Sunitinib malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2, 4, 5, 6, 7, 9, 10, 11, 12
Gastrointestinal Stromal Tumor
Sunitinib malate is used for the treatment of GI stromal tumor (GIST) in adults who are intolerant of or whose disease has progressed during imatinib therapy.1, 2, 9
The current indication for sunitinib malate is based principally on the results of 2 studies (one randomized, double-blind, placebo-controlled, phase 3 study9 and one open-label, single-arm, phase 1/2 dose-escalation study) in patients with GIST who were intolerant of or whose disease had progressed during imatinib therapy.1, 2 In the phase 3 study, 312 patients were randomized in a 2:1 ratio to receive either sunitinib (50 mg) or placebo given once daily for 4 consecutive weeks followed by a 2-week period without treatment.1, 2, 9 Treatment cycles were repeated until disease progression or withdrawal from the study for other reasons occurred.1, 2 A planned interim analysis indicated that patients receiving sunitinib had a longer median time to tumor progression (27.3 versus 6.4 weeks) and a longer median progression-free survival (24.1 versus 6 weeks) than those receiving placebo.1, 2, 9 Following these favorable results, the study was unblinded, and study investigators permitted patients previously randomized to receive placebo to cross over to open-label sunitinib; those previously randomized to receive sunitinib were permitted to continue therapy based on clinical judgment.1, 2, 9 After the study was unblinded, 94.3% of patients initially randomized to receive placebo crossed over to receive sunitinib therapy.1 Updated analysis confirmed that, following administration of a median of 5-6 treatment cycles, patients receiving sunitinib (i.e., those originally randomized to sunitinib and those who switched from placebo to sunitinib) had a longer median time to tumor progression (28.4 weeks) than those who received placebo (8.7 weeks); the time to tumor progression in patients who switched from placebo to sunitinib was not statistically different from that in patients originally randomized to sunitinib therapy.2 At the planned final analysis, median overall survival was 72.7 weeks in patients receiving sunitinib compared with 64.9 weeks in those receiving placebo.1
In the open-label, single-arm, dose-escalation study, treatment with sunitinib given in 6-week cycles at a dosage of 50 mg once daily for 4 consecutive weeks followed by a 2-week drug-free period produced partial responses in 5 of 55 patients (9.1%).1
Treatment of GIST includes surgical resection and/or the use of tyrosine kinase inhibitors depending on the extent of disease and tumor sensitivity to the tyrosine kinase inhibitor.61 Approximately 85% of all GIST contain a mutation in KIT and/or platelet-derived growth factor receptor alpha ( PDGFRA ) which result in constitutive activation of the receptor tyrosine kinase; therefore, inhibition of KIT is a primary therapeutic modality for the treatment of GIST.61 Imatinib is a selective inhibitor of the KIT protein tyrosine kinase, and is considered standard therapy for the treatment of locally advanced, inoperable or metastatic GIST (including patients who did not relapse during therapy with adjuvant imatinib) in patients with imatinib-sensitive mutations.60, 61 Following disease progression or intolerance to imatinib, sunitinib is standard second-line therapy in patients with metastatic or recurrent GIST.60, 61 Regorafenib is generally recommended in the third-line setting in patients with imatinib-sensitive mutations and imatinib-nonsensitive-mutations (e.g., PDGFRA D842V, NTRK -translocated, SDH -deficient).60, 61
Although the majority of GIST cases have either a mutation in KIT or PDGFRA , approximately 10-15% of cases do not have a detectable KIT or PDGFRA mutation.62 Loss-of-function mutations in succinate dehydrogenase ( SDH ) or loss of SDHB expression have been identified in a majority of wild type KIT / PDGFRA GIST (also referred to as SDH -deficient GIST); such tumors are usually resistant to imatinib, but may have some sensitivity to sunitinib and regorafenib.61, 62
Sunitinib malate is used for the adjuvant treatment of renal cell carcinoma in patients at high risk of recurrence following nephrectomy; the drug is also used for the treatment of advanced renal cell carcinoma.1, 2, 7, 10, 19
Efficacy and safety of sunitinib for the adjuvant treatment of renal cell carcinoma are based principally on the results of a randomized, double-blind, placebo-controlled study (S-TRAC) in adult patients at high risk of disease recurrence following nephrectomy.1, 19 In this study, 615 patients were randomized to receive either sunitinib 50 mg once daily for 4 consecutive weeks followed by a 2-week period without treatment or placebo.1, 19 Treatment with sunitinib was continued for 9 cycles until disease recurrence or unacceptable toxicity occurred or withdrawal of consent occurred.1, 19 The median age of patients enrolled in the study was 58 years; 73% were male, 84% were white, 12% were Asian, and most patients had an ECOG performance status score of 0.1, 19 The primary efficacy end point was disease-free survival; overall survival was a secondary endpoint.1, 19
At the time of analysis, median disease-free survival was substantially improved in patients receiving sunitinib (6.8 years) compared with those receiving placebo (5.6 years).1, 19 At the time of data cutoff, overall survival data were not mature.1, 19 In a prespecified subgroup analysis based on disease stage, no substantial difference in median disease-free survival was observed between the treatment arms.1
Efficacy and safety of sunitinib malate for the treatment of advanced renal cell carcinoma are based principally on the results of a large randomized trial1, 15 and 2 uncontrolled studies.1, 7, 10
In a multicenter randomized trial, 750 patients received either sunitinib or interferon alfa as initial treatment for metastatic renal cell cancer.1, 15 Treatment consisted of sunitinib 50 mg once daily for 4 consecutive weeks followed by a 2-week period without treatment, or interferon alfa 9 million units subcutaneously 3 times a week, until disease progression, intolerable toxicity, or withdrawal from the study occurred.1, 15 Progression-free survival was prolonged (47.3 versus 22 weeks) and overall response rate was higher (27.5 versus 5.3%) in patients receiving sunitinib compared with those receiving interferon alfa.1 At the planned final analysis, median overall survival was 114.6 weeks in patients receiving sunitinib compared with 94.9 weeks in those receiving interferon alfa.1 The median overall survival for the interferon alfa-treated group included 6.7% of patients who crossed over to treatment with sunitinib and 32% of patients who received poststudy therapy with sunitinib.1
Patients receiving sunitinib had a greater frequency of ventricular dysfunction, including left ventricular ejection fraction (LVEF) below the lower limit of normal (27 versus 15%) and decline in LVEF (7 versus 2%), than those receiving interferon alfa.1 Hypertension (34 versus 4%), including grade 3 hypertension (13 versus less than 1%), and bleeding events (37 versus 10%) occurred more frequently in patients receiving sunitinib than in those receiving interferon alfa.1
The use of sunitinib also was investigated in 2 single-arm, phase 2 studies in 169 patients with metastatic renal cell carcinoma who were intolerant of cytokine-based therapy (e.g., aldesleukin, interferon alfa, combination of aldesleukin and interferon alfa) and/or whose disease had progressed during or following completion of such therapy.1, 2, 6, 7, 10 Approximately 95% of enrolled patients had at least some component of clear-cell histology, and 97% had undergone nephrectomy.1, 2 Metastatic disease present at the time of study entry included lung (82%), liver (23%), and bone (35%) metastases;2 patients with known brain metastases or leptomeningeal disease were excluded from both studies.1, 10 All patients in both studies received sunitinib (dosage schedule of 50 mg once daily for 4 consecutive weeks followed by a 2-week period without treatment) until disease progression, intolerable toxicity, or withdrawal from the study occurred.1, 2, 6, 7, 10 Data analysis from the first study revealed a partial response rate of 34% and a median progression-free survival of 8.3 months; the median overall survival had not been reached at the time of this analysis.1, 2, 10 Data analysis from the second study revealed a partial response rate of 36.5% and a median time to tumor progression of 8.7 months.1, 7 In these studies, more than 90% of partial responses were observed during the first 4 cycles of sunitinib therapy, with the latest response observed during cycle 10.1
Prognosis is generally poor in patients with metastatic RCC, including those who have undergone complete tumor resection.51 First-line therapy with vascular endothelial growth factor receptor (VEGFR) inhibitors has been shown to provide benefits in patients with advanced RCC; however, relapsed or refractory RCC eventually develops in most patients.52 Combination regimens (e.g., immune checkpoint inhibitor in combination with a tyrosine kinase inhibitor) have generally become a standard for the treatment of advanced RCC.53 A limited number of randomized controlled trials have compared sunitinib with other treatment options for advanced renal cell carcinoma (e.g., pembrolizumab plus axitinib,20 avelumab plus axitinib,21 atezolizumab plus bevacizumab,22 nivolumab plus ipilimumab,23 nivolumab plus cabozantinib,24 or lenvatinib plus pembrolizumab).25 In clinical trials, combination chemotherapy resulted in longer progression-free survival compared with sunitinib alone in patients with previously untreated advanced renal cell carcinoma.20, 21, 22, 23, 24, 25
Some experts state that subsequent monotherapy with a tyrosine kinase inhibitor (e.g., sunitinib, pazopanib) may be offered as an alternative to programmed death 1 (PD-1) inhibitor-based combinations in the first-line setting when immune checkpoint therapy is contraindicated or not available or as a second-line option following disease progression during immune checkpoint inhibitor-based therapy.54
Neuroendocrine Tumors of Pancreatic Origin
Sunitinib malate is used for the treatment of progressive, well-differentiated neuroendocrine tumors (NET) of pancreatic origin in patients with unresectable, locally advanced, or metastatic disease.1, 18
Efficacy and safety of sunitinib malate for the treatment of pancreatic NET are based principally on the results of a randomized, double-blind, placebo-controlled, multicenter, phase 3 study in patients with unresectable, locally advanced, or metastatic well-differentiated pancreatic NET that had progressed within the previous 12 months.1, 18 In this study, 171 patients were randomized in a 1:1 ratio to receive either sunitinib (37.5 mg) or placebo orally once daily; therapy was given continuously (i.e., without a scheduled off-treatment period).1, 18 Approximately 27 or 29% of patients randomized to receive sunitinib or placebo, respectively, also received concomitant therapy with a somatostatin analog.1, 18 Treatment with sunitinib or placebo was continued until disease progression, unacceptable toxicity, or death occurred; upon disease progression, patients previously randomized to receive placebo were permitted to cross over to open-label sunitinib therapy in an extension study.1, 18 The primary end point of this study was progression-free survival; secondary end points included safety, overall response rate, time to tumor response, response duration, and overall survival.1, 18 Median duration of treatment was approximately 4.6 months in patients receiving sunitinib and 3.7 months in those receiving placebo.18 This study was terminated prematurely (prior to the prespecified interim analysis) after an independent data monitoring committee found longer median progression-free survival among patients randomized to receive sunitinib and higher incidences of death and severe adverse effects among those randomized to receive placebo.1, 18 Data analysis revealed a median progression-free survival of 10.2 months in patients receiving sunitinib compared with 5.4 months in patients receiving placebo, although the magnitude of effect on progression-free survival may have been overestimated by early termination of the study.1 Objective response was observed in 9.3% (25% complete and 75% partial responses) of patients receiving sunitinib compared with none of those receiving placebo.1, 18 Overall survival had not been reached at the time of this analysis; however, death had occurred in 9 patients receiving sunitinib compared with 21 patients receiving placebo.1, 18
Treatment options for grade 1 and 2 (G1 and G2) neuroendocrine tumors (NET) include surgery (primary and cytoreductive), liver-directed therapy, and systemic therapy.26, 63 Systemic therapy (e.g., lutetium Lu 177 dotatate, somatostatin analog, targeted therapy, cytotoxic chemotherapy) is generally used for disease control and symptom palliation in patients with metastatic disease.26, 62 Long-acting somatostatin analogs are generally considered first-line therapy for metastatic NET, while sunitinib and everolimus are generally used in the second-line setting.62 Although the role of chemotherapy in NET is evolving and an optimal chemotherapy regimen for grade 3 (G3) neuroendocrine carcinoma (poorly differentiated tumors) has not been established, several studies have shown promising results with combination therapy with capecitabine and temozolomide (CAPTEM).26, 62, 63
Sunitinib also has been studied in nongastrointestinal stromal tumor sarcomas† and thyroid cancer† .27, 28
Sunitinib malate is administered orally without regard to meals.1, 11
Store sunitinib at 20-25ºC; excursions are permitted between 15-30ºC.1
Dosage of sunitinib malate is expressed in terms of sunitinib.1, 2
Gastrointestinal Stromal Tumor
For the treatment of gastrointestinal stromal tumor (GIST) in adults who are intolerant of or whose disease has progressed during imatinib therapy, sunitinib is given in 6-week cycles at a recommended dosage of 50 mg once daily for 4 consecutive weeks followed by a 2-week period without the drug.1 In clinical studies, therapy was continued for as long as the patient derived clinical benefit from the drug or until unacceptable toxicity occurred.1, 2
For the adjuvant treatment of renal cell carcinoma in adults, sunitinib is given in 6-week cycles at a recommended dosage of 50 mg once daily for 4 consecutive weeks followed by a 2-week period without the drug.1 Therapy is continued for 9 cycles.1
For the treatment of advanced renal cell carcinoma in adults, sunitinib is given in 6-week cycles at a recommended dosage of 50 mg once daily for 4 consecutive weeks followed by a 2-week period without the drug.1, 6 In clinical studies, therapy was continued for as long as the patient derived clinical benefit from the drug or until unacceptable toxicity occurred.1, 2
Neuroendocrine Tumors of Pancreatic Origin
For the treatment of progressive, well-differentiated neuroendocrine tumors (NET) of pancreatic origin in adults with unresectable, locally advanced, or metastatic disease, sunitinib is given continuously (i.e., without an off-treatment period) at a recommended dosage of 37.5 mg once daily.1 In the principal efficacy study, sunitinib was continued until disease progression, unacceptable toxicity, or death occurred.1, 18
Dosage of sunitinib should be adjusted in increments or decrements of 12.5 mg daily (i.e., 1 dose level), depending on individual patient safety and tolerability.1, 2
If dosage modification is required, the dosage of sunitinib should be reduced as described in Table 1 in patients with GIST, renal cell carcinoma, or NET of pancreatic origin.1
Dosage Reduction Level | GIST (Starting Dosage = 50 mg daily) | Advanced Renal Cell Carcinoma (Starting Dosage = 50 mg daily) | Adjuvant Treatment of Renal Cell Carcinoma (Starting Dosage = 50 mg daily) | NET of Pancreatic Origin (Starting Dosage = 37.5 mg daily) |
|---|---|---|---|---|
First | Restart at 37.5 mg once daily | Restart at 37.5 mg once daily | Restart at 37.5 mg once daily | Restart at 25 mg once daily |
Second | Restart at 25 mg once daily | Restart at 25 mg once daily | Not applicable | Not applicable |
If grade 3 hepatotoxicity occurs, withhold therapy; when the toxicity resolves or improves to grade 0 or 1, may then resume therapy at a reduced dosage.1 If grade 3 hepatotoxicity recurs, permanently discontinue sunitinib.1
Permanently discontinue sunitinib in patients who experience grade 4 hepatotoxicity.1
If manifestations of congestive heart failure develop, the drug should be discontinued.1 In patients without clinical evidence of congestive heart failure but in whom left ventricular ejection fraction (LVEF) is greater than 20%, but less than 50% below baseline, or below the lower limit of normal if LVEF was not assessed at baseline, sunitinib therapy should be withheld; when the toxicity resolves or improves to grade 0 or 1, may then resume therapy at a reduced dosage.1
For grade 3 hypertension, withhold sunitinib; when hypertension resolves or improves to grade 0 or 1, may then resume therapy at a reduced dosage.1 For grade 4 hypertension, permanently discontinue sunitinib.1
If grade 3 or 4 hemorrhagic events occur, withhold sunitinib therapy; when the toxicity resolves or improves to grade 0 or 1, may then resume therapy at a reduced dosage or discontinue therapy depending on the severity and persistence of the hemorrhagic event.1 If grade 3 or 4 hemorrhagic events do not resolve, discontinue sunitinib therapy.1
Interrupt sunitinib therapy and reduce dosage if proteinuria ≥3 g per 24 hours (in the absence of nephrotic syndrome) occurs.1 When proteinuria resolves or improves to grade 0 or 1, may then resume at a reduced dosage.1 If nephrotic syndrome occurs or if proteinuria recurs despite dosage reduction, permanently discontinue therapy.1
Permanently discontinue sunitinib in patients who experience any grade thrombotic microangiopathy, dermatologic toxicities (i.e., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrotizing fasciitis) or reversible posterior leukoencephalopathy syndrome.1
If osteonecrosis of the jaw or impaired wound healing occurs, sunitinib therapy may be resumed at a reduced dosage or discontinued depending on the severity and persistence of the adverse effects; however, safety of resuming sunitinib therapy in patients who experience osteonecrosis of the jaw or impaired wound healing has not been established.1
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of sunitinib with potent inhibitors or inducers of cytochrome P-450 (CYP) isoenzyme 3A4 may alter the combined plasma concentrations of sunitinib and its primary active metabolite.1
If concomitant use of sunitinib with a potent CYP3A4 inhibitor cannot be avoided, reduction of sunitinib dosage to no less than 37.5 mg daily (in patients receiving sunitinib for GIST or advanced renal cell carcinoma) or no less than 25 mg daily (in patients receiving sunitinib for progressive, well-differentiated NET of pancreatic origin) should be considered.1
The manufacturer states that initial dosage adjustment is not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1
The manufacturer states that initial dosage adjustment is not necessary in patients with mild, moderate, or severe renal impairment; subsequent dosage modifications should be based on safety and tolerability.1 Initial dosage adjustment is not necessary in patients with end-stage renal disease receiving hemodialysis; however, subsequent dosages may be increased gradually up to twofold based on safety and tolerability.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
The manufacturer states there are no known contraindications to the use of sunitinib.1
A boxed warning regarding the risk of severe hepatotoxicity is included in the prescribing information for sunitinib.1 Severe hepatotoxicity, resulting in liver failure or death, has been reported in patients receiving sunitinib.1 Hepatic failure has been reported in patients receiving sunitinib in clinical trials (<1%).1 Manifestations of hepatic failure include jaundice, elevated aminotransferase concentrations and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure.1
Monitor liver function tests (ALT, AST, and bilirubin concentrations) prior to initiation of sunitinib, during each cycle, and as clinically indicated.1 If grade 3 hepatotoxicity occurs, interrupt sunitinib therapy until the toxicity resolves or improves to grade 1 or less, then resume sunitinib at a reduced dosage.1 If grade 4 hepatotoxicity occurs or grade 3 hepatotoxicity persists, discontinue sunitinib therapy.1 Sunitinib should not be restarted in patients who subsequently experience severe changes in liver function tests or exhibit other manifestations of hepatic failure.1
Safety of sunitinib in patients with AST and/or ALT concentrations exceeding 2.5 times the upper limit of normal or, if caused by liver metastases, exceeding 5 times the upper limit of normal has not been established.1
Other Warnings and Precautions
Cardiovascular events (including heart failure, myocardial ischemia, myocardial infarction, and cardiomyopathy), sometimes fatal, have been reported in patients receiving sunitinib during postmarketing surveillance.1
In a pooled safety population, heart failure was reported in 3% of patients (<1% were fatal); however, heart failure resolved in the majority (71%) of these patients.1 In a clinical study, 11 patients receiving sunitinib for the adjuvant treatment of renal cell carcinoma experienced grade 2 decreases in left ventricular ejection fraction (LVEF) (defined as LVEF 40-50% with a 10-19% reduction from baseline values).1 LVEF did not return to ≥50% or baseline by the time of the last measurement in 3 of the 11 patients.1 None of the patients were diagnosed with congestive heart failure.1
Because patients with a history of cardiovascular disease (e.g., myocardial infarction [MI], severe or unstable angina, coronary or peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism) within 12 months prior to sunitinib administration and patients with prior anthracycline use or cardiac radiation were excluded from clinical studies, it is unknown whether such patients have a higher risk of developing drug-related left ventricular dysfunction.1
Consider monitoring LVEF prior to initiating therapy and periodically as clinically indicated.1 Monitor patients for signs and symptoms of congestive heart failure; if manifestations of congestive heart failure develop, discontinue sunitinib.1 In patients without clinical evidence of congestive heart failure but in whom LVEF is greater than 20% but less than 50% below baseline or below the lower limit of normal if LVEF was not assessed at baseline, interrupt therapy and/or reduce the dosage.1
Prolongation of QT Interval and Torsades de Pointes
Sunitinib prolongs the QT interval in a dose-dependent manner, which may increase the risk of ventricular arrhythmias, including torsades de pointes.1 Torsades de pointes has been reported in less than 0.1% of patients receiving sunitinib.1
Monitor patients at high risk of developing QT interval prolongation, including patients with a history of prolongation of the QT interval, those receiving antiarrhythmic agents, and those with relevant preexisting cardiac disease, bradycardia, or electrolyte disturbances.1 Periodic monitoring of ECGs and serum magnesium and potassium concentrations should be considered.1 More frequent QT interval monitoring and reduction of sunitinib dosage should be considered in patients concomitantly receiving potent CYP3A4 inhibitors or drugs known to prolong the QT interval.1
Hypertension1, 9 has been reported in 29% of patients receiving sunitinib in the pooled safety population.1 Grade 3 hypertension occurred in 7% of patients and grade 4 hypertension was reported in 0.2%.1
Monitor blood pressure at baseline and as clinically indicated; treat hypertension as needed with standard antihypertensive therapy.1 If grade 3 hypertension occurs, interrupt sunitinib until hypertension resolves or improves to grade 1 or less; sunitinib therapy may then be resumed at a lower dosage.1 If grade 4 hypertension occurs, discontinue sunitinib therapy.1
Hemorrhagic events (including GI, respiratory, tumor, urinary tract, and brain hemorrhage), sometimes fatal, have been reported in patients receiving sunitinib.1 Hemorrhagic events were reported in 30% of patients in the pooled safety population (grade 3 or 4 in 4.2% of patients).1 The most common hemorrhagic event was epistaxis, and the most common grade 3-5 event was GI hemorrhage.1
Tumor-related hemorrhage has been reported in patients receiving sunitinib.1 These events may occur suddenly and, in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage.1 Pulmonary hemorrhage, sometimes fatal, has been reported in patients receiving sunitinib for GIST, advanced renal cell carcinoma, or metastatic lung cancer†.1
Serious, sometimes fatal GI complications, including GI perforation, have occurred rarely in patients with intra-abdominal malignancies treated with sunitinib.1
The manufacturer recommends clinically monitoring for hemorrhagic events (i.e., serial CBCs, physical examinations).1 If grade 3 or 4 hemorrhagic events occur, withhold sunitinib therapy; when the hemorrhagic event resolves or improves to grade 0 or 1, may then resume therapy at a reduced dosage or discontinue therapy depending on the severity and persistence of the hemorrhagic event.1
Tumor lysis syndrome, sometimes fatal, has been reported principally in patients with GIST or advanced renal cell carcinoma receiving sunitinib in clinical studies and during postmarketing surveillance.1 The risk of tumor lysis syndrome is increased in patients with a large tumor burden; such patients should be monitored closely and treated as clinically indicated.1
Thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, has occurred and sometimes resulted in renal failure or death.1 These events occurred in clinical trials and postmarketing experience when sunitinib was administered alone or in combination with bevacizumab.1 If thrombotic microangiopathy occurs, discontinue sunitinib therapy.1 Reversal of the effects of thrombotic microangiopathy have been observed following discontinuance of sunitinib therapy.1
Proteinuria and nephrotic syndrome, sometimes resulting in renal failure or death, have occurred in patients receiving sunitinib therapy.1 Monitor patients for the development or worsening of proteinuria.1 Perform urinalysis prior to initiation of sunitinib and periodically during therapy; further assessment with a 24-hour urine collection should be performed as clinically indicated.1 Interrupt sunitinib therapy and reduce dosage if proteinuria ≥3 g per 24 hours (in the absence of nephrotic syndrome) occurs.1 If nephrotic syndrome occurs or if proteinuria recurs despite dosage reduction, permanently discontinue therapy.1 The safety of continued sunitinib therapy in patients with moderate to severe proteinuria has not been systematically evaluated.1
Severe and sometimes fatal cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported.1 Cases of necrotizing fasciitis, including fatalities, also have been reported in patients receiving sunitinib.1 Necrotizing fasciitis has occurred secondary to fistula formation and has included sites such as the perineum.1
Permanently discontinue sunitinib if erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, or necrotizing fasciitis occur.1
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS), sometimes fatal, has been reported in less than 1% of patients receiving sunitinib.1 If manifestations of RPLS (e.g., hypertension, headache, decreased alertness, altered mental functioning, visual loss, cortical blindness) occur, discontinue sunitinib therapy.1 Use magnetic resonance imaging (MRI) to confirm diagnosis of RPLS.1
Hyperthyroidism, sometimes followed by hypothyroidism, has been reported in clinical studies and during postmarketing surveillance.1
Thyroid function should be measured in all patients at baseline and periodically during treatment.1 Monitor all patients closely for manifestations of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis during sunitinib therapy; if signs and/or symptoms suggestive of thyroid dysfunction occur, thyroid function tests should be performed and treatment instituted as clinically indicated.1
Symptomatic hypoglycemia, including cases associated with loss of consciousness or hospitalization, has been reported in patients receiving sunitinib.1 Reductions in blood glucose levels may be worse in patients with diabetes.1 In a pooled safety population, hypoglycemia occurred in 2% of patients receiving sunitinib.1 In clinical trials, hypoglycemia was reported in 2% of patients with advanced renal cell carcinoma or GIST and in 10% of patients with NET of pancreatic origin.1 In a clinical trial, patients with NET of pancreatic origin who developed hypoglycemia did not have preexisting glucose abnormalities at baseline.1
In patients with diabetes, assess if antidiabetic therapies need to be adjusted to minimize the risk of hypoglycemia.1
Monitor blood glucose at baseline, regularly during therapy, as clinically indicated, and after discontinuance of sunitinib therapy.1
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving sunitinib.1 The risk of ONJ may be increased in patients with dental disease or in those receiving concomitant bisphosphonate therapy.1
Prior to initiating sunitinib and periodically during therapy, routine oral examinations and appropriate preventive dentistry should be performed.1 If possible, withhold sunitinib at least 3 weeks before scheduled dental surgery or invasive dental treatments.1 If osteonecrosis of the jaw occurs, sunitinib therapy may be resumed at a reduced dosage or discontinued depending on the severity and persistence of the adverse effect; however, safety of resuming sunitinib therapy in patients who develop osteonecrosis of the jaw has not been established.1
Impaired wound healing has been reported during sunitinib therapy.1 Withhold sunitinib at least 3 weeks before elective surgery and for at least 2 weeks after major surgery and until adequate wound healing occurs.1 If impaired wound healing occurs, sunitinib therapy may be resumed at a reduced dosage or discontinued depending on the severity and persistence of the adverse effect; however, safety of resuming sunitinib therapy in patients who experience impaired wound healing has not been established.1
Fetal/Neonatal Morbidity and Mortality
Sunitinib can cause fetal harm because of its inhibitory effects on angiogenesis.1 Teratogenicity, embryotoxicity, and fetotoxicity have been demonstrated in animals.1 Pregnancy should be avoided during therapy.1 Advise females of reproductive potential to use effective methods of contraception during sunitinib therapy and for 4 weeks after the last dose.1 Males who are partners with females of reproductive potential should use effective contraception during treatment and for at least 7 weeks after the last dose.1 If sunitinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Based on animal data, sunitinib can cause fetal harm when administered during pregnancy.1 There are no adequate data regarding the developmental risk associated with the use of sunitinib during pregnancy in humans; however, teratogenic and embryolethal effects have been demonstrated in animal studies with doses similar to or less than those used clinically.1
If sunitinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Sunitinib and/or its metabolites are extensively distributed into milk in rats, with a milk-to-plasma ratio of up to 12:1.1 It is not known whether sunitinib or its primary active metabolite is distributed into human milk.1 Because of the potential for serious adverse reactions to sunitinib in nursing infants, females should not breast-feed during sunitinib therapy and for at least 4 weeks after the last dose.1
Females and Males of Reproductive Potential
Verify pregnancy status of females of reproductive potential prior to initiating therapy.1 Advise females of reproductive potential to use effective methods of contraception during sunitinib therapy and for 4 weeks after the last dose.1 Males who are partners with females of reproductive potential should use effective contraception during treatment and for at least 7 weeks after the last dose.1
Sunitinib may impair male and female fertility based on animal studies.1
Safety and efficacy of sunitinib have not been established in pediatric patients.1
Safety and pharmacokinetics of sunitinib have been assessed in 2 open-label studies in 56 pediatric patients 2 years to <17 years of age with refractory solid tumors, high-grade glioma, or ependymoma.1 The maximum tolerated dose, apparent clearance, and volume of distribution adjusted for body surface area for sunitinib and its major active metabolite were lower in pediatric patients compared to adults.1 In pediatric patients 2 years to <17 years of age with refractory solid tumors, sunitinib was poorly tolerated; the study also was amended to exclude patients with previous exposure to anthracyclines or cardiac radiation due to the occurrence of dose-limiting cardiotoxicity.1 The effect of sunitinib on open tibial growth plates in pediatric patients has not been established.1
Of the 7527 patients receiving sunitinib for GIST, renal cell carcinoma, or NET of pancreatic origin in clinical studies, 32% were 65 years of age or older and 7% were 75 years of age or older.1 The incidence of grade 3 or 4 adverse effects was higher in patients 65 years of age or older compared to younger adults.1
In the clinical studies evaluating sunitinib in patients with GIST or metastatic renal cell carcinoma, 30 or 41% of patients, respectively, were 65 years of age or older.1 No overall differences in safety and efficacy were observed relative to younger adults.1
In the clinical study evaluating sunitinib in patients with NET of pancreatic origin, 27% of patients receiving sunitinib were 65 years of age or older.1 The study did not include sufficient numbers of patients with NET of pancreatic origin to determine if patients 65 years of age or older respond differently relative to younger patients.1
Following administration of a single dose of sunitinib, systemic exposure in patients with mild or moderate (Child-Pugh class A or B) hepatic impairment was similar to that in individuals with normal hepatic function; no initial dosage adjustment is required in patients with mild or moderate hepatic impairment.1, 2, 12 Safety and efficacy of sunitinib have not been established in patients with severe (Child-Pugh class C) hepatic impairment.1
Clinical studies for cancer that were conducted excluded patients with AST or ALT concentrations exceeding 2.5 times the upper limit of normal or, if caused by liver metastases, exceeding 5 times the upper limit of normal.1
Following administration of a single dose of sunitinib, systemic exposure in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) was similar to that in individuals with normal renal function (creatinine clearance exceeding 80 mL/minute).1 In individuals with end-stage renal disease undergoing hemodialysis, systemic exposure to sunitinib was decreased by 47% compared with those with normal renal function.1 No initial dosage adjustment is required in patients with renal impairment or in those with end-stage renal disease undergoing hemodialysis; however, adjustments to subsequent dosages may be necessary.1
The most common adverse effects occurring in 25% or more of patients receiving sunitinib include are fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia.1
Sunitinib and its primary active metabolite are metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1, 5 However, in vitro studies indicate that the drug does not inhibit or induce major CYP isoenzymes.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of sunitinib with potent inhibitors of CYP3A4 (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit) may result in increased plasma concentrations of sunitinib.1 When the potent CYP3A4 inhibitor ketoconazole was administered concomitantly with a single dose of sunitinib in healthy individuals, peak plasma concentrations and area under the plasma concentration-time curve (AUC) of sunitinib and its primary active metabolite increased by 49 and 51%, respectively.1 Selection of an alternative agent with minimal or no enzyme inhibition potential is recommended during sunitinib therapy.1 If concomitant use of sunitinib with a potent CYP3A4 inhibitor cannot be avoided, reduction of sunitinib dosage to no less than 37.5 mg daily (in patients receiving sunitinib for GIST or advanced renal cell carcinoma) or no less than 25 mg daily (in patients receiving sunitinib for progressive, well-differentiated NET of pancreatic origin) should be considered.1
Concomitant use of sunitinib with inducers of CYP3A4 (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort [ Hypericum perforatum ]) may result in decreased plasma concentrations of sunitinib.1 When the potent CYP3A4 inducer rifampin was administered concomitantly with a single dose of sunitinib in healthy individuals, peak plasma concentrations and AUC of sunitinib and its primary active metabolite decreased by 23 and 46%, respectively.1 Selection of an alternative agent with minimal or no enzyme induction potential is recommended during sunitinib therapy.1 If concomitant use of sunitinib with a CYP3A4 inducer cannot be avoided, an increase in sunitinib dosage up to a maximum of 87.5 mg daily (in patients receiving sunitinib for GIST or advanced renal cell carcinoma) or 62.5 mg daily (in patients receiving sunitinib for progressive, well-differentiated NET of pancreatic origin) should be considered, and the patient should be monitored carefully for toxicity.1
Drugs Metabolized by Hepatic Microsomal Enzymes
In vitro studies indicate that sunitinib and its primary active metabolite are unlikely to have clinically relevant interactions with drugs metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11.1
Sunitinib prolongs the QT interval, which may increase the risk of ventricular arrhythmias, including torsades de pointes.1 Monitor the QT interval more frequently in patients taking drugs known to prolong the QT interval.1
Concomitant use of sunitinib with bisphosphonates (e.g., alendronate, etidronate, ibandronate, pamidronate, risedronate, zoledronic acid) may increase the risk of developing osteonecrosis of the jaw (ONJ).1
Sunitinib malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2, 4, 5, 6, 7, 9, 10, 11, 12 Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.1, 2, 4, 6, 7, 11 Although the exact mechanism of antineoplastic activity of sunitinib has not been fully elucidated, data from biochemical and cellular assays indicate that sunitinib may inhibit signal transduction pathways involving multiple receptor (i.e., cell surface) tyrosine kinases, including platelet-derived growth factor receptors (i.e., PDGFR-α, PDGFR-β), vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), stem cell factor receptor (i.e., c-Kit), fms-like tyrosine kinase 3 (Flt-3), colony stimulating factor receptor type 1 (CSF-1R), and the glial cell line-derived neurotrophic factor receptor (RET).1, 2, 4, 5, 9, 10, 11, 12 Sunitinib-induced inhibition of signal transduction pathways involving PDGFR-β, VEGFR-2, and c-Kit has been confirmed in tumor xenografts expressing receptor tyrosine kinase targets in vivo.1, 6 Sunitinib has been shown to inhibit growth of tumor cells expressing dysregulated target receptor tyrosine kinases (i.e., PDGFR, RET, c-Kit) in vitro; the drug also has been shown to inhibit PDGFR-β- and VEGFR-2-dependent tumor angiogenesis in vivo.1
Following oral administration, peak plasma concentrations of sunitinib generally occur within 6-12 hours.1 Food has no effect on bioavailability of sunitinib.1, 11 Sunitinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 to several metabolites.1, 5, 11, 12 The main circulating metabolite, an N -desethyl derivative, has been shown to be equipotent to sunitinib in biochemical and cellular assays;1, 5 this metabolite accounts for approximately 23-37% of total plasma concentrations of the drug and also is metabolized by CYP3A4.1 Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10-14 days.1 Sunitinib and its primary active metabolite are 95 and 90% bound to human plasma proteins in vitro, respectively.1 Following oral administration of a single dose in healthy volunteers, the terminal half-life of sunitinib or its primary active metabolite is approximately 40-60 or 80-110 hours, respectively.1, 12 Approximately 61% of an oral dose of sunitinib is excreted in feces and 16% is eliminated in urine, mainly as sunitinib and the primary metabolite; minor metabolites are recovered in feces and urine but generally are not found in plasma.1, 2
Population pharmacokinetic analyses of demographic data indicate that the pharmacokinetics of sunitinib or its primary active metabolite are not substantially affected by age (18-84 years of age), body weight (34-168 kg), race (white, Black, or Asian), sex, or ECOG performance status.1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Sunitinib can only be obtained through designated specialty pharmacies.32 Contact the manufacturer or consult the Pfizer website for specific availability information.32
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 12.5 mg (of sunitinib)* | Pfizer | |
25 mg (of sunitinib)* | Sutent® | Pfizer | ||
37.5 mg (of sunitinib)* | Sutent® | Pfizer | ||
50 mg (of sunitinib)* | Sutent® | Pfizer |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Pfizer. Sutent® (sunitinib malate) capsules prescribing information. New York, NY: 2021 Aug. [Web]
2. Pfizer Inc., Parsippany, NJ: Personal communication.
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