General

Pronunciation:
tye-voe-za-nib

Trade Name(s)

• Fotivda

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

Relapsed or refractory advanced renal cell carcinoma following ≥2 prior systemic therapies

Action

Acts as a tyrosine kinase inhibitor of several vascular endothelial growth factor (VEGF) receptors, c-kit, and platelet-derived growth factor receptor. Overall effect is decreased angiogenesis, vascular permeability and growth of tumors.

Therapeutic Effect(s):

• Decreased growth and spread of renal cell carcinoma.
• Improvement in progression-free survival.

Pharmacokinetics

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to extravascular tissues.

Protein Binding: ≥99%.

Metabolism and Excretion: Primarily metabolized in the liver via the CYP3A4 isoenzyme. Primarily excreted in feces (26% as unchanged drug) with 12% being excreted in urine.

Half-life: 111 hr.

TIME/ACTION PROFILE (plasma concentrations)

Contraindication/Precautions

Contraindicated in:

• SBP >150 mmHg or DBP >100 mmHg;
• History of symptomatic HF within preceding 6 mo;
• Patients at risk of or with history of arterial thrombotic events, including MI, angina or ischemic stroke within preceding 6 mo;
• Significant bleeding within preceding 6 mo
• End-stage renal disease
• Severe hepatic impairment
• OB:   Pregnancy (may cause fetal harm);
• Lactation:  Lactation.

Use Cautiously in:

• Hypertension (control before initiating therapy)
• Heart failure
• Patients at risk for or with history of venous thromboembolism
• Patients at risk for or with history of bleeding
• Surgery (interruption of therapy recommended);
• Thyroid abnormalities;
• Aspirin or tartrazine hypersensitivity
• Moderate hepatic impairment (↓ dose)
• Rep:   Women of reproductive potential and men with female partners of reproductive potential
• Pedi:   Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: hypertension, DEEP VEIN THROMBOSIS, HF, HYPERTENSIVE CRISES, MYOCARDIAL INFARCTION

Derm: palmar-plantar erythrodysesthesia syndrome, rash, impaired wound healing

Endo: hyperglycemia, hypothyroidism, hyperthyroidism

F and E: hypercalcemia, hyperkalemia, hypomagnesemia, hyponatremia, hypophosphatemia

GI: ↑ amylase, ↑ lipase, ↑ liver enzymes, diarrhea, hyperbilirubinemia, nausea, stomatitis, vomiting

GU: ↑ serum creatinine, ↓ fertility, acute kidney injury, HEPATOBILIARY DISORDERS, proteinuria

Hemat: ↑ activated partial thromboplastin time, ↑ hemoglobin, anemia, BLEEDING, lymphocytopenia, thrombocytopenia, THROMBOEMBOLIC EVENTS

Metabolic: ↓ appetite, ↓ weight

MS: back pain, osteonecrosis

Neuro: delirium, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), STROKE

Resp: cough, dysphonia, dyspnea, PULMONARY EMBOLISM, RESPIRATORY FAILURE

Misc: fatigue

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

 Strong CYP3A inducers, including  rifampin, may ↓ levels and effectiveness; avoid concurrent use.

Route/Dosage

PO (Adults): 1.34 mg once daily on Days 1–21 of a 28-day cycle (i.e. 21 days of tivozanib therapy, followed by 7 days off of therapy); continue until disease progression or unacceptable toxicity.

Hepatic Impairment 
PO (Adults): Moderate hepatic impairment: 0.89 mg once daily on Days 1–21 of a 28-day cycle (i.e. 21 days of tivozanib therapy, followed by 7 days off of therapy); continue until disease progression or unacceptable toxicity.

Availability

Capsules: 0.89 mg, 1.34 mg

Assessment

• Ensure BP is controlled before starting therapy. Monitor BP after 2 wk and at least monthly thereafter during therapy. Treat with antihypertensive therapy when hypertension occurs.  If Grade 3 hypertension occurs:  hold for Grade 3 that persists despite optimal antihypertensive therapy. Resume at reduced dose when hypertension is controlled at ≤Grade 2.  If Grade 4 hypertension occurs:  permanently discontinue tivozanib. If tivozanib is held, monitor patients receiving antihypertensive therapy for hypotension.
• Monitor for signs and symptoms of HF (dyspnea, swelling of ankles) during therapy.  If Grade 3 HF occurs:  hold tivozanib until improves to Grade 0–1 or baseline. Resume at reduced dose or discontinue depending on severity and persistence HF.  If Grade 4 HF occurs:  permanently discontinue tivozanib.
• Monitor for signs and symptoms of cardiac ischemia or arterial thromboembolic events (new chest pain or pressure; numbness or weakness on one side of body; pain in your arms, back, neck or jaw; trouble talking; shortness of breath; sudden severe headache; vision changes; swelling in arms or legs) during therapy. If symptoms occur, permanently discontinue tivozanib.
• Monitor patients who are at risk for or who have a history of bleeding during therapy. If Grade 3 or 4 bleeding occurs: discontinue tivozanib permanently.
• Monitor for signs and symptoms of PRES (seizures, headaches, visual disturbances, confusion, altered mental function) during therapy. If symptoms occur, permanently discontinue therapy.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

• May cause proteinuria. Monitor for proteinuria before starting and periodically during therapy.  If ≥2 grams proteinuria in 24 hr,  hold tivozanib until ≤2 grams of proteinuria per 24 hr. Resume at a reduced dose. Permanently discontinue if nephrotic syndrome occurs.
• Monitor thyroid function before starting and periodically during therapy. Treat hypothyroidism and hyperthyroidism to maintain euthyroid state before and during therapy.

Implementation

• Administer medications for diarrhea, nausea, or vomiting before interrupting or reducing dose. If doe reduction is necessary, reduce dose to 0.89 mg/day for 21 days followed by 7 days off therapy.
• May impair wound healing. Hold tivozanib for at least 24 days before elective surgery. Do not administer for at least 2 wks following major surgery and until adequate wound healing.
• PO Administer daily without regard to food for 21 days followed by 7 days off therapy.  DNC: Swallow capsule whole; do not open, crush, or chew.  Follow with a glass of water.

Patient/Family Teaching

• Instruct patient to take tivozanib as directed. If a dose is missed, omit and take next scheduled dose; do not double doses. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
• Advise patient to notify health care professional if signs and symptoms of hypertension or hypertensive crisis (confusion, headaches, dizziness, chest pain, shortness of breath), HF, heart attack or blood clots, bleeding problems (unusual bleeding from gums; red or black tarry stools, menstrual bleeding or vaginal bleeding that is heavier than normal; bruises that happen without a known cause or get larger; headaches; feeling dizzy or weak; bleeding that is severe or you cannot control; coughing up blood or blood clots; pink or brown urine; vomiting blood or vomit looks like "coffee grounds"; unexpected pain, swelling, or joint pain), PRES (headaches, seizures, confusion, blindness or change in vision, difficulty thinking) occur.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
• Instruct patient to notify health care professional of medication regimen prior to treatment or surgery.
• Rep:   May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 1 month after last dose. Advise patient to avoid breastfeeding during and for 1 month after last dose. Instruct patient to notify health care professional promptly if pregnancy is suspected. May impair female and male fertility.
• Emphasize importance of regular lab tests to monitor for side effects.

Evaluation/Desired Outcomes

• Decreased growth and spread of renal cell carcinoma.
• Improvement in progression-free survival.