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On September 1, 2010, a new study linked the popular weight loss drug Meridia to an increased risk of non-fatal heart attacks and stroke, although taking the drug did not seem to up the risk of death in patients with a history of heart problems, according to a recent HealthDay News report. The FDA, in January 2010 ordered a stronger warning to Meridia’s labeling, which already included warnings against using the drug in patients with numerous cardiovascular ailments

According to the authors of the trial, which was funded by Meridia’s maker, Abbott, the findings are generally in line with what has been known about the drug and shouldn’t change how it is used.

“The only time you’ve got an increase in heart attacks or strokes were in those patients who had had previous heart disease or strokes, in other words, the people who should never have received the drug in the first place,” said Dr. Philip T. James, a professor at the London School of Hygiene and Tropical Medicine in England, and first author on the paper, which appears in the Sept. 2 issue of the New England Journal of Medicine.

Since January, Meridia (sibutramine) has carried a label warning that it should not be used by people with preexisting heart disease, so “the current prescription is entirely appropriate,” James said.

However, not everyone agrees. The FDA is slated to meet in September to decide if more regulatory action perhaps a tougher “black-box” warning or even removing Meridia from the market should be taken.

According to Dr. Greg Curfman, executive editor of the NEJM and co-author of an accompanying editorial, the FDA’s January warning was based on preliminary information only. The new study results represent the first hard data, “the first outcomes trial,” he said.

Based on the findings, he and others wonder if the drug is worth keeping around.

The drug did not seem to make people healthier, Curfman said. “Some people were actually made worse,” he said. “All this taken together results in an unfavorable risk-benefit profile and, based on that, we don’t see a rationale for keeping this on the market.”

Also, he said, “the efficacy of producing weight loss with the drug is very unimpressive. In this trial, patients lost on average less than 4 kilograms [about 9 pounds] and we know that that’s not going to translate into a real health benefit over time. It’s not enough weight loss. The FDA has a benchmark of about 5 percent loss of baseline body weight to consider a weight loss drug [effective].”

A University of Rochester expert concurs.

“I have never really found that people taking Meridia had obtained a real substantive weight loss,” said Dr. J. Chad Teeters, assistant professor of clinical medicine, cardiology division at the University of Rochester Medical Center. “It seems that a lot of these ‘quick fix’ weight loss drugs don’t really live up to the hype and they come with risks. I think there’s probably going to be a significant downturn in the use of the drug given the low efficacy and increased risk of side effects.”

This trial involved almost 11,000 older overweight or obese adults with type 2 diabetes or heart disease or both who were randomized either to take Meridia or a placebo and followed for about 3.4 years.

In the group taking Meridia, 11.4 percent had a heart attack, stroke or died as the result of a heart problem, versus 10 percent in the control group, a 16 percent increase.

People taking Meridia also had a 28 percent higher risk for nonfatal heart attack and a 36 percent raised risk for nonfatal stroke, compared to those taking placebo, the authors found.

All trial participants were also engaged in a diet-and-exercise program to lose weight, whether they were taking the drug or not, said study author James. “Meridia is not a wonder drug that guarantees people lose weight but it is a major additional help for people who change their diet and increase their physical activity,” he said.

But Teeters narrowed the prescription. “Good old-fashioned diet and exercise is the only substantive sustained therapy that’s shown to be helpful,” he said. “There’s no quick-fix pill.”

On June 6, 2007, the FDA announced that it would require a black box warning on the label of Avandia about the risk of heart attack and other cardiovascular problems. Avandia, manufactured by GlaxoSmithKline was given FDA approval in 1999. On June 28, 2010, two newly released studies reported serious heart risks with Avandia, according to an Associated Press news report.

On July 9, 2010, a medical reviewer for the FDA announced that drug maker GlaxoSmithKline misinterpreted crucial details of a study finding that Avandia, its blockbuster diabetes drug, is safe, according to a recent New York Times news story.

On August 19, 2010, federal drug regulators ordered GlaxoSmithKline to send a letter to key doctors describing a July expert advisory panel that discussed the risks of Avandia, the company’s controversial diabetes medicine. But the company’s letter is misleading and could endanger patients, a federal official and some members of the panel said. (Text of the letter.)

The dispute comes as the FDA is expected in the coming weeks to announce either new warnings for Avandia’s label, a program to restrict its sales or the drug’s complete withdrawal from the market.

Doctors who received the letter are investigators in a study called the Tide trial, which is intended to compare the heart risks of Avandia with a similar drug made by Takeda, Actos. The ethics of the Tide trial were a point of contention during the advisory committee hearing, and the F.D.A. ordered GlaxoSmithKline to stop recruiting new patients into the study, although patients already in the study could continue.

Dr. David Graham, an F.D.A. medical officer, gave an impassioned presentation at the advisory meeting arguing that the study should be stopped because patients in the trial are being exploited. None of
these arguments were referenced or described in GlaxoSmithKline’s letter.

“This summary is biased, misleading and not truthful,” Dr. Graham said in an interview. “The whole purpose of this letter is so that they can reassess whether this is an ethical trial going forward, but the step-by-step ethical flaws and problems with the Tide trial are not even referenced.”

Several members of the advisory committee complained that the company’s letter was biased. “This letter is really deceptive,” said Dr. Clifford Rosen, a panel member. Dr. Rosen said that the letter made no reference to a presentation by members of an Institute of Medicine study panel about the usefulness of observational studies.

Dr. Curt D. Furberg, a panel member, described the company’s letter as “very Avandia friendly” that ignored much of the discussion criticizing the validity of the company’s studies. Other panel members expressed similar reservations but Dr. Sanjay Kaul, a panel member, disagreed and said the company’s letter “faithfully reflects the deliberations of the Avandia advisory meeting.”

Erica Jefferson, an F.D.A. spokeswoman, said that after ordering GlaxoSmithKline to send a meeting summary to the Tide investigators, the agency relied on the company to provide a balanced account.

“F.D.A. did not pre-clear or approve the content,” she said. Mary Anne Rhyne, a GlaxoSmithKline spokeswoman, said that the company had only one week to write the summary, which was necessarily brief.

But the company and the leader of the Tide trial agreed that the letter “reflected the science and data discussed at the advisory committee meeting,” she said.

Dr. Steven Nissen, a Cleveland Clinic cardiologist who made a presentation before the committee arguing for Avandia’s withdrawal, said that GlaxoSmithKline’s letter failed to mention that the committee concluded that Avandia carries a higher risk of heart attack than Actos.

“Since the Tide trial compares these two alternative therapies, this omission does not meet any reasonable ethical standards,” Dr. Nissen said.

The dispute is part of a continuing battle over what the committee actually decided in July. The committee’s most important vote was whether Avandia should remain on the market and, if so, how. Five different options were offered. Three panel members voted for no change; 7 voted to add more warnings to the drug’s label; 10 voted to severely restrict the drug’s marketing; and 12 voted that the drug should be withdrawn. One abstained.

Some commentators emphasized that a majority of the panel voted to keep the drug on the market. Others noted that a majority voted to withdraw or severely restrict the drug’s sales. The former group interpreted the meeting as largely positive for GlaxoSmithKline; the latter said it was a blow.

This argument has now spilled into a dispute about a letter attempting to explain the committee’s discussion. If the drug is withdrawn, this latest dispute will disappear since the Tide trial itself would likely end.

Data from new research discovered that teens from around the world who regularly take acetaminophen, best known as Tylenol, were more than twice as likely to have asthma as teens compared to those who never used the over-the-counter pain and fever reducer, according to a recent HealthDay News report.

Teens from around the world who regularly take acetaminophen, best known as Tylenol, were more than twice as likely to have asthma as teens who never take the over-the-counter pain and fever reducer, new research finds. Taking acetaminophen was also linked to an increased chance of eczema and rhinoconjunctivitis, or allergic nasal congestion, in adolescents.

Because the study was epidemiological meaning researchers asked teens to report after-the-fact how often they took acetaminophen researchers said they can’t prove that acetaminophen helps cause asthma. But the study is one of several in recent years that has linked acetaminophen usage during pregnancy or childhood to an increased risk of developing asthma.

“We cannot assume causation, but the association was found in widely different communities, with widely different patterns of illness and lifestyles,” said study author Dr. Richard Beasley, a professor of medicine at the Medical Research Institute of New Zealand. “When you put it together with all of the other studies, clearly there is [cause for concern].”

Nearly 323,000 children between the ages of 13 and 14 who were participating in the International Study of Asthma and Allergies in Childhood answered questionnaires about their use of acetaminophen and history of wheezing, nasal congestion and recurrent, itchy rashes.

“Medium” users of acetaminophen were those who had taken the drug at least once during the prior year; “high” users were those who reported taking acetaminophen at least once a month for the past year.

The risk of having asthma was nearly 2.5 times higher among frequent users, and 43 percent higher among medium users than those who never took acetaminophen.

Frequent users of acetaminophen were also more than twice as likely to have rhinoconjunctivitis as kids who never took the drug, while medium users had a 38 percent greater risk. For eczema, frequent users had a 99 percent increased risk, while medium users had a 31 percent increased risk.

The study also found an association with frequency of use and severity of asthma symptoms. Frequent users of acetaminophen were 2.75 times as likely to say their wheezing was so bad it disturbed their sleep and limited their ability to speak, Beasley said.

The study will be published Aug. 13 on the American Thoracic Society’s Web site and will later appear in the American Journal of Respiratory and Critical Care Medicine.

Marc Boston, a spokesman for McNeil Consumer HealthCare, which makes Tylenol, said in a statement that “there are no prospective, randomized controlled studies that show a causal link between acetaminophen and asthma.”

He also noted that “the authors of this [new] study also published data in the September 2008 edition of The Lancet. In the press release that accompanied that data, they stated that, ‘international asthma guidelines recommend that for both children and adults with asthma, [acetaminophen] is the preferred drug to relieve pain or fever.’”

A second study in the American Journal of Respiratory and Critical Care Medicine, conducted among children in Ethiopia, also found a link between acetaminophen use and asthma, but not eczema.

Researchers followed some 1,065 women during pregnancy and for three years after their children were born. Between ages 1 and 3, about 7.7 percent of children had experienced wheezing.

Children who had taken one to three tablets of acetaminophen in the past month were 88 percent more likely to have asthma, while children who had taken four tablets were more than seven times more likely to have asthma.

“These two studies further contribute to what appears to be mounting evidence of an association between acetaminophen and asthma and potentially other allergic diseases,” said Matthew Perzanowski, an associate professor of environmental health sciences at Columbia University’s Mailman School of Public Health.

So what should parents do?

Experts said a link between ibuprofen, another over-the-counter pain and fever reducer, and asthma has not been reported. Yet experts continue to recommend acetaminophen for asthmatic children, Beasley said, because in some asthmatics, ibuprofen may bring on or worsen asthma symptoms.

“Acetaminophen is still the preferred drug for children to take who have asthma. Its safety profile is better than ibuprofen, and our findings don’t change that,” Beasley said.

Yet limiting the use of acetaminophen is probably a wise idea, said Dr. Andy Nish, an allergist at the Allergy and Asthma Care Center in Gainesville, Ga.

“My personal opinion is it would be reasonable, particularly in families that had the tendency toward allergic diseases such as asthma, hay fever and eczema, to use acetaminophen judiciously, and perhaps consider the use of an alternative,” Nish said.

Young children should not be given aspirin, he noted.

Researchers believe acetaminophen may impact the development of asthma by altering the body’s immune response. Previous studies have suggested that acetaminophen may lower levels of glutathione in the lungs, which is involved in detoxifying the body, Perzanowski said. Other research has found that children with asthma have lower levels of glutathione in the lungs than those without asthma.

Asthma rates have been climbing in developed nations over the last 30 years, leading researchers to wonder what about the modern Western world could be contributing. Previous research found using acetaminophen during the first year of life increased the chances of having asthma at age 6 or 7.

Beasley, Perzanowski and other experts said the next step is conducting a randomized, controlled trial the gold standard of medical studies to see if acetaminophen really is the cause.

But there remain other possible explanations for the asthma-acetaminophen link. Children who have asthma or who will go on to receive an asthma diagnosis may develop more colds and respiratory illnesses, or may seem to have worse colds, than other kids, Perzanowski said. Colds can cause fever, which may prompt parents to give acetaminophen.

Frequency of acetaminophen use varied among countries, with only 2 percent of children in Taiwan taking it more than once a month, while 68 percent of kids in Nigeria did.