BETHESDA, Md. – In a split vote, a Food and Drug Administration advisory panel voted 8-6 that the approved pain indications for duloxetine be expanded to include a broader population of patients with chronic pain, at a meeting on August 19.
However, in separate votes, the panel specifically recommended approving the drug for chronic low back pain but not for management of chronic pain from osteoarthritis.
At the meeting of the FDA’s Anesthetic and Life Support Drugs Advisory Committee, the two adult patient populations considered for the expanded approval, based on data from five clinical studies submitted by duloxetine manufacturer, Eli Lilly and Co., were for those with chronic low back pain and those with chronic pain related to osteoarthritis.
Those voting in favor said that they believed the drug could be a valuable treatment for patients with these conditions, while those who did not support approval cited concerns that included questions about the strength of the studies that were conducted.
But in two other separate votes, the panel split on whether the data from the 12-13 week long clinical trials in the two groups of patients provided adequate evidence of efficacy for the two indications: The panel voted 8-5 with 1 abstention that the clinical data provided enough evidence that duloxetine was effective in managing chronic low back pain. The majority of panelists were not convinced by the data on the osteoarthritis pain indication, voting 9-4 with 1 abstention, that the two studies in OA patients did not provide adequate evidence that duloxetine was an effective treatment for chronic pain due to osteoarthritis – largely because only one of the two studies found that treatment was significantly more effective in alleviating pain, compared with placebo.
Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI) marketed as Cymbalta by Eli Lilly, was previously approved for two other pain indications, pain associated with diabetic peripheral neuropathy (2004) and fibromyalgia (2008). It was first approved in 2004 for major depressive disorder, and was also approved for generalized anxiety disorder (2007).
Representatives of Eli Lilly maintained that duloxetine can provide pain relief via a mechanism that is different from opioids and NSAIDs, and that the efficacy of duloxetine in the studies of patients with OA and chronic low back pain was “at least comparable” to existing treatments.
In the three studies of about 1,000 patients with chronic low (nonradicular) back pain (median age was 51-54 years), the average pain severity decreased more in those on 60 mg or 120 mg of duloxetine in all three studies, compared with placebo; the difference was significant in two of the studies. In the two studies of almost 500 patients with osteoarthritis (median age was 62-63 years), the intensity of pain decreased more in those patients on duloxetine, compared with those on placebo, but the difference was significant only in one study, in which patients were allowed to stay on NSAIDs and acetaminophen.
No new safety issues, other than those already included in the label, surfaced during the studies. Duloxetine can cause increases in aminotransferase levels, and a statement added to the label’s warnings and precautions section when the drug was approved for fibromyalgia in 2008 notes that there have been reports of hepatoxicity, sometimes fatal, in patients treated with duloxetine and recommends that treatment be stopped in patients who become jaundiced or have other signs of clinically significant liver dysfunction.
The potential for hepatoxicity was the main safety issue reviewed by the panel, which voted 9-4 that the drug’s safety profile and overall risk-benefit profile supported expanding the approval.
All but two of the panel members did not believe there was evidence that the 120-mg dose was more effective than the 60-mg dose, largely because there were not enough data on the higher dose.
National outpatient prescription data (in retail settings) presented by the FDA indicated that nearly two-thirds of duloxetine use is off label and that 14% of the use of the off-label use is for pain conditions such as musculoskeletal system and connective tissue diseases (7.3%) and headaches and nerve pain (6.5%).
The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts related to the topic of the meeting, although in some cases, a waiver is granted to a panelist.