Sunitinib Malate
Capsule · Oral
Uses
Sunitinib malate capsules are a kinase inhibitor indicated for: treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. (1.1) treatment of adult patients with advanced renal cell carcinoma (RCC). (1.2) adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. (1.3) treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease. (1.4) 1.1 Gastrointestinal Stromal Tumor Sunitinib malate capsules are indicated for the treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. 1.2 Advanced Renal Cell Carcinoma Sunitinib malate capsules are indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC). 1.3 Adjuvant Treatment of Renal Cell Carcinoma Sunitinib malate capsules are indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. 1.4 Advanced Pancreatic Neuroendocrine Tumors Sunitinib malate capsules are indicated for the treatment of progressive, well differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.
Dosage and administration
2 DOSAGE AND ADMINISTRATION GIST and Advanced RCC: The recommended dosage is 50 mg orally once daily for the first 4 weeks of each 6-week cycle (Schedule 4/2). (2.1) Adjuvant Treatment of RCC: The recommended dosage is 50 mg orally once daily for the first 4 weeks of a 6-week cycle (Schedule 4/2) for a maximum of 9 cycles. (2.2) pNET: The recommended dosage is 37.5 mg orally once daily. (2.3) 2.1 Recommended Dosage for GIST and Advanced RCC The recommended dosage of sunitinib malate capsules for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) until disease progression or unacceptable toxicity. Sunitinib malate capsules may be taken with or without food. 2.2 Recommended Dosage for Adjuvant Treatment of RCC The recommended dosage of sunitinib malate capsules for the adjuvant treatment of RCC is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2), for nine 6-week cycles. Sunitinib malate capsules may be taken with or without food. 2.3 Recommended Dosage for pNET The recommended dosage of sunitinib malate capsules for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity. Sunitinib malate capsules may be taken with or without food. 2.4 Dosage Modifications for Adverse Reactions To manage adverse reactions, the recommended dosage modifications are provided in Table 1. Table 2 provides the recommended dosage reductions of sunitinib malate capsules for adverse reactions. Table 1. Recommended Dosage Reductions of Sunitinib Malate Capsules for Adverse Reactions Indications GIST RCC pNET Advanced RCC Adjuvant RCC First dose reduction 37.5 mg once daily 37.5 mg once daily 37.5 mg once daily 25 mg once daily Second dose reduction 25 mg once daily 25 mg once daily NA NA Table 2. Recommended Dosage Modifications for Sunitinib Malate Capsules for Adverse Reactions Adverse Reaction Severity Dosage Modifications for Sunitinib Malate Capsules Hepatotoxicity [see Warnings and Precautions (5.1)] Grade 3 Withhold until resolution to Grade 0 to 1 or baseline. Resume at a reduced dose. For recurring Grade 3 permanently discontinue. Grade 4 Permanently discontinue. Cardiovascular events [see Warnings and Precautions (5.2)] Asymptomatic cardiomyopathy (left ventricular ejection fraction greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline was not obtained) Withhold until resolution to Grade 0 to 1 or baseline. Resume at reduced dose. Clinically manifested congestive heart failure (CHF) Permanently discontinue. Hypertension [see Warnings and Precautions (5.4)] Grade 3 Withhold until resolution to Grade 0 to 1 or baseline. Resume at a reduced dose. Grade 4 Permanently discontinue. Hemorrhagic events [see Warnings and Precautions (5.5)] Grade 3 or 4 Withhold until resolution to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction. Thrombotic microangiopathy [see Warnings and Precautions (5.7)] Any Grade Permanently discontinue. Proteinuria or Nephrotic syndrome [see Warnings and Precautions (5.8)] 3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome Withhold until resolution to Grade 0 to 1 or baseline. Resume at a reduced dose. Nephrotic syndrome or recurrent proteinuria of 3 or more grams per 24 hours despite dose reductions Permanently discontinue. Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis [see Warnings and Precautions (5.9)] Any Grade Permanently discontinue. Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10)] Any Grade Permanently discontinue. Osteonecrosis of the jaw [see Warnings and Precautions (5.13) ] Any Grade The safety of resumption of sunitinib malate capsules after osteonecrosis has not been established. Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction. Impaired wound healing [see Warnings and Precautions (5.14)] Any Grade The safety of resumption of sunitinib malate capsules after resolution of wound healing has not been established. Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction. 2.5 Dosage Modification for Drug Interactions Strong CYP3A4 Inhibitors Select an alternate concomitant medication with no or minimal enzyme inhibition potential. If coadministration of sunitinib malate capsules with a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction for sunitinib malate capsules to a minimum dosage as follows [see Drug Interactions (7.1)] : GIST and RCC: 37.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) pNET: 25 mg orally once daily Strong CYP3A4 Inducers Select an alternate concomitant medication with no or minimal enzyme induction potential. If coadministration of sunitinib malate capsules with a strong CYP3A4 inducer cannot be avoided, consider a dose increase for sunitinib malate capsules to a maximum dosage as follows: GIST and RCC: 87.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) pNET: 62.5 mg orally once daily If the dose of sunitinib malate capsules is increased, monitor patients carefully for adverse reactions [see Drug Interactions (7.1)] . 2.6 Dosage Modification for End-Stage Renal Disease Patients on Hemodialysis No starting dose adjustment is required in patients with end-stage renal disease (ESRD) on hemodialysis.
Dosage forms and strengths
12.5 mg capsules Hard gelatin capsule with opaque reddish brown cap and opaque reddish brown body, self-lock capsule, imprinted with ‘RM53’ on cap and ‘RM53’ on body in white ink, containing yellow to orange colored powder. 25 mg capsules Hard gelatin capsule with opaque caramel cap and opaque reddish brown body, self-lock capsule, imprinted with ‘RM54’ on cap and ‘RM54’ on body in white ink, containing yellow to orange colored powder. 37.5 mg capsules Hard gelatin capsule with opaque yellow cap and opaque yellow body, self-lock capsule, imprinted with ‘RM55’ on cap and ‘RM55’ on body in black ink, containing yellow to orange colored powder. 50 mg capsules Hard gelatin capsule with opaque caramel cap and opaque caramel body, self-lock capsule, imprinted with ‘RM56’ on cap and ‘RM56’ on body in white ink, containing yellow to orange colored powder. Capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg sunitinib (3)
Contraindications
None None (4)
Warnings and precautions
Hepatotoxicity: Fatal liver failure has been observed. Monitor liver function tests at baseline, during each cycle, and as clinically indicated. Interrupt sunitinib for Grade 3 hepatotoxicity until resolution Grade ≤ 1 or baseline and resume sunitinib at a reduced dose; discontinue if no resolution. Discontinue sunitinib in patients with Grade 4 hepatoxicity, in patients who have subsequent severe changes in liver function tests or other signs and symptoms of liver failure. (2.4, 5.1) Cardiovascular Events: Myocardial ischemia, myocardial infarction, heart failure, cardiomyopathy, and decreased left ventricular ejection fraction (LVEF) to below the lower limit of normal including death have occurred. Monitor for signs and symptoms of congestive heart failure and consider monitoring LVEF at baseline and periodically during treatment. Discontinue sunitinib for clinical manifestations of congestive heart failure. Interrupt and/or dose reduce for decreased LVEF. (5.2) QT Interval Prolongation and Torsade de Pointes: Monitor patients at higher risk for developing QT interval prolongation. Consider monitoring of electrocardiograms and electrolytes. (5.3) Hypertension: Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. Interrupt sunitinib for Grade 3 hypertension until resolution to Grade ≤1 or baseline, then resume sunitinib at a reduced dose. Discontinue sunitinib in patients who develop Grade 4 hypertension. (5.4) Hemorrhagic Events: Tumor-related hemorrhage and viscus perforation (both with fatal events) have occurred. Perform serial complete blood counts and physical examinations. Interrupt sunitinib for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤1 or baseline, then resume at a reduced dose; discontinue if no resolution. (5.5) Tumor Lysis Syndrome (TLS): TLS (some fatal) has been reported primarily in patients with RCC and GIST. Monitor these patients and treat as clinically indicated. (5.6) Thrombotic microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported. Discontinue sunitinib for TMA. (5.7) Proteinuria: Renal failure or a fatal outcome has occurred. Monitor urine protein. Interrupt treatment for 24-hour urine protein of 3 or more grams. Discontinue for repeat episodes of 24-hour urine protein of 3 or more grams despite dose reductions or nephrotic syndrome. (5.8) Dermatologic Toxicities: Necrotizing fasciitis, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (some fatal) have occurred. Discontinue sunitinib for these events. (5.9) Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (some fatal) has been reported. Monitor for signs and symptoms of RPLS. Withhold sunitinib until resolution. (5.10) Thyroid Dysfunction: Monitor thyroid function at baseline, periodically during treatment, and as clinically indicated. Initiate and/or adjust therapy for thyroid dysfunction as appropriate. (5.11) Hypoglycemia: Check blood glucose levels regularly and assess if antidiabetic drug dose modifications are required. (5.12) Osteonecrosis of the Jaw (ONJ): Withhold sunitinib for at least 3 weeks prior to invasive dental procedure and development of ONJ until complete resolution. (5.13) Impaired Wound Healing: Withhold sunitinib for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of sunitinib after resolution of wound healing complications has not been established. (5.14) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.15, 8.1, 8.3) 5.1 Hepatotoxicity Sunitinib can cause severe hepatotoxicity, resulting in liver failure or death. In the pooled safety population, liver failure occurred in < 1% of patients in clinical trials. Liver failure include jaundiced, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) at baseline, during each cycle, and as clinically indicated. Interrupt sunitinib for Grade 3 hepatotoxicity until resolution to Grade ≤ 1 or baseline, then resume sunitinib at a reduced dose. Discontinue sunitinib in patients with Grade 4 hepatotoxicity, in patients without resolution of Grade 3 hepatotoxicity, in patients who subsequently experience severe changes in liver function tests and in patients who have other signs and symptoms of liver failure. Safety in patients with ALT or AST > 2.5 times upper limit of normal (ULN) or with > 5.0 times ULN and liver metastases has not been established. 5.2 Cardiovascular Events Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported. In pooled safety population, 3% of patients experienced heart failure; 71% of the patients with heart failure were reported as recovered. Fatal cardiac failure was reported in < 1% of patients. In the adjuvant treatment of RCC study, 11 patients experienced Grade 2 decreased ejection fraction (left ventricular ejection fraction [LVEF] 40% to 50% and a 10% to 19% decrease from baseline). In 3 of these 11 patients, the ejection fractions arm did not return to ≥ 50% or baseline by the time of last measurement. No patients who received sunitinib were diagnosed with CHF.
Side effects
The following clinically significant adverse reactions are described elsewhere in the labeling. Hepatotoxicity [see Warnings and Precautions (5.1)] Cardiovascular Events [see Warnings and Precautions (5.2)] QT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3)] Hypertension [see Warnings and Precautions (5.4)] Hemorrhagic Events [see Warnings and Precautions (5.5)] Tumor Lysis Syndrome [see Warnings and Precautions (5.6)] Thrombotic Microangiopathy [see Warnings and Precautions (5.7)] Proteinuria [see Warnings and Precautions (5.8)] Dermatologic Toxicities [see Warnings and Precautions (5.9)] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10)] Thyroid Dysfunction [see Warnings and Precautions (5.11)] Hypoglycemia [see Warnings and Precautions (5.12)] Osteonecrosis of the Jaw [see Warnings and Precautions (5.13)] Impaired Wound Healing [see Warnings and Precautions (5.14)] The most common adverse reactions (≥ 25%) 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. (6) To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the Warnings and Precautions reflect exposure to sunitinib in 7527 patients with GIST, RCC (advanced and adjuvant), or pNET. In this pooled safety population, the most common adverse reactions (≥ 25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. Gastrointestinal Stromal Tumor The safety of sunitinib was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib 50 mg daily on Schedule 4/2 (n = 202) or placebo (n = 102). Median duration of blinded study treatment was 2 cycles for patients on sunitinib (mean: 3.0; range: 1 to 9) and 1 cycle (mean; 1.8; range: 1 to 6) for patients on placebo at the time of the interim analysis. Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the sunitinib arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib. Table 3 summarizes the adverse reactions for Study 1. Table 3. Adverse Reactions Reported in ≥ 10% of GIST Patients Who Received Sunitinib in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo* in Study 1 Adverse Reactions GIST Sunitinib (N = 202) Placebo (N = 102) All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Any Adverse Reaction 94 56 97 51 Gastrointestinal Diarrhea 40 4 27 0 Mucositis/stomatitis 29 1 18 2 Constipation 20 0 14 2 Metabolism/Nutrition Anorexia a 33 1 29 5 Asthenia 22 5 11 3 Dermatology Skin discoloration 30 0 23 0 Rash 14 1 9 0 Hand-foot syndrome 14 4 10 3 Neurology Altered taste 21 0 12 0 Cardiac Hypertension 15 4 11 0 Musculoskeletal Myalgia/limb pain 14 1 9 1 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients. a Includes decreased appetite. Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received sunitinib. Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory Abnormalities Reported in ≥ 10% of GIST Patients Who Received Sunitinib or Placebo in the Double-Blind Treatment Phase* in Study 1 Laboratory Abnormality GIST Sunitinib (N = 202) Placebo (N = 102) All Grades * % Grade 3 to 4 *,a % All Grades * % Grade 3 to 4 *,b % Any Laboratory Abnormality 34 22 Hematology Neutrophils decreased 53 10 4 0 Lymphocytes decreased 38 0 16 0 Platelets decreased 38 5 4 0 Hemoglobin decreased 26 3 22 2 Gastrointestinal AST/ALT increased 39 2 23 1 Lipase increased 25 10 17 7 Alkaline phosphatase increased 24 4 21 4 Amylase increased 17 5 12 3 Total bilirubin increased 16 1 8 0 Indirect bilirubin increased 10 0 4 0 Renal/Metabolic Creatinine increased 12 1 7 0 Potassium decreased 12 1 4 0 Sodium increased 10 0 4 1 Cardiac Decreased LVEF 11 1 3 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; GIST=gastrointestinal stromal tumor; LVEF=left ventricular ejection fraction; N=number of patients. a Grade 4 laboratory abnormalities in patients on sunitinib included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%). b Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%). After an interim analysis , the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label sunitinib [see Clinical Studies (14.1)] . For 241 patients randomized to the sunitinib arm, including 139 who received sunitinib in both the double-blind and open-label phases, the median duration of sunitinib treatment was 6 cycles (mean: 8.5; range: 1 to 44). For the 255 patients who ultimately received open-label sunitinib treatment, median duration of treatment was 6 cycles (mean: 7.8; range: 1 to 37) from the time of the unblinding. Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received sunitinib.
Drug interactions
7 DRUG INTERACTIONS CYP3A4 Inhibitors: Consider dose reduction of sunitinib when administered with strong CYP3A4 inhibitors. (7.1) CYP3A4 Inducers: Consider dose increase of sunitinib when administered with strong CYP3A4 inducers. (7.1) 7.1 Effect of Other Drugs on Sunitinib Strong CYP3A4 Inhibitors Co-administration with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations [see Clinical Pharmacology (12.3)] . Select an alternate concomitant medication with no or minimal enzyme inhibition potential. Consider a dose reduction for sunitinib when it is co-administered with strong CYP3A4 inhibitors [see Dosage and Administration (2.5)] . Strong CYP3A4 Inducers Co-administration with strong CYP3A4 inducers may decrease sunitinib plasma concentrations [see Clinical Pharmacology (12.3)] . Select an alternate concomitant medication with no or minimal enzyme induction potential. Consider a dose increase for sunitinib when it must be co-administered with CYP3A4 inducers [see Dosage and Administration (2.5)] . 7.2 Drugs that Prolong QT Interval Sunitinib is associated with QTc interval prolongation [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)] . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.
Use in specific populations
Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, sunitinib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available data in pregnant women to inform a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of sunitinib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity (embryolethality, craniofacial and skeletal malformations) at 5.5 and 0.3 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the recommended daily doses (RDD) of 50 mg, respectively (see Data). Advise females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating. Embryolethality was observed at 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). In embryo-fetal developmental toxicity studies, oral sunitinib was administered to pregnant rats (0.3, 1.5, 3, 5 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) during the period of organogenesis. In rats, embryolethality and skeletal malformations of the ribs and vertebrae were observed at the dose of 5 mg/kg/day (approximately 5.5 times the combined AUC in patients administered the RDD of 50 mg). No adverse fetal effects were observed in rats at doses ≤ 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg). In rabbits, embryolethality was observed at 5 mg/kg/day (approximately 3 times the combined AUC in patients administered the RDD of 50 mg), and craniofacial malformations (cleft lip and cleft palate) were observed at ≥ 1 mg/kg/day (approximately 0.3 times the combined AUC in patients administered the RDD of 50 mg). Sunitinib (0.3, 1, 3 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥ 1 mg/kg/day (approximately 0.5 times the combined AUC in patients administered the RDD of 50 mg). At 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg), reduced neonate body weights were observed at birth and persisted in the offspring of both sexes during the preweaning period and in males during postweaning period. No adverse developmental effects were observed at doses ≤ 1 mg/kg/day. 8.2 Lactation There is no information regarding the presence of sunitinib and its metabolites in human milk. Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12-fold higher than in plasma (see Data) . Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with sunitinib and for at least 4 weeks after the last dose. Data Animal Data In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were excreted in milk at concentrations up to 12-fold higher than in plasma. 8.3 Females and Males of Reproductive Potential Sunitinib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating treatment with sunitinib. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with sunitinib and for at least 4 weeks after the last dose. Males Based on findings in animal reproduction studies, advise males with female partners of reproductive potential to use effective contraception during treatment with sunitinib and for 7 weeks after the last dose. Infertility Based on findings in animals, sunitinib may impair male and female fertility [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use The safety and effectiveness of sunitinib in pediatric patients have not been established. Safety and pharmacokinetics of sunitinib were assessed in an open-label study (NCT00387920) in pediatric patients 2 years to < 17 years of age (n = 29) with refractory solid tumors. In addition, efficacy, safety and pharmacokinetics of sunitinib was assessed in another open-label study (NCT01462695) in pediatric patients 2 years to < 17 years of age (n = 27) with high-grade glioma or ependymoma. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. Sunitinib was poorly tolerated in pediatric patients. The occurrence of dose-limiting cardiotoxicity prompted an amendment of the NCT00387920 study to exclude patients with previous exposure to anthracyclines or cardiac radiation. No responses were reported in patients in either of the trials. Apparent clearance and volume of distribution normalized for BSA for sunitinib and its active major metabolite were lower in pediatrics as compared to adults. The effect on open tibial growth plates in pediatric patients who received sunitinib has not been adequately studied. See Juvenile Animal Toxicity Data below.
Pregnancy
8.1 Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, sunitinib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available data in pregnant women to inform a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of sunitinib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity (embryolethality, craniofacial and skeletal malformations) at 5.5 and 0.3 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the recommended daily doses (RDD) of 50 mg, respectively (see Data). Advise females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating. Embryolethality was observed at 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). In embryo-fetal developmental toxicity studies, oral sunitinib was administered to pregnant rats (0.3, 1.5, 3, 5 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) during the period of organogenesis. In rats, embryolethality and skeletal malformations of the ribs and vertebrae were observed at the dose of 5 mg/kg/day (approximately 5.5 times the combined AUC in patients administered the RDD of 50 mg). No adverse fetal effects were observed in rats at doses ≤ 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg). In rabbits, embryolethality was observed at 5 mg/kg/day (approximately 3 times the combined AUC in patients administered the RDD of 50 mg), and craniofacial malformations (cleft lip and cleft palate) were observed at ≥ 1 mg/kg/day (approximately 0.3 times the combined AUC in patients administered the RDD of 50 mg). Sunitinib (0.3, 1, 3 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥ 1 mg/kg/day (approximately 0.5 times the combined AUC in patients administered the RDD of 50 mg). At 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg), reduced neonate body weights were observed at birth and persisted in the offspring of both sexes during the preweaning period and in males during postweaning period. No adverse developmental effects were observed at doses ≤ 1 mg/kg/day.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of sunitinib in pediatric patients have not been established. Safety and pharmacokinetics of sunitinib were assessed in an open-label study (NCT00387920) in pediatric patients 2 years to < 17 years of age (n = 29) with refractory solid tumors. In addition, efficacy, safety and pharmacokinetics of sunitinib was assessed in another open-label study (NCT01462695) in pediatric patients 2 years to < 17 years of age (n = 27) with high-grade glioma or ependymoma. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. Sunitinib was poorly tolerated in pediatric patients. The occurrence of dose-limiting cardiotoxicity prompted an amendment of the NCT00387920 study to exclude patients with previous exposure to anthracyclines or cardiac radiation. No responses were reported in patients in either of the trials. Apparent clearance and volume of distribution normalized for BSA for sunitinib and its active major metabolite were lower in pediatrics as compared to adults. The effect on open tibial growth plates in pediatric patients who received sunitinib has not been adequately studied. See Juvenile Animal Toxicity Data below. Juvenile Animal Toxicity Data Physeal dysplasia was present in cynomolgus monkeys with open growth plates treated with sunitinib for ≥ 3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) at doses that were > 0.4 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg. The no-effect level (NOEL) was 1.5 mg/kg/day in monkeys treated intermittently for 8 cycles, but was not identified in monkeys treated continuously for 3 months. In developing rats treated continuously for 3 months (1.5, 5.0, and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥ 5 mg/kg (approximately 10 times the combined AUC in patients administered the RDD of 50 mg). Additionally, tooth caries were present in rats at > 5 mg/kg. The incidence and severity of physeal dysplasia were dose related and reversible upon cessation of treatment; however, findings in the teeth were not. In rats, the NOEL in bones was ≤ 2 mg/kg/day.
Geriatric use
8.5 Geriatric Use Of the 7527 patients with GIST, RCC (advanced and adjuvant), or pNET who received sunitinib, 32% were 65 years and older, and 7% were 75 years and older. Patients aged 65 years of age and older had a higher incidence of Grade 3 or 4 adverse reactions (67%) than younger patients (60%). In the GIST study, 73 (30%) of the patients who received sunitinib were 65 years and older. In the mRCC study, 152 (41%) of patients who received sunitinib were 65 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. In the pNET study, 22 (27%) of the patients who received sunitinib were 65 years and older. Clinical studies of sunitinib did not include sufficient numbers of patients with pNET to determine if patients 65 years of age and older respond differently than younger patients.
Overdosage
Treatment of overdose with sunitinib should consist of general supportive measures. There is no specific antidote for overdosage with sunitinib. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of sunitinib, or without adverse reactions. In nonclinical studies, mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m 2 ) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection, and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.
Description
Sunitinib is a kinase inhibitor present in sunitinib malate capsules as the malate salt. Sunitinib malate is described chemically as N-[2-(Diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, compound with (S)-2-hydroxybutanedioic acid. The molecular formula is C 22 H 27 FN 4 O 2 .C 4 H 6 O 5 and the molecular weight is 532.57 Daltons. The chemical structure of sunitinib malate is: Sunitinib malate is light yellow to brownish orange colored powder with a pKa of 8.95. The solubility of sunitinib malate in aqueous media over the range pH 1.2 to pH 6.8 is in the range of 12 to 70 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7 is 5.2. Sunitinib malate capsules are supplied as printed hard shell capsules containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib (equivalent to 16.7 mg, 33.4 mg, 50.1 mg, or 66.8 mg of sunitinib malate, respectively) together with croscarmellose sodium, magnesium stearate, mannitol and povidone (K-30) as inactive ingredients. The reddish brown gelatin capsule shells contain ferric oxide red and titanium dioxide. The caramel gelatin capsule shells contain ferric oxide red, ferric oxide yellow, ferrosoferric oxide and titanium dioxide. The yellow gelatin capsule shells contain ferric oxide yellow and titanium dioxide. The white printing ink contains potassium hydroxide, shellac and titanium dioxide. The black printing ink contains ferrosoferric oxide, potassium hydroxide and shellac. SPL-Sunitinib-Northstar-Molecular structure
Mechanism of action
12.1 Mechanism of Action Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (> 80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo .
How supplied
12.5 mg capsules Hard gelatin capsule with opaque reddish brown cap and opaque reddish brown body, self-lock capsule, imprinted with ‘RM53’ on cap and ‘RM53’ on body in white ink, containing yellow to orange colored powder; available in: Bottles of 28 capsules with child-resistant closure: NDC 16714-676-01 25 mg capsules Hard gelatin capsule with opaque caramel cap and opaque reddish brown body, self-lock capsule, imprinted with ‘RM54’ on cap and ‘RM54’ on body in white ink, containing yellow to orange colored powder; available in: Bottles of 28 capsules with child-resistant closure: NDC 16714-677-01 37.5 mg capsules Hard gelatin capsule with opaque yellow cap and opaque yellow body, self-lock capsule, imprinted with ‘RM55’ on cap and ‘RM55’ on body in black ink, containing yellow to orange colored powder; available in: Bottles of 28 capsules with child-resistant closure: NDC 16714-678-01 50 mg capsules Hard gelatin capsule with opaque caramel cap and opaque caramel body, self-lock capsule, imprinted with ‘RM56’ on cap and ‘RM56’ on body in white ink, containing Yellow to orange colored powder ; available in: Bottles of 28 capsules with child-resistant closure: NDC 16714-679-01 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Keep out of reach of children.
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hepatotoxicity Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.1)] . Cardiovascular Events Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.2)] . QT Prolongation and Torsade de Pointes Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately in the event of syncope, pre-syncopal symptoms, and cardiac palpitations [see Warnings and Precautions (5.3)] . Hypertension Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.4)] . Hemorrhagic Events Advise patients that sunitinib malate capsules can cause severe bleeding. Advise patients to immediately contact their healthcare provider for bleeding or symptoms of bleeding [see Warnings and Precautions (5.5)] . Gastrointestinal Disorders Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during sunitinib malate capsules treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking sunitinib malate capsules [see Warnings and Precautions (5.5), and Adverse Reactions (6.1)]. Dermatologic Effects and Toxicities Advise patients that depigmentation of the hair or skin may occur during treatment with sunitinib malate capsules due to the drug color (yellow). Other possible dermatologic effects may include dryness, thickness or cracking of skin, blister or rash on the palms of the hands and soles of the feet. Severe dermatologic toxicities including Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, erythema multiforme, and necrotizing fasciitis have been reported. Advise patients to immediately inform their healthcare provider if severe dermatologic reactions occur [see Warnings and Precautions (5.9), and Adverse Reactions (6.1)]. Reversible Posterior Leukoencephalopathy Syndrome Inform patients of the signs and symptoms of reversible posterior leukoencephalopathy syndrome. Advise patients to contact their healthcare provider if they develop symptoms of reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10)] . Thyroid Dysfunction Advise patients that sunitinib malate capsules can cause thyroid dysfunction. Advise patient to contact their healthcare provider if symptoms of abnormal thyroid function occur [see Warnings and Precautions (5.11)] . Hypoglycemia Advise patients that sunitinib malate capsules can cause severe hypoglycemia and may be more severe in patients with diabetes taking antidiabetic medications. Inform patients of the signs, symptoms, and risks associated with hypoglycemia. Advise patients to immediately inform their healthcare provider if severe signs or symptoms of hypoglycemia occur [see Warnings and Precautions (5.12)] . Osteonecrosis of the Jaw Advise patients regarding good oral hygiene practices and to inform their healthcare provider of any planned dental procedures. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with osteonecrosis of the jaw [see Warnings and Precautions (5.13)] . Impaired Wound Healing Advise patients that sunitinib malate capsules impairs wound healing. Advise patients to inform their healthcare provider of any planned surgical procedures [see Warnings and Precautions (5.14)] . Concomitant Medications Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements [see Drug Interactions (7)] . Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)] . Advise females of reproductive potential to use effective contraception during treatment and for 4 weeks after receiving the last dose of sunitinib malate capsules [see Use in Specific Populations (8.3)] . Advise males with female partners of reproductive potential to use effective contraception during treatment and for 7 weeks after receiving the last dose of sunitinib malate capsules [see Use in Specific Populations (8.3)] . Lactation Advise women not to breastfeed during treatment with sunitinib malate capsules and for at least 4 weeks after the last dose [see Use in Specific Populations (8.2)] . Infertility Advise patients that sunitinib malate capsules may impair male and female fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)] . Missed Dose Advise patients that miss a dose of sunitinib malate capsules by less than 12 hours to take the missed dose right away. Advise patients that miss a dose of sunitinib malate capsules by more than 12 hours to take the next scheduled dose at its regular time. Medication Guides available at http://www.northstarrxllc.com/products or call 1-800-206-7821 Manufactured for: NorthStar Rx LLC Memphis, TN 38141 Manufactured by: Sun Pharmaceutical Industries Ltd. Survey No. 1012, Dadra-396 193, U.T. of D & NH and Daman & Diu, India. October 2023 FDA-02
Label text from the FDA structured product label by NorthStar RxLLC (revised Jul 8, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Sunitinib Malate in 36 products
Sunitinib Malate NDC products (36)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 59651-467 | Sunitinib Malate 50 mg/1 Capsule | Aurobindo Pharma Limited | ANDA |
| 59651-466 | Sunitinib Malate 37.5 mg/1 Capsule | Aurobindo Pharma Limited | ANDA |
| 59651-465 | Sunitinib Malate 25 mg/1 Capsule | Aurobindo Pharma Limited | ANDA |
| 59651-464 | Sunitinib Malate 12.5 mg/1 Capsule | Aurobindo Pharma Limited | ANDA |
| 42291-901 | Sunitinib Malate 12.5 mg/1 Capsule | AvKARE | ANDA |
| 42291-904 | Sunitinib Malate 50 mg/1 Capsule | AvKARE | ANDA |
| 42291-903 | Sunitinib Malate 37.5 mg/1 Capsule | AvKARE | ANDA |
| 42291-902 | Sunitinib Malate 25 mg/1 Capsule | AvKARE | ANDA |
| 43598-045 | Sunitinib Malate 12.5 mg/1 Capsule | Dr.Reddys Laboratories Inc | ANDA |
| 43598-046 | Sunitinib Malate 25 mg/1 Capsule | Dr.Reddys Laboratories Inc | ANDA |
| 43598-047 | Sunitinib Malate 37.5 mg/1 Capsule | Dr.Reddys Laboratories Inc | ANDA |
| 43598-048 | Sunitinib Malate 50 mg/1 Capsule | Dr.Reddys Laboratories Inc | ANDA |
| 0378-6681 | Sunitinib Malate 37.5 mg/1 Capsule | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-6680 | Sunitinib Malate 50 mg/1 Capsule | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-6679 | Sunitinib Malate 25 mg/1 Capsule | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-6678 | Sunitinib Malate 12.5 mg/1 Capsule | Mylan Pharmaceuticals Inc. | ANDA |
| 16714-676 | Sunitinib Malate 12.5 mg/1 Capsule | NorthStar RxLLC | ANDA |
| 16714-677 | Sunitinib Malate 25 mg/1 Capsule | NorthStar RxLLC | ANDA |
| 16714-678 | Sunitinib Malate 37.5 mg/1 Capsule | NorthStar RxLLC | ANDA |
| 16714-679 | Sunitinib Malate 50 mg/1 Capsule | NorthStar RxLLC | ANDA |
| 72205-116 | Sunitinib Malate 12.5 mg/1 Capsule | Novadoz Pharmaceuticals LLC | ANDA |
| 72205-119 | Sunitinib Malate 50 mg/1 Capsule | Novadoz Pharmaceuticals LLC | ANDA |
| 72205-118 | Sunitinib Malate 37.5 mg/1 Capsule | Novadoz Pharmaceuticals LLC | ANDA |
| 72205-117 | Sunitinib Malate 25 mg/1 Capsule | Novadoz Pharmaceuticals LLC | ANDA |
| 82293-014 | Sunitinib Malate 12.5 mg/1 Capsule | Novugen Pharma (USA) LLC. | ANDA |
| 82293-015 | Sunitinib Malate 25 mg/1 Capsule | Novugen Pharma (USA) LLC. | ANDA |
| 82293-016 | Sunitinib Malate 37.5 mg/1 Capsule | Novugen Pharma (USA) LLC. | ANDA |
| 82293-017 | Sunitinib Malate 50 mg/1 Capsule | Novugen Pharma (USA) LLC. | ANDA |
| 63304-094 | Sunitinib Malate 50 mg/1 Capsule | Sun Pharmaceutical Industries Inc. | ANDA |
| 63304-093 | Sunitinib Malate 37.5 mg/1 Capsule | Sun Pharmaceutical Industries Inc. | ANDA |
| 63304-092 | Sunitinib Malate 25 mg/1 Capsule | Sun Pharmaceutical Industries Inc. | ANDA |
| 63304-091 | Sunitinib Malate 12.5 mg/1 Capsule | Sun Pharmaceutical Industries Inc. | ANDA |
| 0093-8231 | Sunitinib Malate 50 mg/1 Capsule | Teva Pharmaceuticals USA, Inc. | ANDA |
| 0093-8229 | Sunitinib Malate 37.5 mg/1 Capsule | Teva Pharmaceuticals USA, Inc. | ANDA |
| 0093-8224 | Sunitinib Malate 25 mg/1 Capsule | Teva Pharmaceuticals USA, Inc. | ANDA |
| 0093-8199 | Sunitinib Malate 12.5 mg/1 Capsule | Teva Pharmaceuticals USA, Inc. | ANDA |
Sunitinib Malate recalls
- D-0103-2025 Dec 11, 2024 · Class II · Ongoing
Labeling: Label Mix-Up - D-0104-2025 Dec 11, 2024 · Class II · Ongoing
Labeling: Label Mix-Up - D-0913-2023 Jul 19, 2023 · Class II · Terminated
Failed Moisture Limits: Water (moisture) content above the approved product specifications.
Frequently asked questions
What is Sunitinib Malate used for?
Sunitinib malate capsules are a kinase inhibitor indicated for: treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. (1.1) treatment of adult patients with advanced renal cell carcinoma (RCC). (1.2) adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. (1.3) treatment of…
What are the side effects of Sunitinib Malate?
The following clinically significant adverse reactions are described elsewhere in the labeling. Hepatotoxicity [see Warnings and Precautions (5.1)] Cardiovascular Events [see Warnings and Precautions (5.2)] QT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3)] Hypertension [see Warnings and Precautions (5.4)] Hemorrhagic Events [see Warnings and Precautions (5.5)]… See the full label for the complete list.
Who makes Sunitinib Malate?
Sunitinib Malate is listed by 9 labelers in the FDA NDC directory, including Aurobindo Pharma Limited, AvKARE, Dr.Reddys Laboratories Inc, Mylan Pharmaceuticals Inc..
Has Sunitinib Malate been recalled?
The FDA enforcement database lists 3 recalls for Sunitinib Malate, most recently D-0103-2025 (class ii): Labeling: Label Mix-Up