Tivozanib, an inhibitor of multiple kinases including vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), stem cell factor receptor (c-kit), and platelet-derived growth factor receptor (PDGFR) β, is an antineoplastic agent.1
Tivozanib is used for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC) in adults who have received two or more prior systemic therapies.1 The current indication for tivozanib is based on a reduction in risk of disease progression or death by 27% compared to sorafenib in relapsed or refractory advanced RCC in patients previously treated with 2 or 3 systemic therapies.1, 3
The current indication for tivozanib is based principally on the results of the multicenter, open-label, randomized, controlled phase 3 study (TIVO-3) conducted in patients with metastatic RCC previously treated with at least two systemic therapies (including at least one VEGFR inhibitor except for tivozanib or sorafenib).1, 3 In this study, 350 adults were randomly assigned to receive either tivozanib (1.5 mg orally once daily on days 1-21 of each 28-day cycle) or sorafenib (400 mg orally twice daily continuously).1, 3 Treatment was continued until disease progression, unacceptable toxicity, death, or study withdrawal occurred.1, 3 The median duration of exposure to tivozanib or sorafenib was 197 or 141 days, respectively.3 The primary efficacy outcome was progression-free survival as assessed by a blinded independent radiology review committee.1, 3 Additional outcome measures included overall survival and objective response rate.1 The median age of patients enrolled in the study was 63 years (range: 30-90 years); 73% were male, 95% were Caucasian, 97% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 98% had clear cell or clear cell component histology.1 Approximately one-half (45%) of patients had previously received 2 tyrosine kinase inhibitors, 26% had received a tyrosine kinase inhibitor in combination with an immune checkpoint inhibitor, and 29% had received a tyrosine kinase inhibitor in combination with another systemic agent.1 At the time of study entry, International Metastatic RCC Database (IMDC) prognosis was favorable, intermediate, or poor in 20, 61 or 19% of patients, respectively.1
At a median follow-up duration of 19 months, 79% of patients receiving tivozanib and 92% of those receiving sorafenib discontinued treatment; the most common reason for discontinuance of therapy was disease progression.3 At the time of analysis, median progression-free survival was prolonged in patients receiving tivozanib compared with those receiving sorafenib (5.6 versus 3.9 months; hazard ratio of 0.73 with a 95% confidence interval of 0.56-0.95); however, no difference in overall survival was observed between the 2 treatment groups (hazard ratio of 0.99 with a 95% confidence interval of 0.76-1.29).1 Objective response rate was improved in patients receiving tivozanib compared with those receiving sorafenib (18 versus 8%); however, complete responses were not achieved in either treatment group.1, 3 Temporary interruption of therapy (48 versus 63%) and dosage reduction (24 versus 38%) due to adverse effects occurred less frequently in patients receiving tivozanib compared with those receiving sorafenib.3
Prognosis is generally poor in patients with metastatic RCC, including those who have undergone complete tumor resection.17 Combination regimens have become a standard for the treatment of advanced RCC.17
The American Society of Clinical Oncology (ASCO) recommends that all patients with metastatic RCC who require systemic therapy in the first-line setting undergo risk stratification.20 Patients with intermediate- or poor-risk disease should be offered combination treatment with 2 immune checkpoint inhibitors (i.e., ipilimumab and nivolumab) or an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor (e.g., pembrolizumab plus axitinib, nivolumab plus cabozantinib, avelumab plus axitinib, pembrolizumab plus lenvatinib).20 Treatment selection should be based on adverse events, comorbid conditions, provider experience, and treatment cost.20 Patients with favorable-risk disease who require systemic therapy may be offered an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor.20 Tivozanib may be an option for patients who progress after initial therapy combining a VEGFR tyrosine kinase inhibitor with an immune checkpoint inhibitor.20
Administer tivozanib hydrochloride orally once daily without regard to food.1 Swallow capsules whole with a glass of water; do not open the capsules.1
If a dose of tivozanib hydrochloride is missed, take the dose at the next scheduled time.1 Do not take two doses at the same time.1
Store tivozanib hydrochloride at 20-25°C.1 Excursions are permitted between 15-30°C.1
Dosage of tivozanib hydrochloride is expressed in terms of tivozanib.1
For the treatment of relapsed or refractory advanced renal cell carcinoma (RCC) previously treated with at least 2 systemic therapies, the recommended adult dosage is 1.34 mg orally once daily for 21 days followed by a 7-day rest period; courses of therapy are given in 28-day cycles.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse effects occur during tivozanib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary (see Table 1).1 If dosage modification is required, the dosage of tivozanib should be reduced to 0.89 mg for 21 days followed by a 7-day rest period (in 28-day cycles).1
GI adverse effects (i.e., diarrhea, nausea, vomiting) should be managed with appropriate treatment prior to tivozanib dosage reduction or treatment interruption.1
Adverse Reaction and Severity | Modification |
|---|---|
Hypertension | |
Grade 3 (despite optimal antihypertensive therapy) | Withhold therapy; when hypertension improves to grade 2 or less, resume at reduced dosage |
Grade 4 | Permanently discontinue therapy |
Cardiac Failure | |
Grade 3 | Withhold therapy; when toxicity improves to grade 0 to 1 or baseline, resume at a reduced dosage or discontinue therapy depending on severity and persistence of the toxicity |
Grade 4 | Permanently discontinue therapy |
Arterial Thromboembolic Events | |
Any grade | Permanently discontinue therapy |
Hemorrhagic Events | |
Grade 3 or 4 | Permanently discontinue therapy |
Proteinuria | |
≥2 g proteinuria per 24 hours | Withhold therapy, when proteinuria improves to ≤2 g per 24 hours, resume at a reduced dosage |
Nephrotic syndrome | Permanently discontinue therapy |
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) | |
Any grade | Permanently discontinue therapy |
Other Adverse Effects | |
Grade 2 or 3 (persistent or intolerable); Grade 4 laboratory abnormality | Withhold therapy; when toxicity improves to grade 0 to 1 or baseline, resume at a reduced dosage |
Grade 4 | Permanently discontinue therapy |
For patients with moderate hepatic impairment (total bilirubin concentration >1.5-3 times the upper limit of normal [ULN] with any AST concentration) reduce the dosage to 0.89 mg orally once daily for 21 days followed by a 7-day rest period (in 28-day cycles).1
Dosage adjustment is not necessary in patients with mild hepatic impairment (total bilirubin concentration ≤ULN with AST >ULN or total bilirubin >1-1.5 times ULN with any AST concentration).1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Adverse cardiovascular effects (i.e., hypertension, cardiac failure, cardiac ischemic events) may occur in patients receiving tivozanib.1 Blood pressure should be controlled prior to initiating tivozanib therapy and monitored 2 weeks after initiation of therapy, and then at least monthly thereafter.1 If hypertension occurs, initiate anti-hypertensive therapy as appropriate.1 Depending on the severity of the toxicity, temporary interruption of therapy, dosage reduction, or discontinuation of therapy may be necessary.1 The manufacturer recommends closely monitoring patients who are at risk for cardiac ischemic events such as myocardial infarction or stroke (including those with a history of such events) for cardiac ischemic events during therapy.1
Hypertension or Hypertensive Crisis
Hypertension commonly occurs in patients receiving tivozanib.1 Hypertension has been reported in 45% (grade 3 or higher in 22%) of patients receiving tivozanib.1 The median time to onset of hypertension was 2 weeks, but hypertension was reported as late as 192 weeks following initiation of therapy.1 Hypertensive crisis has occurred in 0.8% of patients receiving tivozanib, and resulted in fatality following an overdose of the drug.1 Tivozanib has not been studied in patients with systolic blood pressure exceeding 150 mm Hg or diastolic blood pressure exceeding 100 mm Hg.1
Tivozanib can cause serious or fatal cardiac failure.1 In clinical studies, cardiac failure occurred in 1.6% (grade 3 or higher in 1%) of patients receiving tivozanib.1 Tivozanib has not been studied in patients with a history of symptomatic cardiac failure within 6 months of treatment initiation.1
Serious or fatal cardiac ischemic events can occur in patients receiving tivozanib.1 In clinical studies, cardiac ischemia occurred in 3.2% (grade 3 or higher in 1.5%); fatal events occurred in 0.4% of patients.1 Tivozanib has not been studied in patients with a history of myocardial infarction or unstable angina within 6 months of treatment initiation.1
Serious or fatal arterial or venous thromboembolic events can occur in patients receiving tivozanib.1 In clinical studies, arterial or venous thromboembolic events occurred in 2 or 2.4% of patients receiving tivozanib, respectively; fatal events of these types occurred in 0.1 or 0.3% of patients, respectively.1 Tivozanib has not been studied in patients with a history of an arterial thromboembolic event within 6 months of treatment initiation.1
The manufacturer recommends closely monitoring patients who are at risk for arterial or venous thromboembolism (including those with a history of such events) during therapy with the drug.1 If a severe or life-threatening arterial or venous thromboembolic event occurs, permanently discontinue therapy.1
Tivozanib can cause serious or fatal hemorrhagic events.1 Hemorrhagic events have been reported in 11% (including 0.2% fatal events) of patients receiving tivozanib.1 Tivozanib has not been studied in patients who have experienced significant bleeding within 6 months of treatment initiation.1
The manufacturer recommends closely monitoring patients who are at risk for hemorrhagic events (including those with a history of hemorrhagic events) during therapy with the drug.1 If a severe or life-threatening hemorrhagic event occurs, permanently discontinue therapy.1
Proteinuria has been reported in 8% (grade 3 in 2%) of patients receiving tivozanib.1 Among 81 patients who developed proteinuria, 3 patients developed acute kidney injury either concurrently or later during the course of treatment.1
Patients should be monitored for proteinuria prior to initiation of and periodically during therapy.1 Depending on the severity of proteinuria, temporary interruption of therapy, dosage reduction, or discontinuation of therapy may be necessary.1 If patients develop nephrotic syndrome, permanently discontinue therapy.1
GI Perforation and Fistula Formation
GI perforation, including fatal cases, have been reported with tivozanib therapy.1 Patients should be monitored for symptoms of GI perforation or fistula periodically during treatment.1 Tivozanib should be permanently discontinued in patients who develop severe or life-threatening GI perforation.1
Thyroid dysfunction has been reported in 11% (grade 3 or 4 in 0.3%) of patients receiving tivozanib.1 Hypothyroidism or hyperthyroidism occurred in 8 or 1% of patients receiving tivozanib, respectively.1
Thyroid function should be assessed prior to initiation of and periodically during therapy.1 If hypothyroidism or hyperthyroidism occurs, appropriate treatment should be initiated to maintain a euthyroid state.1 Thyroid function tests must be within normal values prior to initiation of therapy.1
Inhibitors of vascular endothelial growth factor receptor (VEGFR) may impair wound healing.1 The safety of resuming tivozanib treatment following resolution of wound healing complications has not been studied.1
The manufacturer recommends that tivozanib be held at least 24 days prior to elective surgery.1 Following major surgery, tivozanib must be held for at least 2 weeks and until adequate wound healing occurs.1
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) can occur in patients receiving tivozanib.1 RPLS is a syndrome of subcortical vasogenic edema that may manifest with seizures, headache, visual disturbances, confusion, or altered mental function.1 Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.1
The possible diagnosis of RPLS should be considered in any patient receiving tivozanib who presents with neurologic manifestations suggestive of RPLS.1 Tivozanib should be permanently discontinued in patients who develop RPLS.1
Fetal/Neonatal Morbidity and Mortality
Tivozanib may cause fetal harm when administered to pregnant women based on its mechanism of action and animal findings.1 There are no clinical data on the use of tivozanib in pregnant women.1 Maternal toxicity, fetal malformations, and embryo-fetal death were observed when the drug was administered to pregnant animals during the period of organogenesis at doses 0.2 times the maximum recommended clinical dose in humans on a mg/m2 basis.1
Pregnant women and females of reproductive potential should be advised of the potential fetal hazard.1 Pregnancy status should be verified prior to initiation of tivozanib in females of reproductive potential.1 Pregnancy should be avoided during therapy.1 Females of reproductive potential and males who are partners of such females should be advised to use an effective method of contraception while receiving tivozanib and for one month after the last dose.1
Sensitivity Reactions to Tartrazine
Tivozanib contains tartrazine (FD&C Yellow No. 5), which has the potential to cause allergic-type reactions, including bronchial asthma, in certain susceptible patients.1 Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.1
Tivozanib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
Verify pregnancy status prior to initiation of tivozanib in females of reproductive potential.1
It is not known whether tivozanib or its metabolites are distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Patients should not breast-feed while receiving tivozanib and for one month after the last dose.1
Females and Males of Reproductive Potential
Animal studies have shown that tivozanib can impair fertility in both females and males of reproductive potential.1 Patients should be advised to use an effective method of contraception while receiving tivozanib and for one month after the last dose.1
Safety and efficacy of tivozanib have not been established in pediatric patients.1
Growth plate hypertrophy, absence of active corpora lutea, and absence of maturing follicles have been observed in young and growing cynomolgus monkeys receiving repeated dosages of tivozanib at 4.4 times the maximum recommended clinical dose in humans.1 Teeth abnormalities (e.g., malocclusions, tooth loss, brittle teeth) and growth plate hypertrophy also have been observed in rats receiving repeated dosages of tivozanib at 0.7 times the maximum recommended clinical dose in humans.1
In the pooled safety population of 1008 patients in the principal safety and efficacy studies, 29% of patients were ≥65 years of age.1 No overall differences in safety were observed between geriatric patients and younger adults.1
In patients with mild hepatic impairment (total bilirubin concentration ≤ULN with AST concentration >ULN or total bilirubin >1-1.5 times ULN with any AST concentration), AUCtau of tivozanib increased by 1% compared to subjects with normal hepatic function; no dosage adjustment is necessary.1
In patients with moderate hepatic impairment (total bilirubin concentration >1.5-3 times ULN with any AST concentration), AUCtau of tivozanib increased by 62% compared to subjects with normal hepatic function; the manufacturer recommends reducing the dosage of tivozanib to 0.89 mg orally once daily for 21 days followed by a 7-day rest period (in 28-day cycles).1
The pharmacokinetics of tivozanib have not been studied in patients with severe hepatic impairment (total bilirubin concentration >3-10 times the ULN with any AST).1
Population pharmacokinetic analysis indicated that mild to severe renal impairment (estimated creatinine clearance of 15-89 mL/minute) did not appear to substantially affect pharmacokinetics of tivozanib; no dosage adjustment is necessary.1
The pharmacokinetics of tivozanib have not been studied in patients with end-stage renal disease.1
The most common (≥20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis.1 The most common grade 3 or 4 laboratory abnormalities (≥5%) were decreased sodium, increased lipase, and decreased phosphate.1
Tivozanib is metabolized primarily by cytochrome P-450 (CYP) 3A4.1 In vitro studies indicate that tivozanib does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4 or uridine diphosphate-glucuronosyltransferase (UGT) enzymes at clinically relevant concentrations.1 In vitro studies also show that tivozanib does not induce CYP isoenzymes 1A, 2B6, 2C9, 2C19, or 3A at clinically relevant concentrations.1
Tivozanib inhibits breast cancer resistance protein (BCRP).1 The drug does not inhibit P-glycoprotein (P-gp), organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, bile salt export pump (BSEP), multidrug and toxin extrusion (MATE)1, or MATE2-K.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
No clinically significant differences in pharmacokinetics of tivozanib were observed when repeated dosage of ketoconazole (strong CYP3A inhibitor) were administered concomitantly with tivozanib.1
Concomitant use of tivozanib with strong CYP3A inducers may result in a decrease in tivozanib plasma concentrations and reduced anti-tumor activity.1 Concomitant administration of rifampin (strong CYP3A inducer) with tivozanib decreased the AUC of tivozanib by 52%, but did not affect peak plasma concentrations.1
Avoid concomitant use of tivozanib with drugs that are strong CYP3A inducers.1
Tivozanib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1 Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.11, 12 The VEGFR signaling pathway plays an important role in the pathogenesis and progression of several types of tumors since it is a pivotal mediator of tumor angiogenesis; the pathway also regulates tumor growth and metastatic spread.11, 12 Tivozanib inhibits phosphorylation of VEGFR-1, VEGFR-2, and VEGFR-3 and inhibits other kinases such as stem cell factor receptor (c-kit), and platelet-derived growth factor receptor (PDGFR) β.1, 4, 6 The drug has demonstrated inhibition of angiogenesis, vascular permeability, and tumor growth of various tumor cell types (including human renal cell carcinoma) in mice and rats bearing tumor xenografts.1, 6
Peak plasma concentration and systemic exposure to tivozanib are dose-proportional over the oral dosage range of 0.89-1.78 mg once daily.1 Steady state concentrations are achieved in approximately 14 days and peak plasma concentrations are reached in a median of 10 hours (range: 3-24 hours).1 No clinically significant differences in peak plasma concentration or systemic exposure to tivozanib were observed when the drug was administered with a high-fat meal.1 Tivozanib is highly bound (99% or more) to plasma proteins, and binding is independent of tivozanib concentration.1 The half-life of tivozanib is 111 hours.1 Tivozanib is metabolized primarily by CYP3A4.1, 4 Following oral administration of a single dose of radiolabeled tivozanib, 79% is eliminated in feces (approximately 26% as unchanged drug) and 12% of the dose is eliminated in urine.1
Systemic exposure to tivozanib do not appear to be affected by age, sex, race, and body weight (range: 39-158 kg).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Tivozanib hydrochloride can only be obtained through designated specialty pharmacies and distributors.9 Contact manufacturer for specific ordering and availability information.9
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsule | 0.89 mg (of tivozanib) | Fotivda® | Aveo Pharmaceuticals |
1.34 mg (of tivozanib) | Fotivda® | Aveo Pharmaceuticals |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions November 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Aveo Pharmaceuticals. Fotivda®(tivozanib) capsules prescribing information. Boston, MA; 2024 Aug
3. Rini BI, Pal SK, Escudier BJ et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol . 2020; 21:95-104. [PubMed 31810797]
4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212904Orig1s000: Multi-discipline review. From FDA website. [Web]
6. Salgia NJ, Zengin ZB, Pal SK. Tivozanib in renal cell carcinoma: a new approach to previously treated disease. Ther Adv Med Oncol . 2020; 12:1758835920923818. [PubMed 32547647]
9. Aveo Pharmaceuticals. How to access Fotivda®. From the Fotivda for healthcare professionals website. [Web]
11. Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D. 2011; 11:113-26. [PubMed]
12. Hu-Lowe DD, Zou HY, Grazzini ML et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008; 14:7272-83. [PubMed]
17. National Cancer Institute. Renal cell cancer treatment - health professional version. Revised May 13, 2025. [Web]
20. Rathmell WK, Rumble RB, Van Veldhuizen PJ, et al. Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline. J Clin Oncol. 2022;40(25):2957-2995.