Update for Daxas

[Jeannine]

Looks like the approval will come through and only a label change will be made to include the risk of suicidal thoughts.

Daxas (roflumilast) (a once-daily oral treatment)

An FDA Advisory Panel meeting is scheduled for Wednesday and FRX is seeking approval for symptomatic COPD (chronic obstructive pulmonary disease) to reduce exacerbations. Briefing documents filed ahead of the advisory panel meeting noted proposed label changes were submitted by FRX in late January (less than two months ahead of panel review) and the incidence of psychiatric side effects.

[Kaye]

That is wonderful news. If the review recommends approval, how long will it take before they vote on it and how long before we might get the drug? Thanks for all your hard work. I am really hoping that this helps a lot of us.

[Jeannine]

Kaye

I'm not familiar with their formal procedures but I would hope it wouldn;t take too long (six months?) before it's available to us).

I can't believe how the term "moderate success" doesn't seem important to the FDA. For us it's a chance to improve our quality of life. I guess when you're in perfect health it's hard to understand what wwe live with every day.

[Jeannine]

This article is far more detailed and grim about the side effects of Daxas.

FDA Notes Suicides with Forest, Nycomed COPD Drug Daxas



By Donna Young
Washington Editor

WASHINGTON ? The FDA's concerns over suicides linked to Forest Laboratories Inc.'s chronic obstructive pulmonary disease (COPD) drug Daxas (roflumilast) had investors only somewhat worried Monday, with shares slipping just slightly.

In addition to the adverse events, which also included gastrointestinal toxicity, weight loss and the potential for cancer, regulators also noted that Daxas had only a modest effect in improving the lung function of patients with COPD in clinical testing.

In briefing documents released ahead of Wednesday's FDA Pulmonary-Allergy Drugs Advisory Committee meeting, FDA drug reviewers also took issue with the late switch of Daxas' proposed indication.

Swiss drugmaker Nycomed GmbH, the firm that developed Daxas, had submitted the new drug application (NDA) to the agency last July with a proposed indication for the compound as a maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

But New York-based Forest, which licensed Daxas from Nycomed under a deal potentially worth more than $500 million, submitted a new application in late January with what the FDA said were "substantial" changes, including a narrower indication and a new warning about neuropsychiatric events. (See BioWorld Today, Aug. 11, 2009.)

Forest tapered the indication to reduction in COPD exacerbations, which analysts said could be a more winnable indication. But the FDA said the change of indication six months into Daxas' review and two months before the agency's advisory committee meeting was "problematic," because it "shifts the focus of the efficacy analysis, which was based upon the original indication."

Regulators said the application would continue to be evaluated on the originally proposed indication.

The drug reviewers noted that the information in the briefing documents and the agency's draft questions also remained focused on the initial broader indication.

The FDA, however, often changes its questions by the time advisory panel meetings roll around.

While Forest's labeling changes may delay Daxas' approval, in the end, the move could increase the likelihood of the drug getting the FDA's OK, predicted Lazard Capital Markets analyst William Tanner.

Cowen & Co. analyst Ian Sanderson said a leading clinician and investigator in COPD he consulted called Forest's move to the narrower indication a "good strategy." The consultant also said the advisory panel and the FDA would end up using the narrower indication, which Sanderson said would "preclude" the agency's efficacy issues.

While Daxas had a statistically significant, "albeit quite modest," increase in prebronchodilator forced expiratory volume in 1 second, compared with placebo, the FDA said that increase "would not constitute a clinically meaningful benefit."

Although the concerns the FDA raised about gastrointestinal toxicity and weight loss were not a surprise, the suicides, which regulators called a "significant concern," could be perceived as a "negative surprise," said Baird & Co. analyst Thomas Russo.

He noted that the suicidality signal linked to Daxas was not highlighted in published research, nor is it in the labeling of established COPD agents, such as GlaxoSmithKline plc's Advair (fluticasone and salmeterol) and Pfizer Inc.'s Spiriva (tiotropium bromide).

Regulators said none of the three men who committed suicide had a history of depression. In two of those cases, the patients had reportedly stopped taking Daxas about three weeks before the suicide event.

The two women who attempted suicide, however, had psychiatric histories, with depression in one patient and a previous suicide attempt in the other. Both women were receiving Daxas at the time of the suicide attempt.

But Cowen's Sanderson said the suicidality signal may be just "noise." Nonetheless, he said it was something that likely would end up as a warning in the labeling.

Adverse psychiatric events were more common in patients taking Daxas 500 mcg compared with those who received the 250-mcg dosage or placebo, the FDA said. Of the three completed suicides, two received the 500-mcg dosage, with the third receiving the 250-mcg dosage.

Drug reviewers noted that there were 403 adverse psychiatric events reported in patients who received once-daily 500-mcg dosages, or 6 percent of study participants, compared with 190, or 3 percent, in the placebo group.

There were two-to-three times greater adverse events of insomnia, anxiety and depression in the Daxas 500-mcg dosage group, compared with placebo, the FDA said.

The percentage of patients in the COPD safety pool in the Daxas studies who experienced at least one adverse gastrointestinal event in the 500-mcg treatment groups was 22 percent, compared with 11 percent in placebo-treated patients.

Among the adverse GI events, about half experienced diarrhea and up to 25 percent experienced nausea.

While the adverse GI events, such as diarrhea and nausea, were the leading cause of early study termination in patients taking Daxas, a selective phosphodiesterase type 4 (PDE4) inhibitor, the FDA acknowledged that those events are known effects of that class of drugs.

The most severe adverse GI effects in patients taking Daxas were intractable diarrhea and pancreatitis. Two patients who developed acute pancreatitis died. Both were taking the 500-mcg dosage.

In the pivotal trial pool, 62.4 percent of Daxas-treated patients had measurable weight loss, compared with 37.7 percent in the placebo group. Regulators noted that only a fraction of the measured weight loss was reported as adverse events.

The FDA also raised concerns about the carcinogenic effects of Daxas in animal studies, which regulators called a "topic of special interest."

In the overall clinical development program, 60 percent of Daxas-treated patients reported cancer or tumor events, compared with 40 percent in the placebo group.

There were more lung and prostate cancers reported for patients treated with Daxas than in the placebo group, drug reviewers said, insisting that those differences could not be due to preferential dropout in the placebo group, since more patients receiving Daxas withdrew from clinical studies prematurely, compared with placebo.

Shares of Forest (NYSE:FRX) closed at $30.96, down 47 cents.

http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadline s_article&forceid=54083

[barbara]

This is as ominous as the type of consent forms you have to sign before CT scans, surgery, etc. My husband was given a pain killer about a year ago that came with an insert. After reading the insert, the side effects and potential for a hundred other adverse reactions made us wonder why the drug was ever approved for use. His physician was comfortable prescribing it, however. He ended up not having that much pain and didn't take it, but it makes a person wonder just what's up at the FDA.

[barbara]

The latest on the safe drugs that the FDA has already approved. Morphine is a drug prescribed for COPD in some cases.

Scientific American
April 6, 2010

By Katherine Harmon

KILLER PAINKILLERS: As the prevalence of prescription painkillers increases, the number of people hospitalized for overdosing on them appears to, too. High-profile celebrity deaths are just a few instances of this growing problem, say authors of a new study.

The number of deaths and hospitalizations caused by prescription drugs has risen precipitously in the past decade, with overdoses of pain medications, in particular opioids, sedatives and tranquilizers, more than doubling between 1999 and 2006, according to a new study.

In fact, by 2006, overdoses of opioid analgesics alone (a class of pain relievers that includes morphine and methadone) were already causing more deaths than overdoses of cocaine and heroin combined.

"Teens and others have different attitudes in using these drugs," often presuming the prescription substances are safer and less addictive than illegal drugs such as cocaine or heroin, says Jeffrey Coben, a professor of emergency and community medicine at the West Virginia University School of Medicine in Morgantown and lead author of the new study. "I think that's a false assumption. Aside from the fact they can be taken orally rather than injected?[many prescription drugs] really are every bit as powerful, addictive and dangerous as heroin," he notes, adding that, "when you combine them with other sedatives, that mix can become particularly lethal."

Using data collected by the Nationwide Inpatient Sample, which gathers hospital patient information for about 8 million people every year, Coben and his colleagues were able to assess what drugs were implicated in the majority of poisonings?and in many cases whether the poisonings were intentional or not. The team selected opioids, sedatives and tranquilizers as the focus of the analysis because these substances are "contributing the majority of prescription drug overdose deaths," Coben says. These categories of prescription drugs can kill and injure people by suppressing breathing, depriving the body of oxygen.

For prescription opioids, sedatives and tranquilizers?commonly prescribed for pain management?the number of hospitalizations for poisonings increased 65 percent between 1999 and 2006 (the first and last years, respectively, for which data were comparable and collected). The number of hospitalizations for all poisonings, including illegal drugs, other prescription medications and miscellaneous substances, increased during this time period as well, but that jump (33 percent) was about half the rate of those for the prescription pain drugs.

Unintentional poisonings from these drugs climbed 37 percent during the seven-year period, the researchers found. Intentional overdoses, in which people meant to inflict self-harm or death, jumped 130 percent (a far cry more than the 53 percent increase of intentional poisoning from other substances in the same time period). Intent was not listed in all cases and can be subject to reporting error. The results are detailed online April 6 in the American Journal of Preventive Medicine.

Poisonings, from prescription drugs and other substances, are classified in medical records as injurious or accidental deaths. But regardless of whether the incidents are listed as unintentional or intentional, they are rarely true mistakes, noted Leonard Paulozzi, a medical epidemiologist with the U.S. Centers for Disease Control and Prevention, in congressional testimony in 2007. "Most unintentional drug poisoning deaths are not 'accidents' caused by toddlers or the elderly taking too much medication," he noted. "These deaths are largely due to the misuse and abuse of prescription drugs."

Accidents overall were the fifth most common cause of death in the U.S. as of 2005 (accounting for 117,809 deaths?4.8 percent?that year), according to the National Vital Statistics Report [pdf]. Of injury deaths, poisoning is the second most common cause of death in the U.S., having doubled between 1985 and 2004, according to a 2007 Department of Health and Human Services analysis [pdf]. Among people 35 to 54 years old, poisoning is the most common accidental death?even more so than auto-related deaths.

Many experts think that the sheer prevalence of many of these drugs recently has contributed to the drastic increase in poisonings. Although growing illegal markets and distribution of these drugs might be a driving factor in their increasingly large role in poisonings and deaths, perfectly legal prescriptions are probably playing a role as well, Coben says.

"I think the whole issue of the availability of these drugs and whether they're being over-prescribed" should be investigated, says Susan Baker, a professor at Johns Hopkins Center for Injury Research and Policy, who was not involved in the new study but coauthored a 2009 report in the same journal about recent trends in injury mortality.

Many people do rely on pharmacological treatment for withdrawal, anxiety or chronic pain, but when communities have access to an overabundance of these medications, abuse appears to become more likely. If doctors prescribe too much medication or too many refills, excess drugs "are going to be sitting in people's medicine cabinets for someone else to take advantage of," Baker explains. For example, methadone poisonings were four times as frequent in 2006 as they were in 1999, a time period during which retail sales grew more than 1,000 percent, Coben and his team found.

Although the new report details the stark increase in the reported poisoning data, the true number of deaths and hospitalizations in which prescription drugs have played a role might be even higher, the researchers pointed out. The new analysis assessed cases only in which prescription drug overdose was listed as the primary diagnosis. Some prescription drug?related hospitalizations might be classified under other primary categories, and those who abuse the drugs were not always labeled as having been poisoned. Additionally, the researchers explained, many common terms such as overdose, misuse and abuse are not well standardized in hospitals.

"I don't have any sense that it's getting any better," Coben says. With drug companies reporting strong overall sales (including a 5.1 percent increase in U.S. sales in 2009 to $300.3 billion for 3.9 billion individual retail prescriptions), in fact, the problem might be getting worse.

The researchers noted that the details surrounding these hundreds of thousands of overdoses are unknown. The medical data used for the analysis did not include full toxicology reports that would reveal drug-drug interactions. And although the researchers found that the majority of the people hospitalized for poisoning with these prescription drugs were women, they did not have enough other demographic data to propose possible reasons for the overdose increases.

"What we really need is something other than the coded data," Baker says. She notes that researchers need to know more about the circumstances in which people are overdosing before effective prevention measures can be put into place.

"There's a need to have informational interviews with people who have had overdoses and survived them," Coben says. He hopes that future research will "raise some opportunities for interventions with these people."

[carmen868]

So with all these conflicting findings, what do we do? Do we take Daxas or not? ???????

[barbara]

I most certainly will try it if it gets approved.

[Jeannine]

FDA panel rejects Forest lung disease drug
Wednesday, April 7, 2010
(04-07) 14:22 PDT WASHINGTON (AP) --

Federal health experts on Wednesday sided against an experimental lung disease treatment from Forest Laboratories because of potentially dangerous side effects.

The Food and Drug Administration's panel of lung experts voted 10-5 against approving Forest's drug Daxas for pulmonary lung disorder, often called "smoker's cough."

The FDA is not required to follow the group's advice, though it often does.

The rejection followed an earlier vote of 9-6 that Daxas appeared effective for treating the disease, according to an FDA spokeswoman.

Panelists raised concerns about possible side effects, including suicide, weight loss and cancer. Those problems were more frequent among Daxas patients than those taking an alternative drug in company studies.

The FDA is expected to make a decision on the drug by mid-May.

Forest Labs Chief Operating Officer Larry Olanoff said the company was "disappointed" by the final vote, but said it did not preclude approval for the drug.

"We didn't see this as a unanimous vote against approval," said Olanoff. "The questions raised we think are clearly negotiable with the agency."

Forest Labs purchased the U.S. rights to sell Daxas last summer from drugmaker Nycomed for $100 million. Nycomed will also receive royalties on U.S. sales.

Chronic pulmonary obstructive disorder affects roughly 25 million people in the U.S.

Shares of New York-based Forest Labs fell $2.86, or 8.8 percent, to $29.51 in after-hours trading Wednesday.



Read more: http://www.sfgate.com:80/cgi-bin/article.cgi?f=/n/a/2010/04/07/financial/f132953D09.DTL#ixzz0kS717w13