TIVOZANIB: 1,395 Adverse Event Reports & Safety Profile

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

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 )

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 <span class="opacity-50 text-xs">[see USE IN SPECIFIC POPULATIONS (8.7) ]</span>.

None. None. ( 4 )

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

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 <span class="opacity-50 text-xs">[see OVERDOSAGE (10) ]</span> . FOTIVDA has not been studied in patients with systolic blood pressure &gt; 150 mmHg or diastolic blood pressure &gt; 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 <span class="opacity-50 text-xs">[see DOSAGE AND ADMINISTRATION (2.2) ]</span> . 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 <span class="opacity-50 text-xs">[see DOSAGE AND ADMINISTRATION (2.2) ]</span> .

5.3 Cardiac Ischemia and Arterial Thromboembolic Events 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 <span class="opacity-50 text-xs">[see DOSAGE AND ADMINISTRATION (2.2) ]</span> .

5.4 Venous Thromboembolic Events 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 <span class="opacity-50 text-xs">[see DOSAGE AND ADMINISTRATION (2.2) ]</span> .

5.5 Hemorrhagic Events 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 <span class="opacity-50 text-xs">[see DOSAGE AND ADMINISTRATION (2.2) ]</span> .

5.6 Proteinuria 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 <span class="opacity-50 text-xs">[see DOSAGE AND ADMINISTRATION (2.2) ]</span> .

5.7 Gastrointestinal Perforation and Fistula Formation Gastrointestinal perforation including fatal cases, has been reported in patients receiving FOTIVDA. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with FOTIVDA. Permanently discontinue FOTIVDA in patients who develop severe or life-threatening gastrointestinal perforation.

5.8 Thyroid Dysfunction 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.

5.9 Risk of Impaired Wound Healing 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.

5.10 Reversible Posterior Leukoencephalopathy Syndrome 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 <span class="opacity-50 text-xs">[see DOSAGE AND ADMINISTRATION (2.2) ]</span> .

5.11 Embryo-Fetal Toxicity 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/m 2 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 <span class="opacity-50 text-xs">[see USE IN SPECIFIC POPULATIONS (8.1) , (8.3) and CLINICAL PHARMACOLOGY (12.1) ]</span>.

5.12 Allergic Reactions to Tartrazine (FD&amp;C Yellow No.5) FOTIVDA 0.89 mg capsule contains FD&amp;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&amp;C Yellow No.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

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 <span class="opacity-50 text-xs">[see CLINICAL PHARMACOLOGY (12.3) ]</span>, which may reduce FOTIVDA anti-tumor activity. Avoid concomitant use of strong CYP3A inducers with FOTIVDA.