Pazopanib (Votrient) is a multitargeted Tyrosine kinase inhibitor that inhibits angiogenesis and tumor growth.

Indications of Pazopanib (Votrient):

• Advanced Renal cell carcinoma:

  • It is indicated for the treatment of advanced renal cell carcinoma.

• Advanced Soft tissue sarcoma:

  • It is used for the treatment of advanced soft tissue sarcoma (in patients who have received prior chemotherapy)
  • Limitations of use: The efficacy of pazopanib for the treatment of adipocytic soft tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated.

• Off Label Use of Pazopanib in Adults:

  • Advanced differentiated Thyroid cancer

Pazopanib (Votrient) dose in Adults

Pazopanib (Votrient) dose in the treatment of advanced Renal cell carcinoma:

• 800 mg per oral once daily.

Pazopanib (Votrient) dose in the treatment of advanced Soft tissue sarcoma:

• 800 mg per oral once daily.

Pazopanib (Votrient) dose in the treatment of advanced Thyroid cancer, differentiated (off-label):

• 800 mg per oral once daily until disease progression or unacceptable toxicity.

Missed doses:

• If a dose is missed, do not take it if <12 hours until the next dose.

Concomitant CYP3A4 inhibitors/inducers:

• CYP3A4 inhibitors:

  • Concomitant strong CYP3A4 inhibitors can increase pazopanib concentration, therefore reduction of pazopanib to 400 mg once daily with careful monitoring is required.

• CYP3A4 inducers:

  • Concomitant strong CYP3A4 inducers can decrease pazopanib concentrations therefore pazopanib is not recommended in situations where the chronic use of a strong CYP3A4 inducer is required.

Pazopanib (Votrient) use in children:

The efficacy and safety of the drug in children have not been established.

Pregnancy Risk Category: D

• Pazopanib may cause harm to the fetus. Therefore, it is important that you avoid pregnancy before beginning therapy.
• Effective contraception should be used by women during treatment and at least two weeks after stopping.
• Condoms should be used by male patients, including vasectomized patients, during treatment and at least two weeks following the last dose.

Use of Pazopanib while breastfeeding

• It is unknown if Pazopanib is excreted in breast milk.
• Due to the potential for fatal side effects, the manufacturer suggests that you stop breastfeeding during treatment and for at least 2 weeks after your last dose of pazopanib.

Pazopanib (Votrient) Dose adjustment in renal disease:

• Creatinine clearance ≥30 mL/minute:

  • No dosage adjustment necessary.

• Creatinine clearance <30 mL/minute:

  • There are no dosage adjustments provided in the manufacturer’s labeling.

Pazopanib (Votrient) Dose adjustment in liver disease:

• Preexisting impairment:

  • Mild (bilirubin ≤1.5 times upper normal limit or ALT >Upper normal limit):

    • No dosage adjustment required.

  • Moderate (bilirubin >1.5 to 3 times the upper normal limit):

    • Consider alternative therapy or reduce to 200 mg once daily.

  • Severe (bilirubin >3 times upper normal limit with any ALT level):

    • Use is not recommended.

• During treatment:

  • Isolated ALT elevations 3 to 8 times upper normal limit:

    • Continue treatment, monitor liver function weekly until ALT returns to grade 1 or baseline.

  • Isolated ALT elevations >8 times upper normal limit:

    • Interrupt treatment until ALT returns to grade 1 or baseline.
    • Restart treatment at ≤400 mg once daily (with liver function monitored weekly for 8 weeks);
    • permanently discontinue if ALT >3 times ULN occurs with reinitiation.

  • ALT >3 times upper normal limit concurrently with bilirubin >2 times upper normal limit:

    • Permanently discontinue.

  • Gilbert syndrome with mild indirect bilirubin elevation and ALT >3 times upper normal limit:

    • Refer to isolated ALT elevations dosage recommendations above.

Common Side Effects of Pazopanib (Votrient):

• Cardiovascular:

  • Hypertension
  • Bradycardia
  • Peripheral Edema
  • Cardiac Insufficiency

• Central Nervous System:

  • Fatigue
  • Tumor Pain
  • Headache
  • Dizziness

• Dermatologic:

  • Hair Discoloration
  • Exfoliative Dermatitis
  • Alopecia
  • Dermatological Disease
  • Hypopigmentation
  • Palmar-Plantar Erythrodysesthesia

• Endocrine & Metabolic:

  • Weight Loss
  • Increased Serum Glucose
  • Increased Thyroid-Stimulating Hormone
  • Decreased Serum Albumin
  • Decreased Serum Phosphate
  • Decreased Serum Sodium
  • Decreased Serum Magnesium
  • Decreased Serum Glucose
  • Increased Serum Potassium

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Decreased Appetite
  • Anorexia
  • Vomiting
  • Dysgeusia
  • Increased Serum Lipase
  • Gastrointestinal Pain
  • Abdominal Pain
  • Mucositis
  • Stomatitis

• Hematologic & Oncologic:

  • Leukopenia
  • Lymphocytopenia
  • Thrombocytopenia
  • Neutropenia
  • Hemorrhage

• Hepatic:

  • Increased Serum AST
  • Increased Serum ALT
  • Increased Serum Bilirubin
  • Increased Serum Alkaline Phosphatase

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain
  • Myalgia
  • Weakness

• Respiratory:

  • Dyspnea
  • Cough

• Miscellaneous:

  • Tumor Pain

Uncommon Side Effects Of Pazopanib (Votrient):

• Cardiovascular:

  • Chest Pain
  • Left Ventricular Systolic Dysfunction
  • Venous Thrombosis
  • Ischemia
  • Myocardial Infarction
  • Prolonged Q-T Interval On ECG
  • Facial Edema
  • Transient Ischemic Attacks

• Central Nervous System:

  • Insomnia
  • Voice Disorder
  • Chills

• Dermatologic:

  • Skin Rash
  • Skin Depigmentation
  • Xeroderma
  • Nail Disease

• Endocrine & Metabolic:

  • Hypothyroidism

• Gastrointestinal:

  • Dyspepsia
  • Anal Hemorrhage
  • Gastrointestinal Fistula
  • Gastrointestinal Perforation

• Genitourinary:

  • Proteinuria
  • Hematuria

• Hematologic & Oncologic:

  • Oral Hemorrhage
  • Rectal Hemorrhage

• Ophthalmic:

  • Blurred Vision

• Respiratory:

  • Epistaxis
  • Pneumothorax
  • Hemoptysis

Rare side effects of Pazopanib (Votrient):

• Cardiovascular:

  • Decreased Left Ventricular Ejection Fraction
  • Hypertensive Crisis

• Central Nervous System:

  • Reversible Posterior Leukoencephalopathy Syndrome

• Hematologic & Oncologic:

  • Hemolytic-Uremic Syndrome
  • Neutropenic Infection
  • Thrombotic Thrombocytopenic Purpura

• Hepatic:

  • Hepatotoxicity
  • Severe Hepatotoxicity

• Infection:

  • Serious Infection

• Neuromuscular & Skeletal:

  • Arthralgia
  • Muscle Spasm

Contraindication to Pazopanib (Votrient):

The US labeling of the manufacturer does not list any contraindications.

• Canadian labeling
• Hypersensitivity to pazopanib and any component of the formulation
• Patients 2 Years of Age

Warnings and precautions

• Perforation/fistula of the gastrointestinal tract

  • For symptoms such as gastrointestinal perforation or fistula, it is important to monitor closely.

• Reaction to skin on the hand-foot:

  • The hand-foot syndrome is caused by pazopanib and can be localized with hyperkeratotic lesions. It presents with tingling/burning, dysesthesia, and paresthesia of the palms/soles.
  • You might experience blisters, dry/cracked or hyperkeratosis, hyperkeratosis, desquamation, and erythema on flexure surfaces.
  • For hand-foot syndrome, topical steroids and emollients should be used. A temporary reduction or delay may be necessary.

• Heart Failure:

  • This can cause heart failure so it is important to monitor your cardiac health regularly. Pre-existing hypertension increases the risk.

• Hemorrhage

  • Often, pazopanib is used to treat hemorhagic events like epistaxis and hematuria.
  • Avoid it in hemoptysis or cerebral hemorhage, and massive GI hemorhage within six months.

• Hepatotoxicity: [US Boxed Warning]

  • People over 65 years old are more likely to experience severe transaminitis.
  • It is important to monitor the liver function and take appropriate dose reduction, delay, or cessation measures.
  • Patients with Gilbert syndrome may experience mild unconjugated hyperbilirubinemia.
  • Dosage modification is necessary for patients with known Gilbert Syndrome (only a mild indirect bilirubin eleviation and ALT >3x the normal limit).

• Hypertension

  • Pazopanib may raise blood pressure or worsen hypertension.
  • For persistent hypertension, dosage reduction might be necessary. Hypertensive crises should be treated with the drug.

• Infections

  • Sometimes, life-threatening or serious infections may occur and require a temporary or permanent discontinuation of therapy.

• Ocular toxicities:

  • Pazopanib has been shown to cause retinal detachment.

• Proteinuria

  • It is possible to cause proteinuria by using it so regular monitoring of the 24-hour urine protein level and dosage reduction are necessary for proteinuria that exceeds 3 g/24. Recurrent proteinuria should be treated with immediate cessation.

• Toxicity in the lungs:

  • Pneumonitis and interstitial lung disease can lead to fatalities. Therefore, drug therapy should be stopped.

• Extension of QTc:

  • This can cause QTc prolongation and torsade des pointes. Regular electrolyte and ECG monitoring is therefore necessary.
  • You should not use it if you have a history QTc prolongation or are taking medications that prolong the QT interval.

• Reversible posterior Leukoencephalopathy Syndrome (RPLS).

  • It can cause blindness, confusion and headaches, as well as seizure, visual, neurologic, or other symptoms.
  • In the event of RPLS, the drug should be stopped immediately.

• Events that are thromboembolic:

  • These include life-threatening deep venous thrombosis (DVT), pulmonary embolism, angina and TIA.
  • It is important to consider risk factors and not use it within the last 6 months of an arteriothrombotic episode.

• Thrombotic microangiopathy

  • The condition of thrombotic microangiopathy (including thrombotic hemocytopenic purpura or hemolytic uremic disorder) can be caused by either a single drug or combined with topotecan or bevacizumab. It is important to stop the drug immediately.

• Thyroid disorders

  • Hypothyroidism is possible. Therefore, it is important to monitor thyroid function.

• Wound healing complications

  • Vascular endothelial Growth Factor Inhibitors can cause impaired wound healing.
  • The treatment should be stopped for at least a week prior to scheduled surgery. Reinitiation of treatment should only be done under the supervision of a physician.
  • Therapy should be stopped in the event of wound dehiscence.

Pazopanib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Blood pressure
• Liver function tests
• serum electrolytes including calcium, magnesium
• Thyroid function tests
• Pregnancy status
• routine urine exam for proteinuria/24-hour urine protein
• ECG/ Echocardiography
• Signs/symptoms of GI perforation or fistula, venous/arterial thrombotic events, interstitial lung disease/pneumonitis, infection, heart failure, or neurological changes.

How to administer Pazopanib (Votrient)?

• It should be given orally as a whole on an empty stomach, 1 hour before or 2 hours after a meal.
• Crushing of the tablet can increase absorption and effect systemic exposure.

Mechanism of action of Pazopanib (Votrient):

Pazopanib is a tyrosine kinase inhibitor which works by inhibiting cell surface vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet derived growth factor receptors (PDGFR-alpha,beta), fibroblast growth factor receptor (FGFR-1 and -3), cytokine receptor, interleukin-2 receptor inducible T-cell kinase, lymphocyte-specific protein tyrosine kinase and transmembrane glycoprotein receptor tyrosine kinase leading to inhibition of angiogenesis ,thereby arresting tumor growth.

Protein binding: >99%

Metabolism: Occurs in the liver, primarily via CYP3A4, minor metabolism via CYP1A2 and CYP2C8

Bioavailability: Rate and extent of bioavailability are increased with food and increased if tablets are crushed.

Half-life elimination: 31 hours

Time to peak, plasma: 2 to 4 hours

Excretion: Occurs in feces (primarily), urine (<4%)

Pazopanib Brand Names (International):

• Votrient
• Votrieny
• Vottrient

Pazopanib Brand Names in Pakistan:

No Brands Available in Pakistan.