Ribociclib

• HR-Positive Breast Cancer
• Metastatic Breast Cancer
• Advanced Breast Cancer

Ribociclib is a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor used in combination with endocrine therapy for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. It represents an important targeted therapy option that has demonstrated survival benefits.

Mechanism of Action

Ribociclib inhibits CDK4 and CDK6, key regulators of cell cycle progression:

• CDK4/6 inhibition: Blocks the kinase activity of cyclin D-CDK4/6 complexes
• Prevents Rb phosphorylation: Retinoblastoma protein remains hypophosphorylated
• G1 cell cycle arrest: Blocks transition from G1 to S phase
• Synergy with endocrine therapy: HR+ breast cancers depend on cyclin D-CDK4/6 for proliferation

Clinical trials have demonstrated both progression-free and overall survival benefits.

Available Formulations

Ribociclib is available as film-coated tablets:

• 200 mg tablets

Tablets should be swallowed whole; may be taken with or without food.

Medical Uses

FDA-Approved Indications:

• HR-positive, HER2-negative advanced or metastatic breast cancer in combination with:
  • An aromatase inhibitor as initial endocrine-based therapy
  • Fulvestrant as initial endocrine-based therapy or following disease progression

May be used in pre/perimenopausal women when combined with LHRH agonist.

Dosing Guidelines

Standard Dosing:

• 600 mg (three 200 mg tablets) once daily for 21 days followed by 7 days off (28-day cycle)
• Continue until disease progression or unacceptable toxicity

Dose Reductions for Toxicity:

• First reduction: 400 mg daily
• Second reduction: 200 mg daily
• Discontinue if 200 mg not tolerated

QTc Monitoring:

• Obtain ECG before starting, at day 14 of first cycle, and at beginning of second cycle
• More frequent monitoring if QTc prolongation observed

Important Safety Information

Warnings and Precautions:

• QT prolongation: Avoid in patients with long QT syndrome; monitor ECG and electrolytes regularly
• Hepatotoxicity: Monitor LFTs before starting, every 2 weeks for first 2 cycles, then monthly
• Neutropenia: Most common adverse reaction; monitor CBC before starting and at beginning of each cycle
• Interstitial lung disease/Pneumonitis: Monitor for respiratory symptoms
• Embryo-fetal toxicity: Can cause fetal harm

Contraindications:

• No absolute contraindications listed, but avoid in patients with baseline QTc >450 ms

Drug Interactions

Strong CYP3A4 Inhibitors (ketoconazole, ritonavir, clarithromycin):

• Avoid concurrent use if possible
• If unavoidable, reduce ribociclib to 400 mg daily

Strong CYP3A4 Inducers (rifampin, phenytoin):

• Avoid concurrent use

QT-Prolonging Drugs:

• Avoid concurrent use; if necessary, monitor ECG more frequently

CYP3A Substrates with Narrow Therapeutic Index:

• Monitor closely; ribociclib may increase their concentrations

Special Populations

• Hepatic Impairment:
  • Mild: No adjustment
  • Moderate to severe: Reduce starting dose to 400 mg daily
• Renal Impairment: No adjustment for mild to moderate; limited data for severe
• Pregnancy: Avoid; use effective contraception during and for 3 weeks after
• Lactation: Avoid breastfeeding during and for 3 weeks after