HER-2N

• Approved Indications:
• Treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer, in combination with:
• An aromatase inhibitor as initial endocrine-based therapy in postmenopausal women.
• Fulvestrant in women with disease progression following endocrine therapy.
• Used in pre/perimenopausal women in combination with endocrine therapy and ovarian suppression.
• Clinically Accepted Off-Label Uses:
• Investigational use in other HR+ solid tumors or earlier stages of breast cancer under clinical trials.

• Adults:
• Standard dose: 600 mg orally once daily for 21 consecutive days followed by 7 days off treatment (28-day cycle).
• Combine with letrozole, anastrozole, or fulvestrant per indication.
• For pre/perimenopausal women, combine with luteinizing hormone-releasing hormone (LHRH) agonist for ovarian suppression.
• Dose Adjustments:
• Hepatic impairment:
• Mild (Child-Pugh A): No adjustment needed.
• Moderate (Child-Pugh B): Start with 400 mg once daily.
• Severe (Child-Pugh C): Not recommended.
• Renal impairment: No dose adjustment required for mild to moderate impairment; use caution in severe impairment.
• Dose reductions or interruptions recommended for hematologic or non-hematologic toxicities (neutropenia, QT prolongation).
• Pediatrics & Elderly:
• Safety and efficacy not established in pediatrics.
• No dose adjustment required based solely on age; monitor elderly closely.
• Administration:
• Take with water, with or without food, at the same time each day.
• Swallow tablets whole; do not crush or chew.

Ribociclib is a selective, oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), which regulate progression through the G1 phase of the cell cycle. By inhibiting CDK4/6, ribociclib prevents phosphorylation of retinoblastoma protein (Rb), leading to cell cycle arrest at the G1-S checkpoint. This inhibition results in reduced cellular proliferation of HR+ breast cancer cells that are dependent on cyclin D-CDK4/6 pathway activation, thereby delaying tumor growth.

• Absorption:
• Oral bioavailability is moderate; peak plasma concentrations occur approximately 1 to 4 hours post-dose.
• Distribution:
• Volume of distribution approximately 1200 L.
• Approximately 70% protein bound in plasma.
• Metabolism:
• Extensively metabolized in the liver primarily by CYP3A4 isoenzyme.
• Elimination:
• Half-life approximately 32 hours.
• Excreted mainly via feces (~69%) and urine (~22%) mostly as metabolites.

• Pregnancy:
• FDA Pregnancy Category D — causes fetal harm in animal studies; contraindicated in pregnancy.
• Women of reproductive potential must use effective contraception during treatment and for at least 3 weeks after the last dose.
• Lactation:
• Unknown if ribociclib is excreted in human milk. Due to potential serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for at least 3 weeks post-therapy.

• Targeted anticancer agent
• CDK4/6 inhibitor

• Known hypersensitivity to ribociclib or any excipients.
• Concurrent use with strong CYP3A4 inhibitors or inducers unless dosage adjustments are made.
• QT prolongation conditions or use with other QT-prolonging drugs without close monitoring.

• Hematologic toxicities: Neutropenia is common; monitor complete blood counts regularly.
• QT interval prolongation: ECG monitoring recommended; correct electrolyte abnormalities before and during therapy.
• Hepatotoxicity: Monitor liver function tests; dose adjustment or discontinuation may be necessary.
• Interstitial lung disease/pneumonitis: Monitor for respiratory symptoms; discontinue if suspected.
• Embryo-fetal toxicity: Use effective contraception.

• Common (>20%):
• Neutropenia, leukopenia, anemia
• Fatigue
• Nausea, vomiting, diarrhea
• Alopecia
• Headache
• Elevated liver enzymes (ALT, AST)
• Serious (less common):
• Febrile neutropenia
• QT prolongation and arrhythmias
• Hepatotoxicity
• Interstitial lung disease/pneumonitis
• Onset: Neutropenia typically occurs within the first 2 cycles.

• Substrate of CYP3A4: strong inhibitors (e.g., ketoconazole) increase ribociclib levels; strong inducers (e.g., rifampin) decrease levels.
• Avoid or adjust dosage with CYP3A4 modulators.
• Potential additive QT prolongation with other QT-prolonging agents (e.g., antiarrhythmics, antipsychotics).
• No significant food interactions; can be taken with or without food.

• Updated NCCN and ESMO guidelines recommend ribociclib as a preferred first-line CDK4/6 inhibitor in HR+/HER2- advanced breast cancer combined with endocrine therapy.
• FDA label expanded to include premenopausal women with ovarian suppression.
• Ongoing research on expanded indications in earlier breast cancer stages and other solid tumors.

• Store tablets at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep container tightly closed.
• No refrigeration required.