HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use FOTIVDA safely and effectively. See full prescribing information for FOTIVDA.

FOTIVDA® (tivozanib) capsules, for oral use Initial U.S. Approval: 2021

INDICATIONS AND USAGE

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)

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

•   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)

•   Thyroid Dysfunction: Monitor before initiation and throughout treatment with FOTIVDA. (5.7)

•   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. (5.8)

•   Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue FOTIVDA if signs or symptoms of RPLS occur. (5.9)

•   Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.10, 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. (5.11)

for 21 days on treatment followed by 7 days off treatment (28-day cycle).                                            ADVERSE REACTIONS

(2.3)

DOSAGE FORMS AND STRENGTHS

Capsules: 1.34 mg and 0.89 mg (3)

CONTRAINDICATIONS

None. (4)

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)

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.

DRUG INTERACTIONS

CYP3A Inducers: Avoid concomitant use of strong CYP3A inducers. (7.1)

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)

See 17 for PATIENT COUNSELING INFORMATION and FDA-

approved patient labeling.

Revised: 03/2021

FULL PRESCRIBING INFORMATION: CONTENTS*

1     INDICATIONS AND USAGE

2     DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

2.2 Dose Modifications for Adverse Reactions

2.3  Dosage Modifications for Moderate Hepatic Impairment

3     DOSAGE FORMS AND STRENGTHS

4     CONTRAINDICATIONS

5     WARNINGS AND PRECAUTIONS

5.1  Hypertension and Hypertensive Crisis

5.2  Cardiac Failure

5.3  Cardiac Ischemia and Arterial Thromboembolic Events

5.4  Venous Thromboembolic Events

5.5  Hemorrhagic Events

5.6  Proteinuria

5.7  Thyroid Dysfunction

5.8  Risk of Impaired Wound Healing

5.9  Reversible Posterior Leukoencephalopathy Syndrome

5.10Embryo-Fetal Toxicity

5.11Allergic Reactions to Tartrazine (FD&C Yellow No.5)

6     ADVERSE REACTIONS

6.1  Clinical Trial Experience

7     DRUG INTERACTIONS

7.1  Effect of Other Drugs on FOTIVDA

8     USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

8.2  Lactation

8.3  Females and Males of Reproductive Potential

8.4  Pediatric Use

8.5  Geriatric Use

8.6  Renal Impairment

8.7  Hepatic Impairment

10  OVERDOSAGE

11  DESCRIPTION

12  CLINICAL PHARMACOLOGY

12.1Mechanism of Action

12.2Pharmacodynamics

12.3Pharmacokinetics

13  NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility

14  CLINICAL STUDIES

16  HOW SUPPLIED/STORAGE AND HANDLING

17  PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

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.

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.

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.

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*Grades are based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).

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)].

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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.

None.

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 [seeDOSAGE 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.

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 ADMINISTRATION (2.2)].

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FOTIVDA can cause serious, sometimes fatal, cardiac ischemia and arterial thromboembolic events.  Cardiac ischemia in FOTIVDA-treated patients occurred in 3.2%, with 1.5% of events > Grade 3, and 0.4% events were fatal.  Arterial thromboembolic events were reported in 2% of FOTIVDA-treated patients, including death due to ischemic stroke (0.1%).

FOTIVDA has not been studied in patients who had an arterial thrombotic event, myocardial infarction, or unstable angina within the preceding 6 months before FOTIVDA treatment initiation.

Closely monitor patients who are at risk for, or who have a history of these events (such as myocardial infarction and stroke), during treatment with FOTIVDA.

Discontinue FOTIVDA in patients who develop any severe or life-threatening arterial thromboembolic event[see DOSAGE AND ADMINISTRATION (2.2)].

FOTIVDA can cause serious, sometimes fatal, venous thromboembolic events.  Venous thromboembolic events occurred in 2.4% of patients treated with FOTIVDA, including death (0.3%).

Closely monitor patients who are at risk for, or who have a history of these events during treatment with FOTIVDA.

Discontinue FOTIVDA in patients who develop any severe or life-threatening venous thromboembolic event[see DOSAGE AND ADMINISTRATION (2.2)].

FOTIVDA can cause serious, sometimes fatal, hemorrhagic events.  Hemorrhagic events occurred in 11% of patients treated with FOTIVDA, including death (0.2%).

FOTIVDA has not been studied in patients with significant bleeding within the preceding 6 months before FOTIVDA treatment initiation.

Closely monitor patients who are at risk for or who have a history of bleeding during treatment with FOTIVDA.

Discontinue FOTIVDA in patients who develop severe or life-threatening hemorrhagic events

[seeDOSAGE AND ADMINISTRATION (2.2)].

FOTIVDA can cause proteinuria.  Proteinuria occurred in 8% of FOTIVDA-treated patients with 2% of events Grade 3. Of the patients who developed proteinuria, 3/81 (3.7%) had acute kidney injury either concurrently or later during treatment.

Monitor patients for proteinuria before initiation of, and periodically throughout, treatment with FOTIVDA.

For patients who develop moderate to severe proteinuria, reduce the dose or interrupt FOTIVDA treatment.

Discontinue FOTIVDA in patients who develop nephrotic syndrome[see DOSAGE AND ADMINISTRATION (2.2)].

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FOTIVDA can cause thyroid dysfunction. Thyroid dysfunction events in FOTIVDA-treated patients occurred in 11%, with 0.3% Grade 3 or 4 events. Hypothyroidism was reported in 8% of patients and hyperthyroidism was reported in 1% of patients.

Monitor thyroid function before initiation of, and periodically throughout, treatment with FOTIVDA.

Treat hypothyroidism and hyperthyroidism to maintain euthyroid state before and during treatment with FOTIVDA.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway, such as FOTIVDA. Therefore, FOTIVDA has the potential to adversely affect wound healing.

Withhold FOTIVDA for at least 24 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of FOTIVDA after resolution of wound healing complications has not been established.

Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by MRI, can occur with FOTIVDA. Perform an evaluation for RPLS in any patient presenting with seizures, headaches, visual disturbances, confusion, or altered mental function.

Discontinue FOTIVDA in patients who develop RPLS[see DOSAGE AND ADMINISTRATION (2.2)].

Based on findings from animal studies and its mechanism of action, FOTIVDA can cause fetal harm when administered to a pregnant woman. 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.

Advise pregnant woman of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose. 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 USE IN SPECIFIC POPULATIONS (8.1, 8.3) and CLINICAL PHARMACOLOGY (12.1)].

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.

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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)]

•      Thyroid Dysfunction[see WARNINGS AND PRECAUTIONS (5.7)]

•      Risk of Impaired Wound Healing[see WARNINGS AND PRECAUTIONS (5.8)]

•      Reversible Posterior Leukoencephalopathy Syndrome (RPLS)[seeWARNINGS AND PRECAUTIONS (5.9)]

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 reflect 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%).

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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.

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* Includes fatigue and asthenia

† Includes hypertension, blood pressure increased, hypertensive crisis

‡ 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

§ Includes diarrhea and frequent bowel movements

¶ Includes hypothyroidism, blood thyroid stimulating hormone increased, tri-iodothyronine decreased, tri- iodothyronine free decreased

# 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

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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.

1      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.

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.

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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(seeData). 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.

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.

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.

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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)].

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/m2 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/m2 basis).

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.

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)].

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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 Administration (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[seeClinical Pharmacology (12.3)].

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.

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 C22H19ClN4O5 • HCl • H2O and the molecular weight is 509.34 Daltons. The chemical structure is:

H3CO

Cl     H N

O

H N

O       N  O

CH3

H3CO

•HCl N

• H2O

Tivozanib hydrochloride is a white to light brown crystalline powder that is practically insoluble in water (0.09 mg/mL).

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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).

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.

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.

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 Cmax 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%)] Cmax was 86.9 (44.7%) ng/mL and AUC0-24h was 1510 (46.1%) ng*h/mL.

Absorption

The median Tmax of tivozanib is 10 hours with a range of 3 to 24 hours.

Effect of Food

No clinically significant differences in tivozanib AUC or Cmax 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

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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, 8.7)].

Patients with Hepatic Impairment

Compared to subjects with normal hepatic function, tivozanib AUCtau 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 AUCtau 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 Populations (8.7)].

Drug Interaction Studies

Clinical Studies

Strong CYP3A Inducers: Concomitant use of multiple doses of rifampin (strong CYP3A inducer) did not change tivozanib Cmax but decreased tivozanib AUC0-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

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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.

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/m2 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/m2 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/m2 basis).

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.

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Efficacy results are summarized in Table 4 and Figure 1.

CI: Confidence interval; HR: Hazard ratio (FOTIVDA/sorafenib); NE: not estimable.

*Assessed by blinded independent radiology review committee according to RECIST v1.1.

†Based on the Cox proportional hazards model stratified by IMDC prognostic score and prior therapy.

††Based on the log-rank test stratified by IMDC prognostic score and prior therapy.

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How Supplied

FOTIVDA (tivozanib) capsules, for oral use are supplied as follows:

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.

Advise the patient to read the FDA-approved patient labeling (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

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Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage[seeWARNINGS AND PRECAUTIONS (5.5)].

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 (5.8)].

Reverse 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 (5.9)].

Overdosage

Instruct patients to contact their healthcare provider immediately if they inadvertently take too much FOTIVDA [seeOVERDOSAGE (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, 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[seeUSE 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 (5.11)].

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)].

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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)].

Manufactured for: AVEO Pharmaceuticals, Inc. Boston, MA 02108 Manufactured by: Catalent CTS, Inc. Kansas City, MO 64137

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and tell your healthcare provider if you have increased blood pressure. Tell your healthcare provider right away if you get any of the following signs or symptoms:

o     confusion

o     headaches

o     dizziness

o     chest pain

o     shortness of breath

•      Heart failure. FOTIVDA can cause heart failure which can be serious, and sometimes lead to death. Your healthcare provider should check you for symptoms of heart failure regularly during treatment with FOTIVDA. Call your healthcare provider right away if you get symptoms of heart problems, such as shortness of breath or swelling of your ankles.

•      Heart attack and blood clots in your veins or arteries. FOTIVDA can cause blood clots which can be serious, and sometimes lead to death. Tell your healthcare provider or get emergency medical help right away if you get any of the following symptoms:

o     new chest pain or pressure

o     numbness or weakness on one side of your body

o     pain in your arms, back, neck or jaw

o  trouble talking

o     shortness of breath

o     sudden severe headache

o     vision changes

o     swelling in the arms or legs

•      Bleeding problems. FOTIVDA can cause bleeding which can be serious, and sometimes lead to death. Tell your healthcare provider or get medical help right away if you develop any of the following signs or symptoms:

o   unusual bleeding from the gums

o   red or black stools (looks like tar)

o   menstrual bleeding or vaginal bleeding that is heavier than normal

o   bruises that happen without a known cause or get larger

o   headaches, feeling dizzy or weak

o   bleeding that is severe or you cannot control

o   coughing up blood or blood clots

o   pink or brown urine

o   vomiting blood or your vomit looks like “coffee grounds”

o   unexpected pain, swelling, or joint pain

•      Protein in your urine. Your healthcare provider should check your urine for protein before and during your treatment with FOTIVDA.

•      Thyroid gland problems. Your healthcare provider should do blood tests to check your thyroid gland function before and during your treatment with FOTIVDA. Your healthcare provider may prescribe medicine if you develop thyroid gland problems.

•      Risk of wound healing problems. Wounds may not heal properly during FOTIVDA treatment. Tell your healthcare provider if you plan to have surgery before starting or during treatment with FOTIVDA, including dental surgery.

o     You should stop taking FOTIVDA at least 24 days before planned surgery.

o     Your healthcare provider should tell you when you may start taking FOTIVDA again after surgery.

•      Reversible Posterior Leukoencephalopathy Syndrome (RPLS). A condition called reversible posterior leukoencephalopathy syndrome (RPLS) can happen during treatment with FOTIVDA. Tell your healthcare provider right away if you get:

o     headaches

o     seizures

o     confusion

o     blindness or change in vision

o     difficulty thinking

•      Allergic reactions to tartrazine (FD&C Yellow No.5). FOTIVDA 0.89 mg capsules contain a dye called FD&C Yellow No.5 (tartrazine) which may cause allergic-type reactions, including bronchial asthma, in certain people. This allergic reaction is most often seen in people who also have an allergy to aspirin.

The most common side effects of FOTIVDA include:

•      tiredness

•      diarrhea

•      decreased appetite

•      nausea

•      hoarseness

•      low levels of thyroid hormones

•      cough

•      mouth sores

•      decreased levels of salt (sodium) and phosphate in the blood

•      increased levels of lipase in the blood (a blood test done to check your pancreas)

Other side effects include vomiting and weakness or lack of energy.

FOTIVDA may cause fertility problems in males and females, which may affect your ability to have a child. Talk to your healthcare provider if this is a concern for you.

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with FOTIVDA if you have certain side effects.

These are not all of the possible side effects of FOTIVDA.