FOTIVDA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FOTIVDA (FOTIVDA).
Tyrosine kinase inhibitor that selectively targets vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-α, PDGFR-β), and fibroblast growth factor receptors (FGFR-1, FGFR-2, FGFR-3, FGFR-4), thereby inhibiting angiogenesis and tumor growth.
| Metabolism | Primarily metabolized by CYP3A4; also minor contributions from CYP1A2 and CYP2C8. |
| Excretion | Primarily hepatobiliary (fecal) elimination: 87% in feces (15% as unchanged drug, 72% as metabolites). Renal excretion accounts for approximately 6% of the dose (mostly metabolites). |
| Half-life | Terminal elimination half-life is approximately 111 hours (range 79–184 hours) in patients with advanced renal cell carcinoma. This long half-life supports once-daily dosing and steady-state is reached within 2–3 weeks. |
| Protein binding | Approximately 94% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein (AAG). |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 435 L (range 251–858 L) indicating extensive tissue distribution. In L/kg: ~5.8 L/kg (assuming 75 kg body weight). Clinical meaning: extensive extravascular distribution, likely into tissues including tumors. |
| Bioavailability | Absolute oral bioavailability is approximately 50–60% (based on mass balance studies). Food has no significant effect on absorption; can be taken with or without food. |
| Onset of Action | Oral administration: time to maximum plasma concentration (Tmax) is 2–4 hours post-dose. Clinical effect (tumor response) is typically assessed after 8–12 weeks of continuous dosing based on imaging studies. |
| Duration of Action | Sustained inhibition of VEGFR tyrosine kinases persists throughout the dosing interval (24 hours) due to long half-life. Continuous daily dosing maintains therapeutic plasma concentrations; duration of clinical response varies with individual tumor kinetics. |
39 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.
| Dosage form | CAPSULE |
| Renal impairment | No dosage adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min) or ESRD, not recommended due to lack of data. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose to 27 mg once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no specific dosing recommendations available. |
| Geriatric use | No specific dose adjustment required; elderly patients may be more sensitive to adverse effects; monitor renal and hepatic function periodically. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for FOTIVDA (FOTIVDA).
| Breastfeeding | It is not known whether tivozanib is excreted in human milk. However, due to the potential for serious adverse reactions in breastfed infants, women should not breastfeed during treatment with FOTIVDA and for at least 1 month after the last dose. No M/P ratio is available. |
| Teratogenic Risk | FOTIVDA (tivozanib) is a VEGF receptor inhibitor. Based on its mechanism of action and animal studies, it is expected to cause fetal harm when administered to a pregnant woman. In animal reproduction studies, tivozanib was teratogenic, embryotoxic, and fetotoxic at maternal exposures below the recommended human dose. There are no adequate and well-controlled studies in pregnant women. First trimester exposure carries high risk of major malformations including cardiovascular and skeletal defects. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and potential renal impairment due to anti-angiogenic effects. FOTIVDA should not be used during pregnancy unless the potential benefit justifies the risk to the fetus. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None known"]
| Precautions | ["Hepatotoxicity: monitor liver function tests; dose reduce or discontinue for severe elevation.","Hypertension: monitor blood pressure; manage with antihypertensives; hold or discontinue for severe uncontrolled hypertension.","Thromboembolic events: increased risk of venous thromboembolism and arterial thromboembolism including stroke and myocardial infarction.","Hemorrhage: serious or fatal bleeding events have occurred; monitor for signs of bleeding.","Gastrointestinal perforation: may occur; discontinue if suspected.","Thyroid dysfunction: monitor thyroid function prior to and during treatment.","Wound healing complications: hold for at least 24 days prior to elective surgery.","Posterior reversible encephalopathy syndrome (PRES): discontinue if suspected.","Impaired wound healing: hold before surgery."] |
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| Fetal Monitoring | Monitor blood pressure every 2 weeks during treatment; manage hypertension with antihypertensives. Monitor thyroid function, renal function (serum creatinine, urine protein), and hepatic function (ALT, AST, bilirubin) at baseline and periodically. Monitor for thromboembolic events, hemorrhage, and gastrointestinal perforation. In pregnant patients, perform serial fetal ultrasound to assess growth, amniotic fluid volume, and fetal anatomy. |
| Fertility Effects | Tivozanib may impair fertility in females of reproductive potential based on animal studies showing ovarian and uterine changes. In males, animal studies indicate potential impairment of spermatogenesis and reduced fertility. Human data are lacking; advise patients on potential risks to fertility. |