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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:
 |
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).
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.
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.
Table 1. Dosage Modifications for Adverse Reactions
| Adverse Reaction | Severity* | Dosage Modifications for FOTIVDA |
| Hypertension [see WARNINGS AND PRECAUTIONS] |
Grade 3 |
|
| Grade 4 |
|
|
| Cardiac Failure [see WARNINGS AND PRECAUTIONS] |
Grade 3 |
|
| on the severity and persistence of adverse reaction. | ||
| Grade 4 |
|
|
| Arterial Thromboembolic Events [see WARNINGS AND PRECAUTIONS] |
Any Grade |
|
| Hemorrhagic Events [see WARNINGS AND PRECAUTIONS] |
Grade 3 or 4 |
|
| Proteinuria [see WARNINGS AND PRECAUTIONS] |
2 grams or greater proteinuria in 24 hours |
|
| Reversible Posterior Leukoencephalopathy Syndrome [see WARNINGS AND PRECAUTIONS] |
Any Grade |
|
| Other Adverse Reactions | Persistent or intolerableGrade 2 or 3 adverse reaction Grade 4 laboratory abnormality |
|
| Grade 4 adverse reaction |
|
|
| *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].
Capsules:
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 |
| 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 in a Carton | NDC 45629-134-02 |
| 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 in a Carton | NDC 45629-089-02 |
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.
Manufactured by: Catalent CTS, Inc. Kansas City, MO 64137. Revised Jan 2025.
The following clinically significant adverse reactions are also described elsewhere in the labeling:
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.
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]. 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* | 67 | 13 | 48 | 12 |
| Vascular | ||||
| Hypertension† | 44 | 24 | 31 | 17 |
| Bleeding‡ | 17 | 3 | 12 | 1 |
| Gastrointestinal | ||||
| Diarrhea§ | 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¶ | 24 | 1 | 11 | 0 |
| Musculoskeletal | ||||
| Back pain | 19 | 2 | 16 | 2 |
| Skin and subcutaneous tissue disorders | ||||
| Rash# | 18 | 1 | 52 | 15 |
| Palmar-plantar erythrodysesthesia syndrome | 16 | 1 | 41 | 17 |
| Investigations | ||||
| Weight decreased | 17 | 3 | 22 | 3 |
| * 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, triiodothyronine 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 |
||||
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 | FOTIVDA1 (n = 173) | Sorafenib1 (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 |
| 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. | ||||
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.
Concomitant use of FOTIVDA with a strong CYP3A inducer decreases tivozanib exposure [see CLINICAL PHARMACOLOGY], which may reduce FOTIVDA anti-tumor activity.
Avoid concomitant use of strong CYP3A inducers with FOTIVDA.
Included as part of the "PRECAUTIONS" Section
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 OVERDOSE].
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].
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].
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].
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].
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 [see DOSAGE AND ADMINISTRATION].
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].
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.
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].
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, and CLINICAL PHARMACOLOGY].
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.
Advise the patient to read the FDA-approved patient labeling [see PATIENT INFORMATION].
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].
Advise patients to immediately contact their healthcare provider if they develop symptoms of cardiac failure [see WARNINGS AND PRECAUTIONS].
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].
Advise patients to immediately contact their healthcare provider if they develop symptoms of dyspnea or localized limb edema [see WARNINGS AND PRECAUTIONS].
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].
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].
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 and WARNINGS AND PRECAUTIONS].
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].
Instruct patients to contact their healthcare provider immediately if they inadvertently take too much FOTIVDA [see OVERDOSE].
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 and Use In Specific Populations].
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 and Nonclinical Toxicology].
Advise women not to breastfeed during treatment with FOTIVDA and for one month after the last dose [see Use In Specific Populations].
Advise males and females of reproductive potential that FOTIVDA can impair fertility [see Use In Specific Populations].
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].
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].
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].
Advise patients to inform their healthcare provider of all concomitant medications, vitamins, or dietary and herbal supplements [see DRUG INTERACTIONS].
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).
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]. 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.
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.
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 Pregnancy].
Verify pregnancy status of females of reproductive potential prior to starting treatment with FOTIVDA.
Females
Advise females of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose [see Pregnancy].
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].
Females and Males
Based on findings in animal studies, FOTIVDA can impair fertility in females and males of reproductive potential [see Nonclinical Toxicology].
The safety and effectiveness of FOTIVDA in pediatric patients have not been established.
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].
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]. 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].
Overdosage with FOTIVDA can cause severe hypertension and hypertensive crisis that may result in death [see WARNINGS AND PRECAUTIONS].
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.
None.
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.
Tivozanib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.
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.
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.
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.
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).
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].
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 and Use In Specific Populations].
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 co-administered with tivozanib.
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.
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 |
| Progression Free Survival (PFS)* | ||
| 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) † | 0.73 (0.56, 0.95) | |
| P-value†† | 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) |
| 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. |
||
Figure 1. Kaplan-Meier Plot of PFS in TIVO-3
 |
FOTIVDA®
(fo-TIV-dah)
(tivozanib) capsules
What is FOTIVDA?
FOTIVDA is a prescription medicine used to treat adults with advanced kidney cancer (advanced renal cell carcinoma or RCC) that has been treated with 2 or more prior medicines and has come back or did not respond to treatment.
It is not known if FOTIVDA is safe and effective in children.
Before taking FOTIVDA, tell your healthcare provider about all your medical conditions, including if you:
Females who are able to become pregnant:
Males with female partners who are able to become pregnant:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking FOTIVDA with certain other medicines may affect how FOTIVDA works. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take FOTIVDA?
What are the possible side effects of FOTIVDA?
FOTIVDA may cause serious side effects, including:
The most common side effects of FOTIVDA include:
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.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store FOTIVDA?
Keep FOTIVDA and all medicines out of the reach of children.
General information about the safe and effective use of FOTIVDA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use FOTIVDA for a condition for which it was not prescribed. Do not give FOTIVDA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about FOTIVDA that is written for health professionals.
What are the ingredients in FOTIVDA?
Active ingredient: tivozanib hydrochloride
Inactive ingredients: mannitol and magnesium stearate. The capsule contains gelatin, titanium dioxide, FDA yellow iron oxide, and Blue SB-6018 (ink). The 0.89 mg capsule also contains FD&C Blue #2 and Yellow SB-3017 (ink). The Yellow SB-3017 ink contains FD&C Yellow No.5 (tartrazine).
This Patient Information has been approved by the U.S. Food and Drug Administration.
