Friday, December 5, 2008

FDA: Schering's Long-Acting Beta-Agonist, Foradil, to be "Pulled" from Pediatric Shelves?

The Wall Street Journal is suggesting that FDA has grown more concerned about the class of long acting asthma drugs -- especially when used by children. This class of drugs -- now under very-close FDA review (see the prodigious 460-page, 6.35 MB FDA Briefing PDF File on this matter) -- is called "long-acting beta-agonists", or LABAs. FDA has seen significant post-market-approval evidence that LABAs may actually increase a patient's risk of asthma-related death -- especially African-American children. Apparently the already-existing "black box" warnings on the products may not be enough. Nor, it seems, should they be. My bet is that these will no longer be approved for use in children under the age of 12.

Here's a snippet from the Journal's story -- but do go read it all:

. . . .The analysis was prepared for an [FDA] advisory committee meeting next week to discuss the safety of the drugs as a class. The panel will be asked to vote on whether the drugs should continue to be marketed for children and adults.

The FDA's new analysis of data submitted by manufacturers said there was a higher risk of asthma-related side effects among children ages 4 to 11 and among African-Americans. . . .

Overall, the agency said its analysis showed "that LABAs were associated with an increased risk of asthma-related events relative to non-LABA treatment as measured by the asthma composite endpoint consisting of asthma-related death, asthma-related intubation and asthma-related hospitalizations."

Looking at specific drugs, the FDA said the risk was seen with Foradil, Serevent and Symbicort "but was not apparent in Advair." [Editor's Note: GlaxoSmithKline makes Advair.] The agency also said the increased risk was not apparent when patients were also using inhaled corticosteroids, which current asthma treatment guidelines recommend.

The analysis involved 110 trials and 60,954 patients. The bulk of the patients were from Serevent trials, with about 43,000 patients, the agency said.

The agency said there were 20 asthma-related deaths in the studies and of those, 16 were patients on Serevent and four were patients in the non-LABA group. . . .


Anonymous said...

Interesting. African Americans you say. Well African Americans have a tend to produce CYP3A5 to a greater extent than Caucasians, which is genetically mediated. CYP3A5 is closely related to CYP3A4. Now in a recent posting of mine at Pharmalot

I pointed out how Pfizer (right after they dropped a son of zyprexa compound) reported that drugs that are N-Demethylated and hydroxylated and are metab by MAO (and likely by COMT like beta blockers) tend to be agonists at 5HT2B receptors which is what causes Phen-Fen's cardiac toxicity.

Now Zyprexa is N-Demethylated and hydroxylated at the 7 position and Lilly really avoided studying this. In fact they gave piddily doses of carbamazepine which induces CYP3A4 and CYP3A5 and structurally I would expect that that the 7-hydroxylation is mediated by CYP3A4 and 3A5. But Lilly DID NOT study combined use of carbamazepine and Zyprexa in bipolar even though this usage would be common. (I wonder why? Plus why did they give a piddily dose in drug interaction studies.)

Now if I were a betting man I would say that Foradil is metab by CYP3A4 and 3A5 and this metabolite is producing the cardiac toxicities in African Americans and in anyone else in whom CYP3A4 or 3A5 induced.

Now not only might AA kids be more at risk with Foradil but they might also be more at risk of dying due to cardiac toxicity due to Zyprexa AND structurally related drugs. Now considering all the screening for bipolar and the use of antipsychotics especially among the poor, kids in foster care, and the higher incidence of depression in the AA community due to economic stress and the secondary stress this puts on the kids you might expect a much higher death rate to due to use of antipsychotics in AA kids also.

Now none of this is new info so if SP knew of this mechanism they should have known of it years ago (or apparently at least as soon as they bought Organon since apparently Pfizer looked into this very issue with asenapine). If so, why did SP wait so long? Shouldn't they have put a warning in the labeling?

I sure wonder what will come out on discovery.


Anonymous said...

Oh even though these were "asthma" deaths the Phen-Fen cardiac toxicities also causes the pulmonary artery to clamp down resulting in decreased blood flow to the lungs and the ability to oxygenate blood. So if you're already having trouble getting the air down there you sure don't want to compound the problem by diminishing the ability of the body to get the blood to the lungs to pick up the little oxygen that is available.


Condor said...

Fascinating, Salmon -- as ever, thanks!

Keep on stoppin' by to offer these generally-under-appreciated perspectives -- and, go have a great weekend!


Anonymous said...

Additional thought.

Now if this does turn out to be the case. This might qualify for comarketing of drug - device (genetic testing) under the FDAAA 2007 and would allow the drug back on the market but with everyone also having to get tested (another income stream), and they would possibly avoid liability since they pulled the drug ASAP (when there was real clinical data) but years after when they probably suspected there was a problem based on basic science.


Anonymous said...

For those interested:

Joint Meeting of the Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee and Pediatric Advisory Committee
DATE AND TIME: December 10-11, 8:00 a.m.
LOCATION: Hilton Washington DC/ Rockville, MD, Plaza Ballrooms, 1750 Rockville Pike, Rockville, MD
CONTACT: Kristine T. Khuc, Pharm.D., R.Ph., The Committees will discuss the benefit risk assessment of long acting beta-2 adrenergic agonists for the treatment of asthma in adults and children. More Information

Anonymous said...


I think I got it wrong about the LABAs. Sorry I was shooting from the hip and was just so excited about finding that stuff from Pfizer. (I still think I'm right as to the antipsychotics and some other drugs, now back to the LABAs).

The text said it was mainly Serevent (GSK) that caused problems, and yes Servent is metabolized by 3A4 to an inactive alpha Hydroxy but the structure is not right for 5HT receptor activity.

As for Serevent when you add a 3A4 inhibitor bioavailability goes up 16 fold which means that 94% is metabolized by 3A4. So at least for Serevent it's likely that it's loss of activity that's likely the cause.

Now Foradil's second primary pathway is also hydroxylation which is mediated by several CYPs but primarily 2D6 and Ethiopians have a 17% incidence of being extensive metabolizers of CYP2D6.

Now I don't know why SP would pull Foradil.

But I may have some insight on this AC meeting. These LABAs already have black box warnings about these risksm and right now FDA and Pharma is pushing pharmacogenetics and drug device testing. In fact they got language put in the FDAAA 2007 to require it for kids when there's new info. So somebody is likely to make a lot of money off of testing everybody on Serevent, and Serevent is such a perfect case to use to push this and also establish a thought in the minds of physicians for the future.

Now Glaxo has been looking to market drugs and genetic tests together since the late 1980's or early '90's but there has been some issues, e.g. finding genes, industrialization (developing chips to do testing on a mass scale), patent issues. Plus they had to wait until FDA came up with the 'criteria' for approval of these tests and this is also one of the areas where industry has been complaining that FDA science isn't up to speed and will slow up approvals (of genetic tests) if they don't get new people etc.

Well back to GSK back in the mid 90's they helped finance Human Genome Sciences then later they bought Smith Kline. One of the main reasons they bought Smith Kline is because they own Smith Kline Beecham which picks up blood samples from physician offices and runs lab tests. This way GSK will be running the pharmacogenetic tests that this will require, 40,000 x $100 = $40,000,000 on Serevent alone. Plus I don't know who makes the chips but Glaxo has been in codevelopment agreements with Roche and remember SP has SPRI and remember who recently got a big raise.

Now one of the questions people should ask is if this was so obvious about 3A4 and AAs just knowing general info, why wasn't it simply put in the label before then physicians might know to avoid this specific drug in AAs. The only reason I can see is because GSK didn't want to hurt sales (10% drop in sales vs. paying to fight and payoff the legal fees for a couple of dozen kids who died). Plus if preemption passes they won't even have to pay that.

As an aside it was really interesting back in July 2007 right after FDA came out with an approval mechanism for genetic testing that there was test approved for colon cancer. Plus right around the same time President Bush turned over power to Cheney for 1 day so he could undergo a colonoscopy and be checked. Plus this also coincided with a PR campaign by HHS for people to be checked for colon cancer. Yes isn't it great that we have an MBA for a President.