FOTIVDA

1 INDICATIONS AND USAGE FOTIVDA is indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. FOTIVDA is a kinase inhibitor indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. ( 1 )

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) ].

5 WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis: Control blood pressure prior to initiating FOTIVDA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of anti-hypertensive medications, reduce the FOTIVDA dose. ( 5.1 ) Cardiac Failure: Monitor for signs or symptoms of cardiac failure throughout treatment with FOTIVDA. ( 5.2 ) Cardiac Ischemia and Arterial Thromboembolic Events: Closely monitor patients who are at increased risk for these events. Permanently discontinue FOTIVDA for severe arterial thromboembolic events, such as myocardial infarction and stroke. ( 5.3 ) Venous Thromboembolic Events: Closely monitor patients who are at increased risk for these events. Permanently discontinue FOTIVDA for severe venous thromboembolic events. ( 5.4 ) Hemorrhagic Events: Closely monitor patients who are at risk for or who have a history of bleeding. ( 5.5 ) Proteinuria: Monitor throughout treatment with FOTIVDA. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment with FOTIVDA. ( 5.6 ) Perforations and Fistulas: Monitor for symptoms. Discontinue FOTIVDA for severe or life-threatening gastrointestinal perforation. ( 5.7 ) Thyroid Dysfunction: Monitor before initiation and throughout treatment with FOTIVDA. ( 5.8 ) Risk of Impaired Wound Healing: Withhold FOTIVDA for at least 24 days before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of FOTIVDA after resolution of wound healing complications has not been established. ( 5.9 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue FOTIVDA if signs or symptoms of RPLS occur. ( 5.10 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.11 , 8.1 , 8.3 ) Allergic Reactions to Tartrazine: The 0.89 mg capsule of FOTIVDA contains FD&C Yellow No.5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients. ( 5.12 ) 5.1 Hypertension and Hypertensive Crisis FOTIVDA can cause severe hypertension and hypertensive crisis. Hypertension occurred in 45% of patients treated with FOTIVDA, with 22% of the events ≥ Grade 3. Median time to onset of hypertension was 2 weeks (range: 0 – 192 weeks). Hypertensive crisis occurred in 0.8% of patients . One patient (0.1%) died due to hypertensive emergency after FOTIVDA overdose [see OVERDOSAGE (10) ] . FOTIVDA has not been studied in patients with systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg. Control blood pressure prior to treatment with FOTIVDA. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with FOTIVDA. Treat patients with anti- hypertensive therapy when hypertension occurs during treatment with FOTIVDA. Withhold FOTIVDA for severe hypertension despite optimal anti-hypertensive therapy. For persistent hypertension despite use of anti-hypertensive medications, reduce the FOTIVDA dose [see DOSAGE AND ADMINISTRATION (2.2) ] . Discontinue FOTIVDA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of FOTIVDA, or in patients who experience hypertensive crisis. If FOTIVDA is interrupted, monitor patients receiving anti-hypertensive medications for hypotension. 5.2 Cardiac Failure FOTIVDA can cause serious, sometimes fatal, cardiac failure. Cardiac failure in FOTIVDA- treated patients occurred in 1.6%, with 1% of events ≥ Grade 3, and 0.6% events were fatal. FOTIVDA has not been studied in patients with symptomatic cardiac failure within the preceding 6 months before FOTIVDA treatment initiation. Periodically monitor patients for symptoms of cardiac failure throughout treatment with FOTIVDA. Management of cardiac failure events may require interruption, dose reduction, or permanent discontinuation of FOTIVDA therapy [see DOSAGE AND ADMINI…

4 CONTRAINDICATIONS None. None. ( 4 )

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.

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/m 2 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/m 2 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/m 2 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.

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 ap…