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February 23, 2015

On February 23, 2015, the U.S. Food and Drug Administration (FDA) granted accelerated approval to panobinostat (FARYDAK® capsules, Novartis Pharmaceuticals) in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent.  As a condition of this accelerated approval, FDA requires the sponsor to conduct a trial to verify and describe the clinical benefit of panobinostat for patients with multiple myeloma.

Panobinostat is a histone deacetylase inhibitor.

The approval was based on the results of progression-free survival (PFS) in a subgroup of patients from a randomized, international, two-arm, placebo-controlled trial evaluating panobinostat (or placebo) in combination with bortezomib and dexamethasone.  In this pre-specified subgroup of 193 patients who had received prior treatment with bortezomib and an immunomodulatory agent, the median age was 60 years (range 28-79). 

The primary efficacy endpoint was PFS determined by investigators.  The median PFS values were 10.6 and 5.8 months in the panobinostat-containing  arm (panobinostat-bortezomib-dexamethasone) and control (placebo-bortezomib-dexamethasone), respectively [HR 0.52 (95% CI: 0.36, 0.76)].  Overall response rates were 58.5% (95% CI:47.9, 68.6) in the panobinostat arm and 41.4% (95% CI:31.6, 51.8) in the placebo arm.

Safety was evaluated in 758 patients with relapsed multiple myeloma who were treated with panobinostat-bortezomib-dexamethasone or placebo-bortezomib-dexamethasone.  The most common adverse reactions (>20%) on the panobinostat-containing arm were diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting.  Serious adverse reactions included pneumonia, diarrhea, thrombocytopenia, fatigue, and sepsis.  There was an increased incidence in deaths not due to progressive disease (7% vs. 3.2%) on the panobinostat-containing arm.

The most common hematologic abnormalities included thrombocytopenia and neutropenia; the most common chemistry abnormalities were hypophosphatemia and hypokalemia.   ECG changes, including new T-wave changes and ST-segment depressions, occurred in 64% of patients in the panobinostat-containing arm and 42% in the control arm. Arrhythmias occurred more frequently in patients receiving panobinostat compared to the control arm (12% vs. 5%).

Panobinostat is approved with a BOXED WARNING alerting patients and health care providers of severe and fatal cardiac toxicities and severe diarrhea.  Hemorrhage and hepatotoxicity are other important safety concerns with panobinostat and are included in the WARNINGS and PRECAUTIONS section of the label.

Recommended Treatment Regimen for Panobinostat

Treatment Phase 1: Cycles 1-8, 3 week cycles (Total time 24 weeks):

  • Panobinostat 20 mg orally once daily 3 times a week for 2 weeks per 3 week cycle
  • Bortezomib 1.3mg/m2 intravenously twice weekly for 2 weeks per 3 week cycle
  • Dexamethasone 20 mg orally per day of bortezomib and the day after each dose

Treatment Phase 2: Cycles 9-16, 3 week cycles (Total time 24 additional weeks):

Patients achieving clinical benefit (defined as a response category of ‘No Change’, PR, MR, nCR, or CR) without unresolved severe or medically significant toxicity may be considered for another 8 cycles of therapy at modified dosing.

  • Panobinostat 20 mg orally once daily 3 times a week for 2 weeks per 3 week cycle
  • Bortezomib 1.3mg/m2 intravenously once weekly for 2 weeks per 3 week cycle
  • Dexamethasone 20 mg orally per day of bortezomib and the day after each dose

Full prescribing information is available at here

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing an online form at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).