HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use SUTENT safely and effectively. See full prescribing information for SUTENT.
SUTENT® (sunitinib malate) capsules, for oral use
Initial U.S. Approval: 2006
See full prescribing information for complete boxed warning.
Hepatotoxicity has been observed in clinical trials and postmarketing experience. Hepatotoxicity may be severe, and in some cases fatal. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [see Warnings and Precautions (5.1)].
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
SUTENT is a kinase inhibitor indicated for:
DOSAGE AND ADMINISTRATION
GIST and Advanced RCC:
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
1 INDICATIONS AND USAGE
1.1 Gastrointestinal Stromal Tumor (GIST)
SUTENT is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.
1.2 Advanced Renal Cell Carcinoma (RCC)
SUTENT is indicated for the treatment of advanced renal cell carcinoma.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose for GIST and Advanced RCC
The recommended dose of SUTENT for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). SUTENT may be taken with or without food.
2.3 Recommended Dose for pNET
The recommended dose of SUTENT for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. SUTENT may be taken with or without food.
2.4 Dose Modification
Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. A dose reduction for SUTENT to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily should be considered if SUTENT must be coadministered with a strong CYP3A4 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. A dose increase for SUTENT to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily should be considered if SUTENT must be coadministered with a CYP3A4 inducer. If dose is increased, the patient should be monitored carefully for toxicity [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
12.5 mg capsules
Hard gelatin capsule with orange cap and orange body, printed with white ink "Pfizer" on the cap and "STN 12.5 mg" on the body.
25 mg capsules
Hard gelatin capsule with caramel cap and orange body, printed with white ink "Pfizer" on the cap and "STN 25 mg" on the body.
37.5 mg capsules
Hard gelatin capsule with yellow cap and yellow body, printed with black ink "Pfizer" on the cap and "STN 37.5 mg" on the body.
5 WARNINGS AND PRECAUTIONS
Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt SUTENT and dose reduce for 24-hour urine protein ≥3 grams. Discontinue SUTENT for patients with nephrotic syndrome or repeat episodes of urine protein ≥3 grams despite dose reductions. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated.
5.9 Dermatologic Toxicities
Necrotizing fasciitis, including fatal cases, has been reported in patients treated with SUTENT, including of the perineum and secondary to fistula formation. Discontinue SUTENT in patients who develop necrotizing fasciitis.
5.13 Wound Healing
Cases of impaired wound healing have been reported during SUTENT therapy. Temporary interruption of SUTENT therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume SUTENT therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of 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 (TLS) [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)]
- Thyroid Dysfunction [see Warnings and Precautions (5.10)]
- Hypoglycemia [see Warnings and Precautions (5.11)]
- Osteonecrosis of the Jaw (ONJ) [see Warnings and Precautions (5.12)]
- Wound Healing [see Warnings and Precautions (5.13)]
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 data described in the Warnings and Precautions reflect exposure to SUTENT (N = 7527) in GIST, advanced RCC, adjuvant treatment of RCC, and pNET [see Warnings and Precautions (5.1, 5.13)]. In this database, 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.
The data below reflect exposure to SUTENT in 966 patients who participated in the treatment phase of randomized trials of GIST (n=202), advanced RCC (n=375), adjuvant treatment of RCC (n=306), and pNET (n=83) [see Clinical Studies (14.1, 14.2, 14.3)].
Gastrointestinal Stromal Tumor (GIST)
The safety of SUTENT was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received SUTENT 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 SUTENT (mean: 3.0; range: 1–9) and 1 cycle (mean; 1.8; range: 1–6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on SUTENT and none on placebo. Dose interruptions occurred in 59 patients (29%) on SUTENT and 31 patients (30%) on placebo. The rates of treatment-emergent, nonfatal adverse reactions resulting in permanent discontinuation were 7% and 6% in the SUTENT and placebo groups, respectively.
Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56% versus 51% of patients on SUTENT versus placebo, respectively, in the double-blind treatment phase of the trial. Table 1 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.
|SUTENT (N=202)||Placebo (N=102)|
|All Grades %||Grade 3–4 %||All Grades %||Grade 3–4 %|
|Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients.|
|Any Adverse Reaction||94||56||97||51|
In the double-blind treatment phase of GIST Study 1, oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on SUTENT versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on SUTENT versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on SUTENT versus 2 (2%) on placebo.
Table 2 provides common (≥10%) treatment-emergent laboratory abnormalities.
|SUTENT (N=202)||Placebo (N=102)|
|All Grades* %||Grade 3–4*,† %||All Grades* %||Grade 3–4*,‡ %|
|Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; GIST=gastrointestinal stromal tumor; LVEF=left ventricular ejection fraction; N=number of patients.|
|Any||68 (34)||22 (22)|
After an interim analysis, the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label SUTENT treatment [see Clinical Studies (14.1)]. For 241 patients randomized to the SUTENT arm, including 139 who received SUTENT in both the double-blind and open-label treatment phases, the median duration of SUTENT treatment was 6 cycles (mean: 8.5; range: 1–44). For the 255 patients who ultimately received open-label SUTENT treatment, median duration of study treatment was 6 cycles (mean: 7.8; range: 1–37) from the time of the unblinding. A total of 118 patients (46%) required dosing interruptions, and a total of 72 patients (28%) required dose reductions. The incidence of treatment-emergent adverse reactions resulting in permanent discontinuation was 20%. The most common Grade 3 or 4 treatment-related adverse reactions experienced by patients receiving SUTENT in the open-label treatment phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).
Advanced Renal Cell Carcinoma (RCC)
The safety of SUTENT was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received SUTENT 50 mg daily on Schedule 4/2 (n=375) or IFN-α 9 million International Units (MIU) (n=360). The median duration of treatment was 11.1 months (range: 0.4–46.1) for SUTENT treatment and 4.1 months (range: 0.1–45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on SUTENT and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on SUTENT and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for SUTENT and 24% for IFN-α. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on SUTENT versus IFN-α, respectively.
Table 3 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT versus IFN-α.
|Adverse Reaction||Treatment-Naïve RCC|
|SUTENT (N=375)||IFN-α (N=360)|
|All Grades %||Grade 3–4† %||All Grades %||Grade 3–4‡ %|
|Abbreviations: ARs=adverse reactions; IFN=interferon-α; N=number of patients; RCC=renal cell carcinoma.|
|Any Adverse Reaction||99||77||99||55|
|Influenza like illness||5||0||15||<1|
|Ejection fraction decreased||16||3||5||2|
|Skin discoloration/yellow skin||25||<1||0||0|
|Hair color changes||20||0||<1||0|
|Pain in extremity/limb discomfort||40||5||30||2|
|Upper respiratory tract infection||11||<1||2||0|
|Bleeding, all sites||37||4Þ||10||1|
Treatment-emergent Grade 3–4 laboratory abnormalities are presented in Table 4.
|Laboratory Parameter||Treatment-Naïve RCC|
|SUTENT (N=375)||IFN-α (N=360)|
|All Grades* %||Grade 3–4*,† %||All Grades* %||Grade 3–4*,‡ %|
|Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; IFN=interferon-α; N=number of patients; RCC=renal cell carcinoma.|
Long-Term Safety in RCC
The long-term safety of SUTENT in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings. The analysis included 5739 patients, of whom 807 (14%) were treated for at least 2 years and 365 (6%) for at least 3 years. Prolonged treatment with SUTENT did not appear to be associated with new types of adverse reactions. There appeared to be no increase in the yearly incidence of adverse reactions at later time points. Hypothyroidism increased during the second year of treatment with new cases reported up to year 4.
Adjuvant Treatment of RCC
The safety of SUTENT was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received SUTENT 50 mg daily (n=306) on Schedule 4/2 or placebo (n=304). The median duration of treatment was 12.4 months (range: 0.13–14.9) for SUTENT and 12.4 months (range: 0.03–13.7) for placebo. Permanent discontinuation due to an adverse reaction occurred in 28% of patients on SUTENT and 6% on placebo. Adverse reactions leading to permanent discontinuation in >2% of patients include hand-foot syndrome and fatigue/asthenia. Dosing interruptions or delays occurred in 166 (54%) and 84 (28%) patients on SUTENT and placebo, respectively. One hundred forty patients (45.8%) out of 306 patients in the SUTENT arm and 15 patients (5%) out of 304 patients in the placebo arm had dose reductions.
Table 5 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT versus placebo.
|Adverse Reaction||Adjuvant Treatment of RCC|
|SUTENT (N=306)||Placebo (N=304)|
|All Grades %||Grade 3–4 %||All Grades %||Grade 3–4 %|
|Abbreviations: ARs=adverse reactions; N=number of patients; RCC=renal cell carcinoma.|
|Any Adverse Reaction||99||60||88||15|
|Hair color changes||22||0||2||0|
|Skin discoloration/Yellow skin||18||0||1||0|
|Pain in extremity||15||<1||7||0|
|Bleeding events, all sitesß||24||<1||5||<1|
Grade 4 adverse reactions in patients on SUTENT included hand-foot syndrome (1%), fatigue (<1%), abdominal pain (< 1%), stomatitis (<1%), and pyrexia (< 1%). Grade 4 adverse reactions in patients on placebo included asthenia (<1%) and hypertension (<1%).
Grade 3–4 laboratory abnormalities that occurred in ≥2% of patients receiving SUTENT include neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).
Advanced Pancreatic Neuroendocrine Tumors (pNET)
The safety of SUTENT was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received SUTENT 37.5 mg daily continuous dosing (n=83) or placebo (n=82). The median number of days on treatment was 139 days (range: 13–532 days) for patients on SUTENT and 113 days (range: 1–614 days) for patients on placebo. Nineteen patients (23%) on SUTENT and 4 patients (5%) on placebo were on study for >1 year. Dose interruptions occurred in 25 patients (30%) on SUTENT and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on SUTENT and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for SUTENT and 17% for placebo.
Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 54% versus 50% of patients on SUTENT versus placebo, respectively. Table 6 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.
|SUTENT (N=83)||Placebo (N=82)|
|All Grades %||Grade 3–4† %||All Grades %||Grade 3–4 %|
|Abbreviations: N=number of patients; pNET=pancreatic neuroendocrine tumors.|
|Any Adverse Reaction||99||54||95||50|
|Hair color changes||29||1||1||0|
Table 7 provides common (≥10%) treatment-emergent laboratory abnormalities.
|N||All Grades* %||Grade 3–4*,† %||N||All Grades* %||Grade 3–4*,‡ %|
|Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; N=number of patients; pNET=pancreatic neuroendocrine tumors.|
|Alkaline phosphatase increased||82||63||10||80||70||11|
|Total bilirubin increased||82||37||1||80||28||4|
Venous Thromboembolic Events
In patients treated with SUTENT (N=7527) for GIST, advanced RCC, adjuvant treatment of RCC and pNET, 3.5% of patients experienced a venous thromboembolic event; 2.2% Grade 3–4.
Reversible Posterior Leukoencephalopathy Syndrome
There have been reports (<1%), some fatal, of patients presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness, should be controlled with medical management including control of hypertension. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating healthcare provider.
Pancreatitis was observed in 5 patients (1%) receiving SUTENT for treatment-naïve RCC compared to 1 patient (<1%) receiving IFN-α. In a trial of patients receiving adjuvant treatment for RCC, 1 patient (<1%) on SUTENT and none on placebo experienced pancreatitis. Pancreatitis was observed in 1 patient (1%) receiving SUTENT for pNET and 1 patient (1%) receiving placebo.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of SUTENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia1. Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating healthcare provider.
- Gastrointestinal disorders: esophagitis.
- Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis.
- Immune system disorders: hypersensitivity reactions, including angioedema.
- Infections and infestations: serious infection (with or without neutropenia)1. The infections most commonly observed with SUTENT treatment include respiratory, urinary tract, skin infections, and sepsis/septic shock.
- Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression1; myopathy and/or rhabdomyolysis with or without acute renal failure1. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.
- Renal and urinary disorders: renal impairment and/or failure1.
- Respiratory disorders: pulmonary embolism1.
- Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive dechallenges.
- Vascular disorders: arterial thromboembolic events1. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction.
- including some fatalities.
7 DRUG INTERACTIONS
7.1 CYP3A4 Inhibitors
Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Coadministration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for SUTENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.4)].
7.2 CYP3A4 Inducers
CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Coadministration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving SUTENT should not take St. John's Wort concomitantly. A dose increase for SUTENT should be considered when it must be coadministered with CYP3A4 inducers [see Dosage and Administration (2.4)].
7.3 In Vitro Studies of CYP Inhibition and Induction
In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.
8 USE IN SPECIFIC POPULATIONS
Based on animal reproduction studies and its mechanism of action, SUTENT 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 AUC in patients administered the recommended daily doses (RDD), respectively (see Data). Advise pregnant women or females of reproductive potential of the potential hazard to a fetus.
The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the estimated background risk in the United States (U.S.) general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies.
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 AUC in patients administered the RDD of 50 mg/day).
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 systemic exposure [combined AUC of sunitinib + primary active metabolite] in patients administered the RDD). No adverse fetal effects were observed in rats at doses ≤3 mg/kg/day (approximately 2 times the AUC in patients administered the RDD). In rabbits, embryolethality was observed at 5 mg/kg/day (approximately 3 times the AUC in patients administered the RDD), and craniofacial malformations (cleft lip and cleft palate) were observed at ≥1 mg/kg/day (approximately 0.3 times the AUC in patients administered the RDD of 50 mg/day).
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 AUC in patients administered the RDD). At 3 mg/kg/day (approximately 2 times the AUC in patients administered the RDD), 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.
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 from SUTENT, advise a lactating woman not to breastfeed during treatment with SUTENT and for at least 4 weeks after the last dose.
8.3 Females and Males of Reproductive Potential
Females of reproductive potential should have a pregnancy test before treatment with SUTENT is started.
Advise females of reproductive potential to use effective contraception during treatment with SUTENT and for at least 4 weeks after the last dose.
Based on findings in animals, male and female fertility may be compromised by treatment with SUTENT [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and efficacy of SUTENT in pediatric patients have not been established.
Physeal dysplasia was observed in cynomolgus monkeys with open growth plates treated 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) with sunitinib at doses that were >0.4 times the RDD based on systemic exposure (AUC). 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 RDD based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose related and were reversible upon cessation of treatment; however, findings in the teeth were not. A no-effect level was not observed in monkeys treated continuously for 3 months, but was 1.5 mg/kg/day when treated intermittently for 8 cycles. In rats the no-effect level in bones was ≤2 mg/kg/day.
8.5 Geriatric Use
Of 825 patients with GIST or metastatic RCC who received SUTENT on clinical studies, 277 (34%) were 65 and over. In the pNET study, 22 patients (27%) who received SUTENT were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients. Among the 158 patients at least age 65 receiving adjuvant SUTENT/placebo for RCC, the hazard ratio for disease-free survival was 0.59 (95% CI: 0.36, 0.95). Among patients 65 years and older receiving adjuvant SUTENT/placebo for RCC, 50 patients (16%) in the SUTENT arm experienced a Grade 3–4 adverse reaction, compared to 15 patients (5%) in the placebo arm.
8.6 Hepatic Impairment
No dose adjustment to the starting dose is required when administering SUTENT to patients with Child-Pugh Class A or B hepatic impairment. Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of SUTENT were similar in patients with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to patients with normal hepatic function. SUTENT was not studied in patients with severe (Child-Pugh Class C) hepatic impairment. Studies in cancer patients have excluded patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN.
8.7 Renal Impairment
No adjustment to the starting dose is required when administering SUTENT to patients with mild (CLcr 50–80 mL/min), moderate (CLcr 30–<50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis. In patients with end-stage renal disease (ESRD) on hemodialysis, no adjustment to the starting dose is required. However, compared to patients with normal renal function, the sunitinib exposure is 47% lower in patients with ESRD on hemodialysis. Therefore, the subsequent doses may be increased gradually up to 2-fold based on safety and tolerability.
Treatment of overdose with SUTENT should consist of general supportive measures. There is no specific antidote for overdosage with SUTENT. 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 SUTENT, or without adverse reactions. A case of intentional overdose involving the ingestion of 1500 mg of SUTENT in an attempted suicide was reported without adverse reaction. In nonclinical studies, mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m2) 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.
SUTENT, an oral multi-kinase inhibitor, is the malate salt of sunitinib. Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (1:1). The molecular formula is C22H27FN4O2 ∙ C4H6O5 and the molecular weight is 532.6 Daltons.
The chemical structure of sunitinib malate is:
Sunitinib malate is a yellow to orange 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 excess of 25 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7 is 5.2.
SUTENT (sunitinib malate) capsules are supplied as printed hard shell capsules containing sunitinib malate equivalent to 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib together with mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate as inactive ingredients.
The orange gelatin capsule shells contain titanium dioxide and red iron oxide. The caramel gelatin capsule shells contain titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide. The yellow gelatin capsule shells contain titanium dioxide and yellow iron oxide. The white printing ink contains shellac, propylene glycol, sodium hydroxide, povidone, and titanium dioxide. The black printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide.
12 CLINICAL PHARMACOLOGY
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.
The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors.
Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (time to maximum plasma concentration [Tmax]) following oral administration. Food has no effect on the bioavailability of sunitinib. SUTENT may be taken with or without food.
Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no concentration dependence in the range of 100–4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25–100 mg, the AUC and Cmax increase proportionately with dose.
Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23% to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of [14C]sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine, and feces, representing 91.5%, 86.4%, and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces but generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/h with an interpatient variability of 40%.
Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 62.9–101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles in the dosing regimens tested.
The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC.
Pharmacokinetics in Special Populations
Population pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age, body weight, creatinine clearance, race, gender, or Eastern Cooperative Oncology Group (ECOG) score on the pharmacokinetics of SUTENT or the primary active metabolite.
Renal Insufficiency: Sunitinib systemic exposure after a single dose of SUTENT was similar in patients with severe renal impairment (CLcr <30 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). Although sunitinib was not eliminated through hemodialysis, the sunitinib systemic exposure was 47% lower in patients with ESRD on hemodialysis compared to patients with normal renal function.
12.4 Cardiac Electrophysiology
SUTENT can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes [see Warnings and Precautions (5.3)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of sunitinib has been evaluated in 2 species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice, gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at doses ≥25 mg/kg/day following daily dose administration of sunitinib in studies of 1 or 6 months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day (approximately 0.9 times the AUC in patients given the RDD of 50 mg/day). At the high dose of 3 mg/kg/day (approximately 8 times the AUC in patients at the RDD of 50 mg/day), the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal gland.
Sunitinib did not cause genetic damage when tested in in vitro assays (bacterial mutation [Ames test], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test.
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. Preimplantation loss was observed in females administered 5 mg/kg/day (approximately 5 times the AUC in patients administered the RDD of 50 mg/day). No adverse effects on fertility were observed at doses ≤1.5 mg/kg/day (approximately 1 time the clinical AUC at the RDD of 50 mg/day). In addition, effects on the female reproductive system were identified in a 3-month oral repeat-dose monkey study (2, 6, 12 mg/kg/day). Ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (approximately 5 times the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day (approximately 0.4 times the AUC in patients administered the RDD). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day (approximately 0.8 times the AUC in patients administered the RDD) in a 9-month monkey study (0.3, 1.5, and 6 mg/kg/day administered daily for 28 days followed by a 14 day respite).
In a male fertility study, no reproductive effects were observed in male rats dosed with 1, 3, or 10 mg/kg/day oral sunitinib for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤10 mg/kg/day approximately ≥26 times the AUC in patients administered the RDD).
14 CLINICAL STUDIES
14.1 Gastrointestinal Stromal Tumor
Study 1 (NCT#00075218) was a 2-arm, international, randomized, double-blind, placebo-controlled trial of SUTENT in patients with GIST who had disease progression during prior imatinib mesylate (imatinib) treatment or who were intolerant of imatinib. The objective was to compare time-to-tumor progression (TTP) in patients receiving SUTENT plus best supportive care versus patients receiving placebo plus best supportive care. Other objectives included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Patients were randomized (2:1) to receive either 50 mg SUTENT or placebo orally, once daily, on Schedule 4/2 until disease progression or withdrawal from the study for another reason. Treatment was unblinded at the time of disease progression. Patients randomized to placebo were then offered crossover to open-label SUTENT and patients randomized to SUTENT were permitted to continue treatment per investigator judgment.
At the time of a prespecified interim analysis, the intent-to-treat (ITT) population included 312 patients. Two hundred seven (207) patients were randomized to the SUTENT arm and 105 patients were randomized to the placebo arm. Demographics were comparable between the SUTENT and placebo groups with regard to age (69% versus 72% <65 years for SUTENT versus placebo, respectively), gender (male: 64% versus 61%), race (White: 88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and performance status (ECOG 0: 44% versus 46%, ECOG 1: 55% versus 52%, and ECOG 2: 1% versus 2%). Prior treatment included surgery (94% versus 93%) and radiotherapy (8% versus 15%). Outcome of prior imatinib treatment was also comparable between arms with intolerance (4% versus 4%), progression within 6 months of starting treatment (17% versus 16%), or progression beyond 6 months (78% versus 80%) balanced.
The planned interim efficacy and safety analysis was performed after 149 TTP events had occurred. There was a statistically significant advantage for SUTENT over placebo in TTP, meeting the primary endpoint. Efficacy results are summarized in Table 8 and the Kaplan-Meier curve for TTP is shown in Figure 1.
|Abbreviations: CI=confidence interval; GIST=gastrointestinal stromal tumor; HR=hazard ratio; N=number of patients; PR=partial response.|
[median, weeks (95% CI)]
[median, weeks (95% CI)]
|Objective response rate (PR)
[%, (95% CI)]
Figure 1. Kaplan-Meier Curve of TTP in GIST Study 1 (Intent-to-Treat Population)
Abbreviations: CI=confidence interval; GIST=gastrointestinal stromal tumor; N=number of patients; TTP=time-to-tumor progression.
The final ITT population enrolled in the double-blind treatment phase of the study included 243 patients randomized to the SUTENT arm and 118 patients randomized to the placebo arm. After the primary endpoint was met at the interim analysis, the study was unblinded, and patients on the placebo arm were offered open-label SUTENT treatment. Ninety-nine (99) of the patients initially randomized to placebo crossed over to receive SUTENT in the open-label treatment phase. At the protocol specified final analysis of OS, the median OS was 72.7 weeks for the SUTENT arm and 64.9 weeks for the placebo arm [hazard ratio (HR)=0.876, 95% confidence interval (CI) (0.679, 1.129)].
Study 2 was an open-label, multi-center, single-arm, dose-escalation study conducted in patients with GIST following progression on, or intolerance to imatinib. Following identification of the recommended regimen (50 mg once daily on Schedule 4/2), 55 patients in this study received the 50 mg dose of SUTENT on treatment Schedule 4/2. Partial responses (PR) were observed in 5 of 55 patients (9.1% PR rate; 95% CI: 3.0%, 20.0%).
14.2 Renal Cell Carcinoma
Study 3 (NCT#00083889) was a multi-center, international, randomized study comparing single-agent SUTENT with IFN-α was conducted in patients with treatment-naïve RCC. The objective was to compare PFS in patients receiving SUTENT versus patients receiving IFN-α. Other endpoints included ORR, OS, and safety. Seven hundred fifty (750) patients were randomized (1:1) to receive either 50 mg SUTENT once daily on Schedule 4/2 or to receive IFN-α administered subcutaneously at 9 million international units (MIU) 3 times a week. Patients were treated until disease progression or withdrawal from the study.
The ITT population included 750 patients, 375 randomized to SUTENT and 375 randomized to IFN-α. Demographics were comparable between the SUTENT and IFN-α groups with regard to age (59% versus 67% <65 years for SUTENT versus IFN-α, respectively), gender (male: 71% versus 72%), race (White: 94% versus 91%, Asian: 2% versus 3%, Black: 1% versus 2%, remainder not reported), and performance status (ECOG 0: 62% versus 61%, ECOG 1: 38% each arm, ECOG 2: 0 versus 1%). Prior treatment included nephrectomy (91% versus 89%) and radiotherapy (14% each arm). The most common site of metastases present at screening was the lung (78% versus 80%, respectively), followed by the lymph nodes (58% versus 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% versus 77%, respectively).
There was a statistically significant advantage for SUTENT over IFN-α in the endpoint of PFS (see Table 9 and Figure 2). In the prespecified stratification factors of lactate dehydrogenase (LDH) (>1.5 ULN versus ≤1.5 ULN), ECOG performance status (0 versus 1), and prior nephrectomy (yes versus no), the hazard ratio favored SUTENT over IFN-α. The ORR was higher in the SUTENT arm (see Table 9).
|Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; INF-α=interferon-alfa; NA=not applicable; RCC=renal cell carcinoma.|
[median, weeks (95% CI)]
|Objective response rate*
[%, (95% CI)]
Abbreviations: CI=confidence interval; INF-α=interferon-alfa; N=number of patients; PFS=progression-free survival; RCC=renal cell carcinoma.
At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for the SUTENT arm and 94.9 weeks for the IFN-α arm (HR=0.821; 95% CI: 0.673, 1.001). The median OS for the IFN-α arm includes 25 patients who discontinued IFN-α treatment because of disease progression and crossed over to treatment with SUTENT as well as 121 patients (32%) on the IFN-α arm who received post-study cancer treatment with SUTENT.
The use of single-agent SUTENT in the treatment of cytokine-refractory RCC was investigated in 2 single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokine-based therapy. In Study 4 (NCT#00077974), failure of prior cytokine therapy was based on radiographic evidence of disease progression defined by response evaluation criteria in solid tumors (RECIST) or World Health Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy treatment (IFN-α, interleukin-2, or IFN-α plus interleukin-2; patients who were treated with IFN-α alone must have received treatment for at least 28 days). In Study 5 (NCT#00054886), failure of prior cytokine therapy was defined as disease progression or unacceptable treatment-related toxicity. The endpoint for both studies was ORR. Duration of response (DR) was also evaluated.
One hundred and six patients (106) were enrolled into Study 4 and 63 patients were enrolled into Study 5. Patients received 50 mg SUTENT on Schedule 4/2. Therapy was continued until the patients met withdrawal criteria or had progressive disease. The baseline age, gender, race, and ECOG performance statuses of the patients were comparable between Studies 4 and 5. Approximately 86%–94% of patients in the 2 studies were White. Men comprised 65% of the pooled population. The median age was 57 years and ranged from 24 to 87 years in the studies. All patients had an ECOG performance status <2 at the screening visit.
The baseline malignancy and prior treatment history of the patients were comparable between Studies 4 and 5. Across the 2 studies, 95% of the pooled population of patients had at least some component of clear-cell histology. All patients in Study 4 were required to have a histological clear-cell component. Most patients enrolled in the studies (97% of the pooled population) had undergone nephrectomy; prior nephrectomy was required for patients enrolled in Study 4. All patients had received 1 previous cytokine regimen. Metastatic disease present at the time of study entry included lung metastases in 81% of patients. Liver metastases were more common in Study 4 (27% versus 16% in Study 5) and bone metastases were more common in Study 5 (51% versus 25% in Study 4); 52% of patients in the pooled population had at least 3 metastatic sites. Patients with known brain metastases or leptomeningeal disease were excluded from both studies.
The ORR and DR data from Studies 4 and 5 are provided in Table 10. There were 36 PRs in Study 4 as assessed by a core radiology laboratory for an ORR of 34.0% (95% CI: 25.0%, 43.8%). There were 23 PRs in Study 5 as assessed by the investigators for an ORR of 36.5% (95% CI: 24.7%, 49.6%). The majority (>90%) of objective disease responses were observed during the first 4 cycles; the latest reported response was observed in Cycle 10. DR data from Study 4 is premature as only 9 of 36 patients (25%) responding to treatment had experienced disease progression or died at the time of the data cutoff.
|Efficacy Parameter||Study 4
|Abbreviations: CI=confidence interval; N=number of patients; NR=not reached; RCC=renal cell carcinoma.|
|Objective response rate
[%, (95% CI)]
|Duration of response
[median, weeks (95% CI)]
Adjuvant Treatment of RCC
In the adjuvant treatment setting, SUTENT was investigated in S-TRAC (NCT#00375674), a multi-center, international, randomized, double-blind, placebo-controlled, trial in patients with high risk of recurrent RCC following nephrectomy. Patients were required to have clear cell histology and high risk of recurrence defined as ≥T3 and/or N+ tumors. Six hundred fifteen (615) patients were randomized 1:1 to receive either 50 mg SUTENT once daily on Schedule 4/2 or placebo. Patients were treated for 9 cycles (approximately 1 year), or until disease recurrence, unacceptable toxicity, or withdrawal of consent.
Demographics were generally comparable between the SUTENT and placebo arms with regard to age (median age 58 years), gender (73% male), and race (84% White, 12% Asian and 4% Other). At randomization, most patients had an ECOG performance status of 0 (74% SUTENT and 72% placebo). The remainder of the patients had an ECOG performance status of 1; 1 patient on SUTENT had a performance status of 2.
The major efficacy outcome measure was disease-free survival (DFS) in patients receiving SUTENT versus placebo as assessed by blinded independent central review (BICR). Overall survival was an additional endpoint. There was a statistically significant improvement in DFS in patients who were treated with SUTENT compared to placebo (Table 11 and Figure 3). Prespecified subgroup analyses are presented in Table 12. At the time of the DFS analysis, overall survival data were not mature, with 141/615 (23%) patient deaths.
N = 309
N = 306
|p-value*||HR* (95% CI)|
|Abbreviations: BICR=blinded independent central review; CI=confidence interval; DFS=disease-free survival; HR=hazard ratio; N=number of patients; RCC=renal cell carcinoma.|
|Median DFS [years (95% CI)]||6.8 (5.8, NR)||5.6 (3.8, 6.6)||0.03||0.76 (0.59, 0.98)|
|DFS Events||113 (36.6%)||144 (47.1%)|
|5 Year DFS Rate||59.3%||51.3%|
|Number of Events/ Total
[years (95% CI)]
|Abbreviations: CI=confidence interval; DFS=disease-free survival; HR=hazard ratio; N=number of patients; n=number of events; NR=not reached|
Figure 3. Kaplan-Meier Curve of Disease-free Survival as Assessed by BICR (Intent-to-Treat Population)
Abbreviations: BICR=blinded independent central review; CI=confidence interval; N=number of patients.
14.3 Pancreatic Neuroendocrine Tumors
Study 6 (NCT#00428597) was a multi-center, international, randomized, double-blind, placebo-controlled study of single-agent SUTENT conducted in patients with unresectable pNET. Patients were required to have documented RECIST-defined disease progression within the prior 12 months and were randomized (1:1) to receive either 37.5 mg SUTENT (N=86) or placebo (N=85) once daily without a scheduled off-treatment period. The primary objective was to compare PFS in patients receiving SUTENT versus patients receiving placebo. Other endpoints included OS, ORR, and safety. Use of somatostatin analogs was allowed in the study.
Demographics were comparable between the SUTENT and placebo groups. Additionally, 49% of SUTENT patients had nonfunctioning tumors vs 52% of placebo patients, and 92% patients in both arms had liver metastases. A total of 66% of SUTENT patients received prior systemic therapy compared with 72% of placebo patients and 35% of SUTENT patients had received somatostatin analogs compared with 38% of placebo patients. Patients were treated until disease progression or withdrawal from the study. Upon disease progression or study closure, patients were offered access to SUTENT in a separate extension study.
As recommended by the Independent Data Monitoring Committee, the study was terminated prematurely prior to the prespecified interim analysis. This may have led to an overestimate of the magnitude of PFS effect. A clinically significant improvement for SUTENT over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring SUTENT was observed in all subgroups of baseline characteristics evaluated. OS data were not mature at the time of the analysis. There were 9 deaths in the SUTENT arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring SUTENT over placebo was observed. Efficacy results are summarized in Table 13 and the Kaplan-Meier curve for PFS is in Figure 4.
|Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; NA=not applicable; pNET=pancreatic neuroendocrine tumors.|
[median, months (95% CI)]
|Objective response rate
[%, (95% CI)]
Figure 4. Kaplan-Meier Curve of PFS in the pNET Study 6
Abbreviations: CI=confidence interval; N=number of patients; PFS=progression-free survival; pNET=pancreatic neuroendocrine tumors.
16 HOW SUPPLIED/STORAGE AND HANDLING
12.5 mg capsules
Hard gelatin capsule with orange cap and orange body, printed with white ink "Pfizer" on the cap, "STN 12.5 mg" on the body; available in:
Bottles of 28 capsules: NDC 0069-0550-38
25 mg capsules
Hard gelatin capsule with caramel cap and orange body, printed with white ink "Pfizer" on the cap, "STN 25 mg" on the body; available in:
Bottles of 28 capsules: NDC 0069-0770-38
37.5 mg capsules
Hard gelatin capsule with yellow cap and yellow body, printed with black ink "Pfizer" on the cap, "STN 37.5 mg" on the body; available in:
Bottles of 28 capsules: NDC 0069-0830-38
50 mg capsules
Hard gelatin capsule with caramel cap and caramel body, printed with white ink "Pfizer" on the cap, "STN 50 mg" on the body; available in:
Bottles of 28 capsules: NDC 0069-0980-38
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
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)].
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)].
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)].
Advise patients that SUTENT can cause severe bleeding. Advise patients to immediately contact their healthcare provider for bleeding or symptoms of bleeding [see Warnings and Precautions (5.5)].
Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during SUTENT 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 SUTENT [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 SUTENT 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)].
Advise patients that SUTENT can cause thyroid dysfunction. Advise patient to contact their healthcare provider if symptoms of abnormal thyroid function occur [see Warnings and Precautions (5.10)].
Advise patients that SUTENT 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 (5.11)].
Osteonecrosis of the Jaw
Advise patients to consider preventive dentistry prior to treatment with SUTENT. Inform patients being treated with SUTENT, particularly who are receiving bisphosphonates, to avoid invasive dental procedures if possible [see Warnings and Precautions (5.12)].
If possible, avoid invasive dental procedures while on SUTENT treatment, particularly in patients receiving intravenous bisphosphonate therapy.
Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements [see Drug Interactions (7)].
Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see 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 SUTENT [see Warnings and Precautions (5.14) and Use in Specific Populations (8.1, 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 SUTENT [see Warnings and Precautions (5.14) and Use in Specific Populations (8.1, 8.3)].
Advise lactating women not to breastfeed during treatment with SUTENT and for at least 4 weeks after the last dose [see Use in Specific Populations (8.2)].
|This Medication Guide has been approved by the U.S. Food and Drug Administration.||Revised: November 2017|
SUTENT® (su TENT)
What is the most important information I should know about SUTENT?|
SUTENT can cause serious side effects including:
See "What are the possible side effects of SUTENT?" for more information about side effects.
What is SUTENT?|
SUTENT is a prescription medicine used to treat:
Before taking SUTENT tell your healthcare provider about all of your medical conditions, including if you:|
Tell your healthcare provider about all the medicines you take, including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements. Using SUTENT with certain other medicines can cause serious side effects.
You may have an increased risk of severe jaw bone problems (osteonecrosis) if you take SUTENT and a bisphosphonate medicine. Especially tell your healthcare provider if you are taking or have taken an osteoporosis medicine.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take SUTENT?|
What are possible side effects of SUTENT?|
SUTENT may cause serious side effects, including:
|Your healthcare provider may prescribe medicine for you to treat high blood pressure, if needed. Your healthcare provider may temporarily stop your treatment with SUTENT until your high blood pressure is controlled.|
|Your healthcare provider:
|Call your healthcare provider right away if you have any signs or symptoms of severe low blood sugar during your treatment with SUTENT.|
|The medicine in SUTENT is yellow, and it may make your skin look yellow. Your skin and hair may get lighter in color. SUTENT may also cause other skin problems including: dryness, thickness or cracking of the skin. |
These are not all of the possible side effects of SUTENT. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How do I store SUTENT?|
General information about the safe and effective use of SUTENT.|
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SUTENT for a condition for which it was not prescribed. Do not give SUTENT to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your healthcare provider or pharmacist for information about SUTENT that is written for health professionals.
What are the ingredients in SUTENT?|
Active ingredient: sunitinib malate
Inactive ingredients: mannitol, croscarmellose sodium, povidone (K-25), and magnesium stearate.
Orange gelatin capsule shells: titanium dioxide, and red iron oxide.
Caramel gelatin capsule shells: titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide.
Yellow gelatin capsule shells: titanium dioxide and yellow iron oxide.
White printing ink: shellac, propylene glycol, sodium hydroxide, povidone, and titanium dioxide.
Black printing ink: shellac, propylene glycol, potassium hydroxide and black iron oxide.
Gleevec® is a registered trademark of Novartis Pharmaceuticals Corporation.
For more information go to www.SUTENT.com or call 1-877-5-SUTENT.