SUNITEX

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 (2S)-hydroxybutanedioate acid.

The molecular formula is

C 22 H 27 FN 4 O 2.

• C 4 H 6 O and the molecular weight is 532.6 g/mol.

The chemical structure of sunitinib malate is: Sunitinib malate is a yellow or orange-yellow powder with a pKa of 8.95.

The solubility of sunitinib malate is slightly soluble in water, practically insoluble in ethanol.

Sunitinib malate capsules are supplied as printed hard-shell capsules containing 12.5 mg, 25 mg, 37.5 mg, and 50 mg of sunitinib (equivalent to 16.7 mg, 33.4 mg, 50.1 mg, and 66.8 mg of sunitinib malate, respectively).

The capsules contain the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, and povidone.

The orange gelatin capsule shells contain red iron oxide, and titanium dioxide; the caramel gelatin capsule shells contain black iron oxide, red iron oxide, titanium dioxide, and yellow iron oxide; and the yellow gelatin capsule shells contain titanium dioxide, and yellow iron oxide.

The white printing ink contains potassium hydroxide, propylene glycol, shellac, and titanium dioxide and the black printing ink contains black iron oxide, potassium hydroxide, propylene glycol, and shellac. image description.

Sunitinib malate is a kinase inhibitor indicated for: treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. treatment of adult patients with advanced renal cell carcinoma (RCC). adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease. 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.

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. 12.2 Pharmacodynamics Exposure-Response Relationship Based on population pharmacokinetic/pharmacodynamic analyses, there were relationships between changes in different pharmacodynamic endpoints (i.e., safety and efficacy endpoints) over time and sunitinib plasma exposures.

Cardiac Electrophysiology Sunitinib malate can cause

QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. 12.3 Pharmacokinetics The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy subjects and in patients with solid tumors.

Sunitinib AUC and

C max increase proportionately over a dose range of 25 mg to 100 mg (0.5 times to 2 times the approved RDD of 50 mg).

The pharmacokinetics were similar in healthy subjects and in patients with a solid tumor, including patients with GIST and RCC.

No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles.

With repeated daily administration, sunitinib accumulates 3-fold to 4-fold while the primary metabolite accumulates 7-fold to 10-fold.

Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 days to 14 days.

By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 63 ng/mL to 101 ng/mL.

Following oral administration of sunitinib, the time to maximum plasma concentration (T max ) ranged from 6 hours to 12 hours.

The administration of a single dose of sunitinib malate 50 mg with a high-fat, high-calorie meal (consisting of approximately 150 protein calories and to 600 fat calories) in healthy subjects had no clinically significant effect on sunitinib malate or active metabolites exposure.

The apparent volume of distribution (Vd/F) for sunitinib is 2,230 L. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro is 95% and 90%, respectively, with no concentration dependence in the range of 100 ng/mL to 4,000 ng/mL.

Following administration of a single oral dose in healthy subjects, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 hours to 60 hours and 80 hours to 110 hours, respectively.

Sunitinib total oral clearance (CL/F) ranged from 34 L/h to 62 L/h with an interpatient variability of 40%.

Metabolism Sunitinib is metabolized primarily by

CYP3A4 to its primary active metabolite, which is further metabolized by CYP3A4.

The primary active metabolite comprises 23% to 37% of the total exposure.

After a radio-labeled dose, sunitinib and its active metabolite were the major compounds identified in plasma, accounting for 92% of radioactivity.

After a radio-labeled dose of sunitinib, approximately 61% of the dose was recovered in feces and 16% in urine.

Sunitinib and its primary active metabolite were the major compounds identified in urine and feces, representing 86% and 74% of radioactivity, respectively.

No clinically significant differences in the pharmacokinetics of sunitinib or the primary active metabolite were observed based on age (18 years to 84 years), body weight (34 kg to 168 kg), race (White, Black, or Asian), sex, Eastern Cooperative Oncology Group (ECOG) score, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

No clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite were predicted or observed in patients with mild (CLcr 50 mL/min to 80 mL/min), moderate (CLcr 30 mL/min to <50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis, 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 end stage renal disease (ESRD) on hemodialysis compared to patients with normal renal function.

Drug Interaction Studies Clinical Studies Effect of strong CYP3A4 inhibitors on sunitinib: Co-administration of a single sunitinib malate dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite C max and AUC 0-inf by 49% and 51%, respectively, in healthy subjects.

Effect of strong

CYP3A4 inducers on sunitinib: Co-administration of a single sunitinib malate dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite C max and AUC 0-inf by 23% and 46%, respectively in healthy subjects.

In vitro studies in human hepatocytes and microsomes indicated that sunitinib and the primary active metabolite do not induce CYP1A2, CYP2E1, and CYP3A4/5, or inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 at clinically relevant concentrations.

The following clinically significant adverse reactions are described elsewhere in the labeling.

Hepatotoxicity Cardiovascular Events QT Interval Prolongation and Torsade de Pointes Hypertension Hemorrhagic Events Tumor Lysis Syndrome Thrombotic Microangiopathy Proteinuria Dermatologic Toxicities Reversible Posterior Leukoencephalopathy Syndrome Thyroid Dysfunction Hypoglycemia Osteonecrosis of the Jaw Impaired Wound Healing 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.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 malate in 7,527 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.

The safety of sunitinib malate was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib malate 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 malate (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 malate arm.

Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib malate.

Table 3 summarizes the adverse reactions for Study 1.

Table 3.

Reported in ≥10% of GIST Patients Who Received Sunitinib Malate in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo in Study 1 Adverse Reaction GIST Sunitinib Malate (N = 202) Placebo (N = 102) All Grades % Grade to 4 % All Grades % Grade 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.

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 malate.

Table 4 summarizes the laboratory abnormalities in Study 1.

Table 4.

Reported in ≥10% of GIST Patients Who Received Sunitinib Malate or Placebo in the Double-Blind Treatment Phase in Study 1 Laboratory Abnormality GIST Sunitinib Malate (N = 202) Placebo (N = 102) All Grades % Grade to 4 ,a % All Grades % Grade 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.

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 malate 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 malate.

For 241 patients randomized to the sunitinib malate arm, including 139 who received sunitinib malate in both the double-blind and open-label phases, the median duration of sunitinib malate treatment was 6 cycles (mean: 8.5; range: 1 to 44).

For the 255 patients who ultimately received open-label sunitinib malate 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 malate.

Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received sunitinib malate.

The most common

Grade 3 or 4 adverse reactions in patients who received sunitinib malate in the open-label 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%).

The safety of sunitinib malate was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received sunitinib malate 50 mg daily on Schedule 4/2 (n = 375) or interferon alfa 9 million International Units (MIU) (n = 360).

The median duration of treatment was 11.1 months (range: 0.4 to 46.1) for sunitinib malate treatment and 4.1 months (range: 0.1 to 45.6) for interferon alfa treatment.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients in the sunitinib malate arm.

Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received sunitinib malate.

Table 5 summarizes the adverse reactions for Study 3.

Table 5.

Reported in ≥10% of Patients with RCC Who Received Sunitinib Malate or Interferon Alfa in Study 3 Adverse Reaction Treatment-Naïve RCC Sunitinib Malate (N = 375) Interferon Alfa (N = 360) All Grades % Grade to 4 a % All Grades % Grade to 4 b % Any Adverse Reaction 99 77 99 55 Gastrointestinal Diarrhea 66 10 21 <1 Nausea 58 6 41 2 Mucositis/stomatitis 47 3 5 <1 Vomiting 39 5 17 1 Dyspepsia 34 2 4 0 Abdominal pain c 30 5 12 1 Constipation 23 1 14 <1 Dry mouth 13 0 7 <1 Oral pain 14 <1 1 0 Flatulence 14 0 2 0 GERD/reflux esophagitis 12 <1 1 0 Glossodynia 11 0 1 0 Hemorrhoids 10 0 2 0 Constitutional Fatigue 62 15 56 15 Asthenia 26 11 22 6 Fever 22 1 37 <1 Weight decreased 16 <1 17 1 Chills 14 1 31 0 Chest Pain 13 2 7 1 Influenza like illness 5 0 15 <1 Metabolism/Nutrition Anorexia d 48 3 42 2 Neurology Altered taste e 47 <1 15 0 Headache 23 1 19 0 Dizziness 11 <1 14 1 Hemorrhage/Bleeding Bleeding, all sites 37 4 f 10 1 Cardiac Hypertension 34 13 4 <1 Edema peripheral 24 2 5 1 Ejection fraction decreased 16 3 5 2 Dermatology Rash 29 2 11 <1 Hand-foot syndrome 29 8 1 0 Skin discoloration/yellow skin 25 <1 0 0 Dry skin 23 <1 7 0 Hair color changes 20 0 <1 0 Alopecia 14 0 9 0 Erythema 12 <1 1 0 Pruritus 12 <1 7 <1 Musculoskeletal Pain in extremity/limb discomfort 40 5 30 2 Arthralgia 30 3 19 1 Back pain 28 5 14 2 Respiratory Cough 27 1 14 <1 Dyspnea 26 6 20 4 Nasopharyngitis 14 0 2 0 Oropharyngeal pain 14 <1 2 0 Upper respiratory tract infection 11 <1 2 0 Endocrine Hypothyroidism 16 2 1 0 Psychiatric Insomnia 15 <1 10 0 Depression g 11 0 14 1 Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. a Grade 4 ARs in patients on sunitinib malate included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%). b Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%). c Includes flank pain. d Includes decreased appetite. e Includes ageusia, hypogeusia, and dysgeusia. f Includes 1 patient with Grade 5 gastric hemorrhage. g Includes depressed mood.

Table 6 summarizes the laboratory abnormalities in Study 3.

Table 6.

Reported in ≥10% of RCC Patients Who Received Sunitinib Malate or Interferon Alfa in Study 3 Laboratory Abnormality Treatment-Naïve RCC Sunitinib Malate (N = 375) Interferon Alfa (N = 360) All Grades % Grade to 4 ,a % All Grades % Grade to 4 ,b % Hematology Hemoglobin decreased 79 8 69 5 Neutrophils decreased 77 17 49 9 Platelets decreased 68 9 24 1 Lymphocytes decreased 68 18 68 26 Renal/Metabolic Creatinine increased 70 <1 51 <1 Creatine kinase increased 49 2 11 1 Uric acid increased 46 14 33 8 Calcium decreased 42 1 40 1 Phosphorus decreased 31 6 24 6 Albumin decreased 28 1 20 0 Glucose increased 23 6 15 6 Sodium decreased 20 8 15 4 Glucose decreased 17 0 12 <1 Potassium increased 16 3 17 4 Calcium increased 13 <1 10 1 Potassium decreased 13 1 2 <1 Sodium increased 13 0 10 0 Gastrointestinal AST increased 56 2 38 2 Lipase increased 56 18 46 8 ALT increased 51 3 40 2 Alkaline phosphatase increased 46 2 37 2 Amylase increased 35 6 32 3 Total bilirubin increased 20 1 2 0 Indirect bilirubin increased 13 1 1 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; RCC = renal cell carcinoma. a Grade 4 laboratory abnormalities in patients on sunitinib malate included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), glucose increased (<1%), calcium decreased (<1%), phosphorous (<1%), potassium increased (<1%), and sodium decreased (<1%). b Grade 4 laboratory abnormalities in patients on interferon alfa included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%).

The long-term safety of sunitinib malate 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 5,739 patients, of whom 807 (14%) were treated for at least 2 years and 365 (6%) for at least 3 years.

Prolonged treatment with sunitinib malate did not appear.

Treatment of overdose with sunitinib malate should consist of general supportive measures.

There is no specific antidote for overdosage with sunitinib malate.

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 malate, or without adverse reactions.

In nonclinical studies, mortality was observed following as few as 5 daily doses of 500 mg/kg (3,000 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.

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).

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. pNET: The recommended dosage is 37.5 mg orally once daily. 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 Grade 3 Withhold until resolution to Grade to 1 or baseline.

Resume at a reduced dose.

For recurring

Grade 3 permanently discontinue.

Grade 4 Permanently discontinue.

Cardiovascular events

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 to 1 or baseline.

Resume at reduced dose.

Clinically manifested congestive heart failure (CHF) Permanently discontinue.

Grade 3 Withhold until resolution to Grade to 1 or baseline.

Hemorrhagic events

Grade 3 or 4 Withhold until resolution to Grade to 1 or baseline.

Either resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction.

Thrombotic microangiopathy Any Grade

Permanently discontinue.

Proteinuria or

Nephrotic syndrome 3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome Withhold until resolution to Grade to 1 or baseline.

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 Any Grade Permanently discontinue.

Reversible posterior leukoencephalopathy syndrome Any Grade Permanently discontinue.

Osteonecrosis of the jaw 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 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: 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. 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.

However, given the decreased exposure compared to patients with normal renal function, subsequent doses may be increased gradually up to 2-fold based on safety and tolerability.

Sunitinib malate capsules, 12.5 mg are supplied as yellow to orange-yellow granules filled in hard gelatin capsule with orange opaque cap and orange opaque body, imprinted with “STN” on the cap and “12.5 mg” on the body with white ink.

Bottles of 28 capsules: NDC 82293-014-10 Sunitinib malate capsules, 25 mg are supplied as yellow to orange-yellow granules filled in hard gelatin capsule with caramel opaque cap and orange opaque body, imprinted with “STN” on the cap and “25 mg” on the body with white ink.

Bottles of 28 capsules: NDC 82293-015-10 Sunitinib malate capsules, 37.5 mg are supplied as yellow to orange-yellow granules filled in hard gelatin capsule with yellow opaque cap and yellow opaque body, imprinted with “STN” on the cap and “37.5 mg” on the body with black ink.

Bottles of 28 capsules: NDC 82293-016-10 Sunitinib malate capsules, 50 mg are supplied as yellow to orange-yellow granules filled in hard gelatin capsule with caramel opaque cap and caramel opaque body, imprinted with “STN” on the cap and “50 mg” on the body with white ink.

Bottles of 28 capsules: NDC 82293-017-10 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Dispense in tight containers (USP).

Based on animal reproduction studies and its mechanism of action, sunitinib malate can cause fetal harm when administered to a pregnant woman.

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 times 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.

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.

In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5 mg/kg/day, 1.5 mg/kg/day, 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 mg/kg/day, 1.5 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day) and rabbits (0.5 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day, 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 mg/kg/day, 1 mg/kg/day, 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.

The safety and effectiveness of sunitinib malate 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 malate has not been adequately studied.

Data below.

Physeal dysplasia was present in cynomolgus monkeys with open growth plates treated with sunitinib for ≥3 months (3-month dosing 2 mg/kg/day, 6 mg/kg/day, 12 mg/kg/day; 8 cycles of dosing 0.3 mg/kg/day, 1.5 mg/kg/day, 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 mg/kg, 5.0 mg/kg, and 15.0 mg/kg) or 5 cycles (0.3 mg/kg/day, 1.5 mg/kg/day, 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.

Of the 7527 patients with GIST, RCC (advanced and adjuvant), or pNET who received sunitinib malate, 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 malate were 65 years and older.

In the mRCC study, 152 (41%) of patients who received sunitinib malate 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 malate were 65 years and older.

Clinical studies of sunitinib malate did not include sufficient numbers of patients with pNET to determine if patients 65 years of age and older respond differently than younger patients.