Sunitix

Approved Indications:

• Renal Cell Carcinoma (RCC): First-line treatment of advanced or metastatic renal cell carcinoma.
• Gastrointestinal Stromal Tumor (GIST): Treatment of GIST after disease progression or intolerance to imatinib mesylate.
• Pancreatic Neuroendocrine Tumors (pNET): Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable, locally advanced or metastatic disease.

Important Off-Label or Clinically Accepted Uses:

• Thyroid Cancer: Off-label use in advanced or metastatic differentiated thyroid carcinoma resistant to radioactive iodine therapy.
• Hepatocellular Carcinoma (HCC): Investigated as an alternative therapy in patients ineligible for sorafenib.
• Refractory Medulloblastoma or Glioblastoma: Under evaluation for recurrent or refractory CNS malignancies in pediatric and adult populations.

General Administration Guidelines:

• Route: Oral, with or without food.
• Formulation: Available as capsules or tablets (commonly 12.5 mg, 25 mg, 37.5 mg, and 50 mg).
• Cycle: Typical treatment includes 4 weeks on therapy followed by 2 weeks off (6-week cycle), or continuous daily dosing depending on indication.

Recommended Dosing by Indication:

• RCC and GIST (Adults):
  50 mg orally once daily for 4 weeks, followed by 2 weeks off (6-week cycles).
• Pancreatic Neuroendocrine Tumors (Adults):
  37.5 mg orally once daily on a continuous daily dosing schedule.

Special Populations:

• Renal Impairment:
• No dosage adjustment for mild to moderate impairment.
• Use with caution in severe renal impairment; insufficient data in dialysis patients.
• Hepatic Impairment:
• Mild/moderate (Child-Pugh A and B): Use with caution; reduced clearance may occur.
• Severe (Child-Pugh C): Not recommended due to lack of safety data.
• Elderly:
• No specific dose adjustment required; monitor tolerability and organ function.
• Pediatrics:
• Safety and efficacy not established in children for most indications; under investigation for select CNS tumors.

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor. It selectively inhibits several RTKs including VEGFR-1, -2, -3, PDGFR-α and β, c-KIT, FLT3, RET, and CSF-1R. By targeting these receptors, Sunitinib disrupts tumor angiogenesis, tumor cell proliferation, and survival. The anti-angiogenic effect is primarily mediated by inhibition of VEGF and PDGF receptor signaling, thereby reducing tumor blood supply and growth.

• Absorption: Well absorbed orally; peak plasma concentration reached within 6–12 hours.
• Bioavailability: Not precisely quantified but considered high.
• Distribution: Widely distributed; plasma protein binding ~95%.
• Metabolism: Primarily metabolized in the liver via CYP3A4 to an active metabolite (SU12662), which contributes significantly to pharmacologic activity.
• Elimination Half-life:
• Sunitinib: ~40–60 hours
• Active metabolite: ~80–110 hours
• Excretion:
• Feces: ~61% (as metabolites)
• Urine: ~16% (as metabolites)

• Pregnancy:
• FDA Category D (prior system): Positive evidence of human fetal risk. Use only if potential benefits justify the risk.
• May cause fetal harm including embryo-fetal death and structural abnormalities.
• Lactation:
• Excreted in animal milk; human data not available.
• Breastfeeding is not recommended during treatment and for at least 4 weeks after the last dose due to potential infant toxicity.

• Primary Class: Antineoplastic agent
• Subclass: Multi-targeted Tyrosine Kinase Inhibitor (TKI)
• Generation: First-generation oral angiogenesis inhibitor

• Known hypersensitivity to sunitinib malate or any component of the formulation
• Pregnancy (due to fetal toxicity)
• Severe hepatic impairment (Child-Pugh C)
• Recent or active significant bleeding or hemorrhagic conditions

• Cardiotoxicity: Risk of left ventricular dysfunction and heart failure; monitor LVEF before and during treatment.
• Hypertension: Frequently occurs; requires monitoring and management.
• Hemorrhage: Serious or fatal hemorrhages have occurred; caution in patients with bleeding risk.
• Thromboembolic Events: Arterial and venous thrombotic events possible; caution in patients with cardiovascular risk.
• Hepatotoxicity: Cases of fatal liver failure reported; monitor liver function tests regularly.
• Tumor Lysis Syndrome (TLS): Rare but potentially life-threatening; monitor in high tumor burden cases.
• QT Prolongation: Use with caution in patients with QT prolongation risk or those on QT-prolonging drugs.
• Wound Healing: May impair healing; discontinue pre-operatively and resume post-operatively after adequate healing.

Common Adverse Effects:

• Gastrointestinal: Diarrhea, nausea, vomiting, stomatitis
• Dermatologic: Hand-foot syndrome, skin discoloration, rash
• General: Fatigue, anorexia, asthenia
• Hematologic: Neutropenia, thrombocytopenia, anemia
• Musculoskeletal: Myalgia, arthralgia

Serious or Rare Side Effects:

• Congestive heart failure
• Hepatic failure
• Severe hypertension and hypertensive crisis
• Gastrointestinal perforation
• Pancreatitis
• PRES (Posterior Reversible Encephalopathy Syndrome)

• Major Interactions:
• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): Increase plasma concentrations of sunitinib; may enhance toxicity.
• CYP3A4 Inducers (e.g., rifampin, carbamazepine): Decrease sunitinib levels; reduce efficacy.
• QT-prolonging drugs: Additive risk of torsades de pointes.
• Food Interaction:
• Food does not significantly affect absorption; may be taken with or without food.
• Alcohol: No specific interaction, but avoid excessive intake due to liver toxicity risk.

• EMA/FDA Labeling (Recent Years):
• Additional guidance issued for cardiac monitoring in at-risk populations.
• Updated warnings regarding severe hepatic toxicity and bleeding.
• Continuous daily dosing approved in pNET with better tolerability compared to intermittent dosing.
• Clinical Practice Guidelines (NCCN, ESMO):
• Endorsed as first-line or second-line therapy in metastatic RCC and GIST based on progression status and prior treatments.
• NCCN recommends cardiovascular monitoring for all patients on sunitinib.

• Storage Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Light Sensitivity: Protect from light; keep in original container.
• Moisture: Store in a dry place; protect from moisture.
• Handling: Do not crush or open capsules; hazardous drug—use gloves if handling broken tablets.
• Shelf Life: Refer to packaging; generally stable for 2–3 years under proper conditions.