FOTIVDA

6 ADVERSE REACTIONS The following clinically significant adverse reactions are also described elsewhere in the labeling: Hypertension and Hypertensive Crisis [see WARNINGS AND PRECAUTIONS (5.1) ] Cardiac Failure [see WARNINGS AND PRECAUTIONS (5.2) ] Cardiac Ischemia and Arterial Thromboembolic Events [see WARNINGS AND PRECAUTIONS (5.3) ] Venous Thromboembolic Events [see WARNINGS AND PRECAUTIONS (5.4) ] Hemorrhagic Events [see WARNINGS AND PRECAUTIONS (5.5) ] Proteinuria [see WARNINGS AND PRECAUTIONS (5.6) ] Gastrointestinal Perforation and Fistula Formation [see WARNINGS AND PRECAUTIONS (5.7) ] Thyroid Dysfunction [see WARNINGS AND PRECAUTIONS (5.8) ] Risk of Impaired Wound Healing [see WARNINGS AND PRECAUTIONS (5.9) ] Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see WARNINGS AND PRECAUTIONS (5.10) ] The most common (≥20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis, and the most common Grade 3 or 4 laboratory abnormalities (≥5%) were sodium decreased, lipase increased, and phosphate decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AVEO Pharmaceuticals, Inc. at 1-833-FOTIVDA (1-833-368-4832) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to FOTIVDA administered at 1.34 mg orally once daily with or without food for 21 days on treatment followed by 7 days off treatment for a 28-day cycle in 1008 patients with advanced RCC in TIVO-3 and five other monotherapy studies. Among 1008 patients who received FOTIVDA, 52% were exposed for 6 months or longer and 34% were exposed for greater than one year. Relapsed or Refractory Advanced RCC Following Two or More Prior Systemic Therapies The safety of FOTIVDA was evaluated in TIVO-3, a randomized, open-label trial in 350 patients with relapsed or refractory advanced RCC who received 2 or 3 prior systemic treatments [see CLINICAL STUDIES (14) ] . Patients were randomized (1:1) to receive FOTIVDA 1.34 mg orally once daily for 21 days on treatment followed by 7 days off treatment for a 28-day cycle, or to receive sorafenib 400 mg orally twice a day continuously until disease progression or unacceptable toxicity. Among patients who received FOTIVDA, 53% were exposed for 6 months or longer and 31% were exposed for greater than one year. Serious adverse reactions occurred in 45% of patients who received FOTIVDA. Serious adverse reactions in > 2% of patients included bleeding (3.5%), venous thromboembolism (3.5%), arterial thromboembolism (2.9%), acute kidney injury (2.3%), and hepatobiliary disorders (2.3%). Fatal adverse reactions occurred in 8% of patients who received FOTIVDA, including pneumonia (1.7%), hepatobiliary disorders (1.2%), respiratory failure (1.2%), myocardial infarction (0.6%), cerebrovascular accident (0.6%), and subdural hematoma (0.6%). Permanent discontinuation of FOTIVDA due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent discontinuation of FOTIVDA in > 2 patients included hepatobiliary disorders, fatigue, and pneumonia. Dosage interruptions of FOTIVDA due to an adverse reaction occurred in 48% of patients. Adverse reactions which required dosage interruption in > 5% of patients included fatigue, hypertension, decreased appetite, and nausea. Dose reductions of FOTIVDA due to an adverse reaction occurred in 24% of patients. Adverse reactions which required dose reductions in > 3% of patients included fatigue, diarrhea, and decreased appetite. The most common (≥ 20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis, and the most common Grade 3 or 4 laboratory abnormalities (≥ 5%) were sodium decreased, lipase increased, and phosphate decreased. Table 2 summarizes the adverse reactions in TIVO-3. Table 2. Adverse Reactions (≥ 15%) in Patients Who Received FOTIVDA in TIVO-3 Adverse Reaction FOTIVDA (n = 173) Sorafenib (n = 170) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Any 99 67 100 72 General Fatigue Includes fatigue and asthenia 67 13 48 12 Vascular Hypertension Includes hypertension, blood pressure increased, hypertensive crisis 44 24 31 17 Bleeding Includes hematuria, epistaxis, hemoptysis, hematoma, rectal hemorrhage, vaginal hemorrhage, contusion, gastrointestinal hemorrhage, hematochezia, intraocular hematoma, melena, metrorrhagia, pulmonary hemorrhage, subdural hematoma, gingival bleeding, hematemesis, hemorrhage intracranial, hemorrhoidal hemorrhage, splinter hemorrhages 17 3 12 1 Gastrointestinal Diarrhea Includes diarrhea and frequent bowel movements 43 2 54 11 Nausea 30 0 18 4 Stomatitis 21 2 23 2 Vomiting 18 1 17 2 Metabolism and nutrition Decreased appetite 39 5 30 4 Respiratory, thoracic, and mediastinal Dysphonia 27 1 9 0 Cough 22 0 15 1 Dyspnea 15 3 11 1 Endocrine Hypothyroidism Includes hypothyroidism, blood thyroid stimulating hormone increased, tri-iodothyronine decreased, tri-iodothyronine free decreased 24 1 11 0 Musculoskeletal Back pain 19 2 16 2 Skin and subcutaneous tissue disorders Rash Includes dermatitis, dermatitis acneiform, dermatitis contact, drug eruption, eczema, eczema nummular, erythema, erythema multiforme, photosensitivity reaction, pruritus, psoriasis, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, seborrheic dermatitis, skin exfoliation, skin irritation, skin lesion, swelling face, toxic skin eruption, urticaria 18 1 52 15 Palmar-plantar erythrodysesthesia syndrome 16 1 41 17 Investigations Weight decreased 17 3 22 3 Clinically relevant adverse reactions in < 15% of patients who received FOTIVDA included proteinuria, venous thromboembolism, arterial thromboembolism, hyperthyroidism, hepatobiliary disorders, osteonecrosis, cardiac failure, and delirium. Table 3 summarizes the laboratory abnormalities in TIVO-3. Table 3. Select Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with Advanced RCC Who Received FOTIVDA Laboratory Abnormality FOTIVDA The denominator used to calculate the rate varied from 139 to 171 based on the number of patients with a baseline value and at least one post-treatment value. (n = 173) Sorafenib (n = 170) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 25 5 42 6 Hemoglobin increased 19 0 8 0 Platelets decreased 19 0 18 1 Hemoglobin decreased 16 1 27 4 Chemistry Creatinine increased 50 0 37 1 Glucose increased 50 3 40 0 Phosphate decreased 38 5 63 31 Sodium decreased 36 9 30 11 Lipase increased 32 9 36 10 ALT increased 30 4 29 2 Alkaline phosphatase increased 30 4 32 2 AST increased 28 1 31 2 Potassium increased 26 3 23 0 Magnesium decreased 26 0 23 1 Amylase increased 23 2 28 3 Calcium increased 15 2 7 2 Bilirubin increased 11 3 11 0 Coagulation Activated partial thromboplastin time prolonged 26 1 18 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of FOTIVDA. 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. Gastrointestinal disorders: Gastrointestinal perforation and pancreatitis

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Tivozanib is a kinase inhibitor. Tivozanib hydrochloride, the active ingredient, has the chemical name 1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea hydrochloride hydrate. The molecular formula is C 22 H 19 ClN 4 O 5 ∙ HCl ∙ H 2 O and the molecular weight is 509.34 Daltons. The chemical structure is: Tivozanib hydrochloride is a white to light brown crystalline powder that is practically insoluble in water (0.09 mg/mL). FOTIVDA 1.34 mg capsule contains 1.5 mg of tivozanib hydrochloride (equivalent to 1.34 mg tivozanib) with inactive ingredients: mannitol and magnesium stearate. Capsule composition: gelatin, titanium dioxide, FDA yellow iron oxide, and Blue SB-6018 (ink). FOTIVDA 0.89 mg capsule contains 1.0 mg of tivozanib hydrochloride (equivalent to 0.89 mg tivozanib) with inactive ingredients: mannitol and magnesium stearate. Capsule composition: gelatin, titanium dioxide, FDA yellow iron oxide, FD&C Blue #2, Blue SB-6018 (ink) and Yellow SB-3017 (ink). The Yellow SB-3017 ink contains FD&C Yellow No.5 (tartrazine). Chemical Structure

2 DOSAGE AND ADMINISTRATION Recommended Dose: 1.34 mg once daily with or without food for 21 days on treatment followed by 7 days off treatment (28-day cycle) until disease progression or unacceptable toxicity. ( 2.1 ) Dose interruptions and/or dose reduction may be needed to manage adverse reactions. ( 2.2 ) For patients with moderate hepatic impairment, reduce the dose to 0.89 mg for 21 days on treatment followed by 7 days off treatment (28-day cycle). ( 2.3 ) 2.1 Recommended Dosing The recommended dosage of FOTIVDA is 1.34 mg taken orally once daily for 21 days on treatment followed by 7 days off treatment for a 28-day cycle. Continue treatment until disease progression or until unacceptable toxicity occurs. Take FOTIVDA with or without food. Swallow the FOTIVDA capsule whole with a glass of water. Do not open the capsule. If a dose is missed, the next dose should be taken at the next scheduled time. Do not take two doses at the same time. 2.2 Dose Modifications for Adverse Reactions Initiate medical management for diarrhea, nausea, or vomiting prior to dose interruption or reduction. If dose modifications are required for adverse reactions, reduce the dosage of FOTIVDA to 0.89 mg for 21 days on treatment followed by 7 days off treatment for a 28-day cycle. Recommendations for dosage modifications are provided in Table 1 . Table 1. Dosage Modifications for Adverse Reactions Adverse Reaction Severity Grades are based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Dosage Modifications for FOTIVDA Hypertension [see Warnings and Precautions (5.1) ] Grade 3 Withhold for Grade 3 that persists despite optimal anti-hypertensive therapy. Resume at reduced dose when hypertension is controlled at less than or equal to Grade 2. Grade 4 Permanently discontinue. Cardiac Failure [see Warnings and Precautions (5.2) ] Grade 3 Withhold until improves to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction. Grade 4 Permanently discontinue. Arterial Thromboembolic Events [see Warnings and Precautions (5.3) ] Any Grade Permanently discontinue. Hemorrhagic Events [see Warnings and Precautions (5.5) ] Grade 3 or 4 Permanently discontinue. Proteinuria [see Warnings and Precautions (5.6) ] 2 grams or greater proteinuria in 24 hours Withhold until less than or equal to 2 grams of proteinuria per 24 hours. Resume at a reduced dose. Permanently discontinue for nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10) ] Any Grade Permanently discontinue. Other Adverse Reactions Persistent or intolerable Grade 2 or 3 adverse reaction Grade 4 laboratory abnormality Withhold until improves to Grade 0 to 1 or baseline. Resume at reduced dose. Grade 4 adverse reaction Permanently discontinue. 2.3 Dosage Modifications for Moderate Hepatic Impairment Reduce the recommended dosage of FOTIVDA to 0.89 mg capsule taken orally once daily for 21 days on treatment followed by 7 days off treatment for a 28-day cycle for patients with moderate hepatic impairment [see USE IN SPECIFIC POPULATIONS (8.7) ].

10 OVERDOSAGE Overdosage with FOTIVDA can cause severe hypertension and hypertensive crisis that may result in death [see WARNINGS AND PRECAUTIONS (5.1) ] . During clinical studies, three patients inadvertently received doses ≥ 2.68 mg (≥ 2 times the recommended dose) of FOTIVDA. One patient who received two daily doses of 8.9 mg of FOTIVDA experienced hypertensive crisis with severe hypertensive retinopathy; a second patient who received three doses of 1.34 mg in one day experienced fatal uncontrolled hypertension; and a third patient who received two doses of 1.34 mg FOTIVDA in one day experienced persistent hypertension lasting over 5 days. There is no specific treatment or antidote for FOTIVDA overdose. In cases of suspected overdose, withhold FOTIVDA, closely monitor patients for hypertension and hypertensive crisis and other potential adverse reactions. Immediately manage signs or symptoms of hypertension and provide other supportive care as clinically indicated.

7 DRUG INTERACTIONS CYP3A Inducers: Avoid concomitant use of strong CYP3A inducers. ( 7.1 ) 7.1 Effect of Other Drugs on FOTIVDA Strong CYP3A Inducers Concomitant use of FOTIVDA with a strong CYP3A inducer decreases tivozanib exposure [see CLINICAL PHARMACOLOGY (12.3) ], which may reduce FOTIVDA anti-tumor activity. Avoid concomitant use of strong CYP3A inducers with FOTIVDA.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tivozanib is a tyrosine kinase inhibitor. In vitro cellular kinase assays demonstrated that tivozanib inhibits phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3 and inhibits other kinases including c-kit and PDGFR β at clinically relevant concentrations. In tumor xenograft models in mice and rats, tivozanib inhibited angiogenesis, vascular permeability, and tumor growth of various tumor cell types including human renal cell carcinoma. 12.2 Pharmacodynamics Exposure-Response Relationship Tivozanib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology At the recommended dose of FOTIVDA, no large mean increases (i.e., 20 msec) in QTc interval were observed. 12.3 Pharmacokinetics The pharmacokinetics of tivozanib were evaluated in patients with solid tumors administered 1.34 mg once daily unless otherwise specified. Steady-state tivozanib AUC and C max increased in a dose-proportional manner over the dose range of 0.89 to 1.78 mg once daily (0.67 to 1.3 times the recommended dose). Steady-state was reached by 14 days and the accumulation ratio after administration of 1.34 mg once daily was approximately 6- to 7- fold. Mean steady-state tivozanib [coefficient of variation (CV%)] C max was 86.9 (44.7%) ng/mL and AUC 0-24h was 1510 (46.1%) ng*h/mL. Absorption The median T max of tivozanib is 10 hours with a range of 3 to 24 hours. Effect of Food No clinically significant differences in tivozanib AUC or C max were observed following administration of a high fat meal (approximately 500-600 fat calories, 250 carbohydrate calories and 150 protein calories) in healthy subjects. Distribution The apparent volume of distribution (V/F) of tivozanib is 123 L. Protein binding of tivozanib is ≥ 99%, primarily to albumin in vitro and is independent of concentration. The mean blood-to-plasma concentration ratios ranged from 0.495 to 0.615 in healthy subjects. Elimination The apparent clearance (CL/F) of tivozanib is 0.75 L/h and the half-life is 111 hours. Metabolism Tivozanib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 1.34 mg dose of tivozanib to healthy subjects, unchanged tivozanib constituted 90% of the radioactive drug components in serum. Excretion Following oral administration of a single radiolabeled 1.34 mg dose of tivozanib to healthy subjects, 79% of the administered dose was recovered in feces (26% unchanged) and 12% in urine (unchanged tivozanib not detected). Specific Populations No clinically significant differences in the pharmacokinetics of tivozanib were observed based on age (18 years to 88 years), sex, race (93% Caucasian, 3% African American, 2% Asian, 2% others), body weight (39 kg to 158 kg), mild to severe renal impairment (CLcr 15-89 mL/min as estimated by Cockcroft-Gault) or mild hepatic impairment (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST). The effect of end-stage renal disease or severe hepatic impairment on tivozanib pharmacokinetics is unknown [see USE IN SPECIFIC POPULATIONS (8.6) and (8.7) ] . Patients with Hepatic Impairment Compared to subjects with normal hepatic function, tivozanib AUC tau increased by 1% in patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) hepatic impairment. Compared to subjects with normal hepatic function, tivozanib AUC tau increased by 62% in patients with moderate (total bilirubin greater than 1.5 to 3 times ULN with any AST) hepatic impairment. The effect of severe (total bilirubin greater than 3 to 10 times ULN with any AST) hepatic impairment on tivozanib pharmacokinetics has not been studied [see DOSAGE AND ADMINISTRATION (2.3) and USE IN SPECIFIC POPLATIONS (8.7) ]. Drug Interaction Studies Clinical Studies Strong CYP3A Inducers : Concomitant use of multiple doses of rifampin (strong CYP3A inducer) did not change tivozanib C max but decreased tivozanib AUC 0-INF by 52%. Strong CYP3A Inhibitors : No clinically significant differences in the pharmacokinetics of tivozanib were observed when multiple doses of ketoconazole (strong CYP3A inhibitor) was coadministered with tivozanib. In Vitro Studies Cytochrome P450 (CYP) Enzymes : Tivozanib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at clinically relevant concentrations. Tivozanib does not induce CYP1A, CYP2B6, CYP2C9, CYP2C19, or CYP3A at clinically relevant concentrations. Uridine Diphosphate (UDP)-glucuronosyl Transferase (UGT) Enzymes : Tivozanib does not inhibit UGT at clinically relevant concentrations. Transporter Systems : Tivozanib inhibits BCRP but does not inhibit P-gp, OCT1, OATP1B1, OATP1B3, BSEP, OAT1, OAT3, OCT2, MATE1 or MATE2-K at clinically relevant concentrations. Tivozanib is not a substrate for P-gp, MRP2, BCRP, OCT1, OATP1B1, OATP1B3, or BSEP.

12.1 Mechanism of Action Tivozanib is a tyrosine kinase inhibitor. In vitro cellular kinase assays demonstrated that tivozanib inhibits phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3 and inhibits other kinases including c-kit and PDGFR β at clinically relevant concentrations. In tumor xenograft models in mice and rats, tivozanib inhibited angiogenesis, vascular permeability, and tumor growth of various tumor cell types including human renal cell carcinoma.

12.2 Pharmacodynamics Exposure-Response Relationship Tivozanib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology At the recommended dose of FOTIVDA, no large mean increases (i.e., 20 msec) in QTc interval were observed.

12.3 Pharmacokinetics The pharmacokinetics of tivozanib were evaluated in patients with solid tumors administered 1.34 mg once daily unless otherwise specified. Steady-state tivozanib AUC and C max increased in a dose-proportional manner over the dose range of 0.89 to 1.78 mg once daily (0.67 to 1.3 times the recommended dose). Steady-state was reached by 14 days and the accumulation ratio after administration of 1.34 mg once daily was approximately 6- to 7- fold. Mean steady-state tivozanib [coefficient of variation (CV%)] C max was 86.9 (44.7%) ng/mL and AUC 0-24h was 1510 (46.1%) ng*h/mL. Absorption The median T max of tivozanib is 10 hours with a range of 3 to 24 hours. Effect of Food No clinically significant differences in tivozanib AUC or C max were observed following administration of a high fat meal (approximately 500-600 fat calories, 250 carbohydrate calories and 150 protein calories) in healthy subjects. Distribution The apparent volume of distribution (V/F) of tivozanib is 123 L. Protein binding of tivozanib is ≥ 99%, primarily to albumin in vitro and is independent of concentration. The mean blood-to-plasma concentration ratios ranged from 0.495 to 0.615 in healthy subjects. Elimination The apparent clearance (CL/F) of tivozanib is 0.75 L/h and the half-life is 111 hours. Metabolism Tivozanib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 1.34 mg dose of tivozanib to healthy subjects, unchanged tivozanib constituted 90% of the radioactive drug components in serum. Excretion Following oral administration of a single radiolabeled 1.34 mg dose of tivozanib to healthy subjects, 79% of the administered dose was recovered in feces (26% unchanged) and 12% in urine (unchanged tivozanib not detected). Specific Populations No clinically significant differences in the pharmacokinetics of tivozanib were observed based on age (18 years to 88 years), sex, race (93% Caucasian, 3% African American, 2% Asian, 2% others), body weight (39 kg to 158 kg), mild to severe renal impairment (CLcr 15-89 mL/min as estimated by Cockcroft-Gault) or mild hepatic impairment (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST). The effect of end-stage renal disease or severe hepatic impairment on tivozanib pharmacokinetics is unknown [see USE IN SPECIFIC POPULATIONS (8.6) and (8.7) ] . Patients with Hepatic Impairment Compared to subjects with normal hepatic function, tivozanib AUC tau increased by 1% in patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) hepatic impairment. Compared to subjects with normal hepatic function, tivozanib AUC tau increased by 62% in patients with moderate (total bilirubin greater than 1.5 to 3 times ULN with any AST) hepatic impairment. The effect of severe (total bilirubin greater than 3 to 10 times ULN with any AST) hepatic impairment on tivozanib pharmacokinetics has not been studied [see DOSAGE AND ADMINISTRATION (2.3) and USE IN SPECIFIC POPLATIONS (8.7) ]. Drug Interaction Studies Clinical Studies Strong CYP3A Inducers : Concomitant use of multiple doses of rifampin (strong CYP3A inducer) did not change tivozanib C max but decreased tivozanib AUC 0-INF by 52%. Strong CYP3A Inhibitors : No clinically significant differences in the pharmacokinetics of tivozanib were observed when multiple doses of ketoconazole (strong CYP3A inhibitor) was coadministered with tivozanib. In Vitro Studies Cytochrome P450 (CYP) Enzymes : Tivozanib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at clinically relevant concentrations. Tivozanib does not induce CYP1A, CYP2B6, CYP2C9, CYP2C19, or CYP3A at clinically relevant concentrations. Uridine Diphosphate (UDP)-glucuronosyl Transferase (UGT) Enzymes : Tivozanib does not inhibit UGT at clinically relevant concentrations. Transporter Systems : Tivozanib inhibits BCRP but does not inhibit P-gp, OCT1, OATP1B1, OATP1B3, BSEP, OAT1, OAT3, OCT2, MATE1 or MATE2-K at clinically relevant concentrations. Tivozanib is not a substrate for P-gp, MRP2, BCRP, OCT1, OATP1B1, OATP1B3, or BSEP.

20241022

5

3 DOSAGE FORMS AND STRENGTHS Capsules: 1.34 mg: bright yellow opaque cap imprinted with "TIVZ" in dark blue ink and a bright yellow opaque body imprinted with "SD" in dark blue ink. 0.89 mg: dark blue opaque cap imprinted with "TIVZ" in yellow ink and a bright yellow opaque body imprinted with "LD" in dark blue ink. Capsules: 1.34 mg and 0.89 mg ( 3 )

FOTIVDA Tivozanib MANNITOL MAGNESIUM STEARATE TIVOZANIB HYDROCHLORIDE TIVOZANIB Dark Blue Bright Yellow TIVZ;LD FOTIVDA Tivozanib MANNITOL MAGNESIUM STEARATE TIVOZANIB HYDROCHLORIDE TIVOZANIB Bright Yellow TIZV;SD

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with tivozanib. Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay. In animal studies assessing mating and fertility parameters, oral doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m 2 basis) in rats were associated with increased epididymis and testis weights, and doses ≥ 0.3 mg/kg/day (2 times the maximum recommended clinical dose on a mg/m 2 basis) reduced mating and produced infertility. An increase in embryo lethality was noted at doses ≥ 0.1 mg/kg/day (0.7 times the maximum recommended clinical dose on a mg/m 2 basis).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with tivozanib. Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay. In animal studies assessing mating and fertility parameters, oral doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m 2 basis) in rats were associated with increased epididymis and testis weights, and doses ≥ 0.3 mg/kg/day (2 times the maximum recommended clinical dose on a mg/m 2 basis) reduced mating and produced infertility. An increase in embryo lethality was noted at doses ≥ 0.1 mg/kg/day (0.7 times the maximum recommended clinical dose on a mg/m 2 basis).

NDA212904

FOTIVDA

Tivozanib

45629-089

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 0.89 mg Capsule Bottle Label NDC 45629-089-01 FOTIVDA ® (tivozanib) capsules 0.89 mg Contains color additives including FD&C Yellow No. 5 (tartrazine) AVEO ONCOLOGY PRINCIPAL DISPLAY PANEL - 0.89 mg Capsule Bottle Label

Warnings and Precautions ( 5.7 ) 8/2024

Manufactured for: AVEO Pharmaceuticals, Inc., an LG Chem company Boston, MA 02210 Manufactured by: Catalent CTS, Inc. Kansas City, MO 64137 For patent information: www.aveooncology.com/patents ©2024 AVEO Pharmaceuticals, Inc. All rights reserved.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling [see PATIENT INFORMATION ] . Hypertension and Hypertensive Crisis Inform patients that hypertension or hypertensive crisis may occur during FOTIVDA treatment. Advise patients to undergo routine blood pressure monitoring and to contact their healthcare provider if blood pressure is elevated. Advise patients that if they experience signs or symptoms of hypertension to immediately contact their healthcare provider [see WARNINGS AND PRECAUTIONS (5.1) ]. Cardiac Failure Advise patients to immediately contact their healthcare provider if they develop symptoms of cardiac failure [see WARNINGS AND PRECAUTIONS (5.2) ]. Cardiac Ischemia and Arterial Thromboembolic Events Inform patients that arterial thromboembolic events (including fatal outcomes) may occur during FOTIVDA treatment. Advise patients to immediately contact their healthcare provider if new onset of chest discomfort, sudden weakness, or other events suggestive of a thrombotic event occurs [see WARNINGS AND PRECAUTIONS (5.3) ]. Venous Thromboembolic Events Advise patients to immediately contact their healthcare provider if they develop symptoms of dyspnea or localized limb edema [see WARNINGS AND PRECAUTIONS (5.4) ]. Hemorrhagic Events Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see WARNINGS AND PRECAUTIONS (5.5) ] . Perforations and Fistulas Inform patients that gastrointestinal perforations or fistulas may develop during FOTIVDA treatment. Advise patients to immediately contact their healthcare provider if they experience persistent or severe abdominal pain [see WARNINGS AND PRECAUTIONS (5.7) ] . Risk of Impaired Wound Healing Inform patients that FOTIVDA may impair wound healing. Advise patients that temporary interruption of FOTIVDA is recommended prior to elective surgery. Advise patients to contact their healthcare provider before any planned surgeries, including dental surgery [see DOSAGE AND ADMINISTRATION (2.1) and WARNINGS AND PRECAUTIONS (5.9) ] . Reversible Posterior Leukoencephalopathy Syndrome Inform patients that RPLS may occur during FOTIVDA treatment. Advise patients to immediately contact their healthcare provider in the event of seizures, headaches, visual disturbances, confusion or difficulty thinking [see WARNINGS AND PRECAUTIONS (5.10) ]. Overdosage Instruct patients to contact their healthcare provider immediately if they inadvertently take too much FOTIVDA [see OVERDOSAGE (10) ] . Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS (5.10) and USE IN SPECIFIC POPULATIONS (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose [see USE IN SPECIFIC POPULATIONS (8.1) and (8.3) and NONCLINICAL TOXICOLOGY (13.1) ]. Lactation Advise women not to breastfeed during treatment with FOTIVDA and for one month after the last dose [see USE IN SPECIFIC POPULATIONS (8.2) ]. Infertility Advise males and females of reproductive potential that FOTIVDA can impair fertility [see USE IN SPECIFIC POPULATIONS (8.3) ] . Allergic Reactions to Tartrazine (FD&C Yellow No.5) FOTIVDA 0.89 mg capsule contains FD&C Yellow No.5 (tartrazine) as an imprint ink which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients. Although the overall incidence of FD&C Yellow No.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity [see WARNINGS AND PRECAUTIONS (5.12) ] . Other Common Events Advise patients that other adverse reactions with FOTIVDA treatment may include diarrhea, vomiting, dysphonia (hoarseness of voice), fatigue, asthenia and stomatitis (sores in the mouth), and cough [see ADVERSE REACTIONS (6.1) ]. Important Administration Information Instruct patient if a dose of FOTIVDA is missed, the next dose should be taken at the regularly scheduled time. Do not take two doses in the same day [see DOSAGE AND ADMINISTRATION (2.1) ] . Drug Interactions Advise patients to inform their healthcare provider of all concomitant medications, vitamins, or dietary and herbal supplements [see DRUG INTERACTIONS (7) ].

14 CLINICAL STUDIES The efficacy of FOTIVDA was evaluated in TIVO-3 (NCT02627963), a randomized (1:1), open- label, multicenter trial of FOTIVDA versus sorafenib in patients with relapsed or refractory advanced RCC who received 2 or 3 prior systemic treatments including at least one VEGFR kinase inhibitor other than sorafenib or tivozanib. Patients were randomized to receive FOTIVDA 1.34 mg orally once daily for 21 days on treatment followed by 7 days off treatment for a 28-day cycle, or to receive sorafenib 400 mg orally twice a day continuously, until disease progression or unacceptable toxicity. Randomization was stratified by prior therapy [two kinase inhibitors (KIs), a KI plus an immune checkpoint inhibitor, or a KI plus other systemic agents] and by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score. Patients were excluded if they had more than 3 prior treatments or Central Nervous System metastases. The main efficacy outcome measure was progression-free survival (PFS) assessed by a blinded independent radiology review committee. Other efficacy endpoints were objective response rate (ORR) and overall survival (OS). The median age was 63 years (range: 30 to 90 years), 73% were male, 95% were Caucasian, ECOG performance status was 0 in 48% and 1 in 49% of patients (respectively), and 98% of patients had clear cell or clear cell component histology. Prior therapy included two KIs (45%), a KI plus an immune checkpoint inhibitor (26%), and a KI plus another systemic agent (29%). At the time of study entry, 20% of patients had favorable, 61% intermediate, and 19% poor IMDC prognoses. Efficacy results are summarized in Table 4 and Figure 1 . Table 4. Efficacy Results in TIVO-3 (ITT) Endpoint FOTIVDA N= 175 Sorafenib N= 175 CI: Confidence interval; HR: Hazard ratio (FOTIVDA/sorafenib); NE: not estimable. Progression Free Survival (PFS) Assessed by blinded independent radiology review committee according to RECIST v1.1. Events, n (%) 123 (70) 123 (70) Progressive Disease 103 (59) 109 (62) Death 20 (11) 14 (8) Median (95% CI), months 5.6 (4.8, 7.3) 3.9 (3.7, 5.6) HR (95% CI) Based on the Cox proportional hazards model stratified by IMDC prognostic score and prior therapy. 0.73 (0.56, 0.95) P-value Based on the log-rank test stratified by IMDC prognostic score and prior therapy. 0.016 Overall Survival Deaths, n (%) 125 (71) 126 (72) Median (95% CI), months 16.4 (13.4, 21.9) 19.2 (14.9, 24.2) HR (95% CI) 0.97 (0.75, 1.24) Objective Response Rate % (95% CI) 18 (12, 24) 8 (4, 13) Median duration of response in months (95% CI) NE (9.8, NE) 5.7 (5.6, NE) Figure 1. Kaplan-Meier Plot of PFS in TIVO-3 Figure 1

8.5 Geriatric Use Of the 1008 patients with advanced RCC treated with FOTIVDA, 29% were ≥ 65 years of age and 4% were ≥ 75 of age. No overall differences in safety were observed between patients ≥ 65 versus < 65 years of age. Of the 175 patients with advanced RCC following two or more prior systemic therapies randomized to FOTIVDA, 44% were ≥ 65 years of age and 9% were ≥ 75 of age. No overall differences in effectiveness were observed between patients ≥ 65 versus < 65 years of age.

8.4 Pediatric Use The safety and effectiveness of FOTIVDA in pediatric patients have not been established. Animal Data Juvenile animal studies have not been conducted with tivozanib. In a 13-week repeat-dose study, oral administration of tivozanib to young and growing cynomolgus monkeys resulted in growth plate hypertrophy, absence of active corpora lutea, and no maturing follicles at doses ≥ 0.3 mg/kg/day (4.4 times the maximum recommended clinical dose on a mg/m 2 basis). In a 13-week repeat-dose study in rats, teeth abnormalities (thin, brittle teeth, tooth loss, malocclusions) and growth plate hypertrophy were observed following oral administration of tivozanib at doses ≥ 0.1 mg/kg/day (0.7 times the maximum recommended clinical dose on a mg/m 2 basis).

8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, FOTIVDA can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY (12.1) ] . There are no available data on FOTIVDA use in pregnant woman to inform the drug-associated risk. In embryo-fetal developmental studies, oral administration of tivozanib to pregnant animals during the period of organogenesis caused maternal toxicity, fetal malformations and embryo- fetal death at doses below the maximum recommended clinical dose on a mg/m2 basis [see DATA ] . Advise pregnant woman of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is 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 miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20% respectively. Data Animal Data In an embryo-fetal developmental study in pregnant rats, daily oral administration of tivozanib at doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m2 basis) during the period of organogenesis resulted in maternal toxicity, increases in early and late resorptions, and an increase in fetal external malformations (body edema, short/kinked tail), and skeletal developmental delays. In an embryo-fetal developmental study in pregnant rabbits, daily oral administration of tivozanib at 1 mg/kg/day (14.5 times the maximum recommended clinical dose on a mg/m2 basis) during the period of organogenesis resulted in fetal malformations including ventricular septal defects and major vessel anomalies. No maternal toxicity was reported at doses up to 1 mg/kg/day.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Females and Males of Reproductive Potential: Can impair fertility. ( 8.3 ) Hepatic Impairment: Adjust dosage in patients with moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. ( 2.3 , 8.7 ) 8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, FOTIVDA can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY (12.1) ] . There are no available data on FOTIVDA use in pregnant woman to inform the drug-associated risk. In embryo-fetal developmental studies, oral administration of tivozanib to pregnant animals during the period of organogenesis caused maternal toxicity, fetal malformations and embryo- fetal death at doses below the maximum recommended clinical dose on a mg/m2 basis [see DATA ] . Advise pregnant woman of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is 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 miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20% respectively. Data Animal Data In an embryo-fetal developmental study in pregnant rats, daily oral administration of tivozanib at doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m2 basis) during the period of organogenesis resulted in maternal toxicity, increases in early and late resorptions, and an increase in fetal external malformations (body edema, short/kinked tail), and skeletal developmental delays. In an embryo-fetal developmental study in pregnant rabbits, daily oral administration of tivozanib at 1 mg/kg/day (14.5 times the maximum recommended clinical dose on a mg/m2 basis) during the period of organogenesis resulted in fetal malformations including ventricular septal defects and major vessel anomalies. No maternal toxicity was reported at doses up to 1 mg/kg/day. 8.2 Lactation Risk Summary There are no data on the presence of tivozanib in human milk, or the effects of tivozanib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with FOTIVDA and for one month after the last dose. 8.3 Females and Males of Reproductive Potential FOTIVDA can cause fetal harm when administered to a pregnant woman [see USE IN SPECIFIC POPULATIONS (8.1) ] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to starting treatment with FOTIVDA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose [see USE IN SPECIFIC POPULATIONS (8.1) ] . Males Advise males with female partners of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose [see NONCLINICAL TOXICOLOGY (13.1) ] . Infertility Females and Males Based on findings in animal studies, FOTIVDA can impair fertility in females and males of reproductive potential [see NONCLINICAL TOXICOLOGY (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of FOTIVDA in pediatric patients have not been established. Animal Data Juvenile animal studies have not been conducted with tivozanib. In a 13-week repeat-dose study, oral administration of tivozanib to young and growing cynomolgus monkeys resulted in growth plate hypertrophy, absence of active corpora lutea, and no maturing follicles at doses ≥ 0.3 mg/kg/day (4.4 times the maximum recommended clinical dose on a mg/m 2 basis). In a 13-week repeat-dose study in rats, teeth abnormalities (thin, brittle teeth, tooth loss, malocclusions) and growth plate hypertrophy were observed following oral administration of tivozanib at doses ≥ 0.1 mg/kg/day (0.7 times the maximum recommended clinical dose on a mg/m 2 basis). 8.5 Geriatric Use Of the 1008 patients with advanced RCC treated with FOTIVDA, 29% were ≥ 65 years of age and 4% were ≥ 75 of age. No overall differences in safety were observed between patients ≥ 65 versus < 65 years of age. Of the 175 patients with advanced RCC following two or more prior systemic therapies randomized to FOTIVDA, 44% were ≥ 65 years of age and 9% were ≥ 75 of age. No overall differences in effectiveness were observed between patients ≥ 65 versus < 65 years of age. 8.6 Renal Impairment No dosage modification is recommended for patients with mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min, estimated by Cockcroft-Gault). The recommended dosage for patients with end-stage renal disease has not been established [see CLINICAL PHARMACOLOGY (12.3) ] . 8.7 Hepatic Impairment Reduce the dosage when administering FOTIVDA in patients with moderate (total bilirubin greater than 1.5 to 3 times ULN with any AST) hepatic impairment [see DOSAGE AND ADMINSITARTION (2.3) ] . No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) hepatic impairment. The recommended dosage of FOTIVDA in patients with severe (total bilirubin greater than 3 to 10 times ULN with any AST) hepatic impairment has not been established [see CLINICAL PHARMACOLOGY (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied FOTIVDA (tivozanib) capsules, for oral use are supplied as follows: Capsule Strength Opaque Capsule Color Capsule Markings Pack Size NDC Code Tivozanib 1.34 mg (equivalent to 1.5 mg tivozanib hydrochloride) Bright yellow cap and body "TIVZ" imprinted with dark blue ink on cap; "SD" imprinted with dark blue ink on body Bottle of 21 NDC 45629-134-01 Tivozanib 0.89 mg (equivalent to 1.0 mg tivozanib hydrochloride) Dark blue cap and bright yellow body "TIVZ" imprinted with yellow ink on cap; "LD" imprinted with dark blue ink on body Bottle of 21 NDC 45629-089-01 Storage and Handling Store at 20 ° C to 25 ° C (68 ° F to 77 ° F); excursions permitted between 15°C to 30 ° C (59°F to 86 ° F) [see USP CONTROLLED ROOM TEMPERATURE] . Keep out of reach of children.

Storage and Handling Store at 20 ° C to 25 ° C (68 ° F to 77 ° F); excursions permitted between 15°C to 30 ° C (59°F to 86 ° F) [see USP CONTROLLED ROOM TEMPERATURE] . Keep out of reach of children.