Elizabeth Mechcatie

Long-term use of the weight loss drug sibutramine was not associated with an increased risk of death; however, the drug was associated with a significantly increased risk of nonfatal myocardial infarctions and strokes among overweight and obese people with preexisting cardiovascular conditions, based on data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial.

The rate of nonfatal MIs associated with sibutramine was increased by 28% and the rate of nonfatal stroke was increased by 36%, compared with placebo in the randomized, double-blind multicenter study, which was conducted in Europe, Central and South America, and Australia from January 2003 through March 2009 (N. Engl. J. Med. 2010 Sept. 1;363:905-17).

Abbott Laboratories, which has marketed the drug in the United States as Meridia since its approval in 1997, funded SCOUT. Sibutramine is a norepinephrine and serotonin reuptake inhibitor that induces satiety and is known to be associated with modest increases in blood pressure and resting pulse rates.

The results indicate sibutramine “should continue to be excluded from use in patients with pre-existing cardiovascular disease,” concluded Dr. W. Philip T. James of the London School of Hygiene and Tropical Medicine, and the other authors of the study.

In an accompanying editorial, titled “Sibutramine – Another Flawed Diet Pill,” Dr. Gregory Curfman and his coauthors wrote that this conclusion is “based on a narrow interpretation of the SCOUT data, in which only the patients with preexisting cardiovascular disease had an increase in the risk of new cardiovascular events.” While this was a “defensible interpretation” of the data, they pointed out that marketing of sibutramine in the European Union was withdrawn in January 2010 based on early results of SCOUT (N. Engl. J. Med. 2010 Sept. 1;363:972-4).

The SCOUT results will be reviewed at a September 15 meeting of the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Panel.

While noting the need for safe and effective weight loss medications, the authors of the editorial stated: “Given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, a worrisome cardiovascular risk profile, and a plausible mechanism to explain the cardiovascular risk, it is difficult to discern a credible rationale for keeping this medication on the market.”

The study compared the primary outcome – nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death – in about 9,000 obese or overweight men and women. All were randomized to receive placebo or 10 mg/day of sibutramine after both groups had received sibutramine as part of a weight management program for 6 weeks. Study participants were aged 51-88 years (mean age, 63 years) and had preexisting cardiovascular disease, type 2 diabetes, or both. During the initial 6-week phase, the mean weight loss was 2.6 kg. Those who stayed on sibutramine lost a mean of another 1.7 kg after 1 year (for a total of 4.3 kg, or 9.5 pounds), while those on placebo had a mean weight gain of 0.7 kg.

Over a mean 3.4 years of treatment, the rate of the primary outcome was 11.4% among those on sibutramine, compared with 10% among those on placebo, an increased risk of 16% that was statistically significant. There were no significant differences in the cardiovascular death rates and the rate of death from any cause (a secondary outcome) among those on sibutramine, compared with those on placebo.

The nonfatal MI rate in the sibutramine-treated patients was 4.1%, compared with 3.2% in the placebo group, and the rate of nonfatal stroke was 2.6% among those on sibutramine, compared with 1.9% among those on placebo. The rate of resuscitation after cardiac arrest was 0.2% or less in the two groups.

The risk of nonfatal events was increased among sibutramine users with preexisting cardiovascular disease and with cardiovascular disease and type 2 diabetes. Risk was not increased among those with type 2 diabetes alone. The increase in nonfatal events might be caused by the “recognized effect of increased blood pressure on cardiovascular outcomes, and the combined peripheral and central sympathomimetic effects” of the drug, the authors wrote.

During the initial 6 weeks, when all patients were receiving sibutramine, systolic blood pressure dropped by a mean of 4.7 mm Hg and diastolic blood pressure dropped by a mean of 1.7 mm Hg. These values remained below the initial measurements in both groups during the remainder of the study, but were “consistently higher” among those on sibutramine, with mean differences of 1 mm Hg-2 mm Hg.

The mean pulse rate among those on sibutramine was also “consistently higher” than among those on placebo, with mean differences of 2.2 to 3.7 beats per minute.

The SCOUT authors cite several limitations of the study. The enrollment of mostly high-risk patients meant that most of the study patients did not meet the treatment criteria in the drug’s label, which warns against the use of sibutramine in patients with preexisting cardiovascular disease.

The editorialists observed that after 1 year, those on sibutramine gained back about 0.5 kg, so had a net weight loss of about 4 kg – almost 9 pounds – from an average of 96 kg (211 pounds) at baseline. “Thus, in exchange for an average weight loss of less than 4 kg, a subject had a 1 in 70 chance (or a 1 in 52 chance for those with known cardiovascular disease) of having a myocardial infarction or stroke – an unattractive benefit-to-risk ratio,” they wrote.

The study was funded by sibutramine manufacturer Abbott Laboratories. Author disclosures included having received lecture fees and travel reimbursement from Abbott. Abbott employees were among the authors of the study. The lead author has served on advisory boards for and has received travel reimbursements from GlaxoSmithKline, the manufacturer of orlistat, another weight loss drug.

The coauthors of the editorial were Stephen Morrissey, Ph.D., and Dr. Jeffrey Drazen. The authors of the editorial declared no conflicts of interest.

Long-term use of the weight loss drug sibutramine was not associated with an increased risk of death; however, the drug was associated with a significantly increased risk of nonfatal myocardial infarctions and strokes among overweight and obese people with preexisting cardiovascular conditions, based on data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial.

The rate of nonfatal MIs associated with sibutramine was increased by 28% and the rate of nonfatal stroke was increased by 36%, compared with placebo in the randomized, double-blind multicenter study, which was conducted in Europe, Central and South America, and Australia from January 2003 through March 2009 (N. Engl. J. Med. 2010 Sept. 1;363:905-17).

Abbott Laboratories, which has marketed the drug in the United States as Meridia since its approval in 1997, funded SCOUT. Sibutramine is a norepinephrine and serotonin reuptake inhibitor that induces satiety and is known to be associated with modest increases in blood pressure and resting pulse rates.

The results indicate sibutramine “should continue to be excluded from use in patients with pre-existing cardiovascular disease,” concluded Dr. W. Philip T. James of the London School of Hygiene and Tropical Medicine, and the other authors of the study.

In an accompanying editorial, titled “Sibutramine – Another Flawed Diet Pill,” Dr. Gregory Curfman and his coauthors wrote that this conclusion is “based on a narrow interpretation of the SCOUT data, in which only the patients with preexisting cardiovascular disease had an increase in the risk of new cardiovascular events.” While this was a “defensible interpretation” of the data, they pointed out that marketing of sibutramine in the European Union was withdrawn in January 2010 based on early results of SCOUT (N. Engl. J. Med. 2010 Sept. 1;363:972-4).

The SCOUT results will be reviewed at a September 15 meeting of the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Panel.

While noting the need for safe and effective weight loss medications, the authors of the editorial stated: “Given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, a worrisome cardiovascular risk profile, and a plausible mechanism to explain the cardiovascular risk, it is difficult to discern a credible rationale for keeping this medication on the market.”

The study compared the primary outcome – nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death – in about 9,000 obese or overweight men and women. All were randomized to receive placebo or 10 mg/day of sibutramine after both groups had received sibutramine as part of a weight management program for 6 weeks. Study participants were aged 51-88 years (mean age, 63 years) and had preexisting cardiovascular disease, type 2 diabetes, or both. During the initial 6-week phase, the mean weight loss was 2.6 kg. Those who stayed on sibutramine lost a mean of another 1.7 kg after 1 year (for a total of 4.3 kg, or 9.5 pounds), while those on placebo had a mean weight gain of 0.7 kg.

Over a mean 3.4 years of treatment, the rate of the primary outcome was 11.4% among those on sibutramine, compared with 10% among those on placebo, an increased risk of 16% that was statistically significant. There were no significant differences in the cardiovascular death rates and the rate of death from any cause (a secondary outcome) among those on sibutramine, compared with those on placebo.

The nonfatal MI rate in the sibutramine-treated patients was 4.1%, compared with 3.2% in the placebo group, and the rate of nonfatal stroke was 2.6% among those on sibutramine, compared with 1.9% among those on placebo. The rate of resuscitation after cardiac arrest was 0.2% or less in the two groups.

The risk of nonfatal events was increased among sibutramine users with preexisting cardiovascular disease and with cardiovascular disease and type 2 diabetes. Risk was not increased among those with type 2 diabetes alone. The increase in nonfatal events might be caused by the “recognized effect of increased blood pressure on cardiovascular outcomes, and the combined peripheral and central sympathomimetic effects” of the drug, the authors wrote.

During the initial 6 weeks, when all patients were receiving sibutramine, systolic blood pressure dropped by a mean of 4.7 mm Hg and diastolic blood pressure dropped by a mean of 1.7 mm Hg. These values remained below the initial measurements in both groups during the remainder of the study, but were “consistently higher” among those on sibutramine, with mean differences of 1 mm Hg-2 mm Hg.

The mean pulse rate among those on sibutramine was also “consistently higher” than among those on placebo, with mean differences of 2.2 to 3.7 beats per minute.

The SCOUT authors cite several limitations of the study. The enrollment of mostly high-risk patients meant that most of the study patients did not meet the treatment criteria in the drug’s label, which warns against the use of sibutramine in patients with preexisting cardiovascular disease.

The editorialists observed that after 1 year, those on sibutramine gained back about 0.5 kg, so had a net weight loss of about 4 kg – almost 9 pounds – from an average of 96 kg (211 pounds) at baseline. “Thus, in exchange for an average weight loss of less than 4 kg, a subject had a 1 in 70 chance (or a 1 in 52 chance for those with known cardiovascular disease) of having a myocardial infarction or stroke – an unattractive benefit-to-risk ratio,” they wrote.

The study was funded by sibutramine manufacturer Abbott Laboratories. Author disclosures included having received lecture fees and travel reimbursement from Abbott. Abbott employees were among the authors of the study. The lead author has served on advisory boards for and has received travel reimbursements from GlaxoSmithKline, the manufacturer of orlistat, another weight loss drug.

The coauthors of the editorial were Stephen Morrissey, Ph.D., and Dr. Jeffrey Drazen. The authors of the editorial declared no conflicts of interest.

Long-term use of the weight loss drug sibutramine was not associated with an increased risk of death; however, the drug was associated with a significantly increased risk of nonfatal myocardial infarctions and strokes among overweight and obese people with preexisting cardiovascular conditions, based on data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial.

The rate of nonfatal MIs associated with sibutramine was increased by 28% and the rate of nonfatal stroke was increased by 36%, compared with placebo in the randomized, double-blind multicenter study, which was conducted in Europe, Central and South America, and Australia from January 2003 through March 2009 (N. Engl. J. Med. 2010 Sept. 1;363:905-17).

Abbott Laboratories, which has marketed the drug in the United States as Meridia since its approval in 1997, funded SCOUT. Sibutramine is a norepinephrine and serotonin reuptake inhibitor that induces satiety and is known to be associated with modest increases in blood pressure and resting pulse rates.

The results indicate sibutramine “should continue to be excluded from use in patients with pre-existing cardiovascular disease,” concluded Dr. W. Philip T. James of the London School of Hygiene and Tropical Medicine, and the other authors of the study.

In an accompanying editorial, titled “Sibutramine – Another Flawed Diet Pill,” Dr. Gregory Curfman and his coauthors wrote that this conclusion is “based on a narrow interpretation of the SCOUT data, in which only the patients with preexisting cardiovascular disease had an increase in the risk of new cardiovascular events.” While this was a “defensible interpretation” of the data, they pointed out that marketing of sibutramine in the European Union was withdrawn in January 2010 based on early results of SCOUT (N. Engl. J. Med. 2010 Sept. 1;363:972-4).

The SCOUT results will be reviewed at a September 15 meeting of the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Panel.

While noting the need for safe and effective weight loss medications, the authors of the editorial stated: “Given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, a worrisome cardiovascular risk profile, and a plausible mechanism to explain the cardiovascular risk, it is difficult to discern a credible rationale for keeping this medication on the market.”

The study compared the primary outcome – nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death – in about 9,000 obese or overweight men and women. All were randomized to receive placebo or 10 mg/day of sibutramine after both groups had received sibutramine as part of a weight management program for 6 weeks. Study participants were aged 51-88 years (mean age, 63 years) and had preexisting cardiovascular disease, type 2 diabetes, or both. During the initial 6-week phase, the mean weight loss was 2.6 kg. Those who stayed on sibutramine lost a mean of another 1.7 kg after 1 year (for a total of 4.3 kg, or 9.5 pounds), while those on placebo had a mean weight gain of 0.7 kg.

Over a mean 3.4 years of treatment, the rate of the primary outcome was 11.4% among those on sibutramine, compared with 10% among those on placebo, an increased risk of 16% that was statistically significant. There were no significant differences in the cardiovascular death rates and the rate of death from any cause (a secondary outcome) among those on sibutramine, compared with those on placebo.

The nonfatal MI rate in the sibutramine-treated patients was 4.1%, compared with 3.2% in the placebo group, and the rate of nonfatal stroke was 2.6% among those on sibutramine, compared with 1.9% among those on placebo. The rate of resuscitation after cardiac arrest was 0.2% or less in the two groups.

The risk of nonfatal events was increased among sibutramine users with preexisting cardiovascular disease and with cardiovascular disease and type 2 diabetes. Risk was not increased among those with type 2 diabetes alone. The increase in nonfatal events might be caused by the “recognized effect of increased blood pressure on cardiovascular outcomes, and the combined peripheral and central sympathomimetic effects” of the drug, the authors wrote.

During the initial 6 weeks, when all patients were receiving sibutramine, systolic blood pressure dropped by a mean of 4.7 mm Hg and diastolic blood pressure dropped by a mean of 1.7 mm Hg. These values remained below the initial measurements in both groups during the remainder of the study, but were “consistently higher” among those on sibutramine, with mean differences of 1 mm Hg-2 mm Hg.

The mean pulse rate among those on sibutramine was also “consistently higher” than among those on placebo, with mean differences of 2.2 to 3.7 beats per minute.

The SCOUT authors cite several limitations of the study. The enrollment of mostly high-risk patients meant that most of the study patients did not meet the treatment criteria in the drug’s label, which warns against the use of sibutramine in patients with preexisting cardiovascular disease.

The editorialists observed that after 1 year, those on sibutramine gained back about 0.5 kg, so had a net weight loss of about 4 kg – almost 9 pounds – from an average of 96 kg (211 pounds) at baseline. “Thus, in exchange for an average weight loss of less than 4 kg, a subject had a 1 in 70 chance (or a 1 in 52 chance for those with known cardiovascular disease) of having a myocardial infarction or stroke – an unattractive benefit-to-risk ratio,” they wrote.

The study was funded by sibutramine manufacturer Abbott Laboratories. Author disclosures included having received lecture fees and travel reimbursement from Abbott. Abbott employees were among the authors of the study. The lead author has served on advisory boards for and has received travel reimbursements from GlaxoSmithKline, the manufacturer of orlistat, another weight loss drug.

The coauthors of the editorial were Stephen Morrissey, Ph.D., and Dr. Jeffrey Drazen. The authors of the editorial declared no conflicts of interest.

BETHESDA, MD. – Advisers to the Food and Drug Administration voted 20-2 that the risk-benefit profile of sodium oxybate did not support approval of the sedative-hypnotic drug as a treatment for fibromyalgia, citing concerns that included the lack of long-term data and the potential for illicit use of the drug.

At a joint meeting, panelists generally agreed the data from clinical trials showed that sodium oxybate, which is approved for treating cataplexy and daytime sleepiness associated with narcolepsy, was effective in treating fibromyalgia. They said the effect was modest, and that treatment may benefit only a subset of patients. They also said it was unclear whether the results could be generalized to the typical fibromyalgia population and that more studies were needed, including those directly comparing sodium oxybate with other treatments for the disorder–milnacipran (Savella), pregabalin (Lyrica), and duloxetine (Cymbalta).

Sodium oxybate is the sodium salt of gamma hydroxybutyrate, an endogenous neurotransmitter synthesized from gamma aminobutyric acid, and is also known as the “date rape” drug. It was approved in an oral solution in 2002 for narcolepsy and has been marketed as Xyrem by Jazz Pharmaceuticals, with a risk evaluation and mitigation (REMS) program that tightly controls distribution of the drug.

The panelists' and FDA reviewers' main concern was that if the drug were approved for fibromyalgia, its use would increase substantially and its availability as a street drug could also increase, despite the controlled distribution.

They were strongly against the company's proposal to use a different commercial name (Rekinla), concentration, and dose. They also opposed a different REMS for the fibromyalgia indication, which they said was confusing and would increase the likelihood of medication errors.

The company proposed that patients would take two doses, one before going to sleep and the second in the middle of the night, which was also cited as a disadvantage for patients.

In two phase III randomized, double-blind, controlled 14-week studies, two different doses of sodium oxybate were compared with placebo in about 1,000 fibromyalgia patients aged 18 and older, who discontinued opiates, benzodiazepines, muscle relaxants, and other medications or devices. A significantly greater proportion of those on sodium oxybate (36%-46%) met the primary end point, at least a 30% reduction in pain from baseline to the end of treatment, compared with placebo (20%-27%). Adverse events were similar to those observed in Xyrem trials.

The FDA usually follows its advisory panels' recommendations. Panelists have been cleared of potential conflicts related to the meeting topic, although in some cases, a waiver is granted to a panelist.

BETHESDA, MD. – Advisers to the Food and Drug Administration voted 20-2 that the risk-benefit profile of sodium oxybate did not support approval of the sedative-hypnotic drug as a treatment for fibromyalgia, citing concerns that included the lack of long-term data and the potential for illicit use of the drug.

At a joint meeting, panelists generally agreed the data from clinical trials showed that sodium oxybate, which is approved for treating cataplexy and daytime sleepiness associated with narcolepsy, was effective in treating fibromyalgia. They said the effect was modest, and that treatment may benefit only a subset of patients. They also said it was unclear whether the results could be generalized to the typical fibromyalgia population and that more studies were needed, including those directly comparing sodium oxybate with other treatments for the disorder–milnacipran (Savella), pregabalin (Lyrica), and duloxetine (Cymbalta).

Sodium oxybate is the sodium salt of gamma hydroxybutyrate, an endogenous neurotransmitter synthesized from gamma aminobutyric acid, and is also known as the “date rape” drug. It was approved in an oral solution in 2002 for narcolepsy and has been marketed as Xyrem by Jazz Pharmaceuticals, with a risk evaluation and mitigation (REMS) program that tightly controls distribution of the drug.

The panelists' and FDA reviewers' main concern was that if the drug were approved for fibromyalgia, its use would increase substantially and its availability as a street drug could also increase, despite the controlled distribution.

They were strongly against the company's proposal to use a different commercial name (Rekinla), concentration, and dose. They also opposed a different REMS for the fibromyalgia indication, which they said was confusing and would increase the likelihood of medication errors.

The company proposed that patients would take two doses, one before going to sleep and the second in the middle of the night, which was also cited as a disadvantage for patients.

In two phase III randomized, double-blind, controlled 14-week studies, two different doses of sodium oxybate were compared with placebo in about 1,000 fibromyalgia patients aged 18 and older, who discontinued opiates, benzodiazepines, muscle relaxants, and other medications or devices. A significantly greater proportion of those on sodium oxybate (36%-46%) met the primary end point, at least a 30% reduction in pain from baseline to the end of treatment, compared with placebo (20%-27%). Adverse events were similar to those observed in Xyrem trials.

The FDA usually follows its advisory panels' recommendations. Panelists have been cleared of potential conflicts related to the meeting topic, although in some cases, a waiver is granted to a panelist.

BETHESDA, MD. – Advisers to the Food and Drug Administration voted 20-2 that the risk-benefit profile of sodium oxybate did not support approval of the sedative-hypnotic drug as a treatment for fibromyalgia, citing concerns that included the lack of long-term data and the potential for illicit use of the drug.

At a joint meeting, panelists generally agreed the data from clinical trials showed that sodium oxybate, which is approved for treating cataplexy and daytime sleepiness associated with narcolepsy, was effective in treating fibromyalgia. They said the effect was modest, and that treatment may benefit only a subset of patients. They also said it was unclear whether the results could be generalized to the typical fibromyalgia population and that more studies were needed, including those directly comparing sodium oxybate with other treatments for the disorder–milnacipran (Savella), pregabalin (Lyrica), and duloxetine (Cymbalta).

Sodium oxybate is the sodium salt of gamma hydroxybutyrate, an endogenous neurotransmitter synthesized from gamma aminobutyric acid, and is also known as the “date rape” drug. It was approved in an oral solution in 2002 for narcolepsy and has been marketed as Xyrem by Jazz Pharmaceuticals, with a risk evaluation and mitigation (REMS) program that tightly controls distribution of the drug.

The panelists' and FDA reviewers' main concern was that if the drug were approved for fibromyalgia, its use would increase substantially and its availability as a street drug could also increase, despite the controlled distribution.

They were strongly against the company's proposal to use a different commercial name (Rekinla), concentration, and dose. They also opposed a different REMS for the fibromyalgia indication, which they said was confusing and would increase the likelihood of medication errors.

The company proposed that patients would take two doses, one before going to sleep and the second in the middle of the night, which was also cited as a disadvantage for patients.

In two phase III randomized, double-blind, controlled 14-week studies, two different doses of sodium oxybate were compared with placebo in about 1,000 fibromyalgia patients aged 18 and older, who discontinued opiates, benzodiazepines, muscle relaxants, and other medications or devices. A significantly greater proportion of those on sodium oxybate (36%-46%) met the primary end point, at least a 30% reduction in pain from baseline to the end of treatment, compared with placebo (20%-27%). Adverse events were similar to those observed in Xyrem trials.

The FDA usually follows its advisory panels' recommendations. Panelists have been cleared of potential conflicts related to the meeting topic, although in some cases, a waiver is granted to a panelist.

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.

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.

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.

BETHESDA, Md. — Advisors to the Food and Drug Administration voted 20 to 2 that the risk-benefit profile of sodium oxybate did not support approval of the sedative-hypnotic drug as a treatment for fibromyalgia, citing concerns that included the lack of longterm data and the potential for illicit use of the drug.

At a joint meeting of the FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Committee August 20, panelists generally agreed that the data from clinical trials showed that sodium oxybate, which is approved for treating cataplexy and daytime sleepiness associated with narcolepsy, was effective in treating fibromyalgia. Panelists said the effect was modest, and that treatment may benefit only a subset of patients. They also said that it was unclear whether the results could be generalized to the typical fibromyalgia population and that more studies were needed, including those directly comparing sodium oxybate to other treatments for the disorder.

Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB), an endogenous neurotransmitter synthesized from gamma aminobutyric acid, it is also known as the “date rape” drug. Sodium oxybate in an oral solution was approved in 2002 for narcolepsy and has been marketed as Xyrem by Jazz Pharmaceuticals, with a risk evaluation and mitigation (REMS) program that tightly controls availability of the drug and includes restricted distribution of the agent through one centralized pharmacy and other measures.

A main concern voiced by panelists and FDA reviewers was if the drug were approved to treat fibromyalgia, its use would increase substantially—and its availability as a street drug could increase markedly, despite the controlled distribution.

The panelists were strongly against the company’s proposal to use a different commercial name (Rekinla), concentration, and dose. They also opposed a different REMS for the fibromyalgia indication, with distribution through 15 specialized pharmacies, which they said was confusing and would increase the likelihood of medication errors.

The company proposed that patients would take two doses, one before going to sleep and the second in the middle of the night, which was also cited as a disadvantage for patients.

In two phase 3 randomized, double-blind, controlled 14-week studies, two different doses of sodium oxybate were compared to placebo in about 1,000 fibromyalgia patients aged 18 and older, who discontinued opiates, benzodiazepines, muscle relaxants, and other medications or devices before enrollment. A significantly greater proportion of those treated with sodium oxybate (36%-46%) met the primary endpoint, at least a 30% reduction in pain from baseline to the end of treatment, compared with those on placebo (20%-27%). Adverse events were similar to those observed in Xyrem trials.

Xyrem is also approved in the European Union and Canada for the treatment of symptoms associated with narcolepsy. The company anticipates that the drug would be used to treat up to 120,000 people with fibromyalgia in the United States. The other drugs approved by the FDA for treating fibromyalgia are milnacipran (Savella), pregabalin (Lyrica), and duloxetine (Cymbalta).

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.

BETHESDA, Md. — Advisors to the Food and Drug Administration voted 20 to 2 that the risk-benefit profile of sodium oxybate did not support approval of the sedative-hypnotic drug as a treatment for fibromyalgia, citing concerns that included the lack of longterm data and the potential for illicit use of the drug.

At a joint meeting of the FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Committee August 20, panelists generally agreed that the data from clinical trials showed that sodium oxybate, which is approved for treating cataplexy and daytime sleepiness associated with narcolepsy, was effective in treating fibromyalgia. Panelists said the effect was modest, and that treatment may benefit only a subset of patients. They also said that it was unclear whether the results could be generalized to the typical fibromyalgia population and that more studies were needed, including those directly comparing sodium oxybate to other treatments for the disorder.

Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB), an endogenous neurotransmitter synthesized from gamma aminobutyric acid, it is also known as the “date rape” drug. Sodium oxybate in an oral solution was approved in 2002 for narcolepsy and has been marketed as Xyrem by Jazz Pharmaceuticals, with a risk evaluation and mitigation (REMS) program that tightly controls availability of the drug and includes restricted distribution of the agent through one centralized pharmacy and other measures.

A main concern voiced by panelists and FDA reviewers was if the drug were approved to treat fibromyalgia, its use would increase substantially—and its availability as a street drug could increase markedly, despite the controlled distribution.

The panelists were strongly against the company’s proposal to use a different commercial name (Rekinla), concentration, and dose. They also opposed a different REMS for the fibromyalgia indication, with distribution through 15 specialized pharmacies, which they said was confusing and would increase the likelihood of medication errors.

The company proposed that patients would take two doses, one before going to sleep and the second in the middle of the night, which was also cited as a disadvantage for patients.

In two phase 3 randomized, double-blind, controlled 14-week studies, two different doses of sodium oxybate were compared to placebo in about 1,000 fibromyalgia patients aged 18 and older, who discontinued opiates, benzodiazepines, muscle relaxants, and other medications or devices before enrollment. A significantly greater proportion of those treated with sodium oxybate (36%-46%) met the primary endpoint, at least a 30% reduction in pain from baseline to the end of treatment, compared with those on placebo (20%-27%). Adverse events were similar to those observed in Xyrem trials.

Xyrem is also approved in the European Union and Canada for the treatment of symptoms associated with narcolepsy. The company anticipates that the drug would be used to treat up to 120,000 people with fibromyalgia in the United States. The other drugs approved by the FDA for treating fibromyalgia are milnacipran (Savella), pregabalin (Lyrica), and duloxetine (Cymbalta).

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.

BETHESDA, Md. — Advisors to the Food and Drug Administration voted 20 to 2 that the risk-benefit profile of sodium oxybate did not support approval of the sedative-hypnotic drug as a treatment for fibromyalgia, citing concerns that included the lack of longterm data and the potential for illicit use of the drug.

At a joint meeting of the FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Committee August 20, panelists generally agreed that the data from clinical trials showed that sodium oxybate, which is approved for treating cataplexy and daytime sleepiness associated with narcolepsy, was effective in treating fibromyalgia. Panelists said the effect was modest, and that treatment may benefit only a subset of patients. They also said that it was unclear whether the results could be generalized to the typical fibromyalgia population and that more studies were needed, including those directly comparing sodium oxybate to other treatments for the disorder.

Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB), an endogenous neurotransmitter synthesized from gamma aminobutyric acid, it is also known as the “date rape” drug. Sodium oxybate in an oral solution was approved in 2002 for narcolepsy and has been marketed as Xyrem by Jazz Pharmaceuticals, with a risk evaluation and mitigation (REMS) program that tightly controls availability of the drug and includes restricted distribution of the agent through one centralized pharmacy and other measures.

A main concern voiced by panelists and FDA reviewers was if the drug were approved to treat fibromyalgia, its use would increase substantially—and its availability as a street drug could increase markedly, despite the controlled distribution.

The panelists were strongly against the company’s proposal to use a different commercial name (Rekinla), concentration, and dose. They also opposed a different REMS for the fibromyalgia indication, with distribution through 15 specialized pharmacies, which they said was confusing and would increase the likelihood of medication errors.

The company proposed that patients would take two doses, one before going to sleep and the second in the middle of the night, which was also cited as a disadvantage for patients.

In two phase 3 randomized, double-blind, controlled 14-week studies, two different doses of sodium oxybate were compared to placebo in about 1,000 fibromyalgia patients aged 18 and older, who discontinued opiates, benzodiazepines, muscle relaxants, and other medications or devices before enrollment. A significantly greater proportion of those treated with sodium oxybate (36%-46%) met the primary endpoint, at least a 30% reduction in pain from baseline to the end of treatment, compared with those on placebo (20%-27%). Adverse events were similar to those observed in Xyrem trials.

Xyrem is also approved in the European Union and Canada for the treatment of symptoms associated with narcolepsy. The company anticipates that the drug would be used to treat up to 120,000 people with fibromyalgia in the United States. The other drugs approved by the FDA for treating fibromyalgia are milnacipran (Savella), pregabalin (Lyrica), and duloxetine (Cymbalta).

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.

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.

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.

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.

SILVER SPRING, Md. – In a unanimous vote, a federal advisory panel on Aug. 11 agreed that the antiepileptic drug ezogabine had been shown to be effective as adjunctive therapy for partial onset seizures, but recommended that treated patients be closely monitored for the development of urinary retention.

At a meeting the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee also voted 11 to 0, with 2 abstentions, that they agreed that the risk of urinary retention could be mitigated by monitoring patients, pointing out the importance of educating clinicians in how to properly evaluate patients for changes in urinary symptoms. But none of the panel members thought that the urologic or other safety issues associated with ezogabine should preclude the approval of the drug for the proposed indication, as an adjunctive treatment of patients aged 18 and older with partial onset seizures with or without secondary generalization.

The panel was not asked to vote specifically on whether to recommend approval. The recommended starting dose is 300 mg per day, increasing at weekly intervals by a maximum of 150 mg/day, to a maximum dose ranging from 600 mg to 1,200 mg per day (daily dose is divided into three divided doses per day).

If approved, ezogabine would be the first neuronal potassium channel opener for treating epilepsy, according to the manufacturer, Valeant Pharmaceuticals Inc. Neuronal potassium channels “play a major role in the control of neuronal excitability,” according to the company’s background materials.

The three pivotal trials were international, randomized, 24-26 week studies comparing ezogabine (600 mg/day, 900 mg/day and/or 1200 mg/day, in three divided doses) to placebo, as add-on therapy, in about 1,200 patients, aged 16-75 years (their mean age was 35-38 years), who experienced at least four seizures over a 28-day period, with or without secondary generalization, despite treatment with one to three AEDs. (About 800 patients were on ezogabine and 75% were on two or more AEDs.)

In the studies, the primary end point – the percent reduction from baseline in partial seizure frequency over 28 days – was significantly greater among those on ezogabine, compared with placebo. Reductions in the frequency of seizures ranged from 35% to 44% among those on the 1,200 mg dose, 29%-40% among those on 900 mg/day, and 23%-28% among those on the 600 mg dose, compared with 13%-18% among those on placebo.

As with other AEDs, central nervous system-related side effects were the most common adverse events in the pivotal trials, and included dizziness and somnolence; they were generally related to dose, affected patients early in treatment and were the most common cause of discontinuation of the drug. Discontinuation rates in the study were high, which the company attributed to the forced titration design of the study.

Urinary effects, which were observed in animal studies and are attributed to the drug’s inhibition of the contractility of bladder smooth muscle, were more common among treated patients. In the phase III studies, voiding dysfunction and urinary retention were reported in 5% of patients on all doses, compared with 3% of those on placebo, but there was no association with urinary tract infections, according to the company. Among the 1,365 patients who received the drug in phase II/III trials, there were four cases of urinary retention that required catheterization in treated patients, (compared with 1 patient on placebo) in phase II/III studies, all resolved once treatment stopped, except for one patient who required intermittent catheterization.

Other adverse events that were more common in treated patients included hallucinations and psychosis, and abnormal liver function tests, which were infrequent. There was a slight, transient QT prolonging effect of the drug seen in healthy volunteers titrated to 1,200 mg/day, but there was no clinical evidence of QT prolongation in clinical studies.

Valeant plans to study real-world safety in a prospective postmarketing study in the United States and has proposed a risk management plan to address the potential risks of the drug, which includes instructions to clinicians to “consider the potential effects in the bladder when deciding for whom the drug is appropriate” and a medication guide for patients explaining the potential risks associated with treatment, including how to recognize signs of urinary retention.

The FDA is expected to make a decision on approval by Aug. 30.

If approved, Valeant plans to market ezogabine as Potiga. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, Md. – In a unanimous vote, a federal advisory panel on Aug. 11 agreed that the antiepileptic drug ezogabine had been shown to be effective as adjunctive therapy for partial onset seizures, but recommended that treated patients be closely monitored for the development of urinary retention.

At a meeting the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee also voted 11 to 0, with 2 abstentions, that they agreed that the risk of urinary retention could be mitigated by monitoring patients, pointing out the importance of educating clinicians in how to properly evaluate patients for changes in urinary symptoms. But none of the panel members thought that the urologic or other safety issues associated with ezogabine should preclude the approval of the drug for the proposed indication, as an adjunctive treatment of patients aged 18 and older with partial onset seizures with or without secondary generalization.

The panel was not asked to vote specifically on whether to recommend approval. The recommended starting dose is 300 mg per day, increasing at weekly intervals by a maximum of 150 mg/day, to a maximum dose ranging from 600 mg to 1,200 mg per day (daily dose is divided into three divided doses per day).

If approved, ezogabine would be the first neuronal potassium channel opener for treating epilepsy, according to the manufacturer, Valeant Pharmaceuticals Inc. Neuronal potassium channels “play a major role in the control of neuronal excitability,” according to the company’s background materials.

The three pivotal trials were international, randomized, 24-26 week studies comparing ezogabine (600 mg/day, 900 mg/day and/or 1200 mg/day, in three divided doses) to placebo, as add-on therapy, in about 1,200 patients, aged 16-75 years (their mean age was 35-38 years), who experienced at least four seizures over a 28-day period, with or without secondary generalization, despite treatment with one to three AEDs. (About 800 patients were on ezogabine and 75% were on two or more AEDs.)

In the studies, the primary end point – the percent reduction from baseline in partial seizure frequency over 28 days – was significantly greater among those on ezogabine, compared with placebo. Reductions in the frequency of seizures ranged from 35% to 44% among those on the 1,200 mg dose, 29%-40% among those on 900 mg/day, and 23%-28% among those on the 600 mg dose, compared with 13%-18% among those on placebo.

As with other AEDs, central nervous system-related side effects were the most common adverse events in the pivotal trials, and included dizziness and somnolence; they were generally related to dose, affected patients early in treatment and were the most common cause of discontinuation of the drug. Discontinuation rates in the study were high, which the company attributed to the forced titration design of the study.

Urinary effects, which were observed in animal studies and are attributed to the drug’s inhibition of the contractility of bladder smooth muscle, were more common among treated patients. In the phase III studies, voiding dysfunction and urinary retention were reported in 5% of patients on all doses, compared with 3% of those on placebo, but there was no association with urinary tract infections, according to the company. Among the 1,365 patients who received the drug in phase II/III trials, there were four cases of urinary retention that required catheterization in treated patients, (compared with 1 patient on placebo) in phase II/III studies, all resolved once treatment stopped, except for one patient who required intermittent catheterization.

Other adverse events that were more common in treated patients included hallucinations and psychosis, and abnormal liver function tests, which were infrequent. There was a slight, transient QT prolonging effect of the drug seen in healthy volunteers titrated to 1,200 mg/day, but there was no clinical evidence of QT prolongation in clinical studies.

Valeant plans to study real-world safety in a prospective postmarketing study in the United States and has proposed a risk management plan to address the potential risks of the drug, which includes instructions to clinicians to “consider the potential effects in the bladder when deciding for whom the drug is appropriate” and a medication guide for patients explaining the potential risks associated with treatment, including how to recognize signs of urinary retention.

The FDA is expected to make a decision on approval by Aug. 30.

If approved, Valeant plans to market ezogabine as Potiga. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, Md. – In a unanimous vote, a federal advisory panel on Aug. 11 agreed that the antiepileptic drug ezogabine had been shown to be effective as adjunctive therapy for partial onset seizures, but recommended that treated patients be closely monitored for the development of urinary retention.

At a meeting the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee also voted 11 to 0, with 2 abstentions, that they agreed that the risk of urinary retention could be mitigated by monitoring patients, pointing out the importance of educating clinicians in how to properly evaluate patients for changes in urinary symptoms. But none of the panel members thought that the urologic or other safety issues associated with ezogabine should preclude the approval of the drug for the proposed indication, as an adjunctive treatment of patients aged 18 and older with partial onset seizures with or without secondary generalization.

The panel was not asked to vote specifically on whether to recommend approval. The recommended starting dose is 300 mg per day, increasing at weekly intervals by a maximum of 150 mg/day, to a maximum dose ranging from 600 mg to 1,200 mg per day (daily dose is divided into three divided doses per day).

If approved, ezogabine would be the first neuronal potassium channel opener for treating epilepsy, according to the manufacturer, Valeant Pharmaceuticals Inc. Neuronal potassium channels “play a major role in the control of neuronal excitability,” according to the company’s background materials.

The three pivotal trials were international, randomized, 24-26 week studies comparing ezogabine (600 mg/day, 900 mg/day and/or 1200 mg/day, in three divided doses) to placebo, as add-on therapy, in about 1,200 patients, aged 16-75 years (their mean age was 35-38 years), who experienced at least four seizures over a 28-day period, with or without secondary generalization, despite treatment with one to three AEDs. (About 800 patients were on ezogabine and 75% were on two or more AEDs.)

In the studies, the primary end point – the percent reduction from baseline in partial seizure frequency over 28 days – was significantly greater among those on ezogabine, compared with placebo. Reductions in the frequency of seizures ranged from 35% to 44% among those on the 1,200 mg dose, 29%-40% among those on 900 mg/day, and 23%-28% among those on the 600 mg dose, compared with 13%-18% among those on placebo.

As with other AEDs, central nervous system-related side effects were the most common adverse events in the pivotal trials, and included dizziness and somnolence; they were generally related to dose, affected patients early in treatment and were the most common cause of discontinuation of the drug. Discontinuation rates in the study were high, which the company attributed to the forced titration design of the study.

Urinary effects, which were observed in animal studies and are attributed to the drug’s inhibition of the contractility of bladder smooth muscle, were more common among treated patients. In the phase III studies, voiding dysfunction and urinary retention were reported in 5% of patients on all doses, compared with 3% of those on placebo, but there was no association with urinary tract infections, according to the company. Among the 1,365 patients who received the drug in phase II/III trials, there were four cases of urinary retention that required catheterization in treated patients, (compared with 1 patient on placebo) in phase II/III studies, all resolved once treatment stopped, except for one patient who required intermittent catheterization.

Other adverse events that were more common in treated patients included hallucinations and psychosis, and abnormal liver function tests, which were infrequent. There was a slight, transient QT prolonging effect of the drug seen in healthy volunteers titrated to 1,200 mg/day, but there was no clinical evidence of QT prolongation in clinical studies.

Valeant plans to study real-world safety in a prospective postmarketing study in the United States and has proposed a risk management plan to address the potential risks of the drug, which includes instructions to clinicians to “consider the potential effects in the bladder when deciding for whom the drug is appropriate” and a medication guide for patients explaining the potential risks associated with treatment, including how to recognize signs of urinary retention.

The FDA is expected to make a decision on approval by Aug. 30.

If approved, Valeant plans to market ezogabine as Potiga. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.

A warning about the risks of suicide associated with use of the opioid analgesic tramadol in certain patients has been added to the drug's prescribing information, the Food and Drug Administration has announced.

The warnings section advises clinicians against prescribing tramadol to patients who are suicidal or prone to addictions, emphasizing that patients who are addiction-prone or taking tranquilizers or antidepressant drugs are at risk of suicide if they are taking tramadol.

Tramadol-related deaths have been reported in patients with histories of emotional disturbances or suicidal ideation or attempts, and histories of misuse of tranquilizers, alcohol, and other CNS-active drugs, according to the FDA statement.

Tramadol, a centrally acting synthetic opioid analgesic approved for the management of moderate to moderately severe chronic pain, is marketed as Ultram and Ultracet (tramadol with acetaminophen).

The revised warnings are summarized in “Dear Healthcare Professional” letters for Ultram and Ultracet, dated in April, from PriCara, a division of Ortho-McNeil-Janssen Pharmaceuticals Inc. that markets tramadol.

The Ultracet warning letter also points out the risks for acetaminophen overdoses.

The revised label also advises that tramadol tablets be prescribed “with caution” to patients who are treated with tranquilizers or antidepressant drugs, patients who abuse alcohol, and those who have emotional disturbances or depression.

The FDA statement and letters can be found at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213264.htmwww.fda.gov/medwatch

A warning about the risks of suicide associated with use of the opioid analgesic tramadol in certain patients has been added to the drug's prescribing information, the Food and Drug Administration has announced.

The warnings section advises clinicians against prescribing tramadol to patients who are suicidal or prone to addictions, emphasizing that patients who are addiction-prone or taking tranquilizers or antidepressant drugs are at risk of suicide if they are taking tramadol.

Tramadol-related deaths have been reported in patients with histories of emotional disturbances or suicidal ideation or attempts, and histories of misuse of tranquilizers, alcohol, and other CNS-active drugs, according to the FDA statement.

Tramadol, a centrally acting synthetic opioid analgesic approved for the management of moderate to moderately severe chronic pain, is marketed as Ultram and Ultracet (tramadol with acetaminophen).

The revised warnings are summarized in “Dear Healthcare Professional” letters for Ultram and Ultracet, dated in April, from PriCara, a division of Ortho-McNeil-Janssen Pharmaceuticals Inc. that markets tramadol.

The Ultracet warning letter also points out the risks for acetaminophen overdoses.

The revised label also advises that tramadol tablets be prescribed “with caution” to patients who are treated with tranquilizers or antidepressant drugs, patients who abuse alcohol, and those who have emotional disturbances or depression.

The FDA statement and letters can be found at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213264.htmwww.fda.gov/medwatch

A warning about the risks of suicide associated with use of the opioid analgesic tramadol in certain patients has been added to the drug's prescribing information, the Food and Drug Administration has announced.

The warnings section advises clinicians against prescribing tramadol to patients who are suicidal or prone to addictions, emphasizing that patients who are addiction-prone or taking tranquilizers or antidepressant drugs are at risk of suicide if they are taking tramadol.

Tramadol-related deaths have been reported in patients with histories of emotional disturbances or suicidal ideation or attempts, and histories of misuse of tranquilizers, alcohol, and other CNS-active drugs, according to the FDA statement.

Tramadol, a centrally acting synthetic opioid analgesic approved for the management of moderate to moderately severe chronic pain, is marketed as Ultram and Ultracet (tramadol with acetaminophen).

The revised warnings are summarized in “Dear Healthcare Professional” letters for Ultram and Ultracet, dated in April, from PriCara, a division of Ortho-McNeil-Janssen Pharmaceuticals Inc. that markets tramadol.

The Ultracet warning letter also points out the risks for acetaminophen overdoses.

The revised label also advises that tramadol tablets be prescribed “with caution” to patients who are treated with tranquilizers or antidepressant drugs, patients who abuse alcohol, and those who have emotional disturbances or depression.

The FDA statement and letters can be found at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213264.htmwww.fda.gov/medwatch

Pregnant women who are being treated with an atypical antipsychotic can enroll in a national registry that is evaluating the safety of these drugs during pregnancy, according to an announcement posted on the Massachusetts General Hospital's Center for Women's Mental Health Web site.

Women are eligible to enroll in the registry if they are pregnant and are between 18 and 45 years old and are currently being treated with one or more of the following antipsychotic medications: aripiprazole (Abilify), clozapine (Clozaril), ziprasidone (Geodon), paliperidone (Invega), risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), and asenapine (Saphris). Once the participants have registered, they will be asked to participate in three brief phone interviews that will be conducted over an 8-month period.

The National Pregnancy Registry for Atypical Antipsychotics is collecting data to investigate the safety of atypical antipsychotics during pregnancy, when these agents are used to treat a wide range of mood, anxiety, or psychiatric disorders, according to the announcement from the hospital.

The main goal of the National Pregnancy Registry is to determine the frequency of heart defects, cleft lip, neural tube defects, and other major malformations in infants who are exposed to these medications in utero.

To register, or for more information about what participation in the registry involves, call 866-961-2388. The MGH Center for Women's Mental Health provides information on perinatal and reproductive psychiatry at www.womensmentalhealth.org

Pregnant women who are being treated with an atypical antipsychotic can enroll in a national registry that is evaluating the safety of these drugs during pregnancy, according to an announcement posted on the Massachusetts General Hospital's Center for Women's Mental Health Web site.

Women are eligible to enroll in the registry if they are pregnant and are between 18 and 45 years old and are currently being treated with one or more of the following antipsychotic medications: aripiprazole (Abilify), clozapine (Clozaril), ziprasidone (Geodon), paliperidone (Invega), risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), and asenapine (Saphris). Once the participants have registered, they will be asked to participate in three brief phone interviews that will be conducted over an 8-month period.

The National Pregnancy Registry for Atypical Antipsychotics is collecting data to investigate the safety of atypical antipsychotics during pregnancy, when these agents are used to treat a wide range of mood, anxiety, or psychiatric disorders, according to the announcement from the hospital.

The main goal of the National Pregnancy Registry is to determine the frequency of heart defects, cleft lip, neural tube defects, and other major malformations in infants who are exposed to these medications in utero.

To register, or for more information about what participation in the registry involves, call 866-961-2388. The MGH Center for Women's Mental Health provides information on perinatal and reproductive psychiatry at www.womensmentalhealth.org

Pregnant women who are being treated with an atypical antipsychotic can enroll in a national registry that is evaluating the safety of these drugs during pregnancy, according to an announcement posted on the Massachusetts General Hospital's Center for Women's Mental Health Web site.

Women are eligible to enroll in the registry if they are pregnant and are between 18 and 45 years old and are currently being treated with one or more of the following antipsychotic medications: aripiprazole (Abilify), clozapine (Clozaril), ziprasidone (Geodon), paliperidone (Invega), risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), and asenapine (Saphris). Once the participants have registered, they will be asked to participate in three brief phone interviews that will be conducted over an 8-month period.

The National Pregnancy Registry for Atypical Antipsychotics is collecting data to investigate the safety of atypical antipsychotics during pregnancy, when these agents are used to treat a wide range of mood, anxiety, or psychiatric disorders, according to the announcement from the hospital.

The main goal of the National Pregnancy Registry is to determine the frequency of heart defects, cleft lip, neural tube defects, and other major malformations in infants who are exposed to these medications in utero.

To register, or for more information about what participation in the registry involves, call 866-961-2388. The MGH Center for Women's Mental Health provides information on perinatal and reproductive psychiatry at www.womensmentalhealth.org

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel unanimously agreed that concerns about the risks of flibanserin outweighed any evidence that the drug was effective as a treatment for premenopausal women with hypoactive sexual desire disorder.

Moreover, the evidence provided by Boehringer Ingelheim Pharmaceuticals that flibanserin (Girosa) is effective treatment for hypoactive sexual desire disorder (HSDD) did not sway the FDA's Reproductive Health Drugs Advisory Committee, reflected by their 10 to 1 no vote on that question.

The panel was not asked to vote on a separate safety question, but members expressed concerns about adverse effects associated with the drug in clinical trials, including high rates of somnolence and fatigue, a slightly higher rate of depression, the potential for drug and alcohol interactions, the lack of safety data on long-term use and during nursing and pregnancy—as well as the high withdrawal rate for adverse events in clinical trials.

However, panelists encouraged the company to continue studying the drug, noting the importance of finding treatments for HSDD, defined as a persistent or recurrent deficiency or absence of desire for sexual activity.

Boehringer Ingelheim has proposed that 100 mg of flibanserin, a centrally acting drug, taken orally every night at bedtime be approved for the treatment of HSDD in premenopausal women. The drug, first studied for depression, is a postsynaptic 5-HT1A agonist and 5-HT2A antagonist, and results in increases in dopamine and norepinephrine and decreases serotonin. No drug on the market has this neurotransmitter activity, according to the FDA.

In two pivotal, randomized, double-blind trials in the United States and Canada, the 100-mg dose was compared with placebo in healthy, premenopausal adult women (almost 700 patients were in each group with an average age of 35-36 years). Participants were in stable, heterosexual, monogamous relationships and were diagnosed with HSDD based on DSM–IV-TR criteria; most were white and 78% were married and had been with their partner for at least 10 years; exclusions included having a psychiatric disorder or taking a medication that could affect sexual functioning.

The primary end points were the changes from baseline in the number of Satisfying Sexual Events (SSEs), and the sexual desire score (the “eDiary Sexual Desire score), based on answers to questions answered on an online diary every day, regarding the respondent's level of sexual desire, whether she had sex, and whether it was satisfying.

The study failed to meet these two coprimary end points: After 24 weeks, the increase in SSEs was slightly less than one satisfactory event per month more than those in placebo group, in the two studies. (The increase in the mean number of SSEs over placebo was 0.8 per month in both studies.) Changes over 24 weeks in the eDiary Sexual Desire Score increased among those on flibanserin but were not significantly different from those on placebo in the two studies.

A secondary end point, the change in the total distress score on a scale measuring female sexual distress, showed a statistically significant effect of treatment over placebo.

The most common side effects of treatment were dizziness, nausea, fatigue, somnolence, insomnia, dry mouth, and anxiety. Safety concerns raised by the FDA were a higher rate of accidental injuries, syncope, and depression among those treated with the 100-mg dose, compared with lower doses in other studies and placebo, as well as the effects of hepatic impairment and coadministration with drugs that are strong CYP3A4 inhibitors on the concentration of flibanserin.

“I'm concerned about the safety signals that we saw. I'm especially concerned about the risk and the generalizability in a very heterogeneous population that would take this drug if we were to approve it,” committee member Valerie Montgomery Rice, professor of obstetrics and gynecology at Meharry Medical College, Nashville, said. She also cited doubts about generalizability of the efficacy findings to a more heterogeneous population than was studied in the pivotal trials.

The FDA usually follows the recommendations of its advisory panels. Currently, no drug is approved for HSDD, but testosterone and bupropion are used off-label for this indication.

Disclosures: Members of FDA advisory panels have been cleared of conflicts related to the topic under discussion.

Sue Sutter of Elsevier's “The Pink Sheet” contributed to this report.

'I'm especially concerned about the risk and the generalizability in a very heterogeneous population.'

Source DR. RICE

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel unanimously agreed that concerns about the risks of flibanserin outweighed any evidence that the drug was effective as a treatment for premenopausal women with hypoactive sexual desire disorder.

Moreover, the evidence provided by Boehringer Ingelheim Pharmaceuticals that flibanserin (Girosa) is effective treatment for hypoactive sexual desire disorder (HSDD) did not sway the FDA's Reproductive Health Drugs Advisory Committee, reflected by their 10 to 1 no vote on that question.

The panel was not asked to vote on a separate safety question, but members expressed concerns about adverse effects associated with the drug in clinical trials, including high rates of somnolence and fatigue, a slightly higher rate of depression, the potential for drug and alcohol interactions, the lack of safety data on long-term use and during nursing and pregnancy—as well as the high withdrawal rate for adverse events in clinical trials.

However, panelists encouraged the company to continue studying the drug, noting the importance of finding treatments for HSDD, defined as a persistent or recurrent deficiency or absence of desire for sexual activity.

Boehringer Ingelheim has proposed that 100 mg of flibanserin, a centrally acting drug, taken orally every night at bedtime be approved for the treatment of HSDD in premenopausal women. The drug, first studied for depression, is a postsynaptic 5-HT1A agonist and 5-HT2A antagonist, and results in increases in dopamine and norepinephrine and decreases serotonin. No drug on the market has this neurotransmitter activity, according to the FDA.

In two pivotal, randomized, double-blind trials in the United States and Canada, the 100-mg dose was compared with placebo in healthy, premenopausal adult women (almost 700 patients were in each group with an average age of 35-36 years). Participants were in stable, heterosexual, monogamous relationships and were diagnosed with HSDD based on DSM–IV-TR criteria; most were white and 78% were married and had been with their partner for at least 10 years; exclusions included having a psychiatric disorder or taking a medication that could affect sexual functioning.

The primary end points were the changes from baseline in the number of Satisfying Sexual Events (SSEs), and the sexual desire score (the “eDiary Sexual Desire score), based on answers to questions answered on an online diary every day, regarding the respondent's level of sexual desire, whether she had sex, and whether it was satisfying.

The study failed to meet these two coprimary end points: After 24 weeks, the increase in SSEs was slightly less than one satisfactory event per month more than those in placebo group, in the two studies. (The increase in the mean number of SSEs over placebo was 0.8 per month in both studies.) Changes over 24 weeks in the eDiary Sexual Desire Score increased among those on flibanserin but were not significantly different from those on placebo in the two studies.

A secondary end point, the change in the total distress score on a scale measuring female sexual distress, showed a statistically significant effect of treatment over placebo.

The most common side effects of treatment were dizziness, nausea, fatigue, somnolence, insomnia, dry mouth, and anxiety. Safety concerns raised by the FDA were a higher rate of accidental injuries, syncope, and depression among those treated with the 100-mg dose, compared with lower doses in other studies and placebo, as well as the effects of hepatic impairment and coadministration with drugs that are strong CYP3A4 inhibitors on the concentration of flibanserin.

“I'm concerned about the safety signals that we saw. I'm especially concerned about the risk and the generalizability in a very heterogeneous population that would take this drug if we were to approve it,” committee member Valerie Montgomery Rice, professor of obstetrics and gynecology at Meharry Medical College, Nashville, said. She also cited doubts about generalizability of the efficacy findings to a more heterogeneous population than was studied in the pivotal trials.

The FDA usually follows the recommendations of its advisory panels. Currently, no drug is approved for HSDD, but testosterone and bupropion are used off-label for this indication.

Disclosures: Members of FDA advisory panels have been cleared of conflicts related to the topic under discussion.

Sue Sutter of Elsevier's “The Pink Sheet” contributed to this report.

'I'm especially concerned about the risk and the generalizability in a very heterogeneous population.'

Source DR. RICE

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel unanimously agreed that concerns about the risks of flibanserin outweighed any evidence that the drug was effective as a treatment for premenopausal women with hypoactive sexual desire disorder.

Moreover, the evidence provided by Boehringer Ingelheim Pharmaceuticals that flibanserin (Girosa) is effective treatment for hypoactive sexual desire disorder (HSDD) did not sway the FDA's Reproductive Health Drugs Advisory Committee, reflected by their 10 to 1 no vote on that question.

The panel was not asked to vote on a separate safety question, but members expressed concerns about adverse effects associated with the drug in clinical trials, including high rates of somnolence and fatigue, a slightly higher rate of depression, the potential for drug and alcohol interactions, the lack of safety data on long-term use and during nursing and pregnancy—as well as the high withdrawal rate for adverse events in clinical trials.

However, panelists encouraged the company to continue studying the drug, noting the importance of finding treatments for HSDD, defined as a persistent or recurrent deficiency or absence of desire for sexual activity.

Boehringer Ingelheim has proposed that 100 mg of flibanserin, a centrally acting drug, taken orally every night at bedtime be approved for the treatment of HSDD in premenopausal women. The drug, first studied for depression, is a postsynaptic 5-HT1A agonist and 5-HT2A antagonist, and results in increases in dopamine and norepinephrine and decreases serotonin. No drug on the market has this neurotransmitter activity, according to the FDA.

In two pivotal, randomized, double-blind trials in the United States and Canada, the 100-mg dose was compared with placebo in healthy, premenopausal adult women (almost 700 patients were in each group with an average age of 35-36 years). Participants were in stable, heterosexual, monogamous relationships and were diagnosed with HSDD based on DSM–IV-TR criteria; most were white and 78% were married and had been with their partner for at least 10 years; exclusions included having a psychiatric disorder or taking a medication that could affect sexual functioning.

The primary end points were the changes from baseline in the number of Satisfying Sexual Events (SSEs), and the sexual desire score (the “eDiary Sexual Desire score), based on answers to questions answered on an online diary every day, regarding the respondent's level of sexual desire, whether she had sex, and whether it was satisfying.

The study failed to meet these two coprimary end points: After 24 weeks, the increase in SSEs was slightly less than one satisfactory event per month more than those in placebo group, in the two studies. (The increase in the mean number of SSEs over placebo was 0.8 per month in both studies.) Changes over 24 weeks in the eDiary Sexual Desire Score increased among those on flibanserin but were not significantly different from those on placebo in the two studies.

A secondary end point, the change in the total distress score on a scale measuring female sexual distress, showed a statistically significant effect of treatment over placebo.

The most common side effects of treatment were dizziness, nausea, fatigue, somnolence, insomnia, dry mouth, and anxiety. Safety concerns raised by the FDA were a higher rate of accidental injuries, syncope, and depression among those treated with the 100-mg dose, compared with lower doses in other studies and placebo, as well as the effects of hepatic impairment and coadministration with drugs that are strong CYP3A4 inhibitors on the concentration of flibanserin.

“I'm concerned about the safety signals that we saw. I'm especially concerned about the risk and the generalizability in a very heterogeneous population that would take this drug if we were to approve it,” committee member Valerie Montgomery Rice, professor of obstetrics and gynecology at Meharry Medical College, Nashville, said. She also cited doubts about generalizability of the efficacy findings to a more heterogeneous population than was studied in the pivotal trials.

The FDA usually follows the recommendations of its advisory panels. Currently, no drug is approved for HSDD, but testosterone and bupropion are used off-label for this indication.

Disclosures: Members of FDA advisory panels have been cleared of conflicts related to the topic under discussion.

Sue Sutter of Elsevier's “The Pink Sheet” contributed to this report.

'I'm especially concerned about the risk and the generalizability in a very heterogeneous population.'

Source DR. RICE

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel unanimously agreed that the selective progesterone receptor modulator ulipristal acetate is an effective emergency contraceptive with an acceptable safety profile, when used within 5 days of unprotected intercourse or a known or suspected contraceptive failure.

The FDA's Reproductive Health Drugs Advisory Committee voted 11 to 0 that the manufacturer, HRA Pharma, had provided enough information to conclude that the proposed 30-mg dose of micronized ulipristal “reduces the likelihood of pregnancy” when taken as soon as possible within 120 hours after unprotected intercourse or a known or suspected contraceptive failure. The primary mechanism of action of ulipristal, which has a potent affinity for the progesterone receptor, is presumed to be the inhibition or the delay of ovulation, according to the company.

If approved by the FDA, the company plans to market it as a prescription-only product under the trade name “ella.” Ulipristal was approved as an emergency contraceptive in Europe in May 2009 and has been marketed there since October, under the trade name “ellaOne.”

The FDA usually follows the recommendations of its advisory panels.

Currently, the levonorgestrel-based emergency contraceptive marketed as Plan B or Next Choice, is the only available emergency contraceptive in the United States.

Plan B is recommended for use for up to 72 hours within unprotected intercourse or contraceptive failure; it is available by prescription and—for women aged 18 years and older—over the counter, in a 1.5-mg single-dose (Plan B One-Step) and two 0.75-mg doses to be taken 12 hours apart (Plan B or Next Choice).

Ulipristal was evaluated in two phase III prospective, multicenter studies of women aged 18 years and older (in the United States) or aged 16 years and older (in Europe), who received 30 mg of micronized ulipristal within 48-120 hours of unprotected intercourse.

The first trial was an open-label study conducted in the United States of 1,241 women, who were give a dose of ulipristal within 48-120 hours after unprotected intercourse. The pregnancy rate was 2.10%, which was significantly lower than the expected pregnancy rate of 5.53%.

The second study was a randomized, controlled, inferiority study in which ulipristal was compared with levonorgestrel in women in the United States and Europe. Among the 1,694 women who took either medication within 72 hours of unprotected intercourse, the pregnancy rate was 1.78% among those who took ulipristal, which was significantly lower than the expected pregnancy rate of 5.54%. The pregnancy rate among those who received the levonorgestrel emergency contraceptive was 2.59%.

The pregnancy rate was higher among women with a higher body mass index (BMI), in a pooled analysis of the two studies: The pregnancy rate was 3.13% among those with a BMI above 30 kg/m

Among more than 4,700 women in ulipristal studies who received single doses up to 200 mg, including 2,700 women who received the 30-mg proposed dose, the most common side effects reported were headache, nausea, dysmenorrhea, and abdominal pain, according to the company. The one serious adverse event associated with ulipristal was in an 18 year old, who experienced severe dizziness after taking the drug. No ectopic pregnancies were reported; two ruptured ovarian cysts were reported in women who received the 30-mg dose in phase II/III and phase III studies.

The limited data on pregnancies exposed to ulipristal suggest that the miscarriage rate is not increased with exposure, according to the company. Only 21 exposed pregnancies have been reported to date; of those, 14 are ongoing normal pregnancies, 2 were elective terminations, 1 was a miscarriage and 4 were lost to follow-up. The company is planning a postmarketing study in Europe, which will follow up with 1,000 health care practitioners to collect detailed clinical data on the course of pregnancies and outcomes among patients who get pregnant despite treatment with ulipristal. The FDA has proposed that if ulipristal is approved, this program should be expanded to include health care providers in the United States.

Disclosures: Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel unanimously agreed that the selective progesterone receptor modulator ulipristal acetate is an effective emergency contraceptive with an acceptable safety profile, when used within 5 days of unprotected intercourse or a known or suspected contraceptive failure.

The FDA's Reproductive Health Drugs Advisory Committee voted 11 to 0 that the manufacturer, HRA Pharma, had provided enough information to conclude that the proposed 30-mg dose of micronized ulipristal “reduces the likelihood of pregnancy” when taken as soon as possible within 120 hours after unprotected intercourse or a known or suspected contraceptive failure. The primary mechanism of action of ulipristal, which has a potent affinity for the progesterone receptor, is presumed to be the inhibition or the delay of ovulation, according to the company.

If approved by the FDA, the company plans to market it as a prescription-only product under the trade name “ella.” Ulipristal was approved as an emergency contraceptive in Europe in May 2009 and has been marketed there since October, under the trade name “ellaOne.”

The FDA usually follows the recommendations of its advisory panels.

Currently, the levonorgestrel-based emergency contraceptive marketed as Plan B or Next Choice, is the only available emergency contraceptive in the United States.

Plan B is recommended for use for up to 72 hours within unprotected intercourse or contraceptive failure; it is available by prescription and—for women aged 18 years and older—over the counter, in a 1.5-mg single-dose (Plan B One-Step) and two 0.75-mg doses to be taken 12 hours apart (Plan B or Next Choice).

Ulipristal was evaluated in two phase III prospective, multicenter studies of women aged 18 years and older (in the United States) or aged 16 years and older (in Europe), who received 30 mg of micronized ulipristal within 48-120 hours of unprotected intercourse.

The first trial was an open-label study conducted in the United States of 1,241 women, who were give a dose of ulipristal within 48-120 hours after unprotected intercourse. The pregnancy rate was 2.10%, which was significantly lower than the expected pregnancy rate of 5.53%.

The second study was a randomized, controlled, inferiority study in which ulipristal was compared with levonorgestrel in women in the United States and Europe. Among the 1,694 women who took either medication within 72 hours of unprotected intercourse, the pregnancy rate was 1.78% among those who took ulipristal, which was significantly lower than the expected pregnancy rate of 5.54%. The pregnancy rate among those who received the levonorgestrel emergency contraceptive was 2.59%.

The pregnancy rate was higher among women with a higher body mass index (BMI), in a pooled analysis of the two studies: The pregnancy rate was 3.13% among those with a BMI above 30 kg/m

Among more than 4,700 women in ulipristal studies who received single doses up to 200 mg, including 2,700 women who received the 30-mg proposed dose, the most common side effects reported were headache, nausea, dysmenorrhea, and abdominal pain, according to the company. The one serious adverse event associated with ulipristal was in an 18 year old, who experienced severe dizziness after taking the drug. No ectopic pregnancies were reported; two ruptured ovarian cysts were reported in women who received the 30-mg dose in phase II/III and phase III studies.

The limited data on pregnancies exposed to ulipristal suggest that the miscarriage rate is not increased with exposure, according to the company. Only 21 exposed pregnancies have been reported to date; of those, 14 are ongoing normal pregnancies, 2 were elective terminations, 1 was a miscarriage and 4 were lost to follow-up. The company is planning a postmarketing study in Europe, which will follow up with 1,000 health care practitioners to collect detailed clinical data on the course of pregnancies and outcomes among patients who get pregnant despite treatment with ulipristal. The FDA has proposed that if ulipristal is approved, this program should be expanded to include health care providers in the United States.

Disclosures: Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel unanimously agreed that the selective progesterone receptor modulator ulipristal acetate is an effective emergency contraceptive with an acceptable safety profile, when used within 5 days of unprotected intercourse or a known or suspected contraceptive failure.

The FDA's Reproductive Health Drugs Advisory Committee voted 11 to 0 that the manufacturer, HRA Pharma, had provided enough information to conclude that the proposed 30-mg dose of micronized ulipristal “reduces the likelihood of pregnancy” when taken as soon as possible within 120 hours after unprotected intercourse or a known or suspected contraceptive failure. The primary mechanism of action of ulipristal, which has a potent affinity for the progesterone receptor, is presumed to be the inhibition or the delay of ovulation, according to the company.

If approved by the FDA, the company plans to market it as a prescription-only product under the trade name “ella.” Ulipristal was approved as an emergency contraceptive in Europe in May 2009 and has been marketed there since October, under the trade name “ellaOne.”

The FDA usually follows the recommendations of its advisory panels.

Currently, the levonorgestrel-based emergency contraceptive marketed as Plan B or Next Choice, is the only available emergency contraceptive in the United States.

Plan B is recommended for use for up to 72 hours within unprotected intercourse or contraceptive failure; it is available by prescription and—for women aged 18 years and older—over the counter, in a 1.5-mg single-dose (Plan B One-Step) and two 0.75-mg doses to be taken 12 hours apart (Plan B or Next Choice).

Ulipristal was evaluated in two phase III prospective, multicenter studies of women aged 18 years and older (in the United States) or aged 16 years and older (in Europe), who received 30 mg of micronized ulipristal within 48-120 hours of unprotected intercourse.

The first trial was an open-label study conducted in the United States of 1,241 women, who were give a dose of ulipristal within 48-120 hours after unprotected intercourse. The pregnancy rate was 2.10%, which was significantly lower than the expected pregnancy rate of 5.53%.

The second study was a randomized, controlled, inferiority study in which ulipristal was compared with levonorgestrel in women in the United States and Europe. Among the 1,694 women who took either medication within 72 hours of unprotected intercourse, the pregnancy rate was 1.78% among those who took ulipristal, which was significantly lower than the expected pregnancy rate of 5.54%. The pregnancy rate among those who received the levonorgestrel emergency contraceptive was 2.59%.

The pregnancy rate was higher among women with a higher body mass index (BMI), in a pooled analysis of the two studies: The pregnancy rate was 3.13% among those with a BMI above 30 kg/m

Among more than 4,700 women in ulipristal studies who received single doses up to 200 mg, including 2,700 women who received the 30-mg proposed dose, the most common side effects reported were headache, nausea, dysmenorrhea, and abdominal pain, according to the company. The one serious adverse event associated with ulipristal was in an 18 year old, who experienced severe dizziness after taking the drug. No ectopic pregnancies were reported; two ruptured ovarian cysts were reported in women who received the 30-mg dose in phase II/III and phase III studies.

The limited data on pregnancies exposed to ulipristal suggest that the miscarriage rate is not increased with exposure, according to the company. Only 21 exposed pregnancies have been reported to date; of those, 14 are ongoing normal pregnancies, 2 were elective terminations, 1 was a miscarriage and 4 were lost to follow-up. The company is planning a postmarketing study in Europe, which will follow up with 1,000 health care practitioners to collect detailed clinical data on the course of pregnancies and outcomes among patients who get pregnant despite treatment with ulipristal. The FDA has proposed that if ulipristal is approved, this program should be expanded to include health care providers in the United States.

Disclosures: Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.