Panobinostat, Farydak

  • Indications
  1. Multiple Myeloma (relapsed)
  • Mechanism
  1. Antimetabolite, Antineoplastic Agent
  2. Histone Deacetylase Inhibitor (HDAC Inhibitor, cinnamic hydroxamic acid analog)
    1. Histones are the spools around which DNA are wrapped, and which play a role in gene expression
      1. Cancers may be facilitated by abnormally expressed genes in specific histone regions
    2. HDAC Inhibitors block histone deacetylase
      1. Histone deacetylase is an enzyme that catalyzes removal of acetyl groups from core histones
      2. Results in hyperacetylation of histones, suppressing gene expression and cell differentiation
    3. Panobinostat, by selectively inhibiting HDAC, triggers cell cycle arrest in the G2/M phase
  3. Panobinostat also modulates Angiogenesis-related genes, blocking endothelial cell chemotaxis and invasion
    1. Hypoxia-inducible factor-1alpha (HIF-1a)
    2. Vascular Endothelial Growth Factor (VEGF)
  • Medications
  1. Capsules: 10, 15 and 20 mg
  • Dosing
  1. See other references for disease specific dosing protocols
  2. Multiple Myeloma
    1. Panobinostat 20 mg every other day for first 2 weeks of 21 day cycles for 8 cycles
    2. Combined with Bortezomib and Dexamethasone
    3. Richardson (2016) Blood 127(6):713-21 +PMID: 26631116 [PubMed]
  • Adverse Effects
  1. Diarrhea (severe in 25% of patients)
  2. Cardiovascular Effects (Life-threatening, deaths have occurred)
    1. Acute Coronary Syndrome
    2. Cardiac Arrhythmia (esp. if concurrent Electrolyte abnormalities)
  3. Hemorrhage (severe)
    1. Life threatening pulmonary and gastrointestinal Hemorrhage have occurred
    2. Increased risk with significant Thrombocytopenia
  4. Hepatotoxicity
  • Safety
  1. Avoid in Pregnancy (any trimester)
    1. Use reliable Contraception
  2. Avoid in Lactation
  3. Monitoring (including baseline)
    1. Electrocardiogram
    2. Electrolytes
    3. Platelet Count
    4. Liver Function Tests
  • Drug Interactions
  1. Strong CYP3A4 Inhibitors (e.g. Clarithromycin, Erythromycin, Itraconazole, Ketoconazole, Ritonavir, Diltiazem, Verapamil)
    1. Reduce Panobinostat dose
  2. Strong CYP3A4 Inducers (e.g. Rifampin, Phenytoin and Ritonavir)
    1. Avoid in combination with Panobinostat
  3. CYP2D6 Substrates (e.g. Desipramine, Dextromethorphan, Nebivolol)
    1. Avoid in combination with Panobinostat
  4. Antiarrhythmic Agents
    1. Avoid in combination with Panobinostat
  5. Medication Causes of QTc Prolongation
    1. Avoid in combination with Panobinostat