FDA approves panobinostat for treatment of multiple myeloma

Approval Date: February 23, 2015.

  • The U.S. Food and Drug Administration approved panobinostat for the treatment of patients with multiple myeloma.
  • FARYDAK (panobinostat lactate) is a histone deacetylase inhibitor.
  • The chemical name of panobinostat lactate is 2-Hydroxypropanoic acid, compd. with 2-(E)-N-hydroxy-3-[4­[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (1:1).
  • The structural formula is:

panobinostat

——————————–Mechanism of Action ————————————–

  • Panobinostat is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations.
  • HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins.
  • Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation.
  • In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells.
  • Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat.
  • Panobinostat shows more cytotoxicity towards tumor cells compared to normal cells

————————–INDICATIONS AND USAGE—————————-­

  • Panobinostat , a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.
  • This indication is approved under accelerated approval based on progression free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

 ————————DOSAGE AND ADMINISTRATION——————————­

  • 20 mg, taken orally once every other day for 3 doses per week (on Days 1, 3, 5, 8, 10, and 12) of Weeks 1 and 2 of each 21-day cycle for 8 cycles
  • Consider continuing treatment for an additional 8 cycles for patients with clinical benefit, unless they have unresolved severe or medically significant toxicity.

 ———————–DOSAGE FORMS AND STRENGTHS——————————-­

  • Capsules: 10 mg, 15 mg, and 20 mg.

 ———————–WARNINGS AND PRECAUTIONS——————————­

  • Severe diarrhea occurred in 25% of panobinostat treated patients. Monitor for symptoms, institute anti-diarrheal treatment, interrupt panobinostat and then reduce dose or discontinue panobinostat .
  • Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving panobinostat . Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated.
  • Hemorrhage: Fatal and serious cases of gastrointestinal and pulmonary hemorrhage. Monitor platelet counts and transfuse as needed.
  • Hepatotoxicity: Monitor hepatic enzymes and adjust dosage if abnormal liver function tests are observed during panobinostat therapy.
  • Embryo-Fetal Toxicity: can cause fetal harm. Advise women of the potential hazard to the fetus and to avoid pregnancy while taking panobinostat .

 ——————————–ADVERSE REACTIONS—————————————­

  • The most common adverse reactions (incidence of at least 20%) in clinical studies are diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting.
  • The most common non-hematologic laboratory abnormalities (incidence ≥ 40%) are hypophosphatemia, hypokalemia, hyponatremia, and increased creatinine.
  • The most common hematologic laboratory abnormalities (incidence ≥60%) are thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia.

                ——————————DRUG INTERACTIONS———————————–—-­

  • Strong CYP3A4 inhibitors: Reduce drug dose.
  • Strong CYP3A4 inducers: Avoid concomitant use with panobinostat .
  • Sensitive CYP2D6 substrates: Avoid concomitant use with panobinostat .
  • Anti-arrhythmic drugs/QT-prolonging drugs: Avoid concomitant use.

                     ————————-USE IN SPECIFIC POPULATIONS——————-–­

  • Hepatic Impairment: Hepatic impairment can increase panobinostat exposure.
  • Reduce panobinostat dose in patients with mild or moderate hepatic impairment.
  • Avoid use in patients with severe hepatic impairment.

Farydak is marketed by East Hanover, New Jersey-based Novartis Pharmaceuticals.

For more details Click Here.