FDA Panel Rejects Xyrem as Fibromyalgia Treatment

[sleepwalking]

FDA Panel Rejects Xyrem as Fibromyalgia Treatment
Advisory Panel Members Worry About Potential for Abuse of Drug That's Similar to GHB
By Matt McMillen

WebMD Health News
Reviewed by Laura J. Martin, MD

Aug. 20, 2010 -- An FDA advisory panel today overwhelmingly rejected the application of Jazz Pharmaceuticals for the approval sodium oxybate (Xyrem) for the treatment of fibromyalgia.

The drug is chemically similar to GHB, widely considered a date-rape drug. Approving it for such a large patient population -- 5 million people are estimated to suffer from fibromyalgia -- would risk flooding the streets with a pharmaceutical-grade version of the highly controlled substance.

"Sodium oxybate and GHB are the same thing," said panelist Lewis Nelson, MD, of the New York University School of Medicine. "This is much better than the stuff you get on the street, and that is the problem."

Currently, the drug is only approved for the treatment of narcolepsy. It has been prescribed for 35,000 people since it was introduced in 2002.

"When drugs like GHB get out there, we wish it hadn't happened," said Thomas Kosten, MD, a Baylor University professor of psychiatry and addiction.

Slideshow: Fibromyalgia-Friendly Exercises
Risks vs. Benefits

Kosten, who vociferously opposed approval, also cited a lack of convincing evidence by the drugmaker that the risks involved in releasing the drug to such a large population were balanced by its effectiveness in treating fibromyalgia-related pain and sleeping problems, the two conditions for which Jazz was seeking approvals.

"Without any data to show that this is better than existing medications, I think we are foolish to consider approving this drug," Kosten said in the discussion immediately preceding the vote.

The panel's vote contrasted with the FDA's view of the data provided by Jazz, which included two studies measuring pain relief, and another study that tested its effectiveness as a sleep aid.

"The agency agrees that there is evidence of efficacy" for treating pain, said FDA statistician David Petullo, MS, who reviewed the studies. The FDA did not, however, accept Jazz's claims that sodium oxybate had a positive effect on sleep.

In the public comment period, the majority of the speakers supported approval of the drug. Many of them had participated in the Jazz-run studies. They explained, often emotionally, how much they had benefited from sodium oxybate after failing to respond to any of the three drugs approved to treat fibromyalgia.

As many as 50% of those with the disease do not respond to available medications, said Jon Russell, MD, director of the University Clinical Research Center at the University of Texas Health Science Center at San Antonio, who spoke on behalf of Jazz.

"We need more options for the care of fibromyalgia patients," said Russell, "and those should have different mechanisms of action."
Concerns About Drug Abuse

The panelists were not convinced that the company had made enough of an effort to prove sodium oxybate's effectiveness, nor did they have confidence in the company's ability to monitor and manage the potential risks associated with the drug.

The panel cited a lack of data concerning drug interactions for patients on multiple medications, as well as risks for patients with multiple conditions; the likelihood of misuse; and doctor and patient confusion over what one FDA official referred to as the drug's "unusual and complex dosing arrangement."

But it was the link to GHB and the potential for abuse in a vastly expanded, difficult-to-monitor market that drove the 20-2 vote.

Sidney Wolfe, MD, director of Public Citizen's Health Research Group, summed up the panel's position: if a drug needs to get on the market, there needs to be a mechanism in place to mitigate risk, which the panel clearly found lacking.

"The other option," he said, "is to not approve it."

http://www.webmd.com/fibromyalgia/news/20100820/fda-panel-rejects-xyrem-as-fibromyalgia-treatment

 

[Otis]

Thanks for posting. This takes a very good option for many with difficulty getting slow wave (stages 3/4) sleep.

I suspect the concern over GHB's use as a date rape drug, and general abuse, colored the this recommendation.

 

[LaurelW]

:Retro mad:Are they kidding? This is the most highly-controlled drug I've ever used in my life, much more than narcotics, cocaine-derived, anything. You can only get it from one pharmacy in the country, your doctor has to fax them a full-page prescription, they make you watch an educational video and document that you understand the dosing, they refuse to deliver it without your signature, you have to deface the labels before you throw the bottle away. I used it during a period after my husband died of cancer when absolutely nothing else would make me sleep. I have a friend with fibro who was in one of the clinical trials--it changed her life for the better.

And then we hear of sloppy approval processes for Avandia, Midodrine and the fast-tracking of drugs like Viagra. I think I need to go to the burnout bench.:Retro mad:

 

[sensing progress]

Damn. Although I believe it can still be prescribed off-label for ME/Fibro patients if your doctor is willing.

 

[cfs since 1998]

Let's deny millions of sick and disabled people a treatment because we don't want the general population to abuse it. What a bunch of dipshits.

 

[heapsreal]

with my sleep issues and having tried almost everything, i asked for a scipt for rohypnol which has had the same restrictions on it as morphine does as it was supposedly abused as a date rape drug. I have only used this as directed for my condition and i dont think its that strong a drug or any benzo in high enough doses could be used form this purpose. I thinkg the govt just like to get on their high horse once in awhile and do something stupid because they can. Sleeping 100% every night would go along way in improving our quality of life in cfs/fibro.

 

[lucysun]

I attended this meeting Friday and it was both fascinating and frustrating to witness, especially the discussion period where the panel asked questions and provided commentary. The un-founded fear that making this available would cause epidemic GHB abuse was ridiculous.

I recorded most of the public comment - you can listen to it here. It includes NFA president, Lynne Matallana, Neurologist Dr. Victor Rosenfeld, researcher Dr. Muhammad B. Yunus, and many people who have been successfully treated by sodium oxybate for fibromyalgia - their stories were compelling.

http://littlebirdexpress.tumblr.com/post/987729377/public-comment-audio-for-fda-advisory-meeting-sodium

I can post my "review" of the meeting if anyone is interested.

 

[lucysun]

Here is another good article about the hearing:

FDA Panel Roundly Rejects CNS Drug for Fibromyalgia
By Emily P. Walker, Washington Correspondent, MedPage Today
August 20, 2010
BETHESDA, Md. -- A federal advisory panel voted 20-2 to recommend that the FDA not grant approval for an expanded indication for sodium oxybate (Xyrem) -- also known as GHB -- to treat fibromyalgia.

A number of members on the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committees felt the potential for widespread abuse of the "date rape" drug was too great to warrant expanding the indication to a condition that affects an estimated 2% of the U.S. population.

Sodium oxybate, currently approved at a 500 mg/ml dose for narcolepsy-associated cataplexy and excessive daytime sleepiness, is a central nervous system depressant and carries a boxed warning against its use in combination with other similar drugs.

The label information also warns that sodium oxybate is a drug known to be abused. Sodium oxibate is a sodium salt of y-hydroxybutyrate, or GHB.

"Right now it's viewed as a drug for a very rare condition, and that is not fibromyalgia," said panelist Thomas Kosten, MD, professor of psychiatry and addiction at Baylor College of Medicine in Houston. "We've gone from a micro, tiny population, to something that's going to affect a huge population.

"Should we be giving LSD to people because it improves their psychotherapy? Should we give marijuana to people because it improves their well-being?" Kostan said. "What are we thinking?!"

Other panelists weren't as worried -- or as agitated -- as Kostan over the potential for abuse, but they noted that the drug's maker, Jazz Pharmaceuticals, failed to convincingly prove the drug worked. Others were concerned about the odd dosing mechanism of the drug.

The vote came at the end of an unusually tense joint advisory board meeting during which one panelist sparred with an FDA official; fibromyalgia patients pleaded with the panel to give them access to a drug they said helped save them from lives filled with pain; and drug abuse prevention advocates urged the FDA not to add another indication to sodium oxybate out of fear it will increase the amount of GHB on the streets.

Panelists Question Effectiveness Data

Although narcolepsy is a rare disorder, fibromyalgia effects about five million people, or 2% of the U.S. population, according to FDA staff reviewers in briefing documents prepared for the panel. However, if approved, the sodium oxybate would be used in far fewer patients, Jazz Pharmaceuticals argued, largely because many patients would be scared off by all the safety warnings and by horror stories they've heard about GHB.

The committee examined the company's two randomized, double-blind, phase III trials testing sodium oxybate versus placebo.

In one of the trials, involving 548 patients randomized to placebo or to 4.5 g or 6 g per night of the drug, researchers reported the following improvements relative to baseline:

* Pain visual analogue scale (VAS) score: placebo, -18 points; low drug dose, -29 points; high drug dose, -32 points (P<0.001 for both doses)
* Fatigue VAS score: placebo, -17 points; low drug dose, -28 points; high drug dose, -30 points (P<0.001 for both doses)
* Jenkins Sleep Scale score: placebo, -2.9 points; low drug dose, -6.1 points; high drug dose, -6.2 points (P<0.001 for both doses)

At Friday's meeting, FDA staff said there was no question that the drug was effective, but panelists weren't so sure.

For starters, several panelists rejected the idea that a true placebo could exist in Jazz's trials -- or in any trial testing a "hypnotic sedative." One patient who was enrolled in the Jazz trial told the panel she knew she received the test drug from the onset.

"From the very first dose, I knew this was no placebo," patient Barbara Gehr told the panel. She was bedridden for eight months with pain from fibromyalgia before enrolling in a Jazz sodium oxybate trial.

Patients taking the drug pass out almost immediately, with no time to even "send an e-mail" as another patient put it.

Dosing Raises Red Flags

Panelists were also concerned with the unusual dosing mechanism. The drug has an extremely short half-life, so patients must take one dose at bedtime, and set their alarm clocks to wake up and take a second dose four hours later.

The dosing apparatus also has the potential for confusion, panelists pointed out. Patients must empty a solution into a small cup and mix it with water. Several people in the study accidentally took a double dose.

A pediatrician on the panel said she was concerned that children could accidentally ingest the drug, even though the dosing devices are "childproof." Patients might prepare their second dose and set it next to their bed in order to easily take it in the middle of the night, she suggested.

Panel chairwoman Kathleen O'Neil, associate professor of pediatrics at the University of Oklahoma College of Medicine in Oklahoma City, said she worries a child might walk in and take the drug, "because mommy's out cold." (Fibromyalgia is more common in women).

Public Testimony Also Heated

GHB was sold without a prescription in health food stores until 1990 when it was classified as a controlled substance by the FDA. Despite the classification, emergency room visits for GHB increased 100-fold in the '90s. However, abuse has dramatically decreased since then said Janne Wissel, chief regulatory and compliance officer of Jazz.

A drug addiction physician who testified at the hearing disagreed. Alex Stalcup, MD, medical director of the New Leaf Treatment Center, in Lafayette, Calif., said emergency room data on dramatic decreases can't be trusted because GHB is nearly impossible to detect in a toxicology screen, and thus often isn't fingered as the cause of hospital visits.

Stalcup said he's seen a significant increase in people with GHB dependence, almost all of whom were introduced to GHB via Xyrem.
"GHB use is not down based on our stats; it just remains ignored due to testing difficulties," said Trinka Porrata, director of the drug abuse prevention organization, Project GHB. "I consider it the drug from hell having been a cop for 10 years," said Porrata, who spoke during the public comment portion of the meeting. "Approving this will create a new batch of addicts and deaths."

To counter the potential for abuse, Jazz proposed a stringent risk managment program to prevent sodium oxybate from hitting the street.

As is often the case at FDA advisory committee meetings focusing on a drug with a history of abuse, speakers at the public portion the fell into two camps: Those who focus on the potential for widespread misuse and abuse, such as Porrata and Stalcup, and those who say the drug changed their lives for the better.
In that second camp were testimonies like those of fibromyalgia patient Susan Christ, who enrolled in one of Jazz's sodium oxybate trials after a crippling lack of energy and constant pain left her unable to complete daily tasks. After taking the drug and finally being able to get restorative sleep, she said her life was changed -- finally "full and enriched."

"Sodium oxybate was closest to a cure of anything I've found," she said. "Now that the drug study is concluded, my life has began to collapse a bit."

In a statement released following the committee vote, Bruce Cozadd, chairman and CEO of Jazz expressed disappointment with the recommendation, but said the company plans "to work closely with FDA on the continuing review of our new drug application. We will carefully consider the input of the Committee as we seek to address the needs of fibromyalgia patients for new treatment options in a safe and responsible way."

The FDA is not required to follow the advice of its advisory committees, but it often does.

 

[urbantravels]

Should we give marijuana to people because it improves their well-being?

Well, 14 US states have legalized that, but of course it's probably still MORALLY REPREHENSIBLE. Egad.

"We've gone from a micro, tiny population, to something that's going to affect a huge population.

The logic here appears to be that it's ok for a drug to help a small population with a rare condition, but it's a bridge to far to help a larger population with a more common condition.

That it's OK to alleviate suffering for a small group of patients, but you shouldn't be helping TOO MANY patients - the moral justification for this escapes me.

 

[Otis]

I attended this meeting Friday and it was both fascinating and frustrating to witness, especially the discussion period where the panel asked questions and provided commentary. The un-founded fear that making this available would cause epidemic GHB abuse was ridiculous.

I recorded most of the public comment - you can listen to it here. It includes NFA president, Lynne Matallana, Neurologist Dr. Victor Rosenfeld, researcher Dr. Muhammad B. Yunus, and many people who have been successfully treated by sodium oxybate for fibromyalgia - their stories were compelling.

http://littlebirdexpress.tumblr.com/post/987729377/public-comment-audio-for-fda-advisory-meeting-sodium

I can post my "review" of the meeting if anyone is interested.

First off, thanks for your posts. I'm impressed that Dr. Yunis was there. He wrote the first paper linking deep sleep deprivation with fibro-like pain in 1975.

I would very much like to see you review of the meeting.

Thanks again lucysun.
Otis

 

[lucysun]

First off, thanks for your posts. I'm impressed that Dr. Yunis was there. He wrote the first paper linking deep sleep deprivation with fibro-like pain in 1975.

I would very much like to see you review of the meeting.

Thanks again lucysun.
Otis

I will post my writeup. I also was impressed to see Dr. Yunus - I recall seeing him speak in the late 90's years ago about FM - he was one of the first to suggest the concept of central sensitivity syndromes, I think. I actually tried to meet him after the meeting just to thank him for being there and for all of the great work he has done for so many years - but he was on his phone in the lobby and I didn't get the opportunity. Given his long career studying fibromyalgia (his first article in Pubmed dates 1981), and his current clinical expererience using sodium oxybate, I feel his presence and testimony carry a lot of weight in support of this treatment.

 

[zoe.a.m.]

Surprised to hear this since the Director of the Swedish Hospital sleep clinic offered this to me almost 10 years ago... I agree, I've never seen anything as complicated and controlled as Xyrem in terms of pharmaceuticals.

 

[heapsreal]

so now if a legit fibro/cfs person needs help he has to go to snoop the drug deeler hanging out on the corner. dont they realise it just pushes these drugs underground, where theres a demand someone will be their to make money off it.

 

[lucysun]

so now if a legit fibro/cfs person needs help he has to go to snoop the drug deeler hanging out on the corner. dont they realise it just pushes these drugs underground, where theres a demand someone will be their to make money off it.

No - it really is not necessary to go underground to get it. It is now available as Xyrem and apparently being used by many FM patients now. If you can get a doctor to prescribe it and insurance to pay for it you should be good to go. The insurance is what may give people grief, as I think some insurance companies may not cover if not prescribed for the current FDA approved use for narcolepsy/cataplexy. So the cost will be the issue for FM patients if their insurance doesn't cover off-label use of Xyrem.

 

[heapsreal]

are there any aussies with any knowledge of xyrem ie is it available in australia, price etc and its indication here as well.

cheers!!!

 

[LaurelW]

Aye, and there's the rub. I've been trying to get it for several months. My insurance rejected my claim as off-label, so I appealed, then they approved it--but they said more than a months' worth would put me in the doughnut hole. Argggggh. It costs $831 a month retail.

 

[muffin]

I would never want any med that helps people feel or get better damaged by the FDA or others. That does include medical marijuana which I know does help many FM and other major pain disorders get the pain levels down. But, I have heard that Xyrem has some major problems like psychosis and stops working or creates odd side-effects. A guy on another forum was on it and for the first few weeks it did help get him deep sleep but after that it was creating some very serious issues and he came off of it quickly.

I too asked my doctor for this med and he said NO!

 

[August59]

I'm on my 3rd time of taking Xyrem. The first time it was prescribed by my sleep doctor and the diagnosis was EDS - Excessive Daytime Sleepiness. The second time was by my CFS doctor and the diagnosis was fibro/cfs and now my third time is by my neurologist and the diagnosis is narcolepsy, based Multiple Sleep Latency Test - MSLT which confirmed narcolepsy clinicaly. However, my neurologist doesn't feel that it is narcolepsy in it's true form. She believes that it is caused by my CFS. There was a study recently that confirmed "Narcoleptic sleep patterns in people with chronic fatigue syndrome" and it was posted on PR.
Not sure if this is the study or not: http://www.biomedcentral.com/1471-2377/4/6
So, you can see that it can be prescribed if your doctor will do it. The first time I took it w/ BCBS it was only $30/month, second time w/ Cigna at $100/month (didn't last long) and now I'm getting it through Patient Assistance Program, but if someone has to pay for it the price is $1800/month (ridiculous)

I've never had any problem stopping it, although I had ambien to fall back to for sleep. As for a child accidentlly taking it, is absurded because the sodium content makes it terrible to taste and I actually stopped it the first time because of this due to the sodium caused swelling in my calves and caused my vertigo to kick in, which is not fun at all. My biggest surprize while taking Xyrem was when my daughter woke me one night about 2 hours after I took my first dose because she was having a migraine and I had to take her to the emergency room. I geuss because of the instinct of taking care of my daughter or whatever, but I had no problem awaking and I drove to the emergency clinic without the least bit of a problem.

As far it it being used for the date rape drug, that is why they made it with sodium so that it could not be used as the date rape drug. The amount that would be required to render someone helpless is a lot higher than what is prescribed and therefore it could not even be put in a "Salty Dog" without alarming someone.

The biggest abusers of Xyrem/GHB right now are bodybuilders/athletes because again in higher doses they use it to boost Growth Hormone and it works very good for that

Debunk FDA points:
A child is not going to drink this stuff
If someone goes to the emergency room and has over dosed. Check their sodium levels as I'm sure it will be sky high.
Street junkies are not the GHB addicts.
Xyrem is by far the most controlled substance in the US, by far

I sure hope in some way that the ones with Fibro (or CFS) that has a positive response to Xyrem can find a way to get it (legally).

P.S. - They will probably approve Cymbalta for the use in "Chronic Pain". I know it has been submitted, but not sure what the outcome was or will be.

 

[heapsreal]

but like every med, theres side effects and not everyone gets them. I would like to get some more feedback from others who have personally used xyrem and also helped with cfs and not just fibro pain.

cheers!!!

 

[Snow Leopard]

Let's deny millions of sick and disabled people a treatment because we don't want the general population to abuse it. What a bunch of dipshits.

Agreed.

This is what happens when we call for strong government regulation on drugs....