Fotivda (tivozanib HCl)

Dosage of tivozanib hydrochloride is expressed in terms of tivozanib.

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). 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).

GI adverse effects (i.e., diarrhea, nausea, vomiting) should be managed with appropriate treatment prior to tivozanib dosage reduction or treatment interruption.

Table 1. Recommended Dosage Modification for Tivozanib Toxicity.

Adverse Reaction and Severity Modification Hypertension Grade 3 (despite optimal Withhold therapy; when hypertension antihypertensive therapy) 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 Withhold therapy; when toxicity intolerable); Grade 4 laboratory improves to grade 0 to 1 or abnormality baseline, resume at a reduced dosage Grade 4 Permanently discontinue therapy

Administer tivozanib hydrochloride orally once daily without regard to food. Swallow capsules whole with a glass of water; do not open the capsules.

If a dose of tivozanib hydrochloride is missed, take the dose at the next scheduled time. Do not take two doses at the same time.

Store tivozanib hydrochloride at 20-25degreesC. Excursions are permitted between 15-30degreesC.

No dosing information is available for this tab.

Tivozanib is metabolized primarily by cytochrome P-450 (CYP) 3A4. 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. In vitro studies also show that tivozanib does not induce CYP isoenzymes 1A, 2B6, 2C9, 2C19, or 3A at clinically relevant concentrations.

Tivozanib inhibits breast cancer resistance protein (BCRP). 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.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Tivozanib/St. John's Wort

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: St. John's wort may induce the metabolism of tivozanib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of St. John's wort and tivozanib may result in decreased levels of tivozanib, which may lead to treatment failure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tivozanib states that concurrent use with St. John's wort is contraindicated.(1) If a patient is already taking St. John's wort, therapy with St. John's wort should be stopped prior to starting treatment with tivozanib. Effects of St. John's wort may be seen up to 2 weeks after stopping therapy with St. John's wort.(1)

DISCUSSION: In a study in health volunteers, concurrent administration of single dose tivozanib (1340 mcg) with rifampin 600 mg once daily (a strong CYP3A4 inducer) decreased the half-life of tivozanib from 121 to 54 hours and decreased single dose area-under-curve (AUC) by 48%.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Tivozanib/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of tivozanib by CYP3A4.(1,2)

CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inducers and tivozanib may result in decreased levels of tivozanib, which may lead to treatment failure.(1,2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of tivozanib recommends avoiding concomitant use of strong CYP3A4 inducers.(1) The UK manufacturer of tivozanib states that concurrent use with strong CYP3A4 inducers should be undertaken with caution.(2)

DISCUSSION: Concomitant use of multiple doses of rifampin (a strong CYP3A inducer) did not change tivozanib maximum concentration (Cmax) but decreased tivozanib area-under-curve (AUC) by 52%.(1) In a study in health volunteers, concurrent administration of single dose tivozanib (1340 mcg) with rifampin 600 mg once daily (a strong CYP3A4 inducer) decreased the half-life of tivozanib from 121 to 54 hours and decreased single dose AUC by 48%. The clinical effects of strong CYP3A4 inducers on repeated daily dosing has not been studied.(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(3,4)

There are no moderate interactions for this drug.

*None.

• Invasive surgical procedure
• Lactation

• Acute myocardial infarction
• Cerebrovascular accident
• Child-pugh class B hepatic impairment
• Chronic heart failure
• Disease of liver
• Hypertension
• Impaired wound healing
• Increased risk of bleeding
• Pregnancy
• Proteinuria
• Thromboembolic disorder

• Hyperthyroidism
• Hypothyroidism

The most common (>=20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis. The most common grade 3 or 4 laboratory abnormalities (>=5%) were decreased sodium, increased lipase, and decreased phosphate.

More Frequent

• Hypertension
• Hyponatremia
• Hypophosphatemia

Less Frequent

• Arterial thrombosis
• Avascular necrosis of bone
• Heart failure
• Hemorrhage
• Hyperbilirubinemia
• Hyperthyroidism
• Increased alanine transaminase
• Increased aspartate transaminase
• Lymphopenia
• Thrombocytopenic disorder
• Venous thrombosis

Rare or Very Rare

• Gastrointestinal fistula
• Gastrointestinal perforation
• Hypertensive crisis
• Impaired wound healing
• Myocardial ischemia
• Nephrotic syndrome
• Pancreatitis
• Pneumonia
• Posterior reversible encephalopathy syndrome

More Frequent

• Anorexia
• Cough
• Diarrhea
• Elevated serum lipase
• Fatigue
• Hypothyroidism
• Nausea
• Stomatitis
• Voice change

Less Frequent

• Delirium
• Hyperglycemia
• Increased hemoglobin
• Palmar-plantar erythrodysesthesia
• Prolonged activated partial thromboplastin time
• Proteinuria
• Skin rash
• Vomiting
• Weight loss

No enhanced messaging available.

Safety and efficacy of tivozanib have not been established in pediatric patients.

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. 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.

Tivozanib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.

Verify pregnancy status prior to initiation of tivozanib in females of reproductive potential.

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. Patients should not breast-feed while receiving tivozanib and for one month after the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the pooled safety population of 1008 patients in the principal safety and efficacy studies, 29% of patients were >=65 years of age. No overall differences in safety were observed between geriatric patients and younger adults.