Why Were They Approved?

Are You Taking These Asthma Drugs?

Big Pharma has been accused of selling drugs that are so dangerous they cause death and drugs that cause the exact conditions they’re supposed to treat. The popular asthma drugs Symbicort, Advair Diskus, Serevent Diskus, Dulera and Foradil do both and actually warn on their labels that they cause an increased “risk of death from asthma problems.”

Big Pharma and the FDA have known for years that formoterol fumarate, found in Symbicort, Dulera and Foradil, and salmeterol, found in Advair Diskus and Serevent Diskus, can paradoxically cause asthma deaths, especially in children and African-Americans. In fact, the FDA has heightened the warnings on the labels several times and convened several hearings about the drugs’ safety and some doctors have called for their complete ban.

But the drugs, called long acting beta agonists, or LABAs, are so lucrative — Advair was the fourth best selling drug in the US last year, making almost $5 billion — they are marketed despite their estimated US death toll of 4,000 a year. That’s equal to, or even more than, the number who die from asthma itself!

LABAs, whose aggressive marketing coincided with direct-to-consumer drug advertising, are billed as add-on drugs that treat asthma in a different way than traditional steroid asthma drugs. Traditional, inhaled corticosteriods like Flovent, Pulmicort, Asmanex and Qvar treat asthma’s inflammation, while LABAs, prescribed as maintenance or “control” drugs, expand constricted airways and protect against bronchospasm.

But study after study show the “bronchoprotective” effects have a downside. They can “mask” asthma that is actually getting worse though people feel fine, and they can produce “desensitization” or “down regulation” also known as tolerance, in which the more you use them the less they work.

In fact, Salmeterol, the drug in Advair and Serevent, is considered so unsafe, a huge trial called the Salmeterol Multi-center Asthma Research Trial, or SMART was terminated in 2003 after there were 16 deaths, 44 intubations and 369 hospitalizations on LABAs, mostly in African-Americans.

At FDA hearings after SMART, Pharma doctors tried to spin the results by saying the patients had been sicker to begin with, that they were too slow to seek medical care and that their self-reports of LABA use couldn’t be trusted because patients lie. They also said (somewhat contradictorily) that LABAs don’t mask worsening asthma because patients know if they are getting worse (not that they get worse!) — and the deaths can be explained by patients’ DNA types. Whew.

LABA defenders even said the SMART results couldn’t be trusted because the trial was stopped early.

Usually, the justification for unsafe drugs like LABAs is that their benefits outweigh their risk. But at FDA hearings three years later, David Graham, MD, an FDA official, said LABA “benefits, if any, seemed to be small compared to placebo.” He also blew the whistle on the widespread Pharma myth that a decline in US asthma deaths over the last decade is due to LABAs.

“It is true that trend for reported asthma deaths has declined over time, ” he said in the hearings. “But nobody has shown that the decline has anything to do with LABA use.” Fifty percent of the decline “is due to the change in classification coding from IC-9 to ICD-10,” said Graham, known for testifying before Congress about Vioxx dangers.

While the number of asthma deaths is down, the number of asthma sufferers is growing — and no one really knows why. Some cite more pollens in the air from global warming, an excess of allergy causing plug-in air fresheners and the “hygiene theory” that we have created such a germ and dirt free environment, our immune systems can’t differentiate real threats from harmless pollens or dust.

Others cite burgeoning prescription drug use. Researchers at Henry Ford Hospital found children given antibiotics within their first six months of life were more likely to develop allergies. Data presented at the American Academy of Allergy, Asthma & Immunology suggest children whose mothers took prescription acid-blocking drugs like Nexium during pregnancy are more likely to suffer symptoms of asthma. And research in the American Journal of Respiratory and Critical Care Medicine found that Tylenol may be, “an important risk factor for the development and/or maintenance of asthma, rhinoconjunctivitis and eczema in adolescent children.” Meanwhile, a 1999 European Union report speculates about the role of sex hormones and meat additives in asthma.

To prove that LABAs are safe and effective, Pharma not only points to falling US asthma deaths rates, it points to LABAs’ inclusion in government asthma guidelines Even though Pharma doctors virtually wrote the government guidelines!

William W. Busse, MD, from the University of Wisconsin School of Medicine and Public Health, chaired the expert panel which developed the government’s 2007 National Asthma Education and Prevention Program Guidelines — even though he is financially linked to GlaxoSmithKline, Merck, Novartis, Pfizer Genentech/Novartis, Schering and five other Pharma companies according to the guidelines themselves.

No wonder federal guidelines extol the “established beneficial effects of LABA for the great majority of patients who require more therapy than low-dose ICS alone to control asthma,” and call LABAs a “preferred option” that “improves lung function, decreases symptoms [and] reduces exacerbations!” Not that we have an opinion.

Why is a Pharma doctor writing federal disease treatment guidelines? And why, on top of 10 Pharma backers, does he have “research support from the NIH” which is our tax-dollars? Aren’t enough tax dollars buying Medicare and Medicaid-reimbursed LABAs thanks to the “guidelines”?

Since SMART and more reported deaths, the FDA has continued to hold hearings and tighten warnings. Currently, warnings say LABAs should only be used when inhaled corticosteriods don’t control asthma, and for the shortest time possible and should notbe used without corticosteriods or as a “rescue” medication.

Needless to say, if LABAs have to be used in addition to inhaled corticosteriods and in addition to rescue inhalers (like Proventil HFA, ProAir HFA, Ventolin HFA) what they are actually good for is not clear — even as Pharma sells a third, possibly surplus drug. No wonder Forbes magazine calls the LABA-containing Advair, “more a miracle of marketing than of science.” Many also question whether the addition of an inhaled corticosteroid, which Symbicort, Dulera and Advair have, even makes them safer.

Of course, LABA promoters are furious about the warning that LABAs should not be used long term. “Suddenly stopping medication that is providing a protection for individuals — without good literature experience to back it up — is something we’re very concerned about,” said William Busse at an asthma conference. And when the FDA announced this year it will retest LABAs, Busse cowrote an angry letter to the New England Journal of Medicine. New trials are unnecessary he said and calling them “‘safety’ studies suggests that LABAs have some direct toxicity that causes death or leads to hospitalization.”

Some people love LABAs and claim their asthma symptoms have gone away. But the longer they use them, the more likely they are to report Advair or Symbicort “poop-out” (like “Prozac poop-out”) in which the drug stops working and they feel worse than before.

On the drug-rating web site askapatient.com, patients also report feeling “addicted” to the drugs and that their lung capacity is changing. “My lungs feel different than normal, like my lungs are feeling dried out and sticky if that is possible, all at the same time, reports one person about Symbicort. “It seems they are becoming lazy, like now they cannot miss a dose.”

“When I sucked it in, it felt like I was collapsing my lungs,” says an Advair user in Forbes. The man’s doctor told him the drug “couldn’t possibly be making him worse,” but it was.

Twenty-five patients on Advair Diskus 100/50 also report racing and irregular heart beats, palpitations and the feeling of an imminent heart attack.

LABAs are not the only asthma drugs with questionable safety and effectiveness that have become billion dollar businesses for Pharma. Singulair, a leukotriene receptor antagonist or LTRA, was the nation’s seventh most popular drug last year, according to IMS health and earned more than $4 billion.It ranks only two places below Advair. Other LTRAs are Accolate and Zyflo.

Soon after Singulair was released to the market, FDA reviewers cautioned in the New England Journal of Medicine that adult studies of the drug “may not be predictive of the response,” in children. No kidding! In Singulair’s FDA approval documents reviewers note that Singulair levels in adolescents are different from “healthy adults” and that an infant monkey, four weeks old, had to be euthanized because “infants may be more sensitive to the toxicity,” of Singulair. (“Three out of five guinea pigs also died from “severe anaphylactic responses.” If animal tests do not extrapolate to human safety, why are they done?)

Scores of human subjects in the FDA approval documents withdrew from trials because of “worsening” asthma and reviewers even write that one study, “demonstrates that it is better to leave patients on beclomethasone [a corticosteroid] than to switch them to montelukast [Singulair]. There’s an asthma drug for you!

Approval documents include 10 blanked out pages, marked “This section was determined NOT to be releasable,” and the frequent phrase, “Portions of this review were excerpted directly from the sponsor’s submission,” as in we didn’t read it but we waved it through.

William Busse, the guidelines writer, was also an investigator in the Singulair approval trials though not the most compliant one. He was issued an FDA warning letter when an inspection of his facility revealed incorrect consent forms, incorrect patient enrollments, and drug inventory and labeling errors.

Singulair was heavily marketed for allergies, in addition to asthma, and to kids. Marketing included a partnership with Olympic gold-medalist swimmer Peter Vanderkaay, a basketball “skills challenge” for kids 9 to 14 and materials distributed through (and legitimized by)American Academy of Pediatrics said published reports.

Meanwhile, more than 100 parents on askapatient were reporting that Singulair caused hyperactivity, tantrums, depression, crying, school trouble, facial tics, strange eye movements and self-harm in their children, some as young as one. Many were put on the drug for sniffles, wheezing and early “symptoms” of asthma, in keeping with Pharma’s “early treatment” push.

“Last night was a complete meltdown over every single thing that could have possibly been a minor annoyance, such as not being able to squeeze enough toothpaste out of the tube, which culminated in a 30-minute screaming and crying bonanza,” writes the mother of a 7-year-old who has been on Singulair for six months. “I was reading stories to her tonight, and she must have popped her jaw open at least 40 times over the course of two books (mouth open wide like a yawn in fast-forward). I was keeping an eye on her, and a few times I asked her why she kept doing that and she said she didn’t know, and she thought maybe her mouth was ‘itchy.’”

But in 2009, after 15-year-old Cody Miller of Queensbury, NY was given Singulair for hay fever and took his own life 17 days later, the FDA gave Singulair a warning for “neuropsychiatric” side effects. And the next year, Fox TV reported that kids on Singulair are being diagnosed with ADHD, Tourette Syndrome and serious behavioral and neurological conditions. Most are “cured” when they go off the drug. Singulair is no doubt driving other pediatric drugs sales.

Even adults are put on the drug for minor reasons with major consequences. “I was perfectly healthy prior to taking this drug,” reports a 53-year-old woman about Singulair on askapatient.”Doc noticed I had a little wheeze and prescribed Singulair. I began to have the dreams, insomnia and depression after the first few days,” which led to “suicidal thoughts,” she says.

Could there be any more clouds over today’s blockbuster asthma drugs? Yes! Clinical trials on which many of the top asthma drugs were approved were so corrupted at least one researcher went to prison. William H. Ziering, MD was sentenced to six months in prison and lost his medical license for falsification of five drug studies according to government documents.

Ziering conducted trials on Salmeterol (the LABA), Flonase and other respiratory drugs and wrote medication-friendly papers like “Allergic rhinitis. Measures to control the misery,” and “Diagnosis and treatment of allergic rhinitis and asthma in infancy and childhood.”

During the same time period, clinical trials of Singulair and at least five other top asthma drugs conducted at Vivra Asthma & Allergy also came to the attention of federal authorities. A “patient mill” was operated at the Tucson facility to pocket the lucrative compensation paid per subject for trials, says Robert Davidson, MD, a sub-investigator at the facility, regardless of the appropriateness of the subjects. People who participate in drug trials are called subjects, not patients

The irregularities at the Vivra facility led to onsite FDA inspections in which witnesses told inspectors they were told to “NOT mention potential risks” to subjects to not “scare them away,” and subjects were pressured to participate despite risks to their heath. (One subject was hospitalized from the trials.) Enrolling inappropriate subjects risks both their health and future users of the drug, whose safety was “proved” from their participation.

In one study, conducted at Vivra and elsewhere, more than 40 percent of people on Singulair and Salmeterol (the LABA in Advair) had adverse events, two withdrew with –anybody? — “worsening asthma” and “one died as a result of bronchial asthma!” The drugs were “well tolerated,” write the researchers.

There is no evidence that approval of drugs “tested” by Vivra or Ziering was delayed or revoked nor do the related published papers appear retracted.

Among drugs tested at Vivra was the antibiotic Raxar® which was withdrawn from the market for fatal heart rhythm abnormalities and the genetically engineered Xolair which was investigated by the FDA for heart attack and stroke links and carries a severe anaphylaxis warning. Seventy-seven people who took Xolair had life-threatening allergic responses in a year-and-a-half, according to FDA reports.

Genetically engineered drugs like Xolair cost as much as $20,000 a year and cause TB, cancers and super infections because they suppress the immune system. But they seem slated to be the next big thing in asthma.

A study in May says Xolair can provide, “additional clinical benefit” for patients who are “inadequately controlled” on inhaled corticosteroids. That’s exactly what was said about LABAs. The study was funded by Xolair’s manufacturer and one of the authors is William Busse.

Martha Rosenberg is a columnist/cartoonist who writes about public health. Her first book, titled Born with a Junk Food Deficiency: How Flaks, Quacks and Hacks Pimp the Public Health, has just been released by Prometheus Books. She can be reached at: martharosenberg@sbcglobal.net. Read other articles by Martha.