Signera

• Approved Indications:
• Extended adjuvant treatment of early-stage HER2-positive breast cancer following trastuzumab-based therapy, to reduce the risk of disease recurrence.
• Treatment of advanced or metastatic HER2-positive breast cancer as monotherapy after prior trastuzumab-based regimen.
• Clinically Accepted Off-Label Uses:
• Investigational use in other HER2-overexpressing solid tumors (e.g., gastric cancer) under clinical trials.

• Route: Oral administration
• Adults:
• Extended Adjuvant Therapy for Early-Stage Breast Cancer:
  • 240 mg orally once daily with food
  • Recommended duration: 12 months
  • Dose adjustments for toxicity recommended as per protocol
• Advanced or Metastatic Breast Cancer:
  • 240 mg orally once daily with food
  • Continue until disease progression or unacceptable toxicity
• Pediatrics:
• Safety and efficacy not established
• Elderly:
• No specific dose adjustment; monitor for tolerability
• Renal Impairment:
• Mild to moderate impairment: No dose adjustment
• Severe impairment or end-stage renal disease: Use with caution; limited data
• Hepatic Impairment:
• Mild impairment: No adjustment
• Moderate to severe impairment: Dose reduction recommended; monitor closely

Neratinib is an irreversible pan-HER tyrosine kinase inhibitor targeting HER1 (EGFR), HER2, and HER4 receptors. By covalently binding to the ATP-binding site of these receptors, neratinib blocks autophosphorylation and subsequent activation of downstream signaling pathways (such as MAPK and PI3K/AKT). This inhibits tumor cell proliferation and promotes apoptosis in HER2-overexpressing breast cancer cells.

• Absorption:
  Peak plasma concentration (Cmax) reached in 3–7 hours post-dose. Bioavailability increased with food intake.
• Distribution:
  Volume of distribution approximately 2070 L, indicating extensive tissue distribution. >99% plasma protein binding.
• Metabolism:
  Primarily metabolized by CYP3A4 enzyme in the liver to inactive metabolites.
• Elimination:
  Excreted mainly via feces (~92%), with minor renal excretion (~5%).
  Half-life: Approximately 17 hours.

• Pregnancy:
  Category D (Positive evidence of risk). Animal studies show fetal harm. Use only if benefits outweigh risks. Women should avoid pregnancy during treatment and for 1 month after.
• Lactation:
  Unknown if excreted in human milk. Breastfeeding not recommended during treatment and for 1 month after last dose.

• Primary Class: Antineoplastic Agent
• Subclass: Tyrosine Kinase Inhibitor (Pan-HER irreversible inhibitor)

• Known hypersensitivity to neratinib or any formulation excipients
• Severe hepatic impairment without appropriate dose adjustment

• Diarrhea:
  High incidence; can be severe and lead to dehydration. Prophylactic anti-diarrheal therapy (e.g., loperamide) is strongly recommended during initial treatment.
• Hepatotoxicity:
  Monitor liver function tests regularly; discontinue if severe toxicity develops.
• Embryo-Fetal Toxicity:
  Can cause fetal harm; strict contraception required.
• Cardiac Toxicity:
  QT prolongation risk; avoid concomitant QT-prolonging drugs and monitor ECG in high-risk patients.
• Interstitial Lung Disease (ILD)/Pneumonitis:
  Rare but serious; discontinue if suspected.

Common:

• Diarrhea (up to 95%)
• Nausea, vomiting
• Fatigue
• Abdominal pain
• Rash
• Stomatitis
• Elevated liver enzymes (AST, ALT)

Serious (Less Common):

• Severe diarrhea leading to dehydration
• Hepatotoxicity
• QT interval prolongation
• Interstitial lung disease/pneumonitis

• CYP3A4 Inducers (e.g., rifampin, phenytoin):
  May reduce neratinib plasma concentration, decreasing efficacy.
• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin):
  May increase neratinib plasma levels, increasing toxicity risk.
• PPIs and H2 Blockers:
  May reduce neratinib absorption; avoid concomitant use or separate dosing by several hours.
• QT-Prolonging Agents:
  Increased risk of cardiac arrhythmia.

• Neratinib approved by FDA (2017) and EMA for extended adjuvant treatment of HER2-positive early breast cancer post-trastuzumab.
• Updated guidelines emphasize diarrhea prophylaxis to improve tolerability and adherence.
• Ongoing studies investigating expanded indications and combination therapies.

• Store 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.