Version May 2024
Note: Withhold tivozanib for at least 24 days prior to elective surgery. Do not administer tivozanib for at least 2 weeks after major surgery and until adequate wound healing. Each 1.34 mg capsule contains 1.5 mg of tivozanib hydrochloride salt (equivalent to 1.34 mg of tivozanib); each 0.89 mg capsule contains 1 mg of tivozanib hydrochloride salt (equivalent to 0.89 mg of tivozanib). Dosing presented as tivozanib base.
Renal cell carcinoma, advanced, relapsed or refractory:
Note: May be used in patients who have progressed on ≥2 prior therapies, including a VEGFR tyrosine kinase inhibitor (other than tivozanib or sorafenib), and may be an option in patients who have progressed on both immunotherapy and a VEGFR inhibitor (Ref).
Oral: 1.34 mg once daily on days 1 to 21 of a 28-day cycle until disease progression or unacceptable toxicity (Ref).
Missed doses: If a dose is missed, resume dosing with the next scheduled dose. Do not administer 2 doses at the same time.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney function estimated by Cockcroft-Gault formula.
Renal impairment prior to treatment initiation:
CrCl ≥15 mL/minute: No dosage adjustment is necessary.
End-stage renal disease: There are no dosage adjustments provided in the manufacturer's labeling (has not been established).
Renal toxicity during treatment:
Proteinuria (≥2 g per 24 hours): Withhold tivozanib until <2 g per 24 hours, then resume at a reduced dose.
Nephrotic syndrome: Permanently discontinue tivozanib.
Mild impairment (total bilirubin ≤ ULN with AST > ULN or total bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment is necessary.
Moderate impairment (total bilirubin >1.5 to 3 times ULN with any AST): Reduce dose to 0.89 mg once daily for 21 days of a 28-day cycle.
Severe impairment (total bilirubin >3 to 10 times ULN with any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been established).
|
Dose reduction level |
Tivozanib dose |
|---|---|
|
Usual (initial) dose |
1.34 mg on days 1 to 21 of a 28-day cycle |
|
First dose reduction |
0.89 mg on days 1 to 21 of a 28-day cycle |
|
Adverse reaction |
Severity |
Management |
|---|---|---|
|
a Control hypertension prior to tivozanib initiation. If tivozanib is discontinued, a drop in BP is expected and antihypertensive therapy should be reduced and/or interrupted as clinically appropriate (ESC [Lyon 2022]). | ||
|
b ASCO [Armenian 2017]; ESC [Lyon 2022]. | ||
|
Hypertensiona |
If indicated, initiate appropriate antihypertensive therapy to reduce the risk for cardiovascular complications.b | |
|
Grade 3 |
Withhold tivozanib for grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled at ≤ grade 2. | |
|
Grade 4 |
Permanently discontinue tivozanib. | |
|
Hypertensive crisis |
Discontinue tivozanib. | |
|
Cardiac failure |
Grade 3 |
Withhold tivozanib until improvement to grade 0 or 1 or to baseline. Resume at a reduced dose or discontinue (depending on the severity and persistence of adverse reaction). |
|
Grade 4 |
Permanently discontinue tivozanib. | |
|
GI toxicity (diarrhea, nausea, vomiting) |
Any |
Initiate medical management prior to tivozanib therapy interruption or dose reduction. |
|
Arterial thromboembolic events |
Any grade |
Permanently discontinue tivozanib. |
|
Venous thromboembolic events |
Severe or life-threatening |
Discontinue tivozanib. |
|
Hemorrhagic events |
Grade 3 or 4 |
Permanently discontinue tivozanib. |
|
Reversible posterior leukoencephalopathy syndrome |
Any grade |
Permanently discontinue tivozanib. |
|
Thyroid dysfunction (hypothyroidism or hyperthyroidism) |
Any |
Treat hypothyroidism and hyperthyroidism to maintain euthyroid state before and during tivozanib therapy. |
|
Wound healing complications |
Any |
Withhold tivozanib until adequate wound healing. The safety of resuming tivozanib after resolution of wound healing complications is unknown. |
|
Other adverse reactions |
Persistent or intolerable grade 2 or 3 adverse reactions or grade 4 laboratory abnormality |
Withhold tivozanib until improvement to grade 0 or 1 or to baseline. Resume at a reduced dose. |
|
Grade 4 adverse reaction |
Permanently discontinue tivozanib. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Hypertension (44% to 45%; hypertensive crisis: <1%)
Dermatologic: Palmar-plantar erythrodysesthesia (16%), skin rash (18%)
Endocrine & metabolic: Decreased serum magnesium (26%), decreased serum phosphate (38%), decreased serum sodium (36%), hypothyroidism (8% to 24%), increased amylase (23%), increased serum calcium (15%), increased serum glucose (50%), increased serum potassium (26%), thyroid dysfunction (11%), weight loss (17%)
Gastrointestinal: Decreased appetite (39%), diarrhea (43%), increased serum lipase (32%), nausea (30%), stomatitis (21%; grades 3/4: 2%), vomiting (18%)
Hematologic & oncologic: Decreased hemoglobin (16%; grades 3/4: 1%), decreased platelet count (19%), hemorrhage (11% to 17%; grades 3/4: 3%), increased hemoglobin (19%), lymphocytopenia (25%; grades 3/4: 5%), prolonged partial thromboplastin time (26%; grades 3/4: 1%)
Hepatic: Hepatobiliary disease (<15%), increased serum alanine aminotransferase (30%), increased serum alkaline phosphatase (30%), increased serum aspartate aminotransferase (28%), increased serum bilirubin (11%)
Nervous system: Delirium (<15%), fatigue (67%), voice disorder (27%)
Neuromuscular & skeletal: Back pain (19%), osteonecrosis (<15%)
Renal: Increased serum creatinine (50%)
Respiratory: Cough (22%), dyspnea (15%)
1% to 10%:
Cardiovascular: Arterial thromboembolism (2%), cardiac failure (2%), ischemic heart disease (3%), venous thromboembolism (2%)
Endocrine & metabolic: Hyperthyroidism (1%)
Genitourinary: Proteinuria (8%)
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Cardiac effects: Serious or fatal cardiac failure may occur. Tivozanib has not been studied in patients with symptomatic cardiac failure within the 6 months prior to tivozanib therapy initiation. Cardiac ischemia has also been reported, including ≥ grade 3 events and fatality due to ischemic stroke.
• Hemorrhage: Serious or fatal hemorrhagic events have been reported. Tivozanib has not been studied in patients with significant bleeding within the 6 months prior to tivozanib therapy initiation.
• Hypertension: Hypertension commonly occurred with tivozanib, including ≥ grade 3 events. The median time to onset of hypertension was 2 weeks (range: up to 192 weeks). Hypertensive crisis (including 1 fatality) was reported in a small number of patients. Tivozanib has not been studied in patients with systolic BP >150 mm Hg or diastolic BP >100 mm Hg.
• Nephrotoxicity: Proteinuria has occurred, including grade 3 events. Some patients who developed proteinuria also had acute kidney injury either concurrently or later during treatment.
• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS) may occur. Evaluate for RPLS by MRI scan in patients presenting with seizures, headaches, visual disturbances, confusion, or altered mental function.
• Thromboembolism: Arterial and venous thromboembolism have occurred, including fatalities. Tivozanib has not been studied in patients who had an arterial thrombotic event, myocardial infarction, or unstable angina within the 6 months prior to tivozanib therapy initiation.
• Thyroid disorders: Thyroid dysfunction, including rare grade 3 or 4 events, has occurred. Hypothyroidism and hyperthyroidism were reported in ~8% and 1% of patients, respectively.
• Wound healing complications: Wound healing complications may occur with medications that inhibit vascular endothelial growth factor signaling (including tivozanib).
Dosage form specific issues:
• Yellow dye: Tivozanib contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in some patients. While the incidence of tartrazine sensitivity in the overall population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as hydrochloride:
Fotivda: 0.89 mg [contains fd&c blue #2 (indigotine,indigo carmine), fd&c yellow #5 (tartrazine)]
Fotivda: 1.34 mg
No
Capsules (Fotivda Oral)
0.89 mg (per each): $1,680.00
1.34 mg (per each): $1,680.00
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Oral: Administer with or without food. Swallow whole with a glass of water; do not open the capsule.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Tivozanib may cause teratogenicity, reproductive toxicity, and has a structural/toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Renal cell carcinoma, advanced, relapsed or refractory: Treatment of relapsed or refractory advanced renal cell carcinoma in adults following ≥2 prior systemic therapies.
Tivozanib may be confused with axitinib, cabozantinib, lenvatinib, PAZOPanib, regorafenib, SORAfenib, SUNItinib, tepotinib, tucatinib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Tivozanib. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Tivozanib. Risk X: Avoid combination
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Verify pregnancy status prior to treatment initiation.
Patients who may become pregnant should use effective contraception during therapy and for 1 month after the last dose of tivozanib. Patients with partners who may become pregnant should also use effective contraception during therapy and for 1 month after the last tivozanib dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to tivozanib may cause fetal harm.
It is not known if tivozanib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 1 month after the last tivozanib dose.
Kidney function (monitor for proteinuria prior to tivozanib initiation and periodically throughout therapy); hepatic function (baseline); thyroid function (baseline and periodically throughout treatment). Verify pregnancy status prior to treatment initiation (in patients who can become pregnant). Monitor BP (after 2 weeks and at least monthly thereafter); if receiving antihypertensive therapy, monitor for hypotension during tivozanib treatment interruptions. Monitor for signs/symptoms of cardiac failure, arterial or venous thromboembolic events (closely monitor patients at risk for or who have a history of thromboembolic events), and hemorrhagic events. Monitor for signs/symptoms of impaired wound healing or reversible posterior leukoencephalopathy syndrome. Monitor adherence.
Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]). BP at each clinical visit (as well as daily home monitoring for first cycle, after dose increases, and every 2 to 3 weeks thereafter); baseline echocardiography in high- and very high-risk patients (repeat every 3 months during the first year and every 6 to 12 months thereafter); consider baseline echocardiography in low- and moderate-risk patients (consider repeating every 4 months during the first year and every 6 to 12 months thereafter for moderate-risk patients) (ESC [Lyon 2022]).
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Tivozanib is a potent and selective vascular endothelial growth factor receptor (VEGFR) inhibitor (Rini 2020). Tivozanib inhibits phosphorylation of VEGFR-1, VEGFR-2, and VEGFR-3; it also inhibits other kinases (including c-kit and PDGFR β). Tivozanib inhibits angiogenesis, vascular permeability, and tumor growth of various tumor cell types.
Distribution: Vd: 123 L.
Protein binding: ≥99%, primarily to albumin.
Metabolism: Predominantly via CYP3A4.
Half-life elimination: 111 hours.
Time to peak: 10 hours (range: 3 to 24 hours).
Excretion: Feces: 79% (26% as unchanged drug); urine: 12%.
Clearance: 0.75 L/hour.
Hepatic function impairment: Tivozanib AUCtau increased by 1% and 62%, respectively, in patients with mild or moderate hepatic impairment (compared to subjects with normal hepatic function).
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