LuciSun

Sunitinib (Sutent) instructions

Common name: Sunitinib

Trade name: Sutent

All names: sunitinib, Sutent, sunitinib, Sutent, Sunitix

1. Sunitinib is suitable for Indications

(1). Gastrointestinal stromal tumors (GIST) that have failed or are intolerant to imatinib mesylate treatment

(2). Inoperable advanced renal cell carcinoma (RCC)

(3). Adult patients with unresectable, metastatic well-differentiated advanced pancreatic neuroendocrine tumors (pNET). Experience with this product as first-line treatment is limited.

2. Specifications of sunitinib

(1)12.5 mg; (2)25 mg; (3)37.5mg; (4) 50 mg

3. Usage and dosage of sunitinib

The recommended dose of this product for the treatment of gastrointestinal stromal tumors and advanced renal cell carcinoma is 50 mg, taken orally once a day; take the drug for 4 weeks and stop the drug for 2 weeks (4/2 dosage regimen).

For pancreatic neuroendocrine tumors, the recommended dose of this product is 37.5 mg, taken orally, once a day, continuously, without a drug withdrawal period.

Can be taken with or without food.

4. Sunitinib dose adjustment

Safety and tolerability

For gastrointestinal stromal tumors and metastatic renal cell carcinoma, the dose is gradually adjusted in 12.5 mg gradient units based on the individual patient's safety and tolerability. The maximum daily dose does not exceed 75mg and the minimum dose is 25mg.

For pancreatic neuroendocrine tumors, the dose is gradually adjusted in 12.5 mg gradient units based on the safety and tolerability of the individual patient. The maximum dose used in Phase 3 clinical trials was 50 mg daily.

Interruption of treatment may be necessary based on individual patient safety and tolerability.

Strong inhibitors of CYP3A4 (such as ketoconazole) can increase the plasma concentration of this product. It is recommended that drugs with no or minimal inhibitory effect on these enzymes should be selected for co-administration. If concomitant use with strong CYP3A 4 inhibitors is necessary, consideration should be given to reducing the dose of this product to a minimum of 37.5 mg once daily (gastrointestinal stromal tumors and renal cell carcinoma) or 25 mg once daily (pancreatic neuroendocrine tumors) (see Drug Interactions).

CYP3A4 inducers (such as rifampicin) can reduce the plasma concentration of this product. It is recommended that drugs with no or minimal inducing effect on such enzymes should be selected for co-administration. If combined use with CYP3A4 inducers is necessary, consideration should be given to increasing the dose of this product. The maximum dose should not exceed 87.5 mg once daily (gastrointestinal stromal tumors and renal cell carcinoma) and 62.5 mg once daily (pancreatic neuroendocrine tumors). If the dose of this product is increased, the patient should be carefully monitored for toxic effects (see Drug Interactions).

5. Adverse reactions of sunitinib

Since the conditions of each clinical study are different, it is inappropriate to directly compare the incidence of adverse reactions of the two drugs in different clinical studies. The incidence of adverse reactions in clinical studies may also be different from the situation in clinical practice.

Safety data of key clinical studies supporting the marketing of this product in Europe and the United States:

The following data are from 660 subjects, including 202 subjects in the double-blind, placebo-controlled study of gastrointestinal stromal tumor (GIST) (see [Clinical Research]), and the positive drug-controlled study of advanced renal cell carcinoma (RCC) (see There were 375 subjects in the [Clinical Studies]) and 83 subjects in the placebo-controlled study of pancreatic neuroendocrine tumor (pNET) (see [Clinical Studies]). The treatment plan for sunitinib in subjects with gastrointestinal stromal tumors and renal cell carcinoma is a starting dose of 50 mg, taken orally once a day, taking the drug for 4 weeks and stopping the drug for 2 weeks (4/2 regimen). The treatment regimen for subjects with pancreatic neuroendocrine tumors is a starting dose of 37.5 mg, taken orally once a day, continuously, without a drug withdrawal period.

Gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC), or pancreatic neuroendocrine tumor (pNET) The most common adverse reactions (≥20%) in subjects were fatigue, asthenia, pyrexia, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color change, taste change, headache, back pain, joint pain, acral pain, cough, dyspnea, anorexia, and bleeding. See Precautions for a discussion of potentially serious adverse reactions: hepatotoxicity, left ventricular dysfunction, QT prolongation, bleeding, hypertension, thyroid insufficiency, and adrenal function. Other adverse reactions that occurred in studies of gastrointestinal stromal tumors (GIST), advanced renal cell carcinoma (RCC), and pancreatic neuroendocrine tumors (pNET) are as follows.

Adverse Reactions in Gastrointestinal Stromal Tumor (GIST) Study A

The median treatment duration for patients in the double-blind study was 2 cycles (mean, 3.0 cycles, range, 1-9 cycles) in the sunitinib group and 1 cycle (mean, 1.8 cycles, range, 1-6 cycles) in the placebo group. 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, resulted in permanent discontinuation due to treatment-related non-fatal adverse reactions.

During the double-blind treatment period of the trial, most of the adverse reactions that occurred after treatment in the two study groups were grade 1 and grade 2 in severity. The incidence of grade 3 or 4 adverse reactions reported after treatment was 56% in the sunitinib group and 51% in the placebo group. Table 1 compares the incidence rates of common (incidence ≥10%) adverse reactions in the two groups of subjects after treatment. The incidence rate in the sunitinib group was higher.

After an interim analysis, the trial was unblinded. Patients in the placebo group had the opportunity to receive open-label sunitinib treatment (see [Clinical Studies]). Among 241 patients randomized to the sunitinib group, including 139 patients who received sunitinib in both the double-blind phase and the open-label phase, the median treatment time with sunitinib was 6 cycles (mean 8.5, range 1-44). For the 255 patients who ultimately received open-label sunitinib, the median treatment period from the end of the double-blind period was 6 cycles (mean 7.8, range 1-37). A total of 118 (46%) patients required treatment interruption and 72 (28%) patients required dose reduction. 20% of patients permanently discontinued treatment due to adverse reactions after treatment. The most common grade 3 or 4 drug-related adverse reactions in patients receiving sunitinib during the open-label period 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%).

Adverse reactions in previously untreated advanced renal cell carcinoma (RCC) studies

In the advanced renal cell carcinoma (RCC) study, a total of 735 patients actually received treatment, 375 in the sunitinib group and 360 in the IFN-α group. The median treatment duration was 11.1 months (range: 0.4-46.1 months) in the sunitinib group and 4.1 months (range: 0.1-45.6 months) in the IFN-α group. Treatment discontinuation occurred in 202 (54%) patients in the sunitinib group and 141 (39%) patients in the IFN-α group. Dose reduction was required in 194 (52%) patients in the sunitinib group and 98 (27%) patients in the IFN-α group. Adverse reactions after treatment resulted in permanent discontinuation of treatment in 20% and 23% of patients in the sunitinib group and IFN-α group, respectively. Most adverse reactions after treatment were grade 1 or 2. Grade 3 or 4 adverse reactions were reported by 77% and 55% of patients in the sunitinib group and IFN-α group respectively after treatment.

Adverse reactions in phase 3 trials of pancreatic neuroendocrine tumors

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 subjects (23%) in the sunitinib group and 4 subjects (5%) in the placebo group continued taking the drug for >1 year. Discontinuation occurred in 25 subjects (30%) in the sunitinib group and in 10 subjects (12%) in the placebo group. Twenty-six (31%) subjects in the sunitinib group and 9 (11%) subjects in the placebo group had dose reductions. Discontinuation rates due to adverse reactions were 22% in the sunitinib group and 17% in the placebo group.

Most treatment-related adverse reactions were grade 1 or 2 in both treatment groups. Grade 3 or 4 treatment-related adverse reactions were reported by 54% of subjects in the sunitinib group and 50% of subjects in the placebo group. Table 5 compares the incidence of common (≥10%) treatment-related adverse reactions in the sunitinib treatment group that were higher than those in the placebo treatment group.

Safety data in the Chinese population:

Safety data of the Chinese gastrointestinal stromal tumor subject study A6181177 (data as of June 15, 2011)

The following Chinese study data are preliminary analysis results, and the final research results have not yet been obtained.

Study A6181177 is a single-arm, open-label, multi-center, Phase 4 study as a post-approval commitment study to evaluate the efficacy and safety of sunitinib malate as a second-line treatment for Chinese gastrointestinal stromal tumor (GIST) subjects whose disease has progressed after treatment with imatinib mesylate or who are intolerant to imatinib mesylate. This study was conducted in China and is ongoing. The subjects took sunitinib malate, 50 mg, once a day for 4 weeks and then stopped for 2 weeks (4/2 regimen). A 6-week treatment cycle was used, and the treatment was repeated. The study screened 62 subjects, and 60 subjects were enrolled for treatment.

The reference study A6181004 is the Sunitinib GIST global registration study. It is a phase 3, randomized, double-blind, placebo-controlled study, which compared sunitinib in the treatment of patients with malignant gastrointestinal stromal 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 routine standard of care. Common treatment-emergent AEs (≥10%) are adverse events previously reported with sunitinib, including leukopenia, hand-foot syndrome, fatigue, neutropenia, decreased platelet count, increased aspartate aminotransferase, decreased hemoglobin, skin discoloration, and hypertension. Most of the adverse events were grade 1 or 2 in severity, and some were grade ≥3. The overall incidence of treatment-related serious adverse events was low in Study A6181177. The three adverse events with the highest incidence in the study were leukopenia (62.7%), hand-foot syndrome (50.8%) and fatigue (49.2%).

Compared with the subjects in the reference study A6181004, the overall safety profile of sunitinib in Chinese subjects in the A6181177 study is similar, and no unexpected adverse events have occurred so far. The differences in safety between the two studies are: the incidence of hand-foot syndrome, fatigue and some hematological toxicities in Chinese subjects in the A6181177 study was slightly higher than that in Western subjects; the incidence of gastrointestinal adverse events in Chinese subjects was lower than that in Western subjects. The key safety results from both studies are summarized in Table 7 below.

Overall, sunitinib treatment was well tolerated by subjects in both studies, and adverse events were manageable with medication interruption, dose reduction, and/or standard treatment.

Safety data of Chinese renal cell carcinoma subject study A6181132 (clinical study report date April 28, 2012)

Study A6181132 is a single-arm, open-label, multi-center, Phase 4 study as a post-approval commitment study to evaluate the efficacy and safety of sunitinib malate in the first-line treatment of Chinese subjects with metastatic renal cell carcinoma. This study was conducted in China and has been completed. The subjects took 50 mg sunitinib malate capsules once a day for 4 weeks and then stopped for 2 weeks (4/2 regimen). A 6-week treatment cycle was used, and the treatment was repeated. The study enrolled 105 subjects.

Reference study A6181034 was a randomized, open-label, phase 3 clinical trial comparing 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.

98.1% of subjects in the A6181132 study experienced post-treatment adverse events. The most common adverse events (occurring in at least 20% of subjects) are summarized in Table 8. The most common treatment-emergent adverse events were hand-foot syndrome, decreased white blood cell count, and fatigue.

Compared with the subjects in the A6181034 study, the overall safety profile of sunitinib in the Chinese subjects in the A6181132 study is similar to that of the reference study, and no unexpected adverse events have occurred so far. Overall, the safety results were comparable to, but also different from, the A6181034 study; the incidence of treatment-related serious adverse events was lower at 12.4% in the A6181132 study compared to 23.7% in the A6181034 study. Diarrhea and fatigue were common AEs in both studies, with higher incidence rates. The top three most common AEs in the A6181132 study were: hand-foot syndrome (63.8%), decreased white blood cell count (52.4%), and fatigue (51.4%). The top three most common AEs in the A6181034 study were diarrhea (65.6%), fatigue (62.4%) and nausea (57.6%).

Overall, sunitinib treatment was well tolerated by subjects in both studies, and adverse events were manageable with medication interruption, dose reduction, and/or standard treatment.

Venous thrombotic events

During the double-blind period of treatment, 7 (3%) subjects in the sunitinib group in Gastrointestinal Stromal Tumor (GIST) Study A experienced venous thrombotic events, of which 5 subjects had grade 3 deep vein thrombosis events (DVT) and 2 subjects had grade 1 or 2. Four of the seven subjects discontinued treatment after the first observation of deep vein thrombosis. There were no venous thrombotic events in the placebo group.

In previously untreated advanced renal cell carcinoma (RCC) studies, venous thrombotic events were reported in 13 (3%) subjects treated with sunitinib, including pulmonary embolism (1 grade 2 and 6 grade 4) in 7 (2%) and deep vein thrombotic events in 6 (2%) subjects (3 grade 3). One subject withdrew from the sunitinib study due to pulmonary embolism; 2 subjects withdrew from the sunitinib study due to pulmonary embolism, and 1 subject suspended the drug due to a deep vein thrombosis event. In the IFN-α group, 6 (2%) subjects experienced venous thrombosis, including 1 (<1%) grade 3 deep vein thrombosis event and 5 (1%) subjects with pulmonary embolism (all grade 4).

One subject (1%) with pancreatic neuroendocrine tumor who received sunitinib experienced a venous thrombotic event compared with 5 subjects (6%) who received placebo. Subjects in the sunitinib group had grade 2 thrombosis. In the placebo group, 2 cases of deep vein thrombosis events occurred, 1 of which was grade 3; 2 cases of pulmonary embolism, 1 of which was grade 3; 1 case of grade 4; and 1 case of grade 3 jugular venous thrombosis.

Reversible posterior leukoencephalopathy syndrome (RPLS)

Rare seizures and reversible posterior leukoencephalopathy syndrome (RPLS) with radiographic evidence (<1%), some are fatal. Subjects with epileptic seizures and RPLS-related symptoms/signs such as hypertension, headache, decreased alertness, changes in mental function, and vision loss (including cortical blindness) should first receive medical treatment, including blood pressure control, and it is recommended that the product be temporarily discontinued. Thereafter, resumption of treatment may be considered at the physician's discretion.

Pancreatic and Liver Function

If the subject develops symptoms of pancreatitis or liver failure, treatment with this product should be discontinued. Among subjects with previously untreated advanced renal cell carcinoma (RCC), pancreatitis was observed in 5 (1%) subjects in the sunitinib group and 1 (<1%) in the IFN-a group. Among subjects with pancreatic neuroendocrine tumors, 1 subject in the sunitinib group and 1 subject in the placebo group developed pancreatitis. Hepatotoxicity has been observed in subjects treated with this product (see Boxed Warning and Precautions for details).

Hepatobiliary abnormalities

Rare: cholecystitis, especially acalculous cholecystitis.

Laboratory tests

Common: elevated blood uric acid.

Post-marketing experience

After the approval of sunitinib, the following adverse reactions were found. Since these reactions were spontaneously reported by an undetermined number of people, it is impossible to accurately analyze their frequency of occurrence or determine the causal relationship with drug exposure.

Hematological and lymphatic system abnormalities: Thrombotic microangiopathy; thrombocytopenia-related bleeding events*. It is recommended to suspend the use of sunitinib; after treatment, the drug can be resumed under the guidance of a physician.

Immune system abnormalities: Hypersensitivity reactions, including angioedema.

Infections and Infestations: Severe infections (with or without neutropenia)*, necrotizing fasciitis including perineum*. The most common infections in patients receiving sunitinib include respiratory tract infections (e.g., pneumonia, bronchitis) - common, urinary tract infections - common, skin infections (e.g., cellulitis) - common, sepsis/septic shock - rare, and abscesses (e.g., oral, genital, anorectal, skin, extremity, visceral) - common. The infection may be bacterial (eg, intra-abdominal infection, osteomyelitis) - common, viral (eg, nasopharyngitis, oral herpes) - common, or fungal (eg, oral, esophageal Candida infection) - common.

Abnormal metabolism and nutritional status: Tumor lysis syndrome* (see [Precautions] for details). Decreased blood glucose has been reported with sunitinib therapy, in some cases clinically symptomatic.

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 with symptoms or signs of myosis should receive medical treatment.

Abnormalities of the kidneys and urinary system: renal impairment and/or renal failure*; proteinuria; rarely nephrotic syndrome. A baseline urinalysis is recommended to monitor patients for the development or worsening of proteinuria. The safety of continued sunitinib therapy in patients with moderate to severe proteinuria has not been systematically evaluated. In patients with nephrotic syndrome, discontinue sunitinib therapy.

Respiratory system abnormality: Pulmonary embolism* (see [Precautions] for details).

Skin and subcutaneous tissue abnormalities: Pyoderma gangrenosum, including deactivation positivity; 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 malignancy and age ≥65 years, risk factors associated with arterial thromboembolic events include hypertension, diabetes mellitus, and previous thromboembolic disease.

Bleeding events: Lung, gastrointestinal, tumor, urinary tract and cerebral hemorrhage.

Nervous system abnormalities: Taste abnormalities, including loss of taste.

Endocrine abnormalities: Rare reports of hyperthyroidism have been reported in clinical studies and post-marketing use, and some have subsequently developed hypothyroidism; thyroiditis - rare.

Heart abnormality: cardiomyopathy*.

Gastrointestinal abnormalities: Esophagitis - common.

* Contains some lethality.

6. Contraindications of sunitinib

It is prohibited for those who are severely allergic to this product or its inactive ingredients.

7. Precautions for sunitinib

There is still a lack of sufficient clinical research data on the Chinese population. It is recommended to use it under the guidance of doctors who have experience in using this product.

Skin and Tissue

Skin discoloration is a very common adverse reaction reported in clinical trials and may be caused by the color (yellow) of the active substance. Subjects should be informed that hair or skin depigmentation may also occur during treatment with sunitinib. Other possible skin effects include dry, thickened or cracked skin and blisters or occasional rash on the palms and soles of the feet.

The above-mentioned adverse events have no cumulative effect, are generally reversible, and usually do not lead to treatment termination.

Be alert to rare severe skin reactions that can lead to death. Reported cases include erythema multiforme (EM), suspected Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). If symptoms or signs suspected of SJS, TEN, or EM occur (such as progressively worsening rash, often accompanied by blisters or mucosal damage), sunitinib treatment should be suspended. If SJS or TEN is diagnosed, sunitinib must be discontinued. In cases of suspected EM, some patients can tolerate restarting treatment with lower doses of sunitinib after resolution of skin symptoms; some patients can tolerate sunitinib combined with corticosteroids or antihistamines.

Hepatotoxicity

This product is hepatotoxic and may cause liver failure or death. The occurrence of liver failure has been observed in clinical studies (7/2281 [0.3%]) and in post-marketing clinical use. Signs of liver failure include jaundice, elevated transaminases, and/or high bilirubin associated with brain disease, coagulation, and/or renal failure. Liver function (ALT, AST, bilirubin) should be monitored before initiation of treatment, during each treatment cycle, and as clinically necessary. When grade 3 or 4 drug-related adverse reactions to liver function occur, medication should be discontinued. If recovery cannot occur, treatment should be terminated. When the patient shows a serious decline in liver function indicators in subsequent liver function tests or develops other symptoms of liver failure, the medication should not be restarted.

The safety of this product has not been confirmed in patients with ALT or AST >2.5 times ULN or liver aminotransferase greater than 5.0 times ULN.

Left ventricular dysfunction

If clinical manifestations of congestive heart failure (CHF) occur, it is recommended to stop using this product.

Patients with no clinical evidence of congestive heart failure but an ejection fraction less than 50% and an ejection fraction less than 20% below baseline should also discontinue treatment with this product and/or reduce the dose.

Cardiovascular events, including heart failure, myocardial dysfunction and myocardial abnormalities, some of which are fatal, have been reported post-marketing. More patients who received sunitinib experienced a decrease in left ventricular ejection fraction than those who received placebo or IFN-α. In Study A of gastrointestinal stromal tumor (GIST), 22/209 patients (11%) 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). In the sunitinib group, 9 of the 22 patients with altered LVEF recovered spontaneously without treatment; 5 patients returned to normal after treatment (1 patient reduced the dose; 4 patients were additionally given antihypertensive drugs or diuretics); 6 patients ended the study but no recovery was recorded. In addition, 3 patients (1%) in the sunitinib group experienced grade 3 decline in left ventricular systolic function to LVEF<40%, 2 patients died without receiving further treatment with study drugs. No patients in the placebo group experienced grade 3 LVEF decline. In gastrointestinal stromal tumor (GIST) Study A, one patient in each group (<1% in the sunitinib group; 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 the study of patients with previously untreated advanced/metastatic renal cell carcinoma (MRCC), there were 78/375 patients (21%) in the sunitinib group and 44/360 patients in the IFN-α group. (12%) patients had LVEF values lower than the lower limit of normal (LLN); 13 (4%) and 4 (1%) patients had LVEF values lower than 50%, respectively, and decreased by more than 20% from the baseline value. Three patients (1%) in the sunitinib group developed left ventricular dysfunction, and one (<1%) patient was diagnosed with congestive heart failure (CHF).

In a phase 3 study of pancreatic neuroendocrine tumors, 2 of 83 subjects (2%) in the sunitinib group reported heart failure leading to death, compared with none in the placebo group.

Patients with cardiac events within 12 months before treatment, 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, were excluded from clinical studies of this product. It is unclear whether patients with these concomitant conditions are at increased risk for developing drug-related left ventricular dysfunction. Prescribers are advised to weigh the value of the medication against its potential risks. Such patients should be carefully monitored for clinical signs and symptoms of congestive heart failure while receiving treatment with this product, and baseline and periodic LVEF assessments should be considered. In patients without cardiac risk factors, assessment of baseline ejection fraction should be considered.

QT interval prolongation and torsade de pointes

Studies have shown that this product can prolong the QT interval in a dose-dependent manner. QT prolongation may result in an increased risk of ventricular arrhythmias, including torsade de pointes. Torsades de pointes was observed in less than 0.1% of patients treated with this product.

This product should be used with caution in patients with a known history of QT prolongation, patients taking antiarrhythmic drugs, or patients with related underlying heart disease, bradycardia, and electrolyte imbalance. When using this product, regular monitoring of electrocardiogram and electrolytes (magnesium and potassium) should be considered during treatment. When combined with strong CYP3A4 inhibitors, the plasma drug concentration of sunitinib may be increased. It should be used with caution and consideration should be given to reducing the dose of this product (see [Usage and Dosage]).

Hypertension

Patients with hypertension should have their blood pressure monitored and receive standard antihypertensive treatment as needed. If severe hypertension occurs, it is recommended to temporarily discontinue this product until the hypertension is controlled.

In previous studies of untreated advanced/metastatic renal cell carcinoma (MRCC), 111/375 (30%) and 13/360 (4%) patients in the IFN-α group developed hypertension; grade 3 hypertension was 36/375 (10%) and 1/360 (<1%), respectively. 18/375 (5%) patients had the dose of this product reduced or temporarily delayed due to hypertension. Two cases discontinued treatment due to hypertension, one of which was a patient with malignant hypertension.

In the gastrointestinal stromal tumor (GIST) study, the incidence of hypertension at all levels was similar in the sunitinib and placebo groups. Grade 3 hypertension was observed in 9/202 cases (4%) in the sunitinib group; grade 3 hypertension was not observed in the placebo group. There were no reports of grade 4 hypertension in either group. No patient discontinued treatment due to hypertension.

In a phase 3 study of pancreatic neuroendocrine tumor (pNET), 22/83 (27%) subjects in the sunitinib group and 4/82 (5%) subjects in the placebo group developed hypertension. Grade 3 hypertension was reported in 8 of 83 subjects (10%) with pancreatic neuroendocrine tumors in the sunitinib group compared with 1 (1%) of 82 subjects in the placebo group. In 7/83 cases (8%) of subjects with pancreatic neuroendocrine tumors, the dose of this product was reduced or temporarily delayed due to hypertension. One patient discontinued treatment due to hypertension.

No grade 4 hypertension was reported.

In previous studies of untreated advanced renal cell carcinoma (RCC), 32/375 (9%) subjects in the sunitinib group and 3/360 (1%) subjects in the IFN-α group developed severe hypertension (systolic blood pressure >200 mmHg or diastolic blood pressure >110 mmHg). In the gastrointestinal stromal tumor (GIST) study, 8/202 (4%) subjects in the sunitinib group and 1/102 (1%) subjects in the placebo group developed severe hypertension. In the pancreatic neuroendocrine tumor study, 8/80 patients (10%) in the sunitinib group and 2/76 patients (3%) in the placebo group developed severe hypertension.

Bleeding events

In post-marketing reports, bleeding events have been reported, including gastrointestinal, respiratory, tumor, urinary tract and cerebral hemorrhage, some of which were fatal.

In the advanced renal cell carcinoma (RCC) study, bleeding events occurred in 140/375 patients (37%) in the sunitinib group and 35/360 patients (10%) in the IFN-α group. Most were grade 1 or 2; only 1 grade 5 gastric bleeding occurred in a previously untreated subject.

In Gastrointestinal Stromal Tumor (GIST) Study A, 37/202 (18%) patients in the sunitinib group and 17/102 (17%) patients in the placebo group experienced bleeding events; 14/202 (7%) and 9/102 (9%) patients in the two groups experienced grade 3 or 4 bleeding events respectively. In addition, 1 patient in the placebo group experienced fatal gastrointestinal bleeding in cycle 2.

In a phase 3 study of pancreatic neuroendocrine tumors (pNET), 18/83 (22%) subjects in the sunitinib group experienced bleeding events other than epistaxis, compared with 8/82 (10%) in the placebo group. Epistaxis occurred in 17/83 (20%) subjects in the sunitinib group compared with 4 (5%) in the placebo group. In the pancreatic neuroendocrine tumor study, 1/83 (1%) subjects in the sunitinib group experienced grade 3 epistaxis, and no subject experienced other grade 3 or 4 bleeding events. In the placebo group, 3/82 (4%) subjects experienced grade 3 or 4 bleeding events.

Epistaxis is the most common bleeding adverse reaction reported. Rare bleeding adverse reactions in subjects with advanced renal cell carcinoma (RCC), gastrointestinal stromal tumors (GIST), and pancreatic neuroendocrine tumors (pNET) include bleeding from the rectum, gums, upper gastrointestinal tract, genitals, and wounds.

Tumor-related bleeding has been observed in patients treated with sunitinib. These events may occur suddenly, and patients with lung tumors may develop severe and life-threatening hemoptysis or pulmonary embolism. In a clinical study of this product in the treatment of metastatic non-small cell lung cancer (NSCLC), 2 patients suffered from fatal pulmonary hemorrhage, and both histological types were squamous cell carcinoma. This product is not approved for use in patients with metastatic non-small cell lung cancer. In Study A of gastrointestinal stromal tumors (GIST), 5 out of 202 patients (3%) who received this product developed grade 3 and grade 4 tumor bleeding after treatment. Tumor bleeding occurred as early as the 1st cycle and as late as the 6th cycle; among them, 1 patient did not receive further treatment after tumor bleeding, and the remaining 4 patients did not stop treatment or delay treatment due to tumor bleeding. In Study A of gastrointestinal stromal tumor (GIST), no intratumoral bleeding was observed in the placebo group. No tumor bleeding was observed in patients with advanced/metastatic renal cell carcinoma (MRCC). Clinical evaluation for these events should include serial complete blood counts (CBCs) and physical examination.

Gastrointestinal tract

Serious and sometimes fatal gastrointestinal complications, including gastrointestinal perforation, are rare in patients with intra-abdominal tumors treated with this product.

Gastrointestinal adverse events

Nausea, diarrhea, stomatitis, dyspepsia, and vomiting are the most commonly reported treatment-related gastrointestinal adverse events. Supportive care for gastrointestinal adverse events requiring treatment may include antiemetic or antidiarrheal medications.

Pancreatitis

Pancreatitis has been reported during clinical trials of sunitinib. Elevated serum lipase and amylase have been observed in subjects with various solid tumors treated with sunitinib. In subjects with various solid tumors, elevated lipase levels are transient and generally not associated with signs or symptoms of pancreatitis. If symptoms of pancreatitis develop, patients should discontinue sunitinib and receive appropriate supportive care.

Thyroid insufficiency

It is recommended to conduct laboratory tests of baseline thyroid function. Patients with hypothyroidism or hyperthyroidism should be given corresponding standard treatment before receiving this product. All patients should be closely monitored for signs and symptoms of thyroid insufficiency, including hypothyroidism, hyperthyroidism, and thyroiditis while receiving this product. Patients with symptoms and signs of thyroid insufficiency should undergo laboratory monitoring of thyroid function and receive standard treatment accordingly.

In the gastrointestinal stromal tumor (GIST) study, 8 patients (4%) in the sunitinib group and 1 patient (1%) in the placebo group developed hypothyroidism. In the study of previously untreated advanced renal cell carcinoma (RCC), 61 subjects (16%) in the sunitinib group and 3 (1%) in the IFN-α group developed hypothyroidism. In the phase 3 pancreatic neuroendocrine tumor study, adverse events of hypothyroidism were reported in 6/83 (7%) subjects in the sunitinib group and 1/82 (1%) in the placebo group.

Clinical trials and post-marketing drug experience have also reported some incidents of hyperthyroidism, and some have subsequently developed hypothyroidism.

Seizures

In clinical studies of sunitinib, subjects with radiographic evidence of brain metastases developed seizures. In addition, a very small number (<1%) of subjects developed seizures and radiographic evidence of reversible posterior leukoencephalopathy syndrome (RPLS), some of which were fatal. If a patient has a seizure or develops signs/symptoms consistent with RPLS (e.g., hypertension, headache, decreased alertness, changes in mental function, and vision loss, including cortical blindness), the condition should be controlled with medical management, including control of hypertension. It is recommended to temporarily discontinue sunitinib; after symptoms are relieved, treatment can be continued according to the judgment of the attending physician.

Wound Healing

Slow wound healing has been reported in patients receiving sunitinib. It is recommended that patients undergoing major surgical procedures withhold dosing to prevent this phenomenon. Clinical experience is limited on when to initiate treatment after major surgical procedures. Therefore, clinical judgment should be made as to whether to restart dosing based on the patient's degree of recovery after major surgical procedures.

Osteonecrosis of the jaw (ONJ)

ONJ is occasionally seen in clinical studies, and ONJ has been reported after post-marketing use. Most patients who develop ONJ have prior or concomitant intravenous bisphosphonate use, which is a recognized risk factor for ONJ. Therefore, special care is required whether intravenous administration of sunitinib and bisphosphonates is administered concomitantly or sequentially.

Invasive dental procedures have also been identified as a risk factor for ONJ. A dental examination and appropriate preventive measures should be considered before administering sunitinib therapy. Patients with previous or concomitant intravenous bisphosphonate administration or invasive dental procedures should avoid treatment with sunitinib.

Tumor lysis syndrome (TLS)

Tumor lysis syndrome has occasionally been seen in clinical studies, some with fatal consequences, and post-marketing drug experience has also been reported. Patients at this risk group usually have high tumor burden before receiving sunitinib treatment and should be closely monitored and administered in accordance with clinical practice.

Adrenal function

For patients who have experienced stress such as surgery, trauma or severe infection, it is recommended that doctors monitor the patient's adrenal function when prescribing this product.

Adrenal toxicity was reported with sunitinib in repeated-dose nonclinical studies in rats and monkeys ranging from 14 days to 9 months, with plasma exposures being 0.7 times the AUC observed in clinical studies. Adrenal histological changes are characterized by hemorrhage, necrosis, congestion, hypertrophy, and inflammation. In the clinical study, CT/MRI data were obtained from 336 patients who received 1 or more cycles of sunitinib treatment, and no adrenal hemorrhage or necrosis was found. In multiple clinical studies of this product, ACTH stimulation tests were performed on nearly 400 patients. Among patients with normal ACTH stimulation test baseline examinations, 1 patient developed sustained abnormal ACTH stimulation test results during treatment, but the cause could not be explained, which may be related to the treatment of this product. Another 11 patients with normal ACTH stimulation test baseline examination had abnormal final examination results, with peak cortisone levels of 12-16.4 μg/dL after stimulation (normal value >18 μg/dL). There was no clinical evidence of adrenal insufficiency in these patients.

Laboratory tests

Patients receiving this product should have complete blood counts (CBCs), platelet counts, and blood chemistry (including serum phosphorus) checked at the beginning of each treatment cycle.

Necrotizing fasciitis

Rare, sometimes fatal, cases of necrotizing fasciitis involving the perineum have been reported. Patients who develop necrotizing fasciitis should discontinue sunitinib therapy and receive appropriate treatment immediately.

Proteinuria

Proteinuria and rare cases of nephrotic syndrome have been reported. Baseline and periodic urinalysis are recommended, as well as 24-hour follow-up urine protein measurements as clinically indicated, and patients are monitored for the development or worsening of proteinuria. The safety of continued sunitinib therapy in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue sunitinib treatment in patients with nephrotic syndrome or in patients with recurrent urinary protein ≥3 g despite dose reduction.

Hypoglycemia

Sunitinib has been associated with symptomatic hypoglycemia, which may result in loss of consciousness or require hospitalization. In clinical trials, hypoglycemia occurred in 2% of patients with gastrointestinal stromal tumors (GIST) and advanced renal cell carcinoma (RCC) and approximately 10% of patients with pancreatic neuroendocrine tumors (pNET) treated with sunitinib. In patients with pancreatic neuroendocrine tumors (pNET) treated with sunitinib, pre-existing glycemic abnormalities do not occur in all patients who experience hypoglycemia. Lower blood sugar may be more severe in people with diabetes. Blood glucose levels should be checked regularly during and after sunitinib treatment. Assess whether the dose of antidiabetic medications needs to be adjusted to reduce the risk of hypoglycemia.

8. Sunitinib medication for special groups

Pregnant women

Pregnant women receiving sunitinib treatment may harm the fetus. Because blood vessel formation is critical for embryonic and fetal development, sunitinib inhibits blood vessel formation and may have adverse effects on pregnancy. In animal reproduction studies in rats and rabbits, sunitinib demonstrated teratogenicity, embryotoxicity, and fetotoxicity. Adequate, well-controlled studies have not been conducted with this product in pregnant women. If a patient is pregnant while using this product or receiving treatment with this product, the patient should be informed of the potential harm to the fetus. Women of childbearing potential should use contraception when receiving this product.

The effects of sunitinib on embryos were evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/daily dose) and pregnant rabbits (0.5, 1, 5, 20 mg/kg/daily dose). At a dose of 5 mg/kg/day (approximately 5.5 times the human recommended daily dose [RDD] AUC), a significant increase in the incidence of embryonic death and developmental abnormalities was observed in rats. In rabbit experiments, the incidence of embryonic death was significantly increased at the 5 mg/kg/day dose, and developmental abnormalities were found at the dose ≥1 mg/kg/day (approximately 0.3 times the AUC at the recommended human daily dose of 50 mg/day). Developmental effects include an increased incidence of skeletal malformations of the ribs and vertebrae in rat fetuses. In rabbit experiments, cleft lip was observed at the 1 mg/kg/day dose, and cleft lip and palate were observed at the 5 mg/kg/day (approximately 2.7 times the AUC of the recommended daily human dose) dose. In experiments on rats, no fetal miscarriage or malformation was seen when the dose was ≤3 mg/kg/day (approximately 2.3 times the recommended human daily dose).

Sunitinib (0.3, 1.0, and 3.0 mg/kg/day) was evaluated in pre- and postpartum developmental studies in pregnant rats. Maternal weight gain was reduced during pregnancy and lactation at doses of 1 mg/kg/day and above, but no maternal reproductive toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients receiving the recommended daily dose). At the high dose of 3 mg/kg/day, weight loss was observed in both female and male offspring from birth until weaning, while weight loss in male offspring continued after weaning. No other developmental toxicities were observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients receiving the recommended daily dose).

Lactating women

Sunitinib and/or its metabolites can be excreted in rat milk. When lactating female rats were given 15 mg/kg sunitinib, sunitinib and its metabolites were excreted in large quantities in the milk, and its concentration in the milk was as high as 12 times its concentration in plasma. However, it is unknown whether sunitinib and its major active metabolite are excreted in human milk. Because drugs are usually excreted in human milk and have potentially serious adverse reactions in nursing infants, when breastfeeding women receive drug treatment, they should weigh the decision of whether to stop breastfeeding or discontinue treatment while considering the importance of the drug to the mother.

Pediatric Medication

The safety and effectiveness of this product in pediatric patients have not yet been determined.

Geriatric use

Among the 825 patients with gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) treated with this product, 277 (34%) were 65 years old or older. In the phase 3 study of pancreatic neuroendocrine tumors, 22 (27%) subjects who received sunitinib were 65 years of age and older. No differences in safety or effectiveness were found between younger and older subjects.

9. Sunitinib drug interactions

CYP3A4 inhibitors: Strong inhibitors of CYP3A4, such as ketoconazole, can increase the plasma concentration of sunitinib. It is recommended to select concomitant drugs that have no or minimal inhibitory effect on these enzymes. If it must be used simultaneously with strong CYP3A4 inhibitors, you need to consider reducing the dose of this product. A single dose of sunitinib malate administered to healthy volunteers concurrently with a strong CYP3A4 inhibitor (ketoconazole) resulted in an increase in overall Cmax and AUC0-∞ of sunitinib and its major active metabolite by 49% and 51%, respectively. When sunitinib is used simultaneously with strong inhibitors of the CYP3A4 enzyme system (such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), the concentration of sunitinib can be increased. Grapefruit can also increase the plasma concentration of sunitinib. If it must be used together with strong CYP3A4 inhibitors, you need to consider reducing the dose of this product (see [Dosage and Administration]).

CYP3A4 Inducers: CYP3A4 inducers, such as rifampicin, may decrease sunitinib plasma concentrations. It is recommended to select concomitant medications that have no or minimal induction of these enzymes. A single dose of sunitinib administered to healthy volunteers concurrently with a strong CYP3A4 inducer (rifampicin) resulted in a 23% and 46% decrease in overall Cmax and AUC0-∞ of sunitinib and its main active metabolite. Concomitant use of sunitinib with CYP3A4 enzyme inducers (such as dexamethasone, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John's wort) may reduce the concentration of sunitinib. St. John's wort may suddenly reduce the blood concentration of sunitinib, and patients should not take St. John's wort concurrently while receiving sunitinib. If it must be used simultaneously with CYP3A4 inducers, you need to consider increasing the dose of this product (see [Dosage and Administration]).

In vitro studies on CYP inhibition and induction: In vitro study results indicate that sunitinib does not induce or inhibit the major CYP enzymes.

10. Storage of Sutent

Stored at 25℃; the allowable range is 15-30℃