Date of approval.
Date of revision.
Sunitinib Malate Capsules Instructions for Use
Please read the instructions carefully and use under the guidance of a physician
Warning: Hepatotoxicity
Hepatotoxic reactions have been observed in patients in clinical studies and post-marketing clinical applications, and hepatotoxicity may be severe, with reported cases of fatalities. (See “Precautions” for details)
Generic name: Sunitinib Malate Capsules
English name: Sunitinib Malate Capsules
Hanyu Pinyin: Pingguosuan Shunitini Jiaonang
[Ingredients]
The main ingredient of this product is sunitinib malate.
Chemical name: (Z)--N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-3-aminocarbonyl-1H-pyrrole malate
The chemical structure formula is.
Molecular formula: C22H27FN4O2-C4H6O5
Molecular weight: 532.56
Excipients: mannitol, polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, magnesium stearate
[Properties]
This product is a capsule, the contents of which are yellow to orange granules.
[Indications]
1) inoperable advanced renal cell carcinoma (RCC)
2) Gastrointestinal mesenchymal tumor (GIST) that has failed or is intolerant to treatment with imatinib mesylate
3) Unresectable, adult patients with metastatic, highly differentiated progressive pancreatic neuroendocrine tumor (pNET).
[Specifications]
12.5mg (as sunitinib)
[Dosage]
The recommended dose of sunitinib for the treatment of gastrointestinal mesenchymal tumors and advanced renal cell carcinoma is 50 mg orally once daily for 4 weeks and 2 weeks off (4/2 dosing regimen).
For pancreatic neuroendocrine tumors, the recommended dose of sunitinib is 37.5 mg orally once daily for 4 weeks with no discontinuation period.
It can be taken with or without food.
Dose Adjustment
Safety and Tolerability
For gastrointestinal mesenchymal tumors and metastatic renal cell carcinoma, the dose is adjusted gradually in 12.5 mg stepwise units based on individual patient safety and tolerability. The maximum daily dose does not exceed 75 mg, and the lowest dose is 25 mg.
For pancreatic neuroendocrine tumors, the dose was adjusted gradually in 12.5 mg stepwise units based on individual patient safety and tolerability. The maximum dose used in the Phase 3 clinical trial was 50 mg daily.
Treatment may need to be interrupted depending on the safety and tolerability of the individual patient.
Strong inhibitors of CYP3A4 (e.g., ketoconazole) may increase the plasma concentration of sunitinib. It is recommended that the drug with no or minimal inhibition of such enzymes be selected for combination. If a combination with a strong CYP3A4 inhibitor is necessary, a lower dose of sunitinib should be considered, as low as 37.5 mg once daily (gastrointestinal mesenchymal tumors and renal cell carcinoma) and 25 mg once daily (pancreatic neuroendocrine tumors) (see [Drug Interactions]).
CYP3A4 inducers (e.g., rifampin) may reduce the plasma concentration of sunitinib. It is recommended that the drug with no or minimal induction of such enzymes be selected for combination. If a combination with a CYP3A4 inducer is necessary, an increase in the dose of sunitinib should be considered, with the maximum dose not exceeding 87.5 mg once daily (gastrointestinal mesenchymal tumors and renal cell carcinoma) and 62.5 mg once daily (pancreatic neuroendocrine tumors). If the sunitinib dose is increased, patients should be carefully monitored for toxic effects (see [Drug Interactions]).
[Adverse Reactions]
Direct comparison of the incidence of adverse reactions between two drugs in different clinical studies is not appropriate because of the variability of individual clinical studies, and the incidence of adverse reactions in clinical studies may differ from that in clinical practice.
The most common adverse reactions (≥20%) in patients with gastrointestinal mesenchymal tumor (GIST), advanced renal cell carcinoma (RCC), or pancreatic neuroendocrine tumor (pNET) were fatigue, malaise, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color change, taste changes, headache, back pain, joint pain, extremity pain, cough, dyspnea, anorexia, and bleeding. For a discussion of potentially serious adverse reactions: hepatotoxicity, left ventricular dysfunction, QT interval prolongation, bleeding, hypertension, thyroid insufficiency, and adrenal function see [Precautions]. Other adverse reactions that occurred in studies of gastrointestinal mesenchymal tumor (GIST), advanced renal cell carcinoma (RCC), and pancreatic neuroendocrine tumor (pNET) are listed below.
The following data are from 660 patients, including 202 patients in the double-blind, placebo-controlled study of gastrointestinal mesenchymal tumor (GIST) (see [Clinical Studies]), 375 patients in the positive drug-controlled study of advanced renal cell carcinoma (RCC) (see [Clinical Studies]), and pancreatic neuroendocrine tumor (pNET) placebo-controlled study (see [Clinical Studies]) in 83 patients.
Gastrointestinal Mesenchymal Stromal Tumor (GIST)
The safety of sunitinib was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which patients previously treated for GIST received sunitinib 50 mg (n=202) or placebo (n=102) daily according to a 4/2 dosing regimen.
The median duration of treatment for patients in the double-blind study was 2 cycles (mean 3.0 cycles, range 1 to 9 cycles) in the sunitinib group and 1 cycle (mean 1.8 cycles, range 1 to 6 cycles) in the placebo group as of interim analysis. Dose reductions occurred in 23 patients (11%) in the sunitinib group and in no patients in the placebo group. Treatment discontinuation occurred in 59 (29%) patients in the sunitinib group and 31 (30%) patients in the placebo group; 7% and 6% of patients, respectively, had permanent discontinuation due to treatment-related nonfatal adverse effects.
During the double-blind treatment period of the trial, the majority of adverse reactions occurring after treatment in both study groups were grade 1 and 2 in severity. The incidence of grade 3 or 4 adverse reactions occurring after treatment reported in the sunitinib and placebo groups was 56% and 51%, respectively. Table 1 compares the incidence of common (incidence ≥10%) adverse reactions that occurred after treatment in the two groups, with a higher incidence in the sunitinib group.
Table.
Table1. During the double-blind treatment period of the trial, study 1 in the sunitinib and placebo groupsGISTList of Adverse Reactions After Treatment in Patients (Incidence≥10%)*
| |
GIST | |||
| Sunitinib (N=202) | Placebo (N=102) | |||
| All levels (%) |
3/4Levels (%) |
All Levels (%) |
3/4Levels (%) |
|
| All adverse reactions | 94 | 56 | 97 | 51 |
| Gastrointestinal Diarrhea Mucositis/stomatitis Constipation |
40 29 20 |
4 1 0 |
27 18 14 |
0 2 2 |
| Heart Hypertension |
15 |
4 |
11 |
0 |
| Skin Skin discoloration Rash Hand-foot syndrome |
30 14 14 |
0 1 4 |
23 9 10 |
0 0 3 |
| Neurological Taste alterations |
21 |
0 |
12 |
0 |
| Musculoskeletal system Myalgia/Limb Pain |
14 |
1 |
9 |
1 |
| Metabolism/Nutrition Anorexiaa Lack of energy |
33 22 |
1 5 |
29 11 |
5 3 |
* Common Terminology Standard for Adverse Events (CTCAE), version 3.0.
Abbreviations: GIST = gastrointestinal mesenchymal tumor; N = number of patients
a includes decreased appetite.
During the double-blind treatment period of the trial, non-mucositis/stomatitis oral pain occurred in 12 (6%) patients in the sunitinib group and 3 (3%) patients in the placebo group; hair color changes occurred in 15 (7%) patients and 4 (4%) patients, respectively; and hair loss occurred in 10 (5%) patients and 2 (2%) patients, respectively.
Table 2 lists the common post-treatment laboratory test abnormalities (incidence ≥10%).
Table2. During the double-blind treatment period of the trial, the incidence of abnormalities in the study1 in the sunitinib group or the placebo groupGISTPatients with abnormal laboratory tests (incidence≥10%)*
| Laboratory tests |
GIST | |||
| Sunitinib (N=202) | Placebo (N=102) | |||
| All levels (%) |
3/4Levelsa (%) |
All levels (%) |
3/4Levelsb (%) |
|
| All | 34 | 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 |
| Heart LVEF decline |
11 | 1 | 3 | 0 |
| Kidney/Metabolism Creatinine |
12 | 1 | 7 | 0 |
| Decreased blood potassium | 12 | 1 | 4 | 0 |
| Elevated blood sodium | 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 mesenchymal tumor; LVEF=left ventricular ejection fraction; N=number of patients.
a Grade 4 laboratory test abnormalities in patients in the sunitinib group included alkaline phosphatase (1%), lipase (2%), creatinine (1%), decreased blood potassium (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%).
b Grade 4 laboratory test abnormalities in patients in the placebo group included amylase (1%), lipase (1%), and hemoglobin (2%).
After interim analysis, the trial was unblinded. Patients in the placebo group had the opportunity to receive open sunitinib treatment (see [Clinical Study]). For the 241 patients randomized to the sunitinib arm, including 139 who received sunitinib in both the double-blind and open phases, the median duration of sunitinib treatment was 6 cycles (mean 8.5, range 1 to 44). For the 255 patients who eventually received sunitinib in the open phase, the median treatment period was 6 cycles (mean 7.8, range 1 to 37) calculated from the end of the double-blind phase. A total of 118 patients (46%) required treatment interruption and 72 patients (28%) required dose reduction. 20% of patients were permanently discontinued due to post-treatment adverse events. The most common grade 3 or 4 drug-related adverse reactions in patients treated with sunitinib in the open phase were fatigue (10%), hypertension (8%), malaise (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 sunitinib was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received sunitinib 50 mg (n=375) or IFN-α 9 million international units (MIUs) (n=360) daily according to a 4/2 dosing regimen. The median duration of treatment was 11.1 months (range: 0.4 to 46.1 months) and 4.1 months (range: 0.1 to 45.6 months) in the sunitinib and IFN-a groups, respectively. Treatment discontinuation occurred in 202 (54%) and 141 (39%) patients in the sunitinib and IFN-a groups, respectively. Dose reductions were required in 194 (52%) and 98 (27%) patients in the sunitinib and IFN-a groups, respectively. Twenty percent and 23% of patients in the sunitinib and IFN-a groups, respectively, had permanent discontinuation due to post-treatment adverse reactions. Most of the post-treatment adverse reactions were grade 1 or 2. Grade 3 or 4 adverse reactions were reported in 77% and 55% of patients in the sunitinib and IFN-a groups, respectively, after treatment. Table 3 compares the common (≥10%) adverse reactions after treatment in the sunitinib and IFN-a groups.
Table3. Study3 in patients receiving sunitinib or IFN-aa Adverse reactions in RCC-treated patients (incidence≥10%)*
| Primarily treated RCC | ||||
| Sunitinib (N=375) |
IFN-a (N=360) |
|||
| All levels (%) |
3/4Levelsa (%) |
All levels (%) |
3/4Levelsb (%) |
|
| All adverse reactions | 99 | 77 | 99 | 55 |
| General | ||||
| 62 | 15 | 56 | 15 | |
| Lackluster | 26 | 11 | 22 | 6 |
| Fever | 22 | 1 | 37 | <1 |
| weight loss | 16 | <1 | 17 | 1 |
| Chillout | 14 | 1 | 31 | 0 |
| Chest pain | 13 | 2 | 7 | 1 |
| Influenza-like illness | 5 | 0 | 15 | <1 |
| Gastrointestinal Diarrhea |
66 |
10 |
21 |
<1 |
| disgusting | 58 | 6 | 41 | 2 |
| Mucositis/stomatitis | 47 | 3 | 5 | <1 |
| Vomiting | 39 | 5 | 17 | 1 |
| Indigestion | 34 | 2 | 4 | 0 |
| Abdominal painc | 30 | 5 | 12 | 1 |
| Constipation | 23 | 1 | 14 | <1 |
| Dry mouth | 13 | 0 | 7 | <1 |
| GERD/reflux esophagitis | 12 | <1 | 1 | 0 |
| Gastrointestinal distention | 14 | 0 | 2 | 0 |
| Mouth pain | 14 | <1 | 1 | 0 |
| Tongue pain | 11 | 0 | 1 | 0 |
| Hemorrhoids | 10 | 0 | 2 | 0 |
| Heart Hypertension |
34 |
13 |
4 |
<1 |
| Peripheral edema | 24 | 2 | 5 | 1 |
| Decreased ejection fraction | 16 | 3 | 5 | 2 |
| Skin Rash |
29 |
2 |
11 |
<1 |
| Hand-foot syndrome | 29 | 8 | 1 | 0 |
| Skin discoloration/yellowing skin | 25 | <1 | 0 | 0 |
| Dry skin | 23 | <1 | 7 | 0 |
| Hair color change | 20 | 0 | <1 | 0 |
| Hair loss | 14 | 0 | 9 | 0 |
| Erythema | 12 | <1 | 1 | 0 |
| Itching | 12 | <1 | 7 | <1 |
| Neurological Altered tasted |
47 |
<1 |
15 |
0 |
| Headache | 23 | 1 | 19 | 0 |
| Dizziness | 1 | <1 | 14 | 1 |
| Musculoskeletal Back pain |
28 |
5 |
14 |
2 |
| Joint pain | 30 | 3 | 19 | 1 |
| Extremity pain/limb discomfort | 4 | 5 | 30 | 2 |
| Endocrine Hypothyroidism |
16 |
2 |
1 |
0 |
| Respiratory Cough |
27 |
1 |
14 |
<1 |
| Hypopnea | 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 |
| Huge bleeding/Hemorrhage Bleeding (all sites) |
37 |
4f |
10 |
1 |
| Mental Insomnia |
15 |
<1 |
10 |
0 |
| depressiong | 11 | 0 | 14 | 1 |
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
Abbreviations: AR=adverse event; IFN=interferon; N=number of patients; RCC=renal cell carcinoma.
a Grade 4 adverse reactions in the sunitinib group included back pain (1%), arthralgia (<1%), dyspnea (<1%), malaise (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%).
b Grade 4 adverse reactions in the IFN-a group included dyspnea (1%), fatigue (1%), abdominal pain (1%), and depression (<1%).
c Includes low back and rib pain.
d Includes loss of taste, loss of taste, and taste disturbance.
e Includes loss of appetite.
f Includes one case of grade 5 gastric bleeding.
g Includes depressed mood.
Table 4 lists the grade 3/4 laboratory test abnormalities that occurred after treatment.
Table4.Study3 in patients receiving sunitinib or IFN-α Abnormal laboratory tests after treatment (incidence≥10%) in primaryRCC patients treated
| Primary RCC | ||||
| Sunitinib (N=375) | IFN-α (N=360) | |||
| All levels* (%) |
3/4Grade*a (%) |
All levels* (%) |
3/4level*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 |
| Kidney/Metabolism Creatinine |
70 |
<1 |
51 |
<1 |
| Creatine kinase | 49 | 2 | 11 | 1 |
| Uric acid | 46 | 14 | 33 | 8 |
| Decreased blood calcium | 42 | 1 | 40 | 1 |
| Blood phosphorus | 31 | 6 | 24 | 6 |
| albumin | 28 | 1 | 20 | 0 |
| Elevated blood sugar | 23 | 6 | 15 | 6 |
| Lower blood sodium | 20 | 8 | 15 | 4 |
| Glucose drop | 17 | 0 | 12 | <1 |
| Elevated blood potassium | 16 | 3 | 17 | 4 |
| Elevated blood calcium | 13 | <1 | 10 | 1 |
| Decreased blood potassium | 13 | 1 | 2 | <1 |
| Elevated blood sodium | 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 |
| White blood cells | 78 | 8 | 56 | 2 |
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; IFN=interferon; N=number of patients; RCC=renal cell carcinoma.
a Grade 4 laboratory test abnormalities in patients in the sunitinib group included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), elevated glucose (<1%), decreased blood calcium (<1%), blood phosphorus (<1%), elevated blood potassium (<1%), and decreased blood sodium (<1%).
b Grade 4 laboratory test abnormalities in patients in the IFN-α group included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), elevated blood calcium (<1%), decreased blood glucose (<1%), elevated blood potassium (<1%), and hemoglobin (<1%).
Long-term safety in the treatment of renal cell carcinoma
Nine clinical studies completed in first-line treatment with poor bevacizumab and cytokine efficacy were analyzed to assess the long-term safety of sunitinib in patients with metastatic renal cell carcinoma. The analysis included 5739 patients, of whom 807 (14%) received treatment for at least 2 years and 365 (6%) for at least 3 years. Long-term use of sunitinib did not appear to trigger new types of treatment-related adverse reactions. The annual incidence of adverse reactions did not appear to increase at subsequent time points. There was an increased incidence of hypothyroidism in year 2 of treatment and up to 4 years of new cases reported.
Advanced pancreatic neuroendocrine tumor (pNET)
The safety of sunitinib was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received sunitinib 37.5 mg daily as continuous dosing (n=83) or placebo (n=82). The median duration of treatment was 139 days (range 13 to 532 days) in the sunitinib group and 113 days (range 1 to 614 days) in the placebo group. Nineteen patients (23%) in the sunitinib group and 4 patients (5%) in the placebo group continued on the drug >1 year. 25 patients (30%) in the sunitinib group and 10 patients (12%) in the placebo group experienced discontinuation. 26 patients (31%) in the sunitinib group and 9 patients (11%) in the placebo group had dose reductions. Discontinuation rates due to adverse reactions were 22% and 17% in the sunitinib and placebo groups, respectively.
The majority of treatment-related adverse reactions in both treatment groups were grade 1 or 2. Grade 3 or 4 treatment-related adverse reactions were reported in 54% and 50% of patients in the sunitinib and placebo groups, respectively. Table 5 compares the incidence of treatment-related adverse reactions that were common (≥10%) and higher in the sunitinib-treated group relative to the placebo-treated group.
Table5. Sunitinib for pancreatic neuroendocrine tumors6 in the common (≥10% >) and higher than in the placebo-treated group*
| Pancreatic neuroendocrine tumor | ||||
Adverse effects |
Sunitinib (N=83) | Placebo (N=82) | ||
| All levels (%) |
3/4Levelsa (%) |
All levels (%) |
3/4Levels (%) |
|
| All adverse reactions | 99 | 54 | 95 | 50 |
| General Weakness |
34 |
5 |
27 |
4 |
| Fatigue | 33 | 5 | 27 | 9 |
| weight loss | 16 | 1 | 11 | 0 |
| Gastrointestinal Diarrhea |
59 |
5 |
39 |
2 |
| Stomatitis/Oral Syndromeb | 48 | 6 | 18 | 0 |
| disgusting | 45 | 1 | 29 | 1 |
| Vomiting | 34 | 0 | 31 | 2 |
| Indigestion | 15 | 0 | 6 | 0 |
| Abdominal painc | 39 | 5 | 34 | 10 |
| Heart Hypertension |
27 |
10 |
5 |
1 |
| Skin Hair color change |
29 |
1 |
1 |
0 |
| Hand-foot syndrome | 23 | 6 | 2 | 0 |
| Rash | 18 | 0 | 5 | 0 |
| Dry skin | 15 | 0 | 11 | 0 |
| Neurological Taste disorder Headache |
21 18 |
0 0 |
5 13 |
0 1 |
| 15 |
0 |
6 |
0 |
|
| Mental Insomnia |
18 |
0 |
12 |
0 |
| Hemorrhage/Hemorrhage Hemorrhagic eventsdEpistaxis |
22 21 |
0 1 |
10 5 |
4 0 |
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
Abbreviations: n=number of patients; pNET=pancreatic neuroendocrine tumor.
a Grade 4 adverse reactions in patients in the sunitinib group included fatigue (1%).
b Including aphthous stomatitis, gingival pain, gingivitis, tongue inflammation, tongue pain, mouth ulcers, oral discomfort, mouth pain, tongue ulcers, dry mucous membranes, inflammation of mucous membranes, and dry mouth.
c includes abdominal discomfort, abdominal pain, and epigastric pain.
d includes vomiting blood, blood in the stool, hematoma, coughing up blood, bleeding, black stool, and uterine bleeding.
Table 6 provides data on common (≥10%) treatment-related laboratory test abnormalities.
Table6. Sunitinib for pancreatic neuroendocrine tumors in studies6Common (≥< strong>10%) abnormal laboratory tests
| Pancreatic neuroendocrine tumor | ||||||
| Sunitinib | Placebo | |||||
| Cases | All grades* (%) |
3/4Grade*a (%) |
Examples | All levels* (%) |
3/4Grade*b (%) |
|
| Gastrointestinal | ||||||
| AST elevation | 82 | 72 | 5 | 80 | 70 | 3 |
| ALT elevation | 82 | 61 | 4 | 80 | 55 | 3 |
| Elevated alkaline phosphatase | 82 | 63 | 10 | 80 | 70 | 11 |
| Elevated total bilirubin | 82 | 37 | 1 | 80 | 28 | 4 |
| Elevated amylase | 74 | 20 | 4 | 74 | 10 | 1 |
| Elevated lipase | 75 | 17 | 5 | 72 | 11 | 4 |
| Kidney/Metabolism | ||||||
| Elevated blood sugar | 82 | 71 | 12 | 80 | 78 | 18 |
| Decline in albumin | 81 | 41 | 1 | 79 | 37 | 1 |
| Decrease in blood phosphorus | 81 | 36 | 7 | 77 | 22 | 5 |
| Decreased blood calcium | 82 | 34 | 0 | 80 | 19 | 0 |
| Decreased blood sodium | 82 | 29 | 2 | 80 | 34 | 3 |
| Elevated creatinine | 82 | 27 | 5 | 80 | 28 | 5 |
| Blood glucose drop | 82 | 22 | 2 | 80 | 15 | 4 |
| Decreased blood potassium | 82 | 21 | 4 | 80 | 14 | 0 |
| Decreased blood magnesium | 52 | 19 | 0 | 39 | 10 | 0 |
| Elevated blood potassium | 82 | 18 | 1 | 80 | 11 | 1 |
| Hematology Neutropenia |
82 |
71 |
16 |
80 |
16 |
0 |
| hemoglobin reduction | 82 | 65 | 0 | 80 | 55 | 1 |
| Thrombocytopenia | 82 | 60 | 5 | 80 | 15 | 0 |
| Lymphocytopenia | 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 tumor.
a Grade 4 laboratory test abnormalities in sunitinib-treated patients included creatinine (4%), lipase (4%), decreased glucose (2%), elevated glucose (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), elevated potassium (1%), and total bilirubin (1%).
b Grade 4 laboratory test abnormalities in placebo-treated patients included creatinine (3%), alkaline phosphatase (1%), elevated blood glucose (1%), and lipase (1%).
Safety data in the Chinese population:
Safety Data from the A6181177Study in Chinese Patients with Gastrointestinal Mesenchymal Tumors
The A6181177 study was a single-arm, open, multicenter, phase 4 study conducted in China as a post-approval commitment study to evaluate the efficacy and safety of sunitinib malate as second-line therapy in Chinese patients with gastrointestinal mesenchymal tumor (GIST) whose disease progressed after treatment with imatinib mesylate or was intolerant to imatinib mesylate in China. Patients were treated with sunitinib malate, 50 mg once daily for 4 weeks, with 2 weeks off (4/2 regimen) and a repeat treatment cycle of 6 weeks. Sixty-two patients were screened for the study, and 60 patients were enrolled for treatment.
The reference study, A6181004, is the Sunitinib GIST Global Registry Study, a phase 3, randomized, double-blind, placebo-controlled study comparing sunitinib in patients with malignant gastrointestinal mesenchymal tumors who are resistant or intolerant to imatinib mesylate. The study was conducted in the United States, Australia, Italy, the United Kingdom, France, Singapore, Spain, Canada, the Netherlands, Belgium and Sweden.
Sunitinib malate is safe and well tolerated in conventional standard therapy. The common treatment-emergent AEs (≥10%) were all previously reported adverse events with sunitinib, including leukopenia, hand-foot syndrome, fatigue, neutropenia, reduced platelet count, elevated aspartate aminotransferase, decreased hemoglobin, skin discoloration, and hypertension. Most of these adverse events were grade 1 or 2 in severity, with some ≥ grade 3 adverse events. The overall incidence of treatment-related serious adverse events in study A6181177 was low. The three adverse events with the highest incidence in the study were leukopenia (64.4%), fatigue (52.5%), and hand-foot syndrome (50.8%).
The overall safety profile of sunitinib in Chinese patients in study A6181177 was similar when compared with patients in the reference study A6181004, with no unintended adverse events to date. The differences in safety between the two studies were: a slightly higher incidence of hand-foot syndrome, fatigue and some hematologic toxicities in Chinese patients than in Western patients in Study A6181177; and a lower incidence of gastrointestinal adverse events in Chinese patients than in Western patients. The key safety results from both studies are summarized in Table 7 below.
Overall, patients treated with sunitinib in both studies were well tolerated and adverse events were manageable with interruption of dosing, dose reduction and/or standard therapy.
Table 7. Comparison of treatment-related adverse events between Chinese patients in study A6181177 and Western patients in study A6181004
| A6181177(n=59) | A6181004(n=375) | |||
| All levels (%) | Grade 3/4 (%) | All Levels (%) | Grade 3/4 (%) | |
| Leukopenia | 64.4 | 13.6 | 56 | 4 |
| Fatigue | 52.5 | 5.1 | 34 | 10 |
| Hand-foot syndrome | 50.8 | 10.2 | 13 | 4 |
| Neutropenia | 49.2 | 18.7 | 51 | 5 |
| Decreased platelet count | 44.1 | 16.9 | – | – |
| hemoglobin reduction | 39 | 8.5 | – | – |
| Decreased neutrophil count | 37.3 | 15.3 | – | – |
| Elevated aspartate aminotransferase | 35.6 | 3.4 | – | – |
| Depigmentation of the skin | 33.9 | 0 | 25 | 0 |
| Decreased white blood cell count | 32.2 | 5.1 | – | – |
| Diarrhea | 30.5 | 1.7 | 29 | 3 |
| High blood pressure | 28.8 | 3.4 | 11 | 3 |
| Proteinuria | 27.1 | 3.4 | – | – |
| Anemia | 25.4 | 3.4 | 62 | 4 |
| Thrombocytopenia | 25.4 | 8.5 | 40 | 5 |
Skin discoloration is a very common adverse reaction reported in clinical trials and may be caused by the color of the active substance (yellow). Patients should be informed that hair or skin discoloration may also occur during treatment with sunitinib. Other possible skin effects include dry, thickened or cracked skin and blistering or occasional rash on the palms of the hands and soles of the feet. Sunitinib can cause severe hepatotoxicity, which can lead to liver failure or death. The development of liver failure has been observed in clinical studies (incidence<1%). Manifestations of liver failure include jaundice, elevated aminotransferases, and/or hyperbilirubinemia accompanied by brain disease, coagulation, and/or renal failure. Liver function (alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin) should be monitored prior to treatment initiation, at each treatment cycle, and as clinically indicated. Dosing should be discontinued in the event of grade 3 or 4 drug-related hepatic adverse reactions, and treatment should be discontinued if recovery is not possible. When patients show severe abnormal liver function tests on subsequent liver function tests, or other signs of liver failure, dosing should not be restarted. Sunitinib can cause a prolonged QT interval in a dose-dependent manner. prolonged QT interval may lead to an increased risk of ventricular arrhythmias, including tip-twist ventricular tachycardia. Tip-twisting ventricular tachycardia was observed in less than 0.1% of patients treated with sunitinib. Monitor patients for the development of hypertension and administer standard antihypertensive therapy as needed. If severe hypertension occurs, temporary discontinuation of sunitinib is recommended until the hypertension is controlled. Bleeding events, including gastrointestinal, respiratory, oncologic, urinary tract, and cerebral hemorrhage, some fatal, have been reported in postmarketing reports. Laboratory testing for baseline thyroid function is recommended, and patients with hypo- or hyperthyroidism should be given appropriate standard therapy prior to treatment with sunitinib. All patients should be closely monitored for signs and symptoms of thyroid insufficiency, including hypothyroidism, hyperthyroidism and thyroiditis, while receiving sunitinib. Laboratory monitoring of thyroid function should be performed in patients with signs and symptoms of thyroid insufficiency, and standard therapy should be administered accordingly. In clinical studies of sunitinib, epileptic seizures occurred in patients with radiographic evidence of brain metastases. In addition, a very small number (<1%) of patients presented with radiologic evidence of epileptic seizures and reversible posterior leukoencephalopathy syndrome (RPLS), some of which were lethal. If patients have epileptic seizures or develop signs/symptoms consistent with RPLS (e.g., hypertension, headache, decreased alertness, altered psychological functioning, and loss of vision, including cortical blindness), the disease should be managed by medical management, including control of hypertension. Temporary discontinuation of sunitinib is recommended; treatment may be continued at the discretion of the treating physician after symptoms have resolved. Patients treated with sunitinib have reported slow wound healing. Patients undergoing major surgical procedures are advised to withhold dosing to prevent this from occurring. There is limited clinical experience with when to start treatment after major surgery. Therefore, clinical judgment on whether to restart dosing should be based on the degree of recovery of patients undergoing major surgery. ONJ is rare in clinical studies and has been reported with postmarketing use. most patients who present with ONJ have had prior or concomitant intravenous bisphosphonate administration, which is an identified risk factor for possible ONJ. Therefore, special caution is required whether sunitinib and bisphosphonates are given in combination or sequentially for intravenous administration. Fatal tumor lysis syndrome TLS has occurred in clinical trials and has been reported in post-marketing applications. Patients with high tumor load prior to receiving sunitinib are at higher risk for TLS, are given close monitoring, and are dosed as appropriate for their condition. In clinical trials and post-marketing experience with sunitinib alone and in combination with bevacizumab, thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and sometimes leading to renal failure or fatalities, has occurred. Patients who develop TMA should discontinue sunitinib therapy. Reversal of TMA has been observed after discontinuation of the drug. Rare cases of necrotizing fasciitis, including perineum, have been reported, some of which were lethal. Patients presenting with necrotizing fasciitis should discontinue sunitinib therapy and receive immediate and appropriate treatment. Proteinuria and nephrotic syndrome have been reported. Some cases can lead to renal failure and be fatal. Patients should be monitored for the appearance or exacerbation of proteinuria. Baseline and periodic urinalysis is performed during treatment, with follow-up 24-hour urine protein measurements based on clinical indications. Interrupt sunitinib therapy and reduce the dose in patients with 24-hour urine protein ≥3 g. Discontinue sunitinib therapy in patients with nephrotic syndrome or in patients with recurrent urinary protein ≥3 g despite dose reduction. The safety of continued sunitinib treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Sunitinib can trigger hypoglycemia, which may lead to loss of consciousness or require hospitalization. In clinical trials, hypoglycemia occurred in 2% of patients with gastrointestinal mesenchymal tumor (GIST) and advanced renal cell carcinoma (RCC) treated with sunitinib, and in about 10% of patients with pancreatic neuroendocrine tumor (pNET). For patients with pancreatic neuroendocrine tumors (pNET) treated with sunitinib, pre-existing glycemic abnormalities do not occur in all patients who experience hypoglycemia. Hypoglycemia may be more severe in patients with diabetes mellitus. Blood glucose levels should be checked periodically during and after discontinuation of sunitinib therapy. Assess the need to adjust the dose of antidiabetic drugs to reduce the risk of hypoglycemia. Based on the results of animal studies and its mechanism of action, sunitinib can be harmful to the fetus when used by pregnant women. (See [Pharmacologic Toxicology]) Cases of aortic aneurysm and/or coarctation (with fatal outcome) have been reported. Patients with risk factors such as hypertension or a history of aneurysm need to consider this risk carefully before giving sunitinib treatment. The effect of sunitinib on the ability to drive and operate machinery is small and patients should be advised that they may experience dizziness during treatment with sunitinib.
The A6181132 study was a single-arm, open, multicenter, phase 4 study conducted in China as a post-approval commitment study to assess the efficacy and safety of sunitinib malate in the first-line treatment of Chinese patients with metastatic renal cell carcinoma. Patients took sunitinib malate capsules 50 mg once daily for 4 weeks and stopped for 2 weeks (4/2 regimen), with a repeat treatment cycle of 6 weeks. One hundred and five patients were enrolled in the study.
The reference study, A6181034, was a randomized, open phase 3 clinical trial comparing the efficacy of sunitinib with alpha-interferon as first-line treatment for metastatic renal cell carcinoma. The study was conducted at research centers in Australia, Brazil, Canada, France, Germany, Italy, Poland, Russia, the United States, the United Kingdom and Spain.
Adverse events occurring after treatment were seen in 98.1% of patients in the A6181132 study. The most common adverse events (occurring in at least 20% of patients) are summarized in Table 8. the most common post-treatment-emergent adverse events were hand-foot syndrome, thrombocytopenia, and fatigue.
The overall safety profile of sunitinib in Chinese patients in study A6181132 was similar to that of the reference study, with no unintended adverse events to date, compared with patients in study A6181034. Overall, the safety results were comparable to, but different from, the A6181034 study; the incidence of treatment-related serious adverse events was lower in the A6181132 study at 12.4% compared with 23.7% in the A6181034 study. Diarrhea and fatigue were the more common AEs in both studies, with higher incidence rates in both. The top 3 AEs in the A6181132 study were: hand-foot syndrome (63.8%), decreased white blood cell count (52.4%) and fatigue (51.4%). the top 3 AEs in the A6181034 study were: diarrhea (65.6%), fatigue (62.4%) and nausea (57.6%).
Overall, patients treated with sunitinib in both studies were well tolerated and adverse events were manageable with interruption of dosing, dose reduction and/or standard therapy.
Table 8. Comparison of treatment-related adverse events between study A6181132 Chinese patients and study A6181034 Western patients* Adverse events
Adverse Events
A6181132(n=105)
A6181034(n=375)
All levels(%)
Grade 3/4 (%)
All Levels (%)
Grade 3/4 (%)
Hand-foot syndrome
63.8
23.8
28.8
8.5
Decreased white blood cell count
52.4
8.6
10.7
3.5
Fatigue
51.4
6.7
62.1
14.7
Decreased platelet count
51.4
21.9
19.2
9.1
Diarrhea
48.6
6.7
12
2.4
Loss of appetite
42.9
4.8
18.7
10.9
Decreased neutrophil count
39.0
14.3
21.6
8.5
High blood pressure
37.1
7.6
30.4
1.3
hemoglobin reduction
37.1
10.5
46.4
0.3
Mouth ulcers
28.6
1.9
10.7
3.5
Taste disorders
27.6
0
29.1
1.6
Leukopenia
27.6
1.9
–
–
Rash
26.7
4.8
16.3
1.6
increased blood thyroid stimulating hormone
24.8
1.9
10.7
3.5
hypothyroidism
24.8
0
62.1
14.7
* Clinical Study Report from Study A6181132 (April 28, 2012) and Study A6181034 (May 5, 2009).
Specific Adverse Reactions
Venous Thrombotic Events
During the double-blind phase of treatment, 7 patients (3%) in the sunitinib arm of the Gastrointestinal Mesenchymal Stromal Tumor (GIST) study1 experienced venous thrombotic events, including grade 3 deep vein thrombotic events (DVT) in 5 patients and grade 1 or 2 in 2. 4 of the 7 patients discontinued treatment after the first observation of DVT. There were no venous thrombotic events in the placebo group.
Venous thrombotic events were reported in 13 (3%) patients treated with sunitinib in the previous untreated advanced renal cell carcinoma (RCC) study, of which 7 (2%) were pulmonary embolism (grade 2 in 1 and grade 4 in 6) and another 6 (2%) patients had a deep vein thrombotic event (grade 3 in 3). 1 patient withdrew from the study with sunitinib due to pulmonary embolism; 2 patients had pulmonary embolism due to and 1 patient was suspended due to a deep vein thrombotic event. In the IFN-a group, 6 (2%) patients developed venous thrombosis, including 1 (<1%) with a grade 3 deep vein thrombotic event and another 5 (1%) patients with pulmonary embolism (all grade 4).
One patient (1%) with pancreatic neuroendocrine tumor treated with sunitinib had a venous thrombotic event compared with 5 patients (6%) in the placebo group. Patients in the sunitinib group had a grade 2 thrombosis. Two patients in the placebo group had a deep vein thrombotic event, one of which was a grade 3; two had a pulmonary embolism, one of which was a grade 3; one was a grade 4; and one had a grade 3 jugular vein embolism.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
Rare epileptic seizures and reversible posterior leukoencephalopathy syndrome (RPLS) with radiographic evidence (<1%), some of which are lethal. Patients with epileptic seizures and signs/symptoms associated with RPLS such as hypertension, headache, decreased alertness, altered mental function, and loss of vision (including cortical blindness) should be managed medically first, including control of blood pressure, and temporary discontinuation of sunitinib is recommended. Thereafter, resumption of therapy may be considered based on the judgment of medical personnel.
Pancreas and liver function
In patients with previously untreated advanced renal cell carcinoma (RCC), pancreatitis was observed in 5 (1%) and 1 (<1%) patients in the sunitinib and IFN-a groups, respectively. Among patients with pancreatic neuroendocrine tumors, pancreatitis was observed in 1 patient in the sunitinib group and 1 patient in the placebo group.
Lab Tests.
Common: Elevated blood uric acid.
Postmarketing Experience
The following adverse reactions were identified following approval of sunitinib use, and because these reactions were spontaneously reported by an indeterminate number of people, it was not possible to analyze exactly how often they occurred or to determine a causal relationship with drug exposure.
Hematologic and lymphatic system abnormalities: thrombotic microangiopathy; thrombocytopenia-related bleeding events*. Suspension of sunitinib is recommended; resumption of the drug may be considered after treatment and under the guidance of medical personnel.
Hepatobiliary abnormalities: cholecystitis, especially nonstoichiometric cholecystitis.
Immune system abnormalities: hypersensitivity reactions, including angioedema.
Infections and Infections: severe infections (with or without neutropenia)*, necrotizing fasciitis including perineum*. The most common infections in patients receiving sunitinib include respiratory tract infections (eg, pneumonia, bronchitis)-common, urinary tract infections-common, skin infections (eg, cellulitis)-common, sepsis/infectious shock-rare, and abscesses (eg, oral, genital, anorectal, skin, limb, visceral)-common. Infections may be bacterial (e.g., intra-abdominal, osteomyelitis)-common, viral (e.g., nasopharyngitis, oral herpes)-common, or fungal (e.g., oral, esophageal Candida infection)-common.
Abnormal Metabolic and Nutritional Status: Tumor Lysis Syndrome* (see [Precautions] for details). Decreased blood glucose has been reported in sunitinib therapy, in some cases with clinical signs.
Skeletal muscle and connective tissue abnormalities: fistula formation, sometimes associated with tumor necrosis and/or regression*; osteonecrosis of the jaw (ONJ) (see [Precautions] for details); myopathy and/or rhabdomyolysis, with or without acute renal failure*. Patients found to have signs or symptoms of myotonia should be treated with medication.
Renal and urinary tract abnormalities: renal impairment and/or renal failure*; proteinuria; minority nephrotic syndrome. Baseline urinalysis is recommended to monitor patients for the appearance or worsening of proteinuria. The safety of continued sunitinib therapy in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue sunitinib therapy in patients with nephrotic syndrome.
Respiratory Abnormalities: Pulmonary Embolism* (see [Precautions] for details), Pleural Effusion*.
Skin and subcutaneous tissue abnormalities: gangrenous pyoderma, including de-excitation positive; erythema multiforme and Stevens-Johnson syndrome (SJS) – rare.
Vascular abnormalities: arterial thromboembolic events*. The most common events include cerebrovascular accidents, transient ischemic attacks, and cerebral infarction. In addition to underlying malignant disease and age ³65 years, risk factors associated with arterial thromboembolic events include hypertension, diabetes mellitus, and prior thromboembolic disease. Aortic Aneurysm and Coarctation* – Frequency Unknown
bleeding events: pulmonary, gastrointestinal, tumor, urinary tract, and cerebral hemorrhage.
Neurological abnormalities: taste abnormalities, including loss of taste.
Endocrine abnormalities: Rare hyperthyroidism with some subsequent hypothyroidism has been reported in clinical studies and post-marketing dosing; thyroiditis – rare.
Cardiac abnormalities: cardiomyopathy*, myocardial ischemiaa*, myocardial infarctionb*.
Gastrointestinal abnormalities: Esophagitis-common. Colitis-uncommonc.
* contains some lethality.
aAcute coronary syndrome, angina pectoris, unstable angina, coronary artery obstruction, myocardial ischemia.
bAcute myocardial infarction, myocardial infarction, asymptomatic myocardial infarction.
c Colitis and ischemic colitis.
Pediatric Patients
The safety profile of sunitinib has been obtained based on a phase I dose-escalation study, a phase II open study, a phase I/II single-arm study, and in the literature described below.
A phase 1 dose-escalation study of oral sunitinib has been conducted in 35 patients with refractory solid tumors (including 30 pediatric patients [3-17 years of age] and 5 young adult patients [18-21 years of age]), with the majority of patients enrolled with an initial diagnosis of brain tumor. All study participants experienced adverse drug reactions; most were serious (toxicity grade ≥3) and included cardiotoxicity. The most common adverse drug reactions were gastrointestinal (GI) toxicity reactions, neutropenia, fatigue, and ALT elevation. Pediatric patients with prior exposure had a higher risk of cardiac adverse drug reactions compared to pediatric patients with no prior exposure to cardiac radiation and anthracyclines. The maximum tolerated dose (MTD) was determined in these pediatric patients with no prior exposure to anthracyclines or cardiac radiation.
A phase II open study was conducted in 29 patients with recurrent/progressive/refractory high-grade glioma (HGG) or ventricular meningioma (including 27 pediatric patients [3-16 years] and 2 young adult patients [18-19 years]). No grade 5 adverse reactions occurred in either group. The most common (≥10%) treatment-related adverse events were decreased neutrophil count (6 [20.7%] patients) and intracranial hemorrhage (3 [10.3%] patients).
A phase I/II single-arm study was conducted in 6 pediatric patients (13-16 years old) with advanced inoperable GIST resection. The most frequent adverse drug reactions were diarrhea, nausea, decreased WBC count, neutropenia, and headache (each occurring in 3 [50.0%] patients), with a predominant grade 1 or 2 severity. Among these 6 patients, grade 3-4 treatment-related adverse events (grade 3 hypophosphatemia, neutropenia, and thrombocytopenia [each in 1 patient] and 1 case of grade 4 neutropenia [1 patient]) occurred in 4 (66.7%). No serious adverse events (SAEs) or grade 5 adverse drug reactions were reported in this study. In clinical studies and publications, the safety profile obtained was consistent with the known safety profile in adults.
[Contraindication]
Sunitinib is contraindicated in individuals with severe hypersensitivity to sunitinib or to the inactive components of the drug.
[Precautions]
Use under the guidance of a physician experienced in the use of sunitinib is recommended.
Dermal and Tissue
The above adverse events have no cumulative effect, are generally reversible, and do not usually result in treatment discontinuation.
Rare serious skin reactions that can lead to death require caution. Reported cases include erythema multiforme (EM), suspected Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis relaxation (TEN). If signs or symptoms of EM, SJS or TEN are suspected (e.g., progressively worsening rash, often combined with blistering or mucosal damage), sunitinib therapy should be withheld. If SJS or TEN is diagnosed, sunitinib must be discontinued. In cases of suspected EM, some patients may tolerate a restart of lower doses of sunitinib after the skin symptoms have subsided; some patients may receive sunitinib in combination with corticosteroids or antihistamines.
Hepatotoxicity
The safety of sunitinib in patients with ALT or AST>2.5 times the upper limit of normal (ULN) or aminotransferase>5.0 times the ULN has not been confirmed.
Cardiovascular events.Cardiovascular Events
Withhold sunitinib if clinical manifestations of congestive heart failure (CHF) are present. Patients without clinical evidence of congestive heart failure but with an ejection fraction >20% and <50% of baseline value or below the lower limit of normal (if baseline ejection fraction is not obtained) should also discontinue sunitinib therapy and/or reduce the dose.
Assessment of baseline ejection fraction should be considered in patients without cardiac risk factors. Such patients should be carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib therapy, and baseline and periodic left ventricular ejection fraction (LVEF) assessments should also be considered.
Cardiovascular events have been reported post-marketing, including heart failure, cardiomyopathy, myocardial ischemia and myocardial infarction, some of which were lethal.
More patients with gastrointestinal mesenchymal tumors and renal cell carcinoma treated with sunitinib experienced a decrease in left ventricular ejection fraction than in the placebo or IFN-α groups. In the double-blind phase of the Gastrointestinal Mesenchymal Stromal Tumor (GIST) study1, 22/209 (11%) patients in the sunitinib group and 3/102 (3%) patients in the placebo group experienced treatment-related left ventricular ejection fraction (LVEF) below the lower limit of normal (LLN). Nine of the 22 patients in the sunitinib group with altered LVEF recovered on their own without treatment; five patients returned to normal after treatment (one patient had a dose reduction; four patients were given another antihypertensive or diuretic); and six patients ended the study without documented recovery. In addition, 3 patients (1%) in the sunitinib group experienced a grade 3 decrease in LV systolic function to LVEF<40%, and 2 of these patients died without further treatment with the study drug. No patients in the placebo group experienced a grade 3 LVEF decline. During the double-blind phase of the Gastrointestinal Mesenchymal Stromal Tumor (GIST) Study1, one patient in each group (1% in the sunitinib group<1%; 1% in the placebo group) died of heart failure; two patients in each group (1% in the sunitinib group; 2% in the placebo group) died of cardiac arrest after treatment.
In studies of previously untreated patients with advanced renal cell carcinoma (RCC), 103/375 (27%) and 54/360 (15%) patients in the sunitinib and IFN-a groups, respectively, had LVEF values below the lower limit of normal (LLN); 26 (7%) and 7 (2%) patients, respectively, had LVEF values below 50% and decreased from baseline values by more than 20%. Four (1%) patients in the sunitinib group developed left ventricular dysfunction and two (<1%) patients were diagnosed with congestive heart failure (CHF).
In the phase 3 study of pancreatic neuroendocrine tumors, heart failure was reported in 2 (2%) of 83 patients in the sunitinib group and resulted in death, compared with none of the patients in the placebo group.
Patients with cardiac events such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass grafting, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism that occurred within the 12 months prior to treatment were excluded from the sunitinib clinical study. It is not clear whether patients with these concomitant symptoms are at increased risk of developing sunitinib-associated left ventricular dysfunction. Prescribers are advised to weigh the value of the drug application and its potential risks on their own. Such patients should be carefully monitored for clinical signs and symptoms of congestive heart failure while receiving sunitinib therapy, and baseline and periodic LVEF assessments should also be considered. In patients without cardiac risk factors, assessment of baseline ejection fraction should be considered.
Prolonged QT interval and tip-twist ventricular tachycardia
Monitor patients with a history of QT interval prolongation, patients taking antiarrhythmic or prolongable QT interval drugs, or patients with associated underlying cardiac disease, bradycardia, and electrolyte disturbances. When administering sunitinib, regular monitoring of ECG and electrolytes (magnesium and potassium) during treatment should be considered. When combined with strong inhibitors of CYP3A4, which may increase plasma drug concentrations of sunitinib, a lower dose of sunitinib should be considered (see [DOSAGE AND ADMINISTRATION]).
Hypertension
In the previous untreated advanced renal cell carcinoma (RCC) study, 127/375 (34%) and 13/360 (4%) patients in the sunitinib and IFN-a groups, respectively, developed hypertension; of these, grade 3 hypertension was 50/375 (13%) and 1/360 (<1%), respectively. 21/375 (6%) patients had hypertension resulting in Sunitinib dose reduction or temporary delay in dosing. 4 cases had treatment interruption due to hypertension, 1 of which was a patient with malignant hypertension.
The incidence of all grades of hypertension was similar in the sunitinib and placebo groups in the Gastrointestinal Mesenchymal Stromal Tumor (GIST) study. Grade 3 hypertension was 9/202 cases (4%) in the sunitinib group; no grade 3 hypertension was observed in the placebo group. No patients discontinued treatment due to hypertension.
In the phase 3 study of pancreatic neuroendocrine tumors (pNET), hypertension occurred in 22/83 (27%) patients in the sunitinib group and 4/82 (5%) patients in the placebo group. Grade 3 hypertension was reported in 8 (10%) of 83 patients with pancreatic neuroendocrine tumors in the sunitinib group compared with 1 (1%) of 82 patients in the placebo group. 7/83 (8%) patients with pancreatic neuroendocrine tumors had their sunitinib dose reduced or temporarily delayed due to hypertension. 1 case had treatment interruption due to hypertension.
No grade 4 hypertension was reported.
Severe hypertension (systolic >200 mmHg or diastolic >110 mmHg) occurred in 32/375 (9%) patients in the sunitinib group and 3/360 (1%) patients in the IFN-a group in the previous untreated advanced renal cell carcinoma (RCC) study. Severe hypertension occurred in 8/202 patients (4%) in the sunitinib group and 1/102 patients (1%) in the placebo group in the gastrointestinal mesenchymal tumor (GIST) study. Severe hypertension occurred in 8/80 cases (10%) in the sunitinib group and 2/76 cases (3%) in the placebo group in the pancreatic neuroendocrine tumor study.
Hemorrhagic Events and Gastrointestinal Perforation
In the advanced renal cell carcinoma (RCC) study, bleeding events occurred in 140/375 (37%) patients in the sunitinib group and 35/360 (10%) patients in the IFN-a group. Most were grade 1 or 2; only one previously untreated patient had a grade 5 gastric bleed.
Bleeding events occurred in 37/202 (18%) patients in the sunitinib group and 17/102 (17%) patients in the placebo group during the double-blind phase of the Gastrointestinal Mesenchymal Stromal Tumor (GIST) Study1. Grade 3 or 4 bleeding events occurred in 14/202 (7%) and 9/102 (9%) patients in the two groups, respectively. In addition, one patient in the placebo group had a fatal gastrointestinal bleed in cycle 2 of treatment.
In the pancreatic neuroendocrine tumor (pNET) phase 3 study, bleeding events other than epistaxis occurred in 18/83 (22%) patients in the sunitinib group compared with 8/82 (10%) in the placebo group. epistaxis occurred in 17/83 (20%) patients in the sunitinib group compared with 4 (5%) in the placebo group. In the pancreatic neuroendocrine tumor study, 1/83 (1%) patients in the sunitinib group had grade 3 epistaxis and none had any other grade 3 or 4 bleeding events. This compares with 3/82 (4%) patients in the placebo group who experienced grade 3 or 4 bleeding events.
Epistaxis was the most common bleeding adverse reaction, while gastrointestinal bleeding was the most common ≥ grade 3 event.
Tumor-associated bleeding has been observed in patients treated with sunitinib. These events may occur suddenly, and patients with lung tumors may experience severe and life-threatening hemoptysis or pulmonary embolism. For patients treated with sunitinib for metastatic renal cell carcinoma, gastrointestinal mesenchymal tumors and metastatic lung cancer, cases of pulmonary hemorrhage, some of which were fatal, have been observed in clinical trials and have been reported during post-marketing use. Sunitinib has not been approved for use in patients with lung cancer. Clinical evaluation for bleeding events should include serial complete blood counts (CBCs) and physical examinations.
Severe and sometimes fatal gastrointestinal complications, including gastrointestinal perforation, have been reported in patients with intra-abdominal tumors treated with sunitinib.
Gastrointestinal events
Nausea, diarrhea, stomatitis, dyspepsia, and vomiting were the most frequently reported treatment-related gastrointestinal adverse events. Supportive care for gastrointestinal adverse reactions that require treatment may include antiemetic or antidiarrheal medications.
Pancreatitis.
Pancreatitis
Pancreatitis has been reported in clinical trials of sunitinib. Elevated serum lipase and amylase have been observed in patients with various solid tumors treated with sunitinib. In patients with various solid tumors, elevated lipase levels are transient and are generally not accompanied by signs or symptoms of pancreatitis. If symptoms of pancreatitis develop, patients should discontinue sunitinib and receive appropriate supportive care.
Thyroid insufficiency
Clinical trials and postmarketing experience with the drug have also reported some hyperthyroid events, with some subsequent occurrence of hypothyroidism.Epileptic seizures
Wound healing
Osteonecrosis of the jaw (ONJ)
Invasive dental procedures have also been identified as a risk factor for ONJ. Dental examination and appropriate prophylactic measures should be considered prior to the administration of sunitinib therapy. Patients with prior or concomitant intravenous bisphosphonate administration and invasive dental procedures should avoid treatment with sunitinib.Tumor lysis syndrome (TLS)
Thrombotic microangiopathy
Necrotizing fasciitis
Proteinuria
Hypoglycemia
Embryo-fetal toxicity
Pregnant women should be informed of the potential risks to the fetus with sunitinib. Women of childbearing potential are advised to use effective contraception during sunitinib treatment and for 4 weeks after the last dose (see [Pharmacologic Toxicology] and [Use in Pregnant and Lactating Women]).
Aortic Aneurysm and Coarctation
Effect on the ability to drive and use machines
[Use in pregnant and lactating women]
Pregnancy
Risk Summary.
Based on animal reproduction studies and its mechanism of action, treatment with sunitinib in pregnant women may harm the fetus (see [Pharmacologic Toxicology]). There are no available data on the reported drug-related risks of sunitinib use in pregnant women. In animal developmental and reproductive toxicity studies, teratogenicity (embryonic death, craniofacial and skeletal malformations) was seen following oral administration of sunitinib to pregnant rats and rabbits during organogenesis at doses 5.5 and 0.3 times the patient’s recommended daily dose (RDD) AUC, respectively (see [Pharmacologic Toxicology]). Females of childbearing potential should be informed of the potential hazards of the drug to the fetus.
For the indication population, the background risk of major birth defects and miscarriage is unknown. However, in the general US population, the estimated background risk of clinically confirmed pregnancies with major birth defects is 2%-4% and the background risk of miscarriage is 15%-20%.
Lactation
Lactation
No information is available on the presence of sunitinib and its metabolites in human breast milk. Sunitinib and its metabolites can be secreted into rat milk at concentrations up to 12 times the plasma level (see [Pharmacologic Toxicology]). Because of the potential for serious adverse effects of sunitinib in breastfed children, breastfeeding women are advised not to breastfeed during treatment and for at least 4 weeks after the last dose.
Females and males with reproductive capacity
Based on animal reproduction studies and its mechanism of action, the use of sunitinib in pregnant women may be harmful to the fetus (see [Pharmacologic Toxicology]).
Pregnancy Tests
For women of reproductive potential, a pregnancy trial should be performed before starting sunitinib treatment.
Contraception
Females
Women of reproductive potential should be advised to use effective contraception during sunitinib treatment and for at least 4 weeks after the last dose.
Men
Based on the results of animal reproduction studies, male patients with fertile female partners are advised to use effective contraception during treatment with sunitinib and for at least 7 weeks after the last dose.
Infertility
Sunitinib treatment can impair fertility in both men and women based on findings related to animal studies (see [Pharmacology and Toxicology]).
[Pediatric Dosing]
The safety and efficacy of sunitinib in pediatric patients are not known.
The available data are presented in [Adverse Reactions], but sunitinib is not yet recommended for this population.
[Geriatric Use]
277 (34%) of the 825 patients with gastrointestinal mesenchymal stromal tumor (GIST) or metastatic renal cell carcinoma (RCC) treated with sunitinib were 65 years of age or older. In the pancreatic neuroendocrine tumor study, 22 (27%) patients treated with sunitinib were 65 years of age and older. No differences in safety or efficacy were found between younger and older patients.
[Drug Interactions]
CYP3A4 Inhibitors: Strong inhibitors of CYP3A4, such as ketoconazole, may increase plasma concentrations of sunitinib. It is recommended that a combination of drugs with no or minimal inhibition of such enzymes be selected. A single dose of sunitinib malate given with a strong inhibitor of CYP3A4 (ketoconazole) in healthy volunteers resulted in a 49% and 51% increase in overall (sunitinib and its major active metabolite) Cmax and AUC0-∞, respectively. Sunitinib increased sunitinib concentrations when administered concomitantly with strong inhibitors of the CYP3A4 enzyme family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, naftazodone, nafinavir, ritonavir, saquinavir, telithromycin, voriconazole), and grapefruit also increased sunitinib blood concentrations. If concomitant application with strong inhibitors of CYP3A4 is necessary, a lower dose of sunitinib needs to be considered (see [Dosage and Administration]).
CYP3A4 Inducing Agents: CYP3A4 inducers, such as rifampin, may reduce the plasma concentration of sunitinib. It is recommended to choose a combination of drugs that have no or minimal induction of such enzymes. Administration of a single dose of sunitinib with a strong inducer of CYP3A4 (rifampin) in healthy volunteers resulted in a 23% and 46% reduction in overall (sunitinib and its major active metabolite) Cmax and AUC0-∞, respectively. Sunitinib may reduce sunitinib concentrations when administered concomitantly with CYP3A4 enzyme inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s wort). St. John’s Wort may abruptly decrease blood concentrations of sunitinib and patients should not take St. John’s Wort concomitantly with sunitinib therapy. If concomitant application with CYP3A4 inducers is necessary, an increase in the dose of sunitinib needs to be considered (see [Dosage and Administration]).
In vitro studies of CYPinhibition and induction: The results of in vitro studies indicate that sunitinib does not induce or inhibit the major CYP enzymes. In vitro studies on human liver microsomes and hepatocyte CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11) indicate that sunitinib and its major active metabolites do not interact with drugs that depend on the metabolism of these enzymes in a clinically meaningful interactions with drugs that depend on the metabolism of these enzymes.
Breast Cancer Resistance-Related Protein (BCRP) Inhibitors: Clinical data on the interaction of sunitinib with BCRP inhibitors are limited and cannot rule out a sunitinib the possibility of interaction of sunitinib with other BCRP inhibitors (see [Pharmacokinetics]).
[Drug Overdose]
Management of sunitinib overdose includes general supportive measures. There is no specific antidote for sunitinib overdose. When clinically indicated, emetic or gastric lavage should be used to remove unabsorbed drug. Unexpected drug overdoses have been reported in cases either consistent with known adverse effects of sunitinib or without adverse effects. One case of artificial overdose was caused by ingestion of sunitinib 1500 mg in a suicide attempt, but there were no adverse effects. Death was observed in rats administered at 500 mg/kg (3000 mg/m2)/day for a minimum of 5 days in a nonclinical study. At this dose level, signs of toxicity included impaired muscle coordination, head shaking, decreased activity, eye discharge, vertical hair and gastrointestinal discomfort. Death and similar signs of toxicity were observed at lower dose levels but for longer treatment durations.
[Pharmacology and Toxicology]
Pharmacology
Sunitinib malate is a small molecule that inhibits multiple receptor tyrosine kinases (RTK), some of which are involved in tumor growth, pathological angiogenesis, and tumor metastasis. By evaluating the activity of sunitinib to inhibit various kinases (more than 80 kinases), it was demonstrated that sunitinib inhibits platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), 1 type 1 colony-stimulating factor receptor (CSF-1R) and glial cell line-derived neurotrophic factor receptor (RET). Biochemical and cellular assays confirmed that sunitinib inhibited the tyrosine kinase (RTK) activity of these receptors, and the inhibitory effect of sunitinib was demonstrated in a cell proliferation assay. Biochemical and cellular assays demonstrated similar activity of the major metabolites to sunitinib.
In in vivo assays in tumor models expressing receptor tyrosine kinase targets, sunitinib inhibited the phosphorylation process of multiple receptor tyrosine kinases (PDGFRβ, VEGFR2, KIT); showed inhibition of tumor growth or led to tumor regression, and/or inhibition of tumor metastasis in certain animal tumor models. The results of in vitro experiments showed that sunitinib malate inhibited the growth of tumor cells with dysregulated expression of target receptor tyrosine kinases (PDGFR, RET or KIT), and the results of in vivo tests showed that it inhibited PDGFRβ- and VEGFR2-dependent tumor angiogenesis.
Toxicological studies
Genotoxicity: Sunitinib Ames test, human lymphocyte chromosome aberration and rat bone marrow micronucleus test results were all negative.
Reproductive Toxicity:
In female fertility and early embryonic development toxicity assays, female rats were given sunitinib orally (0.5, 1.5, and 5 mg/kg/day) from 21 days prior to mating to 7 days post-mating. preimplantation loss was observed at the 5 mg/kg/day dose (approximately 5 times the AUC at RDD). No adverse effects on fertility were observed at doses ≤1.5 mg/kg/day (approximately 1 times the AUC at RDD). In a 9-month repeated administration toxicity test in monkeys (0.3, 1.5, and 6 mg/kg/day for 28 days and 14 days off), 6 mg/kg/day (approximately 0.8 times the AUC at RDD) had effects on the uterus and ovaries in addition to vaginal atrophy.
In the male fertility test, male rats were given sunitinib 1, 3, or 10 mg/kg/day orally for 58 days prior to mating with unadministered females. No significant effects on fertility, mating, fertility index and sperm examination (morphology, sperm count and motility) were seen at sunitinib doses ≤10 mg/kg/day (approximately 26 times the AUC at [RDD).
In embryo-fetal developmental toxicity tests, sunitinib was administered orally to pregnant rats and pregnant rabbits at doses of 0.3, 1.5, 3, and 5 mg/kg/day and 0.5, 1, 5, and 20 mg/kg/day, respectively, during the organogenesis phase. Embryonic death and malformation of ribs and vertebrae were seen in rats at a dose of 5 mg/kg/day (approximately 5.5 times the AUC at RDD). No adverse effects on fetuses were observed in rats at ≤3 mg/kg/day (approximately 2 times the AUC at RDD). In rabbits, embryonic death was seen at 5 mg/kg/day (approximately 3 times the AUC at RDD), and cleft lip and palate were seen at ≥1 mg/kg/day (approximately 0.3 times the AUC at RDD).
Sunitinib doses of 0.3, 1, and 3 mg/kg/day were used in perinatal toxicity tests in rats. At doses ≥1 mg/kg/day (approximately 0.5 times the AUC at RDD), decreased maternal weight gain was seen during pregnancy and lactation. at 3 mg/kg/day (approximately 2 times the AUC at RDD), decreased body weight was seen from birth until weaning in female and male offspring, and decreased body weight was still seen after weaning in male offspring. No adverse developmental effects were seen at doses ≤1 mg/kg/day.
Female rats were given sunitinib 15 mg/kg and sunitinib and its metabolites were secreted from the milk at concentrations up to 12 times higher in the milk than in the plasma.
Epiphyseal dysplasia was seen in crab monkeys with open growth plates given sunitinib for ≥3 months (doses of 2, 6, and 12 mg/kg/day for 3 months of administration; 0.3, 1.5, and 6.0 mg/kg/day for 8 cycles of administration), as extrapolated from systemic exposure (AUC), which was greater than 0.4 times that seen at RDD. Skeletal abnormalities, including thickened epiphyseal cartilage in the femur and increased tibial fractures, were seen in developing rats given sunitinib for 3 consecutive months (1.5, 5.0, and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day) at doses ≥5 mg/kg (approximately 10 times the RDD). In addition, an increased incidence of dental caries was seen in rats at a dose of >5 mg/kg. The incidence and severity of epiphyseal dysplasia were dose dependent and recovered with the exception of teeth when dosing was discontinued. No NOAEL was observed in the 3-month continuous administration trial in monkeys, but the NOAEL for the 8-cycle intermittent administration trial was 1.5 mg/kg/day. The NOAEL for bone in the rat test was ≤2 mg/kg/day.
Carcinogenicity:
Carcinogenicity tests were performed in rasH2 transgenic mice and SD rats, and similar positive results were seen. rasH2 transgenic mice given sunitinib for 1 or 6 months at ≥25 mg/kg dose were seen to have gastroduodenal cancer and/or gastric mucosal hyperplasia, and increased incidence of angiosarcoma; no proliferative changes were seen at 8 mg/kg/day dose.
In a 2-year carcinogenicity test in rats, a repeat cycle of 28 days of administration and 7 days of discontinuation, duodenal cancer was seen at doses as low as 1 mg/kg/day (approximately 0.9 times the AUC at RDD). At high doses of 3 mg/kg/day (approximately 7.8 times the AUC at RDD), an increased incidence of duodenal tumors was seen, along with increased incidence of gastric mucosal cell hyperplasia and pheochromocytoma and adrenal hyperplasia.
[Pharmacokinetics].
The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and 266 patients with solid tumors.
Absorption, Distribution, Metabolism, and Excretion
Sunitinib generally reaches maximum plasma concentration (Cmax) 6 to 12 hours after oral administration (time to reach maximum plasma concentration [Tmax]). Eating and drinking had no effect on sunitinib bioavailability. It can be taken with or without food.
In vitro experiments showed that the human plasma protein binding of sunitinib and its major active metabolite was 95% and 90%, respectively, with no concentration dependence in the range of 100 to 4000 ng/ml. The apparent volume of distribution (Vd/F) of sunitinib was 2230 L. The area under the plasma drug-time curve (AUC) and maximum plasma concentration (Cmax) increased proportionally with dose over the dose range of 25 to 100 mg.
Sunitinib is primarily metabolized by cytochrome P450 CYP3A4, producing a major active metabolite that is further metabolized by CYP3A4. The major active metabolites account for 23-37% of the total exposure. It is excreted mainly through feces. In a [14C]-labeled human trial of sunitinib mass balance, 61% of the dose was excreted in the feces, while renal excretion of the drug and metabolites accounted for approximately 16% of the dose. The major drug-related components of sunitinib and the major active metabolite were found in plasma, urine, and feces, representing 91.5%, 86.4%, and 73.8% of the radioactivity in the combined specimens, respectively. Minor metabolites were detected in urine and feces, but generally failed to be detected in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hour, with a coefficient of variation of 40% between patients.
The terminal half-lives of sunitinib and the major active metabolite after oral administration of a single dose of sunitinib in healthy volunteers were 40 to 60 hours and 80 to 110 hours, respectively. After repeated daily dosing, sunitinib accumulates 3 to 4 times, while its major metabolite accumulates 7 to 10 times, and sunitinib and the major active metabolite reach steady-state concentrations within 10 to 14 days. The total plasma sunitinib and major active metabolite concentrations on day 14 ranged from 62.9 to 101 ng/ml. no significant changes in the pharmacokinetics of sunitinib and the major active metabolite were observed with repeated daily dosing or repeated cycles of dosing according to the treatment regimen.
The pharmacokinetics were similar in healthy volunteers and patients with solid tumors tested, including patients with gastrointestinal mesenchymal tumors (GIST) and advanced/metastatic renal cell carcinoma (RCC).
Combination with drugs that are BCRPinhibitors
In vitro, sunitinib is a substrate for the efflux-type transporter BCRP. In study A6181038, combination with the BCRP inhibitor gefitinib did not produce clinically relevant effects on Cmax or AUC of sunitinib or total drug (sunitinib + metabolites) (see [Drug Interactions]). This study is a multicenter, open, phase I/II study designed to assess the safety/tolerability, maximum tolerated dose, and antitumor activity of sunitinib in combination with gefitinib in patients with MRCC. The secondary study objective was to evaluate the pharmacokinetics of gefitinib (250 mg daily) and sunitinib (37.5 mg daily [cohort 1, n=4] or 50 mg [cohort 2, n=7] administered on a 4-week dosing schedule followed by a 2-week discontinuation) when the two were combined. Changes in sunitinib pharmacokinetic parameters were not clinically significant and did not suggest any drug-drug interactions; however, given the relatively small number of patients (i.e., N=7+4) and the moderate to high interpatient variability in pharmacokinetic parameters, the results of the pharmacokinetic drug-drug interaction analysis derived from this study need to be interpreted with caution.
Special Populations
Demographic data from population pharmacokinetic analyses suggest no clinically relevant effect of age, weight, creatinine clearance, ethnicity, gender, or Eastern Oncology Collaborative Group (ECOG) physical status score on the pharmacokinetics of sunitinib or its active metabolite.
Hepatic insufficiency
No initial dose adjustment is required for treatment with sunitinib in patients with Child-Pugh class A or Child-Pugh class B hepatic impairment. Sunitinib and its major metabolites are primarily metabolized by the liver. Systemic exposure to a single dose of sunitinib is similar in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment compared to patients with normal hepatic function. Studies have not been conducted in patients with severe (Child-Pugh Class C) hepatic impairment. Clinical studies in patients with cancer excluded patients with ALT or AST>2.5 times ULN, or ALT or AST>5.0 times ULN due to liver metastases.
Renal insufficiency
Systemic exposure to single-dose sunitinib was similar in patients with severe renal impairment (CLcr>30 ml/min) compared with patients with normal renal function (CLcr>80 ml/min).
No initial dose adjustment is required for treatment with sunitinib in patients with mild (CLcr 50-80 mL/min), moderate (CLcr 30-<50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not receiving dialysis. Subsequent dose adjustments should be based on patient safety and tolerability see [Dose Adjustment]. No initial dose adjustment is required for patients with end-stage renal disease (ESRD) on hemodialysis. Sunitinib exposure was 47% lower in patients with end-stage renal disease on hemodialysis than in patients with normal renal function. Therefore, subsequent doses may need to be gradually doubled from the initial dose depending on patient safety and tolerability.
Race
The PK study, RTKC-0511-009, was conducted in Singapore in 14 healthy male volunteers of Asian (including 11 Chinese) and 13 Western origin. After sunitinib administration alone or in combination with ketoconazole, mean exposure to sunitinib and its major metabolites (Cmax, AUC0-last, and AUC0-¥) was higher in Asians than in Westerners, but ketoconazole had a PK parameters were affected to a similar extent in both groups, suggesting similar metabolism in Asians and Westerners. Higher drug exposure was associated with body weight, and comparison of weight-standardized CLPO values showed no significant difference in mean CLPO values between the two races during the same treatment period (sunitinib monotherapy, P=0.091; combined with ketoconazole treatment P=0.353).
[Storage].
Seal and store below 30°C.
[Packaging]
PVC aluminum-plastic packaging, outer laminated film bag; 7 capsules/plate x 1 plate/bag x 2 bags/box
[Expiration date]
24 months
[Executive Standard]
[Approval number]
[Marketing license holder]
Company Name: Jiangsu Haosen Pharmaceutical Group Co.
Address: Lianyungang Economic and Technological Development Zone, Jiangsu Province
Name of manufacturer: Jiangsu Haosen Pharmaceutical Group Co.
Address: No. 8 Lushan Road, Lianyungang Economic and Technological Development Zone
Postal code: 222047
Customer service telephone: 4008285227 Monday to Friday 9:00-17:00 (except holidays)
Web address: http://www.hansoh.cn