Tivozanib – Uses, Dosage, Side Effects, Interaction

Tivozanib inhibits growth factor receptors, treating renal cell carcinoma. In mice and rats, tivozanib inhibits tumor angiogenesis, tumor growth, and vascular permeability. Tivozanib was shown to frequently cause hypertension? in clinical? trials; hypertension must be managed before initiating therapy. Cardiac QT segment prolongation was reported in a tivozanib cardiac safety study, however, the reactions were not considered clinically serious. In clinical studies, levels of serum soluble VEGFR2 (sVEGFR2) decreased with time and this effect increased with tivozanib exposure, and sVEGFR2 may serve as a pharmacodynamic marker of VEGFR inhibition.

Use in Cancer

Tivozanib hydrochloride is approved to treat:

• Renal cell carcinoma (a type of kidney cancer) is advanced. It is used in adults whose disease has relapsed (come back) or is refractory (does not respond to treatment) after at least two other types of systemic therapy.

Tivozanib hydrochloride is also being studied in the treatment of other types of cancer.

Contraindications

• overactive thyroid? gland
• a condition with low thyroid hormone levels
• an increased risk of bleeding
• high blood pressure
• a heart attack?
• chronic? heart failure?
• a stroke?
• nephrotic syndrome?, a type of kidney disorder
• recent operation
• elevation of proteins in the urine
• impaired wound healing
• pregnancy
• a patient who is producing milk and breastfeeding
• a type of brain disorder called posterior reversible encephalopathy syndrome?

Dosage?

Strengths: 890 mcg; 1340 mcg

Renal Cell Carcinoma

• 1.34 mg orally once a day for 21 days followed by 7 days off (28-day cycle) until disease progression or unacceptable toxicity
• For adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following 2 or more prior systemic therapies

Renal Dose Adjustments

• Mild?/moderate?/severe? renal impairment (CrCl 15 to 89 mL/min): No adjustment recommended.
• End-stage? renal disease: Data not available

Liver? Dose Adjustments

• Mild (total bilirubin? less than or equal to the upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 x ULN with any AST) hepatic impairment: No adjustment recommended.
• Moderate (total bilirubin greater than 1.5 to 3 x ULN with any AST) hepatic impairment: Reduce dose to 0.89 mg orally once a day for 21 days followed by 7 days off (28-day cycle)
• Severe (total bilirubin greater than 3 to 10 x ULN with any AST) hepatic impairment: Data not available

Dose Adjustments

Initiate medical management for diarrhea?, nausea?, or vomiting prior to dose interruption or reduction.

Recommended dose modifications:

• Reduce the dose to 0.89 mg orally once a day for 21 days followed by 7 days off for a 28-day cycle.

Dose Modifications for Adverse Reactions:
HYPERTENSION:

• Grade 3: Withhold therapy for Grade 3 that persists despite antihypertensive therapy; resume at reduced dose when hypertension is controlled at less than or equal to Grade 2.
• Grade 4: Permanently discontinue therapy.

CARDIAC FAILURE:

• Grade 3: Withhold until improvement to Grade 0, 1, or baseline; resume at reduced dose or discontinue therapy based on severity and persistence of adverse reaction.
• Grade 4: Permanently discontinue therapy.

ARTERIAL THROMBOEMBOLIC EVENTS:

• Any Grade: Permanently discontinue therapy.

HEMORRHAGIC EVENTS:

• Grade 3 or 4: Permanently discontinue therapy.

PROTEINURIA:

• Two grams or greater proteinuria in 24 hours: Withhold therapy until less than or equal to 2 grams of proteinuria in 24 hours; resume at a reduced dose; permanently discontinue for nephrotic syndrome.

REVERSE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME:

• Any Grade: Permanently discontinue therapy.

OTHER ADVERSE REACTIONS:

• Persistent or intolerable Grade 2 or 3 adverse reaction:
• Grade 4 laboratory abnormality: Withhold therapy until improvement to Grade 0, 1, or baseline; resume at a reduced dose.
• Grade 4 adverse reaction: Permanently discontinue therapy.

Administration advice:

• This drug can be taken with or without food.
• Swallow the capsule whole with a glass of water.
• Swallow the capsule whole; do not open, crush, or chew the capsule.
• If a dose is missed, the next dose should be taken at the next scheduled time; do not take two doses at the same time.
• In the case of vomiting, a replacement dose should not be taken; the next dose should be taken at the next scheduled time.

Side Effects

The Most Common

• diarrhea
• nausea
• vomiting
• fatigue
• loss of appetite
• weight loss
• voice hoarseness
• back pain
• mouth sores
• cough
• shortness of breath
• unusual bruising or bleeding
• bloody or black and tarry stools
• blood in urine
• vomiting or coughing up blood
• bleeding from gums
• seizures, headaches, vision changes, or confusion
• redness, swelling, and pain on hands and/or feet
• confusion, headache, dizziness, chest pain, or shortness of breath
• shortness of breath or swelling of ankles
• chest pain or pressure; numbness or weakness on one side of body; pain in arms, back, neck or jaw; difficulty talking; shortness of breath; sudden severe headache; vision changes; or swelling in arms or legs

More common

• Agitation
• back pain
• black, tarry stools
• bleeding from the rectum or bloody stools
• bleeding gums
• blood in the urine
• bloody nose
• blurred vision
• change in consciousness
• cloudy urine
• collection of blood under the skin
• confusion
• confusion as to time, place, or person
• constipation
• coughing or spitting up blood
• decreased urine output
• deep, dark purple bruise
• depressed mood
• depression
• difficulty in swallowing
• dilated neck veins
• dizziness
• drowsiness
• dry skin and hair
• enlarged pupils
• feeling cold
• fever
• hair loss
• heavy nonmenstrual vaginal bleeding
• hoarseness or husky voice
• holding false beliefs that cannot be changed by fact
• hostility
• increased menstrual flow or vaginal bleeding
• increased sensitivity of the eyes to light
• increased sweating, possibly with fever or cold, clammy skin
• irregular breathing
• irregular heartbeat
• irritability
• itching
• lethargy
• loss of consciousness
• muscle cramps, stiffness, twitching
• nausea
• nervousness
• nosebleeds
• pain or discomfort in the arms, jaw, back, or neck
• pain, redness, or swelling in the arm or leg
• pains in the chest, groin, or legs, especially calves of the legs
• paralysis
• pounding in the ears
• prolonged bleeding from cuts
• red or dark brown urine
• red or black, tarry stools
• seeing, hearing, or feeling things that are not there
• seizures
• sensitivity to heat
• severe chest pain
• severe headache
• slow or fast heartbeat
• sore throat
• stiff or sore neck
• stupor
• sudden loss of coordination
• sudden onset of slurred speech
• sudden onset of trouble breathing for no apparent reason
• sudden vision changes
• swelling of the face, fingers, feet, or lower legs
• tightness in the chest
• trouble breathing
• trouble healing
• trouble sleeping
• unusual excitement, nervousness, or restlessness
• unusual tiredness or weakness
• voice changes
• vomiting
• vomiting of blood or material that looks like coffee grounds
• weight gain or loss

Rare

• Blistering, crusting, irritation, itching, or reddening of the skin
• blistering, peeling, loosening of the skin
• cracked, dry, scaly skin
• cough
• decreased appetite
• diarrhea
• dry, flaky, scaling skin on the scalp, eyebrows, near the ears, and around the nose
• increased sensitivity of skin to sunlight
• joint or muscle pain
• lack or loss of strength
• rash with flat lesions or small raised lesions on the skins
• red, irritated eyes
• redness or other discoloration of skin
• severe sunburn
• skin rash, encrusted, scaly and oozing
• sores, ulcers, or white spots in the mouth or on the lips
• swelling
• swelling or inflammation of the mouth

Drug interactions

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on findings in animal studies and its mechanism of action, this drug can cause fetal harm when administered during pregnancy. This drug can harm a developing fetus. Adequate methods of contraception should be encouraged. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.  Advise females of reproductive potential to use effective contraception during therapy and for 1 month after. Advise males with female partners of reproductive potential to use effective contraception during therapy and for 1 month after. This drug can impair fertility in females and males of reproductive potential.

Lactation

• Use is not recommended.
• Excreted into human milk: Unknown
• Excreted into animal milk: Data not available
• Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during therapy and for 1 month after the last dose.

References