Fotivda Drug Information

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.

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 . 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

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

Effect of Other Drugs on

FOTIVDA Strong CYP3A Inducers Concomitant use of FOTIVDA with a strong CYP3A inducer decreases tivozanib exposure, which may reduce FOTIVDA anti-tumor activity. Avoid concomitant use of strong CYP3A inducers with FOTIVDA.

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 . 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 . 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.

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).

Overdosage with FOTIVDA can cause severe hypertension and hypertensive crisis that may result in death . 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.