Regotab

• Metastatic Colorectal Cancer (mCRC):
  Treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and if RAS wild-type, anti-EGFR therapy.
• Advanced Gastrointestinal Stromal Tumor (GIST):
  For patients with unresectable or metastatic GIST who have been previously treated with imatinib and sunitinib.
• Hepatocellular Carcinoma (HCC):
  Treatment of patients with HCC who have previously received sorafenib.
• Off-label/Investigational:
  Under evaluation in various solid tumors including pancreatic neuroendocrine tumors, but not approved.

• Adults:
• Recommended dose: 160 mg orally once daily for 3 weeks on, 1 week off (28-day cycle).
• Tablets should be taken with a low-fat meal.
• Treatment is continued until disease progression or unacceptable toxicity.
• Dose Adjustments:
• Modify dose or interrupt therapy for adverse reactions.
• Dose reductions to 120 mg, then 80 mg, and then 40 mg daily may be required.
• Pediatrics:
  Safety and efficacy not established.
• Elderly:
  No initial dose adjustment; monitor closely due to potential increased toxicity.
• Hepatic Impairment:
  Not recommended in severe hepatic impairment (Child-Pugh C). Use caution in moderate impairment.
• Renal Impairment:
  No dose adjustment required for mild to moderate impairment; insufficient data in severe impairment.

Regorafenib is an oral multikinase inhibitor targeting several protein kinases involved in tumor angiogenesis, oncogenesis, and the tumor microenvironment. It inhibits vascular endothelial growth factor receptors (VEGFR1-3), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), KIT, RET, and RAF kinases. By blocking these pathways, regorafenib impedes tumor angiogenesis, reduces tumor blood supply, and inhibits tumor cell proliferation and survival.

• Absorption:
  Peak plasma concentrations reached within 3–4 hours after oral administration. Bioavailability increased when taken with a low-fat meal.
• Distribution:
  Highly protein-bound (~99.5%).
• Metabolism:
  Extensively metabolized in the liver primarily by CYP3A4 to active metabolites M-2 and M-5.
• Half-life:
  Terminal half-life of regorafenib ~28 hours; active metabolites have similar half-lives.
• Excretion:
  Eliminated mainly via feces (approximately 71%); renal elimination is minimal (~19%).

• Pregnancy:
  Category D. Regorafenib is teratogenic and embryotoxic in animal studies. Women of childbearing potential must use effective contraception during treatment and for at least 2 months after the last dose.
• Lactation:
  It is unknown whether regorafenib is excreted in human milk. Breastfeeding is not recommended during treatment and for 2 months after the last dose due to potential risks to the infant.

• Antineoplastic agent; multikinase inhibitor.

• Known hypersensitivity to regorafenib or any excipients.
• Severe hepatic impairment (Child-Pugh C).
• Concurrent use with strong CYP3A4 inducers or inhibitors (relative contraindication; careful monitoring required).

• Hepatotoxicity:
  Monitor liver function tests regularly; severe hepatic injury, including fatal cases, reported.
• Hypertension:
  Common; monitor blood pressure and manage appropriately.
• Hemorrhage:
  Severe bleeding events possible; discontinue if life-threatening bleeding occurs.
• Gastrointestinal Perforation:
  Rare but serious; discontinue if perforation occurs.
• Wound Healing Complications:
  Avoid starting therapy until surgical wounds are healed.
• Cardiac Ischemia and Infarction:
  Monitor patients with cardiac risk factors closely.
• Hand-Foot Skin Reaction (HFSR):
  Common; manage with supportive care and dose modification.
• Thyroid Dysfunction:
  Monitor thyroid function during treatment.

• Common (>20%):
  Fatigue, diarrhea, hypertension, decreased appetite, hand-foot skin reaction, rash, dysphonia, mucositis.
• Serious:
  Hepatotoxicity, hemorrhage, gastrointestinal perforation, cardiac ischemia, thromboembolic events.
• Onset:
  Most adverse effects occur within the first 2 months but can occur at any time.
• Dose-dependent:
  Many toxicities are dose-related and improve with dose reduction or interruption.

• CYP3A4 inhibitors (e.g., ketoconazole):
  Increase regorafenib plasma concentrations, raising toxicity risk.
• CYP3A4 inducers (e.g., rifampin):
  Decrease regorafenib efficacy by lowering plasma levels.
• P-glycoprotein substrates:
  Potential altered plasma levels; monitor accordingly.
• Avoid grapefruit and grapefruit juice as they may increase drug exposure.

• FDA Approvals:
  Regorafenib approved for mCRC, GIST, and HCC with dosing and safety profile updates.
• Dose Optimization:
  Recent trials explore lower starting doses to improve tolerability without compromising efficacy.
• Safety Warnings:
  Updated labeling includes boxed warnings for hepatotoxicity and hemorrhage.
• Guideline Inclusion:
  Incorporated into NCCN and ESMO guidelines as a standard third-line or later treatment option for indicated cancers.

• Store tablets at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep in original packaging until use.
• Do not freeze.