Dosing & Uses
Dosage Forms & Strengths
capsule
- 0.89mg
- 1.34mg
Renal Cell Carcinoma
Indicated for relapsed or refractory advanced renal cell carcinoma in patients previously treated with ≥2 systemic therapies
1.34 mg PO qDay on Days 1-21 of repeated 28-day cycles
Continue until disease progression or unacceptable toxicity
Dosage Modifications
If dose modifications are required for adverse reactions, reduce to 0.89 mg qDay for 21 days followed by 7 days off treatment
Initiate medical management for diarrhea, nausea, or vomiting prior to dose interruption or reduction
Hypertension
-
Grade 3
- Withhold for persistent Grade 3 despite optimal antihypertensive therapy
- Resume at reduced dose when hypertension controlled at Grade ≤2
-
Grade 4
- Permanently discontinue
Cardiac failure
-
Grade 3
- Withhold until improves to Grade ≤1 or baseline
- Resume at reduced dose or discontinue depending on severity and persistence
-
Grade 4
- Permanently discontinue
Arterial thromboembolic events or reverse posterior leukoencephalopathy syndrome (RPLS)
- Any grade: Permanently discontinue
Hemorrhagic events
- Grade 3 or 4: Permanently discontinue
Proteinuria
-
2 grams or greater proteinuria in 24 hr
- Withhold until less than or equal to 2 grams of proteinuria per 24 hr
- Resume at a reduced dose
- Permanently discontinue for nephrotic syndrome
Other adverse reactions
-
Persistent or intolerable Grade 2 or 3 OR Grade 4 laboratory abnormality
- Withhold until improves to Grade ≤1 or baseline; resume at reduced dose
-
Grade 4
- Permanently discontinue
Renal impairment
- Mild-to-severe (CrCl 15-89 mL/min): No dosage modifications
- End-stage renal disease: Recommend dose not established
Hepatic impairment
- Mild (total bilirubin [TB] ≤1.5x ULN with any AST): No dosage adjustment necessary
- Moderate (TB >1.5 to 3x ULN with any AST): Reduce to 0.89 mg qDay
- Severe (TB 3 to 10x ULN with any AST): Not established
Dosing Considerations
Verify pregnancy in females of reproductive potential before initiation
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (26)
- amobarbital
amobarbital will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- apalutamide
apalutamide will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- bosentan
bosentan will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- butabarbital
butabarbital will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- butalbital
butalbital will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- carbamazepine
carbamazepine will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- dabrafenib
dabrafenib will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- efavirenz
efavirenz will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- enzalutamide
enzalutamide will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- etrasimod
etrasimod, tivozanib. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Risk of additive immune system effects with etrasimod has not been studied in combination with antineoplastic, immune-modulating, or noncorticosteroid immunosuppressive therapies. Avoid coadministration during and in the weeks following administration of etrasimod.
- etravirine
etravirine will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- fosphenytoin
fosphenytoin will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- ivosidenib
ivosidenib will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- lumacaftor/ivacaftor
lumacaftor/ivacaftor will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- mitotane
mitotane will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- nafcillin
nafcillin will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- palifermin
palifermin increases toxicity of tivozanib by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.
- pentobarbital
pentobarbital will decrease the level or effect of tivozanib by affecting hepatic enzyme CYP2E1 metabolism. Avoid or Use Alternate Drug.
- phenobarbital
phenobarbital will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- phenytoin
phenytoin will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- primidone
primidone will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- rifabutin
rifabutin will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- rifampin
rifampin will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- rifapentine
rifapentine will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- secobarbital
secobarbital will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- St John's Wort
St John's Wort will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
Monitor Closely (12)
- armodafinil
armodafinil will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- bexarotene
bexarotene will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- brigatinib
brigatinib will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- clobazam
clobazam will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- elagolix
elagolix will increase the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- encorafenib
encorafenib will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- eslicarbazepine acetate
eslicarbazepine acetate will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- lorlatinib
lorlatinib will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- pexidartinib
pexidartinib will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- ponesimod
ponesimod and tivozanib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.
- siponimod
siponimod and tivozanib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.
- telotristat ethyl
telotristat ethyl will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
Minor (0)
Adverse Effects
>10%
All grades
- Fatigue (67%)
- Creatinine increased (50%)
- Glucose increased (50%)
- Hypertension (44%)
- Diarrhea (43%)
- Decreased appetite (39%)
- Phosphate decreased (38%)
- Sodium decreased (36%)
- Lipase increased (32%)
- ALT increased (30%)
- Alkaline phosphatase increased (30%)
- Nausea (30%)
- AST increased (28%)
- Dysphonia (27%)
- aPTT prolonged (26%)
- Potassium increased (26%)
- Magnesium decreased (26%)
- Lymphocytes decreased (25%)
- Hypothyroidism (24%)
- Amylase increased (23%)
- Cough (22%)
- Stomatitis (21%)
- Hemoglobin increased (19%)
- Platelets decreased (19%)
- Back pain (19%)
- Rash (18%)
- Vomiting (18%)
- Bleeding (17%)
- Weight decreased (17%)
- Hemoglobin decreased (16%)
- Palmoplantar erythrodysesthesia syndrome (16%)
- Calcium increased (15%)
- Dyspnea (15%)
- Proteinuria (<15%)
- Venous thromboembolism (<15%)
- Arterial thromboembolism (<15%)
- Hyperthyroidism (<15%)
- Hepatobiliary disorders (<15%)
- Osteonecrosis (<15%)
- Cardiac failure (<15%)
- Delirium (<15%)
- Bilirubin increased (11%)
Grade 3 or 4
- Hypertension (24%)
- Fatigue (13%)
1-10%
Grade 3 or 4
- Sodium decreased (9%)
- Lipase increased (9%)
- Phosphate decreased (5%)
- Lymphocytes decreased (5%)
- Decreased appetite (5%)
- ALT increased (4%)
- Alkaline phosphatase increased (4%)
- Glucose increased (3%)
- Potassium increased (3%)
- Bilirubin increased (3%)
- Bleeding (3%)
- Dyspnea (3%)
- Decreased weight (3%)
- Amylase increased (2%)
- Calcium increased (2%)
- Diarrhea (2%)
- Stomatitis (2%)
- Back pain (2%)
- aPTT prolonged (1%)
- AST increased (1%)
- Hemoglobin decreased (1%)
- Vomiting (1%)
- Dysphonia (1%)
- Hypothyroidism (1%)
- Rash (1%)
- Palmoplantar erythrodysesthesia syndrome (1%)
Warnings
Contraindications
None
Cautions
May cause fetal harm
Imprint ink on 0.89-mg capsule contains FD&C yellow No.5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients; sensitivity is commonly seen in patients who also have aspirin hypersensitivity
RPLS can occur; evaluate for RPLS in any patient presenting with seizures, headaches, visual disturbances, confusion, or altered mental function
May cause thyroid dysfunction; monitor thyroid function before initiation of, and periodically throughout, treatment; treat hypothyroidism and hyperthyroidism to maintain euthyroid state before and during treatment
Can cause serious, sometimes fatal, cardiac ischemia and arterial thromboembolic events; not studied in patients with significant bleeding or who have had an arterial thrombotic event, myocardial infarction, or unstable angina within the preceding 6 months before initiating
Proteinuria reported; monitor for proteinuria before initiating, and periodically during treatment; discontinue if nephrotic syndrome develops
Hypertension and hypertensive crisis
- May cause severe hypertension and hypertensive crisis
- Median time to onset of hypertension was 2 weeks
- Not studied in patients with systolic blood pressure (BP) >150 mmHg or diastolic BP >100 mmHg
- Control BP before treatment
- Monitor BP after 2 weeks and at least monthly thereafter during treatment
- Treat with antihypertensive therapy when hypertension occurs
- If therapy interrupted, monitor patients receiving antihypertensive medications for hypotension
Cardiac failure
- Serious, sometimes fatal, cardiac failure may occur
- Not studied in patients with symptomatic cardiac failure within the preceding 6 months before initiating
- Periodically monitor for symptoms of cardiac failure throughout treatment
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 tivozanib
- May adversely affect wound healing
- Withhold 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
- Safety of resumption after resolution of wound healing complications has not been established
Drug interaction overview
- CYP3A4 substrate; inhibits BCRP
-
Strong CYP3A4 inducers
- Avoid coadministration
- Strong CYP3A4 inducers may decrease exposure and efficacy of tivozanib
Pregnancy & Lactation
Pregnancy
No data are available on use
Verify pregnancy status of females of reproductive potential before starting treatment
Animal data
- Oral administration of tivozanib to pregnant animals during organogenesis caused maternal toxicity, fetal malformations and embryofetal death at doses below the maximum recommended clinical dose on a mg/m2 basis
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 1 month after last dose
- Males with female partners of reproductive potential: Use effective contraception during treatment and for 1 month after last dose
Fertility
- Females and males of reproductive potential: Can impair fertility
Lactation
There are no data on presence in human milk, effects on the breastfed children, or on milk production
Advise not to breastfeed during treatment and for 1 month after last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
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-beta at clinically relevant concentrations
Absorption
Peak plasma concentration: 86.9 ng/mL
Peak plasma time: 10 hr
AUC: 1510 ng⋅hr/mL
Distribution
Protein bound: ≥99%
Vd: 123 L
Mean blood-to-plasma concentration ratios: 0.495-0.615 (healthy subjects)
Metabolism
Metabolized predominately by CYP3A4
Elimination
Half-life: 111 hr
Clearance: 0.75 L/hr
Excretion (single 1.34-mg dose): Feces (79%; 26% unchanged); urine (12%; unchanged not detected)
Administration
Oral Administration
Take with or without food
Swallow capsule whole with a glass of water; do NOT open capsule
Missed dose: Skip dose; take next dose at next scheduled time; do NOT take 2 doses at the same time
Storage
Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
Keep out of reach of children
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