Pazotab

Approved Indications:

• Advanced Renal Cell Carcinoma (RCC):
  First-line treatment of advanced RCC in adults.
  Also indicated for patients previously treated with cytokine therapy.
• Advanced Soft Tissue Sarcoma (STS):
  Approved for the treatment of advanced soft tissue sarcoma in adults who have received prior chemotherapy (excluding those with adipocytic STS or gastrointestinal stromal tumors).

Clinically Accepted Off-Label Uses:

• Thyroid Cancer (refractory differentiated thyroid carcinoma):
  Used in some cases resistant to radioactive iodine therapy.
• Ovarian Cancer (recurrent):
  Under investigation and sometimes used with other agents in platinum-resistant/refractory cases.

Route of Administration: Oral
Dosage Form: Tablets (200 mg, 400 mg)

Adults:

• Advanced Renal Cell Carcinoma (RCC):
  Recommended dose: 800 mg once daily without food (at least 1 hour before or 2 hours after a meal).
• Advanced Soft Tissue Sarcoma (STS):
  Recommended dose: 800 mg once daily under the same conditions as above.

Elderly Patients:

• No specific dose adjustment required. However, monitor closely due to increased susceptibility to adverse effects.

Pediatric Use:

• Safety and effectiveness not established in children.

Renal Impairment:

• No dose adjustment for mild to moderate renal impairment.
• Use with caution in severe renal impairment due to lack of data.

Hepatic Impairment:

• Mild (Child-Pugh A): No dosage adjustment needed.
• Moderate (Child-Pugh B): Reduce dose to 200 mg once daily.
• Severe (Child-Pugh C): Use not recommended.

Administration Instructions:

• Swallow tablets whole with water. Do not crush or chew.
• Take on an empty stomach (avoid food 1 hour before and 2 hours after).
• Avoid grapefruit juice during therapy.
• Missed dose: Skip and resume normal schedule. Do not double dose.

Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). It selectively inhibits vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), fibroblast growth factor receptors (FGFR-1 and FGFR-3), and c-Kit. By blocking these kinases, pazopanib disrupts angiogenesis—the process by which new blood vessels form to supply nutrients to tumors. This leads to the inhibition of tumor growth and progression, particularly in highly vascularized tumors like RCC and STS.

• Absorption: Oral bioavailability is ~21%; peak plasma concentration reached in 2–4 hours.
• Food Effect: High-fat meals significantly increase drug exposure (AUC and Cmax).
• Distribution: Highly protein-bound (>99%); volume of distribution ~160 L.
• Metabolism: Extensively metabolized in the liver, primarily via CYP3A4; minor involvement of CYP1A2 and CYP2C8.
• Elimination: Excreted primarily via feces (~82%), with minimal urinary excretion (~4%).
• Half-life: Approximately 30 hours
• Steady State: Achieved within 7 days of daily dosing.

• Pregnancy:
  FDA Pregnancy Category D – Positive evidence of fetal risk. Pazopanib may cause fetal harm when administered to pregnant women. Use only if the potential benefit justifies the risk. Avoid during pregnancy.
• Lactation:
  Unknown if excreted in human milk. Due to potential harm to the nursing infant, breastfeeding is not recommended during treatment and for at least 2 weeks after the final dose.

• Primary Class: Antineoplastic agent
• Subclass: Tyrosine Kinase Inhibitor (TKI)
• Targeted Class: VEGFR/PDGFR Inhibitor

• Known hypersensitivity to pazopanib or any excipients
• Severe hepatic impairment (Child-Pugh C)
• Recent history of significant hemoptysis
• Uncontrolled hypertension
• Use with strong CYP3A4 inducers or inhibitors without dose management

• Hepatotoxicity: Boxed warning; monitor ALT, AST, and bilirubin before and during treatment
• Cardiotoxicity: Risk of QT prolongation, myocardial infarction, and heart failure
• Hypertension: Common; monitor blood pressure regularly and treat appropriately
• Thromboembolic Events: Increased risk of arterial and venous events including stroke and DVT
• Hemorrhagic Events: Risk of serious bleeding, including fatal pulmonary, cerebral, and GI hemorrhage
• Gastrointestinal Perforation and Fistula: Rare but life-threatening; monitor for symptoms
• Wound Healing Complications: Discontinue before surgery; resume postoperatively once healing is adequate
• Proteinuria: Monitor urine protein; may require treatment interruption
• Posterior Reversible Encephalopathy Syndrome (PRES): Rare; presents with seizures, confusion, vision loss
• Thyroid Dysfunction: Monitor TSH regularly

Common Side Effects (≥10% incidence):

• Gastrointestinal: Diarrhea, nausea, vomiting, anorexia, abdominal pain
• Dermatologic: Hair color changes, hand-foot syndrome, rash
• General: Fatigue, weight loss
• Hepatic: Elevated ALT, AST, bilirubin
• Cardiovascular: Hypertension

Serious or Rare Side Effects:

• Hepatotoxicity (including fatal liver failure)
• QT interval prolongation
• Thromboembolism (stroke, MI, DVT, PE)
• Hemorrhage (cerebral, pulmonary, GI)
• GI perforation or fistula
• PRES (Posterior Reversible Encephalopathy Syndrome)
• Heart failure
• Reversible hair depigmentation

Onset: Most side effects occur within the first 3 months of treatment
Dose-dependence: Some effects, particularly hepatotoxicity and hypertension, are dose-related

• Strong CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): ↑ pazopanib levels → risk of toxicity
• Strong CYP3A4 Inducers (e.g., rifampin, phenytoin): ↓ pazopanib levels → reduced efficacy
• Grapefruit Juice: Avoid—may increase plasma concentration via CYP3A4 inhibition
• Proton Pump Inhibitors / Antacids: May reduce pazopanib absorption by increasing gastric pH
• QT-Prolonging Agents: Additive risk of QT prolongation
• Anticoagulants (e.g., warfarin): Increased bleeding risk—monitor INR closely
• Herbal Supplements (e.g., St. John’s Wort): Avoid—induces CYP3A4, reduces drug efficacy

• FDA Label Update: Enhanced hepatic monitoring guidance and boxed warning clarification on hepatotoxicity
• EMA Advisory (2024): Reinforced caution in patients with cardiovascular risk due to thrombotic and QT risks
• Updated NCCN Guidelines (2025): Pazopanib remains a preferred option for advanced RCC, with more emphasis on liver function monitoring
• Dosing Update: New data support reduced dose (200 mg) for moderate hepatic impairment

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C
• Humidity: Store in a dry environment, away from moisture
• Light Protection: Store in the original container; protect from light
• Handling Precautions: Do not break or crush tablets
• Reconstitution Needs: Not applicable