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 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 1Adverse 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. |
|
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. |
|
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 3Adverse 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. |
|
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 3Laboratory 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. |
|
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. |
|
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. |
|
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 6Laboratory 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. |
|
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.