Tivozanib is an oral kinase inhibitor targeting VEGFR-1, VEGFR-2, and VEGFR-3; it also inhibits other kinases including c-kit and PDGFR-beta at clinically relevant concentrations. Tivozanib is indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma following 2 or more prior systemic therapies. Patients should not receive tivozanib for at least 24 days before elective surgery due to wound healing complications that may be associated with treatment; do not administer tivozanib for at least 2 weeks after major surgery and until adequate wound healing has occurred.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer tivozanib with or without food.
-Swallow the tivozanib capsules whole with a glass of water. Do not open the capsule.
-If a dose is missed, administer the next dose at the next scheduled time. Do not take 2 doses at the same time.
Hypertension occurred in 45% (grade 3 or higher, 22%) of patients treated with tivozanib in a pooled safety population from 6 monotherapy studies (n = 1,008); the median time to onset was 2 weeks. Hypertensive crisis occurred in 0.8% of tivozanib-treated patients; one patient (0.1%) died due to hypertensive emergency after tivozanib overdose. Control blood pressure prior to treatment with tivozanib. Monitor blood pressure 2 weeks after starting therapy and at least monthly thereafter during treatment with tivozanib. If hypertension occurs, treat patients with appropriate medical therapy. Hold tivozanib for severe hypertension despite optimal antihypertensive therapy; for persistent hypertension despite treatment, reduce the dose of tivozanib. If tivozanib is interrupted, monitor patients receiving antihypertensive medications for hypotension. Discontinue treatment if hypertension is severe and persistent despite antihypertensive treatment, or in patients who experience hypertensive crisis.
Heart failure occurred in 1.6% (grade 3 or higher, 1%; grade 5, 0.6%) of patients treated with tivozanib in a pooled safety population from 6 monotherapy studies (n = 1,008). Periodically monitor patients for symptoms of heart failure during treatment. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary if heart failure occurs. Tivozanib has not been studied in patients with symptomatic heart failure in the 6 months prior to initiation of tivozanib therapy.
Cardiac ischemia (myocardial infarction) occurred in 3.2% (grade 3 or higher, 1.5%; grade 5, 0.4%) of patients treated with tivozanib in a pooled safety population from 6 monotherapy studies (n = 1,008). Arterial thromboembolic events occurred in 2% of tivozanib-treated patients, including death due to ischemic stroke (0.1%). Closely monitor patients who have a history of myocardial infarction or stroke or patients who are at risk for these events. Discontinue tivozanib in patients who develop any severe or life-threatening arterial thromboembolic event. Tivozanib has not been studied in patients who had an arterial thrombotic event, myocardial infarction, or unstable angina within the 6 months prior to initiating therapy.
Venous thromboembolism (VTE) occurred in 2.4% (grade 5, 0.3%) of patients treated with tivozanib in a pooled safety population from 6 monotherapy studies (n = 1,008). Closely monitor patients who have a history of VTE or those at risk for VTE. Discontinue tivozanib therapy in patients who develop severe or life-threatening venous thromboembolic events.
Bleeding events occurred in 17% (grade 3 or 4, 3%) of patients with relapsed or refractory advanced renal cell cancer treated with tivozanib in a randomized clinical trial and in 11% (grade 5, 0.2%) of patients treated with tivozanib in a pooled safety population from 6 monotherapy studies (n = 1,008), including hematuria, epistaxis, hemoptysis, hematoma, rectal hemorrhage, vaginal bleeding, contusion, GI bleeding, hematochezia, intraocular hematoma, melena, metrorrhagia, pulmonary hemorrhage, subdural hematoma, gingival bleeding, hematemesis, intracranial bleeding, hemorrhoidal hemorrhage, and splinter hemorrhage; fatal subdural hematoma occurred in 0.6%. Prolonged bleeding time (activate partial thromboplastin time, aPTT) occurred in 26% (grade 3 or 4, 1%) of tivozanib-treated patients in the randomized trial. Closely monitor patients who are at risk for bleeding or those who have a history of bleeding. Discontinue tivozanib in patients who develop severe or life-threatening hemorrhagic events. Tivozanib has not been studied in patients with significant bleeding in the 6 months prior to initiation of therapy.
Proteinuria occurred in 8% (grade 3, 2%) of patients treated with tivozanib in a pooled safety population from 6 monotherapy studies (n = 1,008); 3.7% of patients with proteinuria had acute kidney injury either concurrently or later during treatment. Mild (grade 1 or 2) increases in creatinine occurred in 50% of tivozanib-treated patients with recurrent or refractory advanced renal cell cancer in a randomized, open-label clinical trial (n = 173). Monitor patients for proteinuria at baseline and periodically throughout treatment with tivozanib. An interruption of therapy or dose reduction is necessary for patients who develop moderate to severe proteinuria; discontinue tivozanib in patients who develop nephrotic syndrome.
Hypothyroidism occurred in 8% and hyperthyroidism in 1% of patients treated with tivozanib in a pooled safety population from 6 monotherapy studies (n = 1,008); overall, thyroid disorders occurred in 11% (grade 3 or 4, 0.3%) of tivozanib-treated patients. Monitor thyroid function at baseline and periodically throughout treatment with tivozanib. Treat thyroid disorders to maintain euthyroid state before and during treatment with tivozanib. Hypothyroidism occurred in 24% (grade 3 or 4, 1%) of patients with recurrent or refractory advanced renal cell cancer treated with tivozanib in a randomized, open-label trial.
Serious hepatobiliary disorders occurred in 2.3% of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial; fatal events occurred in 1.2% of patients. Elevated hepatic enzymes including increased ALT (30%; grade 3 or 4, 4%) and increased AST (28%; grade 3 or 4, 1%) occurred, as well as hyperbilirubinemia in 11% (grade 3 or 4, 3%) of tivozanib-treated patients; increased alkaline phosphatase also occurred in 30% (grade 3 or 4, 4%) of those treated with tivozanib.
Diarrhea (43%; grade 3 or 4, 2%), nausea (30%), stomatitis (21%; grade 3 or 4, 2%), and vomiting (18%; grade 3 or 4, 1%) occurred in patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial.
Fatigue including asthenia occurred in 67% (grade 3 or 4, 13%) of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial.
Decreased appetite (anorexia) occurred in 39% (grade 3 or 4, 5%) and weight loss in 17% (grade 3 or 4, 3%) of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial.
Cough occurred in 22% and dyspnea in 15% (grade 3 or 4, 3%) of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial.
Dysphonia occurred in 27% (grade 3 or 4, 1%) of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial.
Back pain occurred in 19% (grade 3 or 4, 2%) of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial.
Rash occurred in 18% (grade 3 or 4, 1%) of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial, including acneiform rash, contact dermatitis, eczema, eczema nummular, erythema, erythema multiforme, photosensitivity reaction, pruritus, psoriasis, maculopapular rash, morbilliform rash, seborrheic dermatitis, exfoliative dermatitis, skin lesion, swelling face, toxic skin eruption, and urticaria. Palmar-plantar erythrodysesthesia (hand and foot syndrome) occurred in 16% (grade 3 or 4, 1%) of tivozanib-treated patients in this trial.
Osteonecrosis occurred in less than 15% of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial.
Delirium occurred in less than 15% of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial.
Hematologic abnormalities including lymphopenia, anemia, and thrombocytopenia have been reported in patients treated with tivozanib. In a randomized clinical trial, decreases from baseline in lymphocytes (25%; grade 3 or 4, 5%), platelets (19%), and hemoglobin (16%; grade 3 or 4, 1%) occurred in patients with relapsed or refractory advanced renal cell cancer treated with tivozanib; an increase in hemoglobin from baseline occurred in 19% of tivozanib-treated patients in this trial.
Electrolyte abnormalities including hypophosphatemia, hyponatremia, hyperkalemia, hypomagnesemia, and hypercalcemia have been reported in patients treated with tivozanib. In a randomized clinical trial, decreases from baseline in serum phosphate (38%; grade 3 or 4, 5%), sodium (36%; grade 3 or 4, 9%), and magnesium (26%) occurred in patients with relapsed or refractory advanced renal cell cancer treated with tivozanib; increases from baseline in potassium (26%; grade 3 or 4, 3%) and calcium (15%; grade 3 or 4, 2%) were also reported in tivozanib-treated patients.
Hyperglycemia has been reported in patients treated with tivozanib. In a randomized clinical trial, an increase in blood glucose from baseline occurred in 50% (grade 3 or 4, 3%) of patients with relapsed or refractory advanced renal cell cancer treated with tivozanib.
Hyperamylasemia occurred in 23% (grade 3 or 4, 2%) of patients with relapsed or refractory advanced renal cell cancer who received tivozanib in a randomized clinical trial; increased lipase concentrations occurred in 32% (grade 3 or 4, 9%) of tivozanib-treated patients in this trial.
Use tivozanib with caution in patients with a history of hypertension. Treatment with tivozanib can cause severe hypertension and hypertensive crisis; one patient died due to hypertensive emergency after tivozanib overdose. Control blood pressure prior to treatment with tivozanib. Monitor blood pressure 2 weeks after starting therapy and at least monthly thereafter during treatment with tivozanib. If hypertension occurs, treat patients with appropriate medical therapy. Hold tivozanib for severe hypertension despite optimal antihypertensive therapy; for persistent hypertension despite treatment, reduce the dose of tivozanib. If tivozanib is interrupted, monitor patients receiving antihypertensive medications for hypotension. Discontinue treatment if hypertension is severe and persistent despite antihypertensive treatment, or in patients who experience hypertensive crisis. Tivozanib has not been studied in patients with systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg.
Use tivozanib with caution in patients with heart failure. Treatment with tivozanib can cause serious, sometimes fatal, heart failure. Periodically monitor patients for symptoms of heart failure during treatment. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary if heart failure occurs. Tivozanib has not been studied in patients with symptomatic heart failure in the 6 months prior to initiation of tivozanib therapy.
Use tivozanib with caution in patients with a history of thromboembolic disease, myocardial infarction, stroke, or unstable angina. Treatment with tivozanib can cause serious cardiac ischemia and arterial or venous thromboembolic events; deaths have occurred. Closely monitor patients who have a history of myocardial infarction or stroke, or patients at risk for arterial or venous thromboembolic events. Discontinue tivozanib in patients who develop any severe or life-threatening arterial thromboembolic event. Tivozanib has not been studied in patients who had an arterial thrombotic event, myocardial infarction, or unstable angina within the 6 months prior to initiating therapy.
Serious bleeding events, sometimes fatal, have occurred during treatment with tivozanib. Closely monitor patients who are at risk for bleeding or those who have a history of bleeding. Discontinue tivozanib in patients who develop severe or life-threatening hemorrhagic events. Tivozanib has not been studied in patients with significant bleeding in the 6 months prior to initiation of therapy.
Severe proteinuria has been reported with tivozanib therapy; renal impairment has also occurred. Monitor patients for proteinuria at baseline and periodically throughout treatment with tivozanib. An interruption of therapy or dose reduction is necessary for patients who develop moderate to severe proteinuria; discontinue tivozanib in patients who develop nephrotic syndrome.
Use tivozanib with caution in patients with a history of thyroid disease. Treatment with tivozanib can cause hyperthyroidism and hypothyroidism. Monitor thyroid function at baseline and periodically throughout treatment with tivozanib. Treat thyroid disorders to maintain euthyroid state before and during treatment with tivozanib.
Impaired wound healing can occur in patients treated with vascular endothelial growth factor (VEGF) inhibitors such as tivozanib. Discontinue tivozanib at least 24 days prior to elective surgery; do not administer tivozanib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming tivozanib after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), which is a syndrome of subcortical vasogenic edema also known as Posterior Reversible Encephalopathy Syndrome (PRES), can occur with tivozanib use. Evaluate any patient with symptoms of RPLS including seizures, headache, visual disturbances, confusion, and altered mental status. Discontinue tivozanib therapy if RPLS is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging.
The tivozanib 0.89 mg capsules contains tartrazine dye (FD&C yellow no. 5). Patients with tartrazine dye hypersensitivity who take tivozanib may be at risk for developing allergic reactions (e.g., bronchial asthma). Tartrazine sensitivity frequently occurs in patients who also have aspirin hypersensitivity.
Pregnancy should be avoided by females of reproductive potential during tivozanib treatment and for at least 1 month after the last dose. Although there are no adequately controlled studies in pregnant women, tivozanib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving tivozanib should be apprised of the potential hazard to the fetus. In embryo-fetal development studies, oral administration of tivozanib to pregnant rats during organogenesis caused maternal toxicity, increases in early and late resorptions, fetal malformations (body edema, short/kinked tail), skeletal developmental delays, and embryo-fetal death at doses below the maximum recommended clinical dose on a mg/m2 basis. Daily administration of tivozanib to pregnant rabbits at doses 14.5 times the maximum recommended clinical dose on a mg/m2 basis during organogenesis resulted in fetal abnormalities including ventricular septal defects and major vessel anomalies.
Counsel patients about the reproductive risk and contraception requirements during tivozanib treatment. Tivozanib can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 1 month after treatment with tivozanib. Females of reproductive potential should undergo pregnancy testing prior to initiation of tivozanib. Women who become pregnant while receiving tivozanib should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should avoid fathering a child and use effective contraception during and for at least 1 month after treatment with tivozanib. Although there are no data regarding the effect of tivozanib on human fertility, male and female infertility has been observed in animal studies.
Due to the potential for serious adverse reactions in nursing infants from tivozanib, advise women to discontinue breast-feeding during treatment and for 1 month after the final dose. It is not known whether tivozanib is present in human milk, although many drugs are excreted in human milk.
For the treatment of renal cell cancer:
-for the treatment of patients with relapsed or refractory advanced renal cell cancer (RCC) following 2 or more prior systemic therapies:
Oral dosage:
Adults: 1.34 mg PO once daily for 21 days, followed by 7 days off treatment, every 28 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, open-label, phase 3 clinical trial, treatment with tivozanib significantly improved the median progression-free survival (5.6 months vs. 3.9 months) compared with sorafenib in patients with relapsed or refractory advanced RCC who had previously received at least one other VEGF inhibitor; median overall survival was lower in the tivozanib arm (16.4 months vs. 19.2 months). The overall response rate was 18% for a median duration that was not estimable in patients treated with tivozanib, compared with 8% for a median duration of 5.7 months in those who received sorafenib.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities
Arterial Thrombotic Events
-Any grade: Permanently discontinue tivozanib therapy.
Heart Failure
-Grade 3: Hold tivozanib therapy. When heart failure improves to baseline or grade 1 or less, resume treatment at a reduced dose of tivozanib (0.89 mg PO once daily for 21 days on treatment followed by 7 days off therapy). Alternatively, discontinue treatment depending upon severity and persistence.
-Grade 4: Permanently discontinue tivozanib therapy.
Hemorrhagic Events
-Grade 3 or 4: Permanently discontinue tivozanib therapy.
Hypertension
-Persistent grade 3 hypertension despite optimal medical management: Hold tivozanib therapy. When hypertension is controlled at grade 2 or less, resume treatment at a reduced dose of tivozanib (0.89 mg PO once daily for 21 days on treatment followed by 7 days off therapy).
-Grade 4: Permanently discontinue tivozanib therapy.
Proteinuria
-2 grams proteinuria or more per 24 hours: Hold tivozanib therapy. When proteinuria improves to 2 grams of proteinuria or less per 24 hours, resume treatment at a reduced dose of tivozanib (0.89 mg PO once daily for 21 days on treatment followed by 7 days off therapy).
-Nephrotic syndrome: Permanently discontinue tivozanib therapy.
Reverse Posterior Leukoencephalopathy Syndrome
-Any grade: Permanently discontinue tivozanib therapy.
Other Adverse Reactions
-Persistent or intolerable grade 2 or 3, or grade 4 laboratory abnormality: Hold tivozanib therapy. When the adverse reaction improves to baseline or grade 1 or less, resume treatment at a reduced dose of tivozanib (0.89 mg PO once daily for 21 days on treatment followed by 7 days off therapy).
-Grade 4: Permanently discontinue tivozanib therapy.
Maximum Dosage Limits:
-Adults
1.34 mg/day PO.
-Geriatric
1.34 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild hepatic impairment (total bilirubin at the upper limit of normal (ULN) or less with AST greater than ULN; or total bilirubin 1.1 to 1.5 times ULN with any AST): No dosage adjustment is necessary.
-Moderate hepatic impairment (total bilirubin 1.6 to 3 times ULN with any AST): Reduce the dose of tivozanib to 0.89 mg PO once daily for 21 days, followed by 7 days off treatment, every 28 days.
-Severe hepatic impairment (total bilirubin 3.1 to 10 times ULN with any AST): The recommended dosage of tivozanib has not been established.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
-Mild to severe renal impairment (CrCl 15 to 89 mL/min): No dosage adjustment is necessary.
-End-stage renal disease: The recommended dosage has not been established.
*non-FDA-approved indication
Amobarbital: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Apalutamide: (Major) Avoid concomitant use of tivozanib with apalutamide due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Barbiturates: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Carbamazepine: (Major) Avoid concomitant use of tivozanib with carbamazepine due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Encorafenib: (Major) Avoid concomitant use of tivozanib with encorafenib due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the overall exposure of tivozanib by 52%.
Enzalutamide: (Major) Avoid concomitant use of tivozanib with enzalutamide due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Fosphenytoin: (Major) Avoid concomitant use of tivozanib with fosphenytoin due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of tivozanib with rifampin due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the overall exposure of tivozanib by 52%.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of tivozanib with rifampin due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the overall exposure of tivozanib by 52%.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of tivozanib with lumacaftor; ivacaftor due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of tivozanib with lumacaftor; ivacaftor due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Methohexital: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Mitotane: (Major) Avoid concomitant use of tivozanib with mitotane due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Pentobarbital: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Phenobarbital: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Phenytoin: (Major) Avoid concomitant use of tivozanib with phenytoin due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Primidone: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Rifampin: (Major) Avoid concomitant use of tivozanib with rifampin due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the overall exposure of tivozanib by 52%.
Rifapentine: (Major) Avoid concomitant use of tivozanib with rifapentine due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of tivozanib with St. Johns Wort due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Tivozanib is a tyrosine kinase inhibitor that inhibits phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3; it also inhibits other kinases including c-kit and PDGFR-beta 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 is administered orally. Protein binding is 99% or higher in vitro, primarily to albumin and independent of concentration. The apparent volume of distribution of tivozanib is 123 liters; mean blood-to-plasma concentration ratios ranged from 0.495 to 0.615 in healthy subjects. The apparent clearance of tivozanib is 0.75 liters/hour and the half-life is 111 hours; steady state was reached by 14 days when administered at a dose of 1.34 mg once daily. After oral administration of a single radiolabeled 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).
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Tivozanib is primarily metabolized by CYP3A4; after administration of a single radiolabeled dose, 90% of the drug components in serum were unchanged. While administration with multiple doses of a strong CYP3A inducer (rifampin) decreased tivozanib exposure by 52%, no clinically significant differences in the pharmacokinetics of tivozanib were observed when administered with multiple doses of a strong CYP3A inhibitor. In vitro, tivozanib inhibits BCRP.
-Route-Specific Pharmacokinetics
Oral Route
The median Cmax of tivozanib at steady-state was 86.9 ng/mL (CV, 44.7%) and the AUC was 1,510 ng x hour/mL (CV, 46.1%); the median Tmax was 10 hours (range, 3 to 24 hours). The steady-state Cmax and AUC increased in a dose proportional manner over the range of 0.89 to 1.78 mg once daily (0.67 to 1.3 times the recommended dose). The accumulation ratio at steady-state after administration of 1.34 mg once daily was approximately 6- to 7-fold. Administration of a high fat meal (approximately 500-600 fat calories, 250 carbohydrate calories, and 150 protein calories) did not have a clinically significant effect on the Cmax or AUC of tivozanib in healthy subjects.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] with AST greater than ULN; or total bilirubin 1.1 to 1.5 times ULN with any AST) increased the AUC of tivozanib by 1% compared to subjects with normal hepatic function, which was not clinically significant. The tivozanib AUC increased by 62% in patients with moderate hepatic impairment (total bilirubin 1.6 to 3 times ULN with any AST). The effect of severe hepatic impairment (total bilirubin 3.1 to 10 times ULN with any AST) on the pharmacokinetics of tivozanib has not been studied.
Renal Impairment
Mild to severe renal impairment (CrCl 15 to 89 mL/min) did not have a clinically significant effect on the pharmacokinetics of tivozanib. The effect of end-stage renal disease on tivozanib pharmacokinetics is unknown.
Geriatric
Age (18 to 88 years) did not have a clinically significant effect on the pharmacokinetics of tivozanib.
Gender Differences
Sex did not have a clinically significant effect on the pharmacokinetics of tivozanib.
Ethnic Differences
Ethnicity (Caucasian, 93%; African American, 3%; Asian patients, 2%; Other, 2%) did not have a clinically significant effect on the pharmacokinetics of tivozanib.
Obesity
Body weight (39 to 158 kg) did not have a clinically significant effect on the pharmacokinetics of tivozanib.