Tivozanib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

The VHL mutation-HIF upregulation-VEGF transcription is the main pathway implicated in the growth of renal cell carcinoma. Vascular endothelial growth factor receptors (VEGFR receptors) are important targets for tyrosine kinase inhibitors, which halt the growth of tumors. Tivozanib is a tyrosine kinase inhibitor that exerts its actions by inhibiting the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 and inhibits other kinases such as c-kit and platelet-derived growth factor beta (PDGFR β). The above actions inhibit tumor growth and progression, treating renal cell carcinoma.

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.

Indications

  • Tivozanib is approved in the USA for the treatment of relapsed or refractory renal cell carcinoma in adult patients who have undergone two or more systemic therapies. In the UK and other countries, is indicated as the first-line therapy of adults with advanced renal cell carcinoma (RCC) and VEGFR and mTOR pathway inhibitor-naïve patients after disease progression following one previous treatment with cytokine therapy for advanced disease.
  • Fotivda is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC.
  • Treatment of advanced renal cell carcinoma.
  • Tivozanib hydrochloride is approved to treat: Renal cell carcinoma (a type of kidney cancer) that 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.
  • Tivozanib is used for the treatment of adults with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies
  • Tivozanib is a kinase inhibitor to treat adult patients with renal cell carcinoma (RCC) who have failed prior systemic therapies or experienced relapsed disease.

Use in Cancer

Tivozanib hydrochloride is approved to treat:

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

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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.

How should this medicine be used?

Tivozanib comes as a capsule to take by mouth. It is usually taken once daily with or without food for the first 21 days of a 28-day cycle. The cycle may be repeated as recommended by your doctor. Take tivozanib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tivozanib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole with a glass of water; do not open them.

Your doctor may decrease your dose or temporarily or permanently stop your treatment if you experience certain side effects. This depends on how well the medication works for you and the side effects you experience. Be sure to tell your doctor how you are feeling during your treatment with tivozanib.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking tivozanib,

  • tell your doctor and pharmacist if you are allergic to tivozanib, aspirin, tartrazine (a yellow dye in some processed foods and drugs), any other medications, or any of the ingredients in tivozanib capsules. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: apalutamide (Erleada), carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Teril), enzalutamide (Xtandi), phenytoin (Dilantin, Phenytek), and rifampin (Rifadin, Rimactane, in Rifamate, in Rifater). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor and pharmacist what herbal products you are taking, especially St. John’s wort. Do not take St. John’s wort while taking tivozanib.
  • tell your doctor if you have an unhealed wound or if you have or have ever had a bleeding problem; a blood clot; heart failure; a heart attack; high blood pressure; seizures; or heart, thyroid, kidney or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or if you plan to father a child. You or your partner should not become pregnant while you are taking tivozanib. If you are female, you will need to have a pregnancy test before you start treatment, and you should use birth control to prevent pregnancy during your tivozanib treatment and for 1 month after your final dose. If you are male, you and your partner should use birth control to prevent pregnancy during your treatment with tivozanib and for 1 month after your final dose. Talk to your doctor about birth control methods that you can use during your treatment. Tivozanib may decrease fertility in men and women. However, you should not assume that you or your partner cannot become pregnant. If you or your partner become pregnant while taking tivozanib, call your doctor. Tivozanib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed during your treatment with tivozanib and for 1 month after your final dose.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tivozanib. Your doctor will probably tell you to stop taking tivozanib at least 24 days before your scheduled surgery because it can affect wound healing. Your doctor will tell you when to start taking tivozanib again after your surgery.
  • you should know that tivozanib may cause high blood pressure. Your blood pressure should be checked regularly while you are taking tivozanib.

References

  1. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-fotivda-tivozanib-adult-patients-relapsed-or-refractory
  2. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/212904Orig1s000ltr.pdf
  3. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/212904Orig1s000AdminCorres.pdf
  4. https://www.cancer.gov/about-cancer/treatment/drugs/tivozanibhydrochloride
  5. https://pubchem.ncbi.nlm.nih.gov/compound/Tivozanib
  6. https://pubchem.ncbi.nlm.nih.gov/compound/Tivozanib-hydrochloride
  7. https://en.wikipedia.org/wiki/Tivozanib
  8. https://go.drugbank.com/drugs/DB11800
  9. https://medlineplus.gov/druginfo/meds/a621018.html
  10. https://www.drugs.com/mtm/tivozanib.html
  11. https://www.mayoclinic.org/drugs-supplements/tivozanib-oral-route/side-effects/drg-20510803
  12. https://www.webmd.com/drugs/2/drug-181152/tivozanib-oral/details/list-contraindications
  13. Guide to Pharmacology Target Classification
  14. ChemIDplus Chemical Information Classification
  15. CompTox Chemicals Dashboard Chemical Lists
  16. NCI Thesaurus Tree
  17. PubChem
  18. Protein Kinase Inhibitors
  19. Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
  20. NORMAN Suspect List Exchange Classification
  21. NCBI