Asthma Drugs Too Dangerous For Kids: FDA
7 CommentsBy Ed Silverman // December 5th, 2008 // 5:24 pm
In an advance of an advisory committee meeting next week, FDA staffers are recommending approval be withdrawn for several asthma meds known as long-acting beta agonists, or LABAs, for children younger than 18 years old, due to an increased risk of asthma-related deaths and attacks (back story here and here on FDA concerns and requests for more data).
The drugs include Glaxo’s Advair and Serevent, AstraZeneca’s Symbicort and Novartis’ Foradil, which Schering-Plough markets in the US. The FDA staffers, in fact, also urge yanking approval of Serevent and Foradil for asthma in people of all ages and question whether LABAs should still be approved for treating ashtma (these are the FDA briefing materials). Serevent and Foradil contain LABAs only, while Advair and Symbicort combine LABAs with an inhaled steroid.
An FDA meta-analysis of 110 trials involving 60,954 patients found the risk “was not apparent” in Advair or when a LABA was used with a steroid, according to agency documents. Kids between 4 and 11 years old appear to be at greatest risk, African Americans had elevated risks relative to other races and women had elevated risks compared with men. Advair, by the way, is Glaxo’s best-selling drug.
In a memo, Badrul Chowdhury, who heads the pulmonary and allergy drug division, wrote a “serious and significant safety risk” exists, but asthma-related deaths were “numerically small” and benefits were “not trivial…Removal of inhaled LABAs from the market as a treatment for asthma is a way of managing the risk of these drugs, but would be an extreme approach that could be problematic.”
The FDA’s latest analysis found 2.8 more serious asthma events for every 1,000 asthma patients treated with a LABA. Chowdury questioned whether using steroids removes the risk with LABAs, noting there was no data on that point from prospectively designed and controlled studies.
Deutsche Bank analyst Brian Bourdot wrote in a research note that the FDA position is “no worse than expected” and the consequences for Glaxo “would appear to be limited” since most use is in adults. The drugmakers wrote Reuters that their meds, which are also approved for treating chronic obstructive pulmonary disease, have safe and effective track records.
Here are the briefing materials filed by Glaxo, Novartis and AstraZeneca.
Condor
That keen science-of-chemistry-mind, “Salmon”, had some very interesting observations on all of this, and African-American genetic factors, in the comment box, at my blog, earlier today:
http://shearlingsplowed.blogspot.com/2008/12/fda-scherings-long-acting-beta-agonist.html
Well worth the read. Provocative, and enlightened.
Salmon sees meta-structures, chemical, and collusive — where others see. . . . only coincidences. On balance, I think he may be right.
Salmon
I made a big mistake in my initial shoot from the hip comment at Shearlings got Plowed. The corrected comment follows.
But do read the rest it’s still of interest for antipsychotics and antinflammatory effect of Statins.
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.
Salmon
Justice in Michigan
This question for anyone who knows:
We commonly hear the claim (it was in today’s NYT) that when a LABA is combined with a steroid, as in Advair, the risk of AE’s significantly reduces.
Does the science support this claim? Can anyone refer me to relevant and reliable studies? Does whatever differential risk vary across age group? And how does dose impact? (e.g., does the lowest dose Advair, 100/50 differ in AEs from salmeterol alone?)
Thank you.
Ed Silverman
Hi Justice,
The reference to a reduced risk when combining Advair with a steroid comes from the FDA briefing materials. There’s a lot there and I confess I haven’t read all 460 pages, but if you click on the link I provided in the post, you may find something to help you.
Best
ed
LILLI
The news media does not tell all the information.
Based on their findings, the FDA proposed a number of changes to the Advair Diskus product label, stating that although LABAs decrease the number of asthma episodes, the medications may increase the severity of those episodes, which can potentially cause death. Additional documented side effects from the Advair Diskus asthma medication include:
Severe asthma episodes, potentially resulting in death
Immune system effect and a higher chance for infections
Lower bone mineral density
Glaucoma and cataracts
Slowed growth in children
Increased blood pressure
Difficulty speaking
Fast and irregular heartbeat
Allergic reactions including rash, hives and swelling of the face, mouth and tongue
Headache
Tremors
Nervousness
Justice in Michigan
Thanks, Ed! I will have to dig.
Re: AE’s in general, many on LILLI’s list are “standard” for steroids, along with some that our LABA specific.
We hear versions of some of them on Advair DTC ads. Personally, I find the ads’ reference to “certain eye probelms” - rather than explicitly naming cataracts and glaucoma - to head toward misleading, if not actually false. But DDMAC presumably approved it, so who I am I to say….
Justice in Michigan
….given that thinking about such things is preemptedd once FDA has made a determination.
I apologize.