Votrient200 mg

Votrient is an oral, multi-targeted tyrosine kinase inhibitor with established (FDA-approved) indications in oncology. It is not indicated for use outside these settings.

Established/FDA-Approved Indications

• Advanced Renal Cell Carcinoma (RCC): Indicated for treatment of adult patients with advanced renal cell carcinoma, based on demonstrated improvement in progression-free survival.
• Advanced Soft Tissue Sarcoma (STS): Indicated for patients with advanced soft tissue sarcoma who have received prior chemotherapy. Votrient has not demonstrated efficacy in adipocytic soft tissue sarcoma or gastrointestinal stromal tumors (GIST), and is not indicated for these subtypes.

Not Indicated / Off-Label Use

Votrient is not approved for pediatric use, and there is insufficient evidence to support routine off-label use outside advanced RCC and non-adipocytic STS. Any use outside these approved settings should occur only within a clinical trial or under close specialist oncology supervision.

Each film-coated tablet contains Pazopanib Hydrochloride equivalent to 200 mg of pazopanib base, together with standard pharmaceutical excipients. Tablets are available in strengths used to build the 800 mg once-daily regimen and its reduced doses.

Votrient is the hydrochloride salt of pazopanib, an orally administered, small-molecule inhibitor of multiple receptor tyrosine kinases. It belongs to the class of antiangiogenic anticancer agents and is used in the management of specific advanced solid tumors, primarily renal cell carcinoma and soft tissue sarcoma. Votrient works by blocking signaling pathways that tumors use to develop new blood vessels (angiogenesis), thereby limiting tumor growth and spread. It is supplied as film-coated tablets for oral use and must be prescribed and monitored by an oncologist because of its serious potential toxicities.

Votrient belongs to the therapeutic class of antineoplastic agents, specifically multi-targeted tyrosine kinase inhibitors (TKIs) with antiangiogenic activity.

Mechanism of Action

Pazopanib Hydrochloride inhibits multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR-1, -2, and -3), platelet-derived growth factor receptors (PDGFR-alpha and -beta), fibroblast growth factor receptors (FGFR-1 and -3), the stem cell factor receptor (c-Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms).

By blocking these receptors, Pazopanib Hydrochloride inhibits angiogenesis (new blood vessel formation that tumors need to grow) and directly suppresses tumor cell proliferation, reducing tumor growth.

Pharmacokinetics

• Absorption: Variable and significantly increased by food; Pazopanib Hydrochloride must therefore be taken on an empty stomach.
• Metabolism: Primarily metabolized by hepatic CYP3A4, with minor contributions from CYP1A2 and CYP2C8; also an inhibitor of UGT1A1.
• Protein binding: Highly protein bound (greater than 99%), which limits removal by dialysis.
• Elimination: Eliminated mainly via feces, with a long elimination half-life supporting once-daily dosing.

Votrient tablets should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal, as food significantly increases absorption. Tablets should be swallowed whole with water and must not be crushed or broken, as this can increase the rate of absorption and toxicity.

CYP3A4 Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice): increase pazopanib exposure and toxicity risk; avoid concurrent use, or reduce the dose of Votrient to 400 mg daily if concomitant use cannot be avoided.
• Strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, St. John's Wort): decrease pazopanib exposure and may reduce efficacy; avoid concurrent use or select an alternative with less enzyme-inducing potential.

Gastric pH-Altering Agents

Proton pump inhibitors and H2-receptor antagonists reduce the solubility and absorption of Votrient and should be avoided; if an acid-reducing agent is needed, a short-acting antacid may be used, separated in time from the Votrient dose.

Other Significant Interactions

• Narrow therapeutic index CYP substrates (e.g., simvastatin and other CYP3A4/2D6/2C8 substrates): concurrent use with Votrient may increase toxicity risk (e.g., higher rates of ALT elevation with simvastatin); use with caution and monitor closely.
• QT-prolonging drugs: combining Votrient with other drugs known to prolong the QT interval increases the risk of arrhythmia; use with caution and monitor ECG and electrolytes.

Very Common Side Effects

• Diarrhea
• Hypertension
• Hair color changes (depigmentation)
• Nausea and vomiting
• Decreased appetite (anorexia)
• Fatigue
• Headache
• Taste alteration (dysgeusia)
• Weight loss
• Abdominal pain

Serious Side Effects (Seek Medical Attention)

• Signs of liver injury: yellowing of skin/eyes, dark urine, severe fatigue, right upper abdominal pain (see Precautions and Warnings).
• Signs of bleeding: coughing up blood, black or bloody stools, severe headache.
• Signs of blood clots: chest pain, shortness of breath, leg swelling or pain, sudden weakness.
• Severe or persistent high blood pressure.
• Severe abdominal pain (possible bowel perforation).
• New or worsening shortness of breath or cough (possible lung toxicity).

Patients experiencing any serious side effect while taking Votrient should contact their physician immediately.

Pregnancy

Votrient can cause fetal harm and has produced embryo-fetal toxicity in animal studies at exposures below the human therapeutic dose. It should be used during pregnancy only if clearly needed and the potential benefit justifies the potential risk to the fetus; a physician must be consulted before use in pregnancy. Pregnancy testing is recommended prior to starting therapy, and effective contraception is required for females of reproductive potential during treatment and for at least 2 weeks after the last dose. Male patients with female partners of reproductive potential should also use effective contraception during treatment and for 2 weeks after the last dose.

Lactation

It is not known whether Votrient passes into human breast milk. Because of the potential for serious adverse effects in a breastfed infant, breastfeeding is not recommended during treatment with Votrient and for at least 2 weeks after the final dose; consult a physician regarding infant feeding options.

Boxed Warning: Hepatotoxicity

Votrient carries a boxed warning for severe and fatal hepatotoxicity. Liver function tests (ALT, AST, bilirubin) must be checked at baseline and periodically thereafter (e.g., weeks 3, 5, 7, and 9, then months 3 and 4, and periodically thereafter or as clinically indicated). Treatment must be interrupted, dose-reduced, or permanently discontinued based on the severity of liver enzyme elevations.

QT Prolongation and Cardiac Dysfunction

Votrient can prolong the QT interval and has been associated with torsades de pointes. Baseline and periodic ECG and electrolyte monitoring (potassium, magnesium, calcium) is recommended, particularly in patients with pre-existing cardiac disease, electrolyte abnormalities, or those taking other QT-prolonging drugs. Left ventricular ejection fraction should be monitored, especially in patients at risk for cardiac dysfunction.

Hypertension

Blood pressure should be well controlled before starting Votrient and monitored regularly throughout treatment; most hypertension occurs early in treatment. Persistent or severe hypertension may require dose interruption, reduction, or permanent discontinuation.

Arterial and Venous Thromboembolic Events

Votrient has been associated with arterial thromboembolic events (including myocardial infarction and stroke) and venous thromboembolic events (including pulmonary embolism), some fatal. Use with caution in patients at increased risk; permanently discontinue after an arterial thromboembolic event.

Hemorrhage

Fatal hemorrhagic events have been reported with Votrient. It should not be used in patients with a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal bleeding within the previous 6 months.

Gastrointestinal Perforation and Fistula

Cases of gastrointestinal perforation or fistula, including fatal cases, have occurred with Votrient. Monitor for symptoms and permanently discontinue if perforation occurs.

Wound Healing

Votrient may impair wound healing. Treatment should be stopped at least 1 week before scheduled elective surgery and not resumed until the wound is adequately healed (generally at least 2 weeks post-surgery).

Interstitial Lung Disease/Pneumonitis

Cases of interstitial lung disease and pneumonitis, some fatal, have been reported. Monitor for pulmonary symptoms and permanently discontinue Votrient if ILD/pneumonitis is confirmed.

Proteinuria

Proteinuria has been reported; periodic urinalysis is recommended, and treatment should be discontinued if nephrotic syndrome develops.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS/PRES)

Rare cases of RPLS have occurred; symptoms include headache, seizure, lethargy, confusion, and visual disturbance. Diagnosis should be confirmed with MRI, and Votrient should be permanently discontinued if RPLS develops.

Other Precautions

Hypothyroidism (monitor thyroid function), serious infections, and thrombotic microangiopathy have also been reported; monitor patients accordingly and manage per standard oncology practice.

Overdose with Votrient may cause worsening of expected adverse effects, particularly fatigue, hypertension, and low blood counts. There is no specific antidote for Votrient overdose. Anyone who has taken more than the prescribed dose of Votrient should seek immediate medical attention or contact emergency services or a poison control center. Management is supportive, with close monitoring of vital signs and organ function; hemodialysis is not expected to significantly enhance elimination because Votrient is highly protein-bound.

Store Votrient at room temperature (below 30°C), away from light and moisture. Keep out of reach of children.

Pediatric Use

The safety and efficacy of Votrient in pediatric patients have not been established. Use is not recommended in this population.

Geriatric Use

No overall differences in effectiveness were observed between elderly and younger patients; however, elderly patients may have a higher likelihood of certain adverse effects such as elevated liver enzymes, and should be monitored closely while on Votrient.

Hepatic Impairment

See Dosage and Administration for hepatic dose adjustments; Votrient is not recommended in severe hepatic impairment.

Renal Impairment

No dose adjustment is required for mild-to-moderate renal impairment; data are limited in severe renal impairment and dialysis.

Treatment with Votrient is generally continued as long as clinical benefit is observed and the patient tolerates therapy without unacceptable toxicity, as determined by the treating oncologist. There is no fixed treatment duration; ongoing use requires regular clinical and laboratory monitoring (liver function, blood pressure, ECG, urinalysis) throughout therapy.

Pazopanib Hydrochloride is classified as an antineoplastic agent, specifically a multi-targeted receptor tyrosine kinase inhibitor (TKI) with antiangiogenic properties.

Pazopanib Hydrochloride works by selectively inhibiting multiple receptor tyrosine kinases (VEGFR-1, -2, -3; PDGFR-alpha, -beta; FGFR-1, -3; c-Kit; and others), which blocks the signaling pathways tumors rely on for angiogenesis (new blood vessel formation) and proliferation. This inhibition limits tumor blood supply and slows tumor growth.

The safety and efficacy of Votrient have not been established in pediatric patients. Animal studies have shown toxic effects on growing organ systems, particularly in very young animals, raising concern for similar effects in children. Votrient is therefore not recommended for use in the pediatric population outside of a clinical trial setting.