Sunitinib Malate

RECENT MAJOR CHANGES SECTION Dosage and Administration, Dosage Modifications for Adverse Reactions ( 2.4 ) 8/2021 Dosage and Administration, Dosage Modification for Drug Interactions ( 2.5 ) 8/2021 Warnings and Precautions, Hepatotoxicity ( 5.1 ) 8/2021 Warnings and Precautions, Hypertension ( 5.4 ) 8/2021 Warnings and Precautions, Hemorrhagic Events and Viscous Perforation ( 5.5 ) 8/2021 Warnings and Precautions, Reversible Posterior Leukoencephalopathy Syndrome ( 5.10 ) 8/2021 Warnings and Precautions, Hypoglycemia ( 5.12 ) 8/2021 Warnings and Precautions, Osteonecrosis of the Jaw ( 5.13 ) 8/2021

1 INDICATIONS AND USAGE Sunitinib malate capsules are a kinase inhibitor indicated for: • treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. ( 1.1 ) • treatment of adult patients with advanced renal cell carcinoma (RCC). ( 1.2 ) • adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. ( 1.3 ) • treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease. ( 1.4 ) 1.1 Gastrointestinal Stromal Tumor Sunitinib malate capsules are indicated for the treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. 1.2 Advanced Renal Cell Carcinoma Sunitinib malate capsules are indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC). 1.3 Adjuvant Treatment of Renal Cell Carcinoma Sunitinib malate capsules are indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. 1.4 Advanced Pancreatic Neuroendocrine Tumors Sunitinib malate capsules are indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.

2 DOSAGE AND ADMINISTRATION GIST and Advanced RCC : • The recommended dosage is 50 mg orally once daily for the first 4 weeks of each 6-week cycle (Schedule 4/2). ( 2.1 ) Adjuvant Treatment of RCC : • The recommended dosage is 50 mg orally once daily for the first 4 weeks of a 6-week cycle (Schedule 4/2) for a maximum of 9 cycles. ( 2.2 ) pNET : • The recommended dosage is 37.5 mg orally once daily. ( 2.3 ) 2.1 Recommended Dosage for GIST and Advanced RCC The recommended dosage of sunitinib malate capsules for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) until disease progression or unacceptable toxicity. Sunitinib malate capsules may be taken with or without food. 2.2 Recommended Dosage for Adjuvant Treatment of RCC The recommended dosage of sunitinib malate capsules for the adjuvant treatment of RCC is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2), for nine 6-week cycles. Sunitinib malate capsules may be taken with or without food. 2.3 Recommended Dosage for pNET The recommended dosage of sunitinib malate capsules for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity. Sunitinib malate capsules may be taken with or without food. 2.4 Dosage Modifications for Adverse Reactions To manage adverse reactions, the recommended dosage modifications are provided in Table 1. Table 2 provides the recommended dosage reductions of sunitinib malate capsules for adverse reactions . Table 1. Recommended Dosage Reductions of Sunitinib Malate Capsules for Adverse Reactions Indications GIST RCC pNET Advanced RCC Adjuvant RCC First dose reduction 37.5 mg once daily 37.5 mg once daily 37.5 mg once daily 25 mg once daily Second dose reduction 25 mg once daily 25 mg once daily NA NA Table 2. Recommended Dosage Modifications for Sunitinib Malate Capsules for Adverse Reactions Adverse Reaction Severity Dosage Modifications for Sunitinib Malate Capsules Hepatotoxicity [see Warnings and Precautions (5.1) ] Grade 3 • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. • For recurring Grade 3 permanently discontinue. Grade 4 • Permanently discontinue. Cardiovascular events [see Warnings and Precautions (5.2) ] Asymptomatic cardiomyopathy (left ventricular ejection fraction greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline was not obtained) • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at reduced dose. Clinically manifested congestive heart failure (CHF) • Permanently discontinue. Hypertension [see Warnings and Precautions (5.4) ] Grade 3 • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. Grade 4 • Permanently discontinue. Hemorrhagic events [see Warnings and Precautions (5.5) ] Grade 3 or 4 • Withhold until resolution to Grade 0 to 1 or baseline. • Either resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction. Thrombotic microangiopathy [see Warnings and Precautions (5.7) ] Any Grade • Permanently discontinue. Proteinuria or Nephrotic syndrome [see Warnings and Precautions (5.8) ] 3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. Nephrotic syndrome or recurrent proteinuria of 3 or more grams per 24 hours despite dose reductions • Permanently discontinue. Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis [see Warnings and Precautions (5.9) ] Any Grade • Permanently discontinue. Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10) ] Any Grade • Permanently discontinue. Oste …

3 DOSAGE FORMS AND STRENGTHS Sunitinib Malate Capsules are available containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib equivalent to 16.7 mg, 33.4 mg, 50.1 mg or 66.8 mg of sunitinib malate, respectively. • The 12.5 mg capsules are hard-shell gelatin capsules with a pink-brown opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 12.5 in black ink on cap and body. • The 25 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 25 in black ink on cap and body. • The 37.5 mg capsules are hard-shell gelatin capsules with an ivory opaque cap and ivory opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 37.5 in black ink on cap and body. • The 50 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and yellow opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 50 in black ink on cap and body. • Capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg sunitinib ( 3 )

4 CONTRAINDICATIONS None. • None ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. Hepatotoxicity [see Warnings and Precautions (5.1)] Cardiovascular Events [see Warnings and Precautions (5.2)] QT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3)] Hypertension [see Warnings and Precautions (5.4)] Hemorrhagic Events [see Warnings and Precautions (5.5)] Tumor Lysis Syndrome [see Warnings and Precautions (5.6)] Thrombotic Microangiopathy [see Warnings and Precautions (5.7)] Proteinuria [see Warnings and Precautions (5.8)] Dermatologic Toxicities [see Warnings and Precautions (5.9)] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10)] Thyroid Dysfunction [see Warnings and Precautions (5.11)] Hypoglycemia [see Warnings and Precautions (5.12)] Osteonecrosis of the Jaw [see Warnings and Precautions (5.13)] Impaired Wound Healing [see Warnings and Precautions (5.14)] The most common adverse reactions (≥ 25%) are fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the Warnings and Precautions reflect exposure to sunitinib in 7527 patients with GIST, RCC (advanced and adjuvant), or pNET. In this pooled safety population, the most common adverse reactions (≥ 25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. Gastrointestinal Stromal Tumor The safety of sunitinib was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib 50 mg daily on Schedule 4/2 (n = 202) or placebo (n = 102). Median duration of blinded study treatment was 2 cycles for patients on sunitinib (mean: 3.0; range: 1 to 9) and 1 cycle (mean; 1.8; range: 1 to 6) for patients on placebo at the time of the interim analysis. Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the sunitinib arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib. Table 3 summarizes the adverse reactions for Study 1. Table 3. Adverse Reactions Reported in ≥ 10% of GIST Patients Who Received Sunitinib in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo* in Study 1 Adverse Reactions GIST Sunitinib (N = 202) Placebo (N = 102) All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Any Adverse Reaction 94 56 97 51 Gastrointestinal Diarrhea 40 4 27 0 Mucositis/stomatitis 29 1 18 2 Constipation 20 0 14 2 Metabolism/Nutrition Anorexia a 33 1 29 5 Asthenia 22 5 11 3 Dermatology Skin discoloration 30 0 23 0 Rash 14 1 9 0 Hand-foot syndrome 14 4 10 3 Neurology Altered taste 21 0 12 0 Cardiac Hypertension 15 4 11 0 Musculoskeletal Myalgia/limb pain 14 1 9 1 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients. a Includes decreased appetite. Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received sunitinib. Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory …

7 DRUG INTERACTIONS • CYP3A4 Inhibitors : Consider dose reduction of sunitinib malate capsules when administered with strong CYP3A4 inhibitors. ( 7.1 ) • CYP3A4 Inducers : Consider dose increase of sunitinib malate capsules when administered with strong CYP3A4 inducers. ( 7.1 ) 7.1 Effect of Other Drugs on Sunitinib Malate Capsules Strong CYP3A4 Inhibitors Co-administration with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations [see Clinical Pharmacology (12.3) ] . Select an alternate concomitant medication with no or minimal enzyme inhibition potential. Consider a dose reduction for sunitinib malate capsules when it is co-administered with strong CYP3A4 inhibitors [see Dosage and Administration (2.5) ] . Strong CYP3A4 Inducers Co-administration with strong CYP3A4 inducers may decrease sunitinib plasma concentrations [see Clinical Pharmacology (12.3) ]. Select an alternate concomitant medication with no or minimal enzyme induction potential. Consider a dose increase for sunitinib malate capsules when it must be co-administered with CYP3A4 inducers [see Dosage and Administration (2.5) ] . 7.2 Drugs that Prolong QT Interval Sunitinib malate capsules are associated with QTc interval prolongation [see Warnings and Precautions (5.3) , Clinical Pharmacology (12.2) ] . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, sunitinib malate 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 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 (see Data). Advise females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5 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. 8.2 Lactation There is no information regarding the presence of sunitinib and its metabolites in human milk. Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12-fold higher than in plasma (see Data) . Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with sunitinib malate and for at least 4 weeks after the last dose. Data Animal Data In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were excreted in milk at concentrations up to 12-fold higher than in plasma. 8.3 Females and Males of Reproductive Potential Sunitinib malate can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status of …

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 .

11 DESCRIPTION Sunitinib is a kinase inhibitor present in sunitinib malate capsules as the malate salt. Sunitinib malate is described chemically as (2S)-2-hydroxybutanedoic acid 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 C 22 H 27 FN 4 O 2 • C 4 H 6 O 5 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 8.56.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. Sunitinib malate capsules, for oral use, are supplied as printed hard shell capsules containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib (equivalent to 16.7 mg, 33.4 mg, 50.1 mg, or 66.8 mg of sunitinib malate, respectively). The capsules contain the following inactive ingredients: croscarmellose sodium, mannitol, magnesium stearate and pregelatinized starch as inactive ingredients. In addition 12.5 mg capsule shell contains gelatin, titanium dioxide and red iron oxide. The white printing ink contains shellac, propylene glycol, potassium hydroxide and titanium dioxide. In addition 25 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide and red iron oxide. The white printing ink contains shellac, propylene glycol, potassium hydroxide and titanium dioxide. In addition 37.5 mg capsule shell contains gelatin, titanium dioxide and yellow iron oxide. The black printing ink contains shellac, propylene glycol, potassium hydroxide and black iron oxide. In addition 50 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, red iron oxide and black iron oxide. The white printing ink contains shellac, propylene glycol, potassium hydroxide and titanium dioxide. sunitinib-structure

10 OVERDOSAGE Treatment of overdose with sunitinib malate capsules should consist of general supportive measures. There is no specific antidote for overdosage with sunitinib malate capsules. 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 capsules, or without adverse reactions. In nonclinical studies, mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m 2 ) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection, and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

16 HOW SUPPLIED/STORAGE AND HANDLING Sunitinib Malate Capsules are available containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib equivalent to 16.7 mg, 33.4 mg, 50.1 mg or 66.8 mg of sunitinib malate, respectively. The 12.5 mg capsules are hard-shell gelatin capsules with a pink-brown opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 12.5 in black ink on cap and body. They are available as follows: NDC 0378-6678-28 bottles of 28 capsules The 25 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 25 in black ink on cap and body. They are available as follows: NDC 0378-6679-28 bottles of 28 capsules The 37.5 mg capsules are hard-shell gelatin capsules with an ivory opaque cap and ivory opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 37.5 in black ink on cap and body. They are available as follows: NDC 0378-6681-28 bottles of 28 capsules The 50 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and yellow opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 50 in black ink on cap and body. They are available as follows: NDC 0378-6680-28 bottles of 28 capsules Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.