Alpelisib

• Breast Cancer:
  Approved for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer with a PIK3CA mutation.
• Use is specifically indicated in combination with fulvestrant for postmenopausal women, and men, who have progressed on or after endocrine therapy.
• Off-label Uses (clinically accepted):
  Investigation in other PIK3CA-mutated solid tumors; however, use outside breast cancer remains experimental.

• Adults:
  Recommended dose is 300 mg orally once daily with food.
• Dose adjustments:
• For adverse reactions, dose interruptions and reductions to 200 mg and then 150 mg daily may be required.
• Dose modification guidelines should be followed strictly for hyperglycemia, rash, diarrhea, or pneumonitis.
• Pediatrics:
  Safety and efficacy not established; use not recommended.
• Elderly:
  No specific dose adjustment, but monitor closely for toxicity.
• Renal Impairment:
  No dosage adjustment required in mild to moderate impairment; use with caution in severe impairment.
• Hepatic Impairment:
  No dose adjustment for mild or moderate impairment; not studied in severe impairment.
• Route: Oral administration.

Alpelisib is a selective inhibitor of the alpha isoform of phosphatidylinositol 3-kinase (PI3Kα), encoded by the PIK3CA gene. By inhibiting PI3Kα, it blocks the PI3K/AKT/mTOR signaling pathway, which is often aberrantly activated in cancers harboring PIK3CA mutations. This inhibition decreases cellular proliferation, growth, and survival signals in cancer cells, thereby slowing tumor growth and progression. The selectivity for PI3Kα allows targeted suppression of cancer cells with PIK3CA mutations while sparing other isoforms to reduce toxicity.

• Absorption:
  Rapid oral absorption; peak plasma concentrations occur approximately 2 to 4 hours post-dose.
• Bioavailability: High; not affected significantly by food intake but administration with food is recommended to improve tolerability.
• Distribution: Volume of distribution approximately 305 L; extensively bound (~94%) to plasma proteins.
• Metabolism: Primarily metabolized by CYP3A4 and non-CYP pathways.
• Half-life: Approximately 8 to 9 hours.
• Elimination: Excreted mainly via feces (~80%), with about 6% eliminated in urine.

• Pregnancy:
  No adequate human studies. Animal studies have shown fetal toxicity and developmental abnormalities at clinically relevant exposures. Use in pregnancy is contraindicated unless benefits outweigh risks.
• Lactation:
  Unknown if excreted in human milk. Breastfeeding is not recommended during treatment due to potential adverse reactions in infants.

• Primary Class: Antineoplastic Agent
• Subclass: PI3K Inhibitor, Targeted Therapy

• Known hypersensitivity to alpelisib or any of its excipients
• Pregnancy (due to teratogenicity and fetal toxicity)
• Severe hypersensitivity reactions to the drug previously

• Hyperglycemia:
  Common and sometimes severe; monitor blood glucose regularly. Manage with antihyperglycemics as needed.
• Severe Cutaneous Reactions:
  Including Stevens-Johnson syndrome and toxic epidermal necrolysis reported; discontinue immediately if suspected.
• Diarrhea:
  May be severe; monitor and manage promptly with hydration and anti-diarrheal agents.
• Pneumonitis:
  Monitor for new or worsening respiratory symptoms; interrupt or discontinue if pneumonitis suspected.
• Embryo-Fetal Toxicity:
  Use effective contraception during and for 2 weeks after treatment.
• Infections:
  Monitor closely; treat infections promptly.
• Renal and Hepatic Impairment:
  Use caution; limited data in severe impairment.

Common:

• Hyperglycemia
• Diarrhea
• Nausea
• Rash
• Decreased appetite
• Fatigue
• Stomatitis
• Weight loss

Serious (Less Common):

• Severe hyperglycemia
• Pneumonitis
• Severe cutaneous adverse reactions (SJS, TEN)
• Hypersensitivity reactions
• Pancreatitis

• CYP3A4 substrates and inhibitors:
  Alpelisib is metabolized partly by CYP3A4; strong inhibitors may increase alpelisib exposure.
• Antidiabetic agents:
  Monitor blood glucose closely when used with insulin or oral hypoglycemics due to potential additive effects.
• Other anticancer agents:
  No major specific interactions but monitor for overlapping toxicities.

• Alpelisib remains a recommended targeted therapy option for HR+/HER2- PIK3CA-mutated advanced breast cancer post endocrine therapy failure per guidelines from ASCO and NCCN.
• Updated safety data emphasizes vigilant monitoring for hyperglycemia and serious skin reactions.
• Ongoing clinical trials are investigating broader indications in other PIK3CA-mutated malignancies.

• Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Protect from moisture and light.
• Keep in original packaging until use.
• Do not freeze.