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 * . 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 sunitinib malate 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 * .
Renal and urinary disorders: renal impairment and/or failure * . Respiratory disorders: pulmonary embolism * , pleural effusion * . Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive de‑challenges. 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. General disorders and administration site conditions: impaired wound healing. * including some fatalities