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.
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.
The two adult patient populations considered for the expanded approval, based on data from five clinical studies submitted by duloxetine manufacturer, Eli Lilly & Co., were for those with chronic low back pain and those with chronic pain related to osteoarthritis.
Those voting in favor said they believed the drug could be a valuable treatment for patients with these conditions; those who did not support approval cited concerns that included questions about the strength of the studies.
But in two other separate votes, the panel split on whether the data from the 12- to 13-week 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. Most of the 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 studies found that treatment was significantly more effective in alleviating pain, compared with placebo.
Eli Lilly markets duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), as Cymbalta. It was previously approved for pain associated with diabetic peripheral neuropathy (2004) and fibromyalgia (2008). It was first approved in 2004 for major depressive disorder, and also approved for generalized anxiety disorder (2007).
Eli Lilly representatives 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” with existing therapies.
In the three studies of about 1,000 patients with chronic low (nonradicular) back pain (median age, 51-54 years), 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, 62-63 years), intensity of pain decreased more in those on duloxetine, compared with 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 there have been reports of hepatoxicity, sometimes fatal, in patients treated with duloxetine and recommends 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. It voted 9-4 that the drug's safety profile and overall risk-benefit profile supported expanding the approval.
All but two of the panelists 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.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts related to the topic of the meeting, although in some cases, a waiver is granted to a panelist.