Sunitix

Sunitinib (Sutent) instructions

Common name: Sunitinib

Trade name: Sutent

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

1. Sunitinib indications

(1). Gastrointestinal stromal tumors (GIST) who 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. Sunitinib usage and dosage

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 steps according to the safety and tolerability of the individual patient. The maximum daily dose is not to exceed 75 mg and the minimum dose is 25mg.

For pancreatic neuroendocrine tumors, the dose is gradually adjusted in steps of 12.5 mg 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 necessary with CYP3A When 4 strong inhibitors are used together, the dose of this product should be considered to be reduced, to a minimum of 37.5 mg once a day (gastrointestinal stromal tumor and renal cell carcinoma), 25 mg once a day (Pancreatic Neuroendocrine Tumor) (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 necessary with CYP3A4 When inducers are used together, an increase in the dose of this product should be considered. The maximum dose should not exceed 87.5 mg once a day (gastrointestinal stromal tumor and renal cell carcinoma) and 62.5 mg once a day (pancreatic neuroendocrine tumors). . If the dose of this product is increased, the patient should be carefully monitored for toxic reactions (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 come 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 [Clinical Studies]) and 83 subjects in the placebo-controlled study of pancreatic neuroendocrine tumor (pNET) (see [Clinical Studies]). The treatment regimen for sunitinib in subjects with gastrointestinal stromal tumors and renal cell carcinoma is a starting dose of 50 mg. Take once a day orally for 4 weeks and 2 weeks off (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. For a discussion of potentially serious adverse reactions: hepatotoxicity, left ventricular dysfunction, QT prolongation, bleeding, hypertension, thyroid insufficiency, adrenal insufficiency see 【Notes】. 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%) in the placebo group; 7% and 6% in the placebo group, respectively. of patients permanently discontinued treatment 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 have the opportunity to receive open sunitinib treatment (see [Clinical Research]). 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 3 or Grade 4 drug-related adverse reactions were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), Anorexia (3%), mucositis (2%), vomiting (2%), 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 of whom were in the sunitinib group. There were 360 ​​cases 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. There were 194 cases (52%) in the sunitinib group and 194 cases (52%) in the IFN-α group. Dose reduction was required in 98 patients (27%). 20% in the sunitinib group and 20% in the IFN-α group Adverse effects after treatment resulted in permanent discontinuation of treatment in 23% of patients. 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 Trial in Pancreatic Neuroendocrine Tumor

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.

The A6181177 study was a single-arm, open-label, multicenter, 4- The Phase 1 study, as a post-approval commitment study, aims 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, continuously 4 weeks, 2 weeks off (4/2 regimen), 6 weeks as a treatment cycle, repeat treatment. The study screened 62 subjects, and 60 subjects were enrolled for treatment.

The reference study A6181004 is the global registration study of sunitinib in GIST, which is a phase 3, randomized, double-blind, placebo-controlled study. Sunitinib was compared in subjects with malignant gastrointestinal stromal tumors who were 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. The severity of most of these adverse events was Grade 1 or 2, and some grade ≥3 adverse events. The overall incidence of treatment-related serious adverse events was low in Study A6181177. Highest incidence in the study 3 The most common adverse events 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 in Western subjects; Chinese subjects had lower rates of gastrointestinal adverse events than 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 through 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, multicenter, Phase 4 study as a post-approval commitment study to evaluate the efficacy and safety of sunitinib malate as first-line treatment in 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), 6 Weekly is a treatment cycle, and the treatment is repeated. The study enrolled 105 subjects.

Reference study A6181034 was a randomized, open-label, phase 3 clinical trial comparing sunitinib with Efficacy of alpha-interferon as first-line therapy 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 treatment-emergent adverse events. The most common adverse events (occurring in at least 20% of subjects) are summarized in the 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 in the A6181132 study was lower. 12.4%, A6181034 study 23.7%. Diarrhea and fatigue were common AEs in both studies, occurring at higher rates. Among the top 3 most common in the A6181132 study AEs were: hand-foot syndrome (63.8%), decreased white blood cell count (52.4%), and fatigue (51.4%). A6181034 Top 3 most common AEs in the study They 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 through 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, including 5 subjects (3%). grade deep vein thrombosis (DVT), 2 cases were 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.

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

Venous thrombotic events occurred in 1 (1%) subject with pancreatic neuroendocrine tumor who received sunitinib compared with 5 (6%) subjects in the placebo group. Subjects in the sunitinib group were 2 grade thrombosis. There were 2 deep vein thrombosis events in the placebo group, 1 of which was grade 3; 2 of pulmonary embolism, 1 of grade 3; 1 of grade 4; and 1 of pulmonary embolism. Grade 3 jugular vein thrombosis.

Reversible posterior leukoencephalopathy syndrome (RPLS)

Rare epileptic seizures and reversible posterior leukoencephalopathy syndrome (RPLS) with radiographic evidence (<1%), some are fatal. Seizures and having RPLS Subjects with related symptoms/signs such as hypertension, headache, decreased alertness, changes in mental function, and vision loss (including cortical blindness) should first undergo medical treatment, including blood pressure control, and it is recommended to temporarily discontinue this product. 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. In subjects with previously untreated advanced renal cell carcinoma (RCC), an increase in sunitinib and IFN-a was observed. Pancreatitis occurred in 5 (1%) and 1 (<1%) subjects. Among subjects with pancreatic neuroendocrine tumors, pancreatitis was observed in one subject in the sunitinib group and in the placebo group. Hepatotoxicity has been observed in subjects treated with this product (see Boxed Warning and Precautions).

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: Because these reactions are reported voluntarily by an undetermined number of people, it is not possible to accurately analyze their frequency or establish a 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 infection (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 metabolic 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]); 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 abnormalities: 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. Except for underlying malignancy and age ≥65 Beyond age, risk factors associated with arterial thromboembolic events include hypertension, diabetes, and previous thromboembolic disease.

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

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

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

Heart abnormalities: Cardiomyopathy*.

Gastrointestinal abnormalities: Esophagitis - common.

* Contains some lethality.

6. Contraindications of sunitinib

Contraindicated 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. May be caused by the color of the active substance (yellow). 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 serious 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 diagnosed with SJS or TEN, sunitinib must be discontinued. In cases of suspected EM, some patients may tolerate restarting sunitinib therapy at a lower dose after resolution of skin symptoms; Some patients may be treated with sunitinib in combination 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 the start 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 in patients with ALT or AST >2.5 times ULN or liver aminotransferase greater than 5.0 times ULN has not been confirmed.

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 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. Research in gastrointestinal stromal tumors (GIST) In A, 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). 9 of 22 patients with altered LVEF in the sunitinib group One patient recovered spontaneously without treatment; 5 patients returned to normal after treatment (1 patient reduced the dose; 4 patients were additionally treated with antihypertensive drugs or diuretics); 6 patients One patient ended the study with no record of recovery. In addition, 3 patients (1%) in the sunitinib group experienced grade 3 decline in left ventricular systolic function to LVEF <40%, 2 of which One patient died without further treatment with the study drug. No patients in the placebo group experienced grade 3 decrease in LVEF. In gastrointestinal stromal tumor (GIST) Study A, 1 patient in each group patients (<1% in the sunitinib group; 1% in the placebo group) died of heart failure; 2 patients in each group (1% in the sunitinib group; 2% in the placebo group) died of cardiac arrest after treatment.

In studies of patients with previously untreated advanced/metastatic renal cell carcinoma (MRCC), 78/375 (21%) in the sunitinib group and 44/360 in the IFN-alpha group (12%) patients had LVEF values ​​below the lower limit of normal (LLN); 13 (4%) and 4 (1%) patients respectively had LVEF values ​​below 50% and decreased by 20% from the baseline value. above. Three patients (1%) in the sunitinib group developed left ventricular dysfunction, and 1 (<1%) patient was diagnosed with congestive heart failure (CHF).

In a phase 3 study of pancreatic neuroendocrine tumors, heart failure leading to death was reported in 2 of 83 subjects (2%) in the sunitinib group 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 artery/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 this product, and baseline and periodic LVEF measurements should be considered. Evaluate. 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 Interval 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 known to have QT Patients with a history of prolonged intervals, patients taking antiarrhythmic drugs, or patients with associated underlying heart disease, bradycardia, and electrolyte imbalances. When using this product, regular monitoring of electrocardiogram and electrolytes (magnesium and potassium) should be considered during treatment. with CYP3A4 The combined use of strong inhibitors may increase the plasma drug concentration of sunitinib. 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), there were 111/375 cases (30%) in the sunitinib group and 13/360 cases in the IFN-α group. Hypertension occurred in 36/375 (10%) and 1/360 (<1%) patients, respectively. 18/375 In 5% of patients, the dose of this product was reduced or temporarily delayed due to hypertension. Two patients discontinued treatment due to hypertension, one of whom was a patient with malignant hypertension.

In the gastrointestinal stromal tumor (GIST) study, the occurrence of various grades of hypertension was similar in the sunitinib group and the placebo group. Grade 3 hypertension was observed in 9/202 cases (4%) in the sunitinib group; no 3 cases were observed in the placebo group. grade hypertension. No grade 4 hypertension was reported 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%) Participants 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 of 82 subjects in the placebo group (1%). 7/83 (8%) subjects with pancreatic neuroendocrine tumors had a dose reduction or temporary delay in administration of this product due to hypertension. One patient discontinued treatment due to hypertension.

No grade 4 hypertension was reported.

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

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, 140/375 cases (37%) in the sunitinib group and 35/360 cases in the IFN-α group (10%) patients experienced bleeding events. 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 patients (18%) in the sunitinib group and 17/102 patients (17%) in the placebo group experienced bleeding events; 14/202 patients in the two groups respectively Grade 3 or 4 bleeding events occurred in 9/102 patients (7%) and 9/102 patients (9%). In addition, 1 patient in the placebo group experienced fatal gastrointestinal bleeding during 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 contrast, 3/82 (4%) subjects in the placebo group 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 Two patients developed fatal pulmonary hemorrhage, and their histological types were all squamous cell carcinomas. This product is not approved for use in patients with metastatic non-small cell lung cancer. In Study A of gastrointestinal stromal tumor (GIST), 5 of 202 patients treated with this product 3% of cases (3%) developed grade 3 and 4 tumor bleeding after treatment. Tumor bleeding occurred as early as the 1st cycle and as late as the 6th cycle. Among them, 1 case did not receive further treatment after tumor hemorrhage, and the remaining 4 cases None of the patients stopped treatment or delayed treatment due to tumor bleeding. In study A of gastrointestinal stromal tumors (GIST), No intratumoral hemorrhage 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 are 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, and 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 (4%) subjects in the sunitinib group and 1 (1%) in the placebo group developed hypothyroidism. Previously untreated advanced renal cell carcinoma (RCC) In the study, 61 subjects (16%) in the sunitinib group and 3 subjects (1%) in the IFN-α group developed hypothyroidism. Pancreatic Neuroendocrine Tumor 3 In the phase 1 study, 6/83 (7%) subjects in the sunitinib group and 1/82 (1%) subjects in the placebo group reported adverse events of hypothyroidism.

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

Seizures

In clinical studies of sunitinib, subjects with radiographic evidence of brain metastases developed seizures. In addition, a rare minority (<1%) of subjects developed seizures and reversible posterior cerebral leukoencephalopathy syndrome Radiological evidence of (RPLS), partially lethal. If a patient has a seizure or signs/symptoms consistent with RPLS (e.g., hypertension, Headache, decreased alertness, changes in mental function, and loss of vision, including cortical blindness) should be managed 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.

Adrenotoxicity with sunitinib was reported in repeated-dose nonclinical studies in rats and monkeys ranging from 14 days to 9 months, with plasma exposures of 0.7 of the AUC observed in clinical studies. times. 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 underwent 1 No adrenal hemorrhage or necrosis was found during one or more cycles of sunitinib treatment. In multiple clinical studies of this product, ACTH stimulation tests were conducted on nearly 400 patients. Among patients with normal baseline stimulation test results, 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 cases of ACTH Patients with normal baseline examinations in the stimulation test 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, 2% of gastrointestinal stromal tumors (GIST) and advanced renal cell carcinoma treated with sunitinib (RCC) patients, and approximately 10% of patients with pancreatic neuroendocrine tumors (pNET) develop hypoglycemia. 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. Since blood vessel formation is critical for embryonic and fetal development, Sunitinib inhibits vascularization 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 becomes 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 5 mg/kg/daily dose (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 observed when the dose was ≤3 mg/kg/day (approximately 2.3 times the recommended human daily dose).

In a pre- and postpartum developmental study of pregnant rats, sunitinib (doses 0.3, 1.0, 3.0 mg/kg/day) were assessed. 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 a high dose of 3 mg/kg/day, Weight loss was observed in both female and male offspring from birth until weaning, whereas weight loss in male offspring continued after weaning. The dose is up to 3 mg/kg/day (approximately 2.3 times the AUC in patients receiving the recommended daily dose), no other developmental toxicities were observed.

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 amounts in the milk. Its concentration in breast milk is up to 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 patients (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 necessary with CYP3A4 When strong inhibitors are used simultaneously, it is necessary to consider reducing the dose of this product. Healthy volunteers received a single dose of sunitinib malate and concurrently administered CYP3A4 A strong inhibitor (ketoconazole), which resulted in an overall (sunitinib and its main active metabolite) Cmax and AUC0-∞ increase of 49% and 51%, respectively. Sunitinib and CYP3A4 Strong enzyme inhibitors (such as ketoconazole, itraconazole, clarithromycin, atazanavir , indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) can increase the concentration of sunitinib when used simultaneously, and grapefruit can also increase the plasma concentration of sunitinib. If necessary with CYP3A4 When strong inhibitors are used at the same time, it is necessary to consider reducing the dose of this product (see [Dosage and Administration]).

CYP3A4 inducer: 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. Healthy volunteers took a single dose of sunitinib and were given CYP3A4 A strong inducer (rifampicin) can lead to a 23% and 46% decrease in Cmax and AUC0-∞ of the total (sunitinib and its main active metabolite). Sunitinib and CYP3A4 The concentration of sunitinib can be reduced when enzyme inducers (such as dexamethasone, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John's wort) are used simultaneously. 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 necessary with CYP3A4 When inducers are used at the same time, it is necessary to consider increasing the dose of this product (see [Dosage and Administration]).

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

10. Sutent storage

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