The group enumerated its concerns in a full petition, citing both safety and efficacy issues. Adverse events linked to Avandia and listed in the petition include liver failure, myocardial ischemia (increased risk of heart attack), congestive heart failure, macular edema (vision loss), anemia, and bone fractures.

One new analysis of the FDA’s Adverse Event Reporting System (AERS) data revealed that of 14 Avandia users who experienced kidney failure, 12 died.

“The evidence for this unique combination of toxicities is compounded by the accompanying lack of evidence of any clinical benefit, compared to other approved drugs for diabetes,” the petition states.

The petition also refers to statements released earlier by both the American Diabetes Association and the European Association for the Study of Diabetes advising against the use of Avandia given the availability of better options.

To support its claim, Public Citizen also included a graph highlighting the dwindling sales of Avandia from the first quarter of 2006 to the second quarter of 2008. 13.3 million Avandia prescriptions were written in 2006, yet only 4.6 million were written in the last year. Avandia prescriptions have declined steadily since late 2006.

“The FDA is in possession of clear, unequivocal evidence that (Avandia) causes a wide variety of toxicities,” Public Citizen said in its petition to the FDA.

Drugmaker GlaxoSmithKline issued a response to the petition on Friday, standing by Avandia.

“The safety of patients using our medicine is very important to us. On a continual basis, an external Hepatic Safety Board reviews any adverse event report received by GSK of liver failure, liver-related deaths and liver transplants for possible relationship to AVANDIA. As recently as July 2008, this panel of experts continued to endorse a favorable hepatic safety profile for AVANDIA,” the statement said.

Public Citizen is a nonprofit consumer advocacy organization representing more than 80,000 consumers in the U.S. It was founded in 1971 to “represent consumer interests to Congress, the executive branch, and the courts.”

SOURCE: Avandia Recall › Consumer watchdog urges immediate Avandia ban

The maker of the drug, GlaxoSmithKline (GSK), disputes the osteoporosis finding. The company said in a statement today that their ADOPT studies showed no increase in spine or hip fractures which are associated with osteoporosis.

The company says they will be looking further into the subject.There are other possibly safer alternative treatments for diabetes, according to Paul Brandt, an associate professor of neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine. “Anyone who is already at risk for osteoporotic fractures should consider an alternative anti-diabetic drug.”

Amanda Gardner of HealthDay News reports that Avandia affects a key cellular protein called the peroxisome proliferator-activated receptor (PPAR-gamma). The mice studies by the Salk Institute for Biological Studies in La Jolla California found that activating this receptor stimulates the production of osteoclasts. These osteoclasts degrade bone.

Avandia recently received some bad press concerning the relation of the drug with heart problems. Avandia, along with four other drugs in the same class, were given blackbox warnings by the Food and Drug Administration (FDA). These warnings are the strictest advisories offered by the FDA for products that they have approved. The drug was linked to heart failure in some patients.

SOURCE: Avandia Recall › Type 2 diabetes drug Avandia linked to osteoporosis and bone loss

For four years, the study followed patients over age 65, who have the highest rate of type 2 diabetes but aren’t well represented in clinical trials, says lead author Lorraine Lipscombe, a Toronto endocrinologist and researcher at the Institute for Clinical Evaluative Science, funded by the Ontario government.

Lipscombe’s team looked at how patients fared on Avandia or Actos, the only two drugs in their class, compared with those on other diabetes pills.

Since August, the U.S. labels for Avandia and Actos have carried a “black box” warning against their use in patients with advanced congestive heart failure. But the new study found Avandia raised heart failure risk even in patients with no history of the condition, suggesting the heart failure warning doesn’t go far enough, Lipscome’s team writes in The Journal of the American Medical Association.

About 8 percent of patients went to a hospital for congestive heart failure or a heart attack during the study. Compared with patients on other diabetes pills, those on only Avandia or Actos had a 60 percent higher risk of congestive heart failure and a 40 percent higher heart attack risk. They also had a 29 percent higher risk of death.

For reasons not yet clear, the increased heart risks seen in the Avandia/Actos group were predominantly in those on Avandia. That doesn’t mean Actos is safer, Lipscombe says. Her study might have had too few Actos patients – half the number on Avandia – to detect a higher risk, she says.

In observational studies such as this, factors other than the drugs in question might skew results, so clinical trials that randomly assign patients to treatments are considered the gold standard.

“The problems with the study become obvious with regard to the CHF (congestive heart failure) findings,” Nancy Pekarek, spokeswoman for Avandia maker Glaxo-SmithKline, said in an e-mail. “We know (Avandia and Actos) have well-documented and similar CHF events, yet this study somehow finds an increase in these events with Avandia versus Actos.”

But Steven Nissen, the Cleveland Clinic’s chief of cardiovascular surgery, says Lipscombe’s study “has a lot of appeal. It’s independent, it’s not funded by industry, and it’s huge.” And, “it’s real-life data.”

Nissen reported in The New England Journal of Medicine in May the pooled results of 42 short-term clinical trials showed Avandia patients were 43 percent more likely to have a heart attack or be hospitalized for blocked coronary arteries than others in the trials.

Based on Nissen’s study and others, the Food and Drug Administration last month added information to Avandia’s black box about a potential increased heart attack risk. The FDA has asked Glaxo to compare Avandia’s heart attack risk with those of other diabetes pills. That clinical trial is not expected to be done until March 2014.

January 8th, 2008 by RITA RUBIN with APP.com

SOURCE: Avandia Recall › Avandia study shows increased heart risks or death

Compared with other diabetes pills, Avandia’s use was associated with a 60 percent higher risk of heart failure, 40 percent higher risk of heart attack and 30 percent higher risk of death in patients 65 and older, the researchers found.

“The risks associated with these drugs may outweigh the benefits, at least for older populations,” said Dr. Lorraine L. Lipscombe, the lead author of the study and a researcher at a health research agency funded by the Ontario government.

The findings, published in the influential Journal of the American Medical Association, will probably intensify pressure on the government to restrict sales of the oral diabetes medicine.

“It should come off the market,” said Dr. Sidney M. Wolfe, director of health research at Public Citizen, a liberal interest group preparing to petition the Food and Drug Administration to pull the drug.

Sales of Avandia have plummeted since Dr. Steven Nissen, a prominent cardiologist, reported in May that it raised the risk of heart attack. His report prompted congressional hearings and demands to stop sales.

The FDA decided against that last month, instead adding a label warning that urges users to consult a doctor if they have serious heart problems.

The decision divided agency staff. Ultimately, FDA officials decided the scientific evidence wasn’t conclusive, and they asked Avandia’s manufacturer to conduct a long-term study.

In a statement, the FDA said it would review the results from the Canadian study, but it needs more evidence before taking any further action. “This new study we have just seen today does not change FDA’s recommendations,” the agency said.

GlaxoSmithKline, Avandia’s maker, dismissed the Canadians’ findings as limited and misleading because the elderly studied might have been at higher risk of heart problems.

The Philadelphia company, which is conducting a long-term study of Avandia’s side effects, said in a statement that many other studies show Avandia is safe and effective.

The new study is the first to review side effects in real patients, rather than test subjects, according to Lipscombe, a researcher at the Institute for Clinical Evaluative Sciences in Toronto.

Beginning in March, Lipscombe and her colleagues analyzed health care records for all elderly Ontario residents who took an oral diabetes medicine between 2002 and 2006.

Lipscombe said they focused on the elderly because 40 percent of diabetes patients in Ontario are 65 and older, but the elderly tend to be underrepresented in scientific drug studies.

The researchers didn’t find a higher heart risk among users of Actos, an Avandia competitor that belongs to the same class of diabetes drugs, but Lipscombe said there weren’t enough Actos users to draw a firm conclusion.

December 12th, 2007 by Jonathan D. Rockoff with baltimoresun.com

SOURCE: Avandia Recall › Avandia risks highlighted

For four years, the study followed patients over age 65, who have the highest rate of type 2 diabetes but aren’t well-represented in clinical trials, says lead author Lorraine Lipscombe, a Toronto endocrinologist and researcher at the Institute for Clinical Evaluative Science, funded by the Ontario government.

Lipscombe’s team looked at how patients fared on Avandia or Actos, the only two drugs in their class, compared with those on other diabetes pills.

Since August, the U.S. labels for Avandia and Actos have carried a “black box” warning against their use in patients with advanced congestive heart failure. However, the new study found Avandia raised heart failure risk even in patients with no history of the condition, suggesting the heart failure warning doesn’t go far enough, Lipscome’s team writes in The Journal of the American Medical Association.

About 8% of patients went to a hospital for congestive heart failure or a heart attack during the study. Compared with patients on other diabetes pills, those on only Avandia or Actos had a 60% higher risk of congestive heart failure and a 40% higher heart attack risk. They also had a 29% higher risk of death.

For reasons not yet clear, the increased heart risks seen in the Avandia/Actos group were predominantly in those on Avandia. That doesn’t mean Actos is safer, Lipscombe says. Her study might have had too few Actos patients – half the number on Avandia – to detect a higher risk, she says.

In observational studies such as this, factors other than the drugs in question might skew results, so clinical trials that randomly assign patients to treatments are considered the gold standard.

“The problems with the study become obvious with regard to the CHF (congestive heart failure) findings,” Nancy Pekarek, spokeswoman for Avandia maker Glaxo-SmithKline, said in an e-mail. “We know (Avandia and Actos) have well-documented and similar CHF events, yet this study somehow finds an increase in these events with Avandia vs. Actos.”

But Steven Nissen, the Cleveland Clinic’s chief of cardiovascular surgery, says Lipscombe’s study “has a lot of appeal. It’s independent, it’s not funded by industry, and it’s huge.” And, “it’s real-life data.”

Nissen reported in The New England Journal of Medicine in May the pooled results of 42 short-term clinical trials showed Avandia patients were 43% more likely to have a heart attack or be hospitalized for blocked coronary arteries than others in the trials.

Based on Nissen’s study and others, the Food and Drug Administration last month added information to Avandia’s black box about a potential increased heart attack risk. The FDA has asked Glaxo to compare Avandia’s heart attack risk with those of other diabetes pills. That clinical trial is not expected to be done until March 2014.

December 11th, 2007 by Rita Rubin USA TODAY with USA Today

SOURCE: Avandia Recall › New Avandia study reaffirms heart risk

Experts fear that, over the long term, Avandia (rosiglitazone) may speed osteoporosis, the thinning of the bones that can lead to dangerous and even fatal fractures.

The findings appear in the Dec. 2 online issue of Nature Medicine.
“Our study suggests that long-term rosiglitazone usage in the treatment of type II diabetes may cause osteoporosis due to both increased bone resorption and decreased bone formation,” said study senior author Ron Evans, a professor at the Salk Institute for Biological Studies in La Jolla, Calif. “Because Avandia is effective in controlling glucose and restoring the body’s sensitivity to insulin, we do not recommend that people stop their treatment. You must balance the benefits against the complications.”

“Anyone who is already at risk for osteoporotic fractures should consider an alternative anti-diabetic drug,” added Paul Brandt, an associate professor of neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine, in College Station. “There are many alternatives, ” he said.

“It may [also] be possible to blunt some of Avandia’s effects with anti-osteoporosis drugs such as bisphosphonates, raloxifene, vitamin D and calcium,” Brandt added.

Earlier this year, Avandia and four other diabetes drugs from the same class were given a “black box” warning by the U.S. Food and Drug Administration. That warning advises users of an increased risk of heart failure while on the drug.

The black box message is the FDA’s strongest label warning.

With an estimated 3.5 million or more U.S. patients taking Avandia, the public health impact from the point of view of both heart failure and bone degradation could be substantial, experts say.

Avandia affects a key cellular protein called the peroxisome proliferator-activated receptor (PPAR-gamma). In their study, the California team discovered that, in mice, activating this receptor also stimulates the production of osteoclasts, cells whose key function is to degrade bone.

Proper bone health is maintained by a balance between osteoclasts and osteoblasts, the cells that build bone up.

If either side is out of whack, so to speak, bones become thinner, more fragile and prone to fracture.

The current results are particularly disturbing in light of prior studies, the experts said.

“It was previously known that Avandia mediates bone loss by inhibiting bone formation,” Evans explained. “Our work identified an additional mechanism, in which Avandia promotes bone resorption. These are the two parts of the checks-and-balance system that maintains bone in good shape. The drug weakens both sides of the balance mechanism, leading to an increased risk for osteoporosis.”

“Previous research showed that Avandia reduced osteoblasts,” Brandt added. “Combine the two, and you’re going to get thinning of the bone.”

December 2nd, 2007 by Amanda Gardner with U.S. News

SOURCE: Avandia Recall › Diabetes drug Avandia could weaken bones

The moves by Prime Therapeutics and HealthTrans mark the latest example of U.S. healthcare providers deciding to limit access to the drug, following an earlier decision by the U.S. Department of Veterans Affairs to severely restrict use.

Such actions, particularly if followed by others, may further undermine sales of the once-popular medicine, which have been hit hard recently by a report linking it to heart attacks.

Prime and HealthTrans said in separate statements they had made their decisions after a thorough analysis of the clinical literature examining the safety and efficacy of Avandia.

“Prime takes drug safety warnings very seriously and our primary concern is the safety of our members,” said Craig Mattson, senior director of drug technology assessment and formulary development.

Britain-based Glaxo, Europe’s biggest drugmaker, said it was surprised and disappointed.

“It limits options for treatment and could be detrimental for patients. The FDA (Food and Drug Administration) has said the data remains inconclusive and therefore to limit patients’ options in this is disappointing,” a spokeswoman said.

Concerns about the safety of Avandia were triggered in May by a U.S. analysis linking it to a 43 percent higher risk of heart attack. Avandia was Glaxo’s second-biggest drug in 2006, with worldwide revenue of 1.6 billion pounds ($3.2 billion), but sales have plunged since May, with revenue in the United States down 48 percent in the third quarter from the year-ago period.

SOURCE: Avandia Recall › Two U.S. healthcare providers drop Glaxo’s Avandia

The U.S. Food and Drug Administration (FDA) advised that GlaxoSmithKline, Avandia’s maker, agreed to add the new warning to the existing black box warning. But, despite the revision, the FDA will not withdraw Avandia from the market, claiming that evidence for increased heart attack is inconclusive and does not appear to be higher in Avandia than other type 2 diabetes treatments. In the meantime, the FDA asked GlaxoSmithKline to conduct a long-term study comparing Avandia with other type 2 diabetes drugs. The trial will likely commence in a year; however, full results will not be available until 2014. Patient advocates and FDA critics consider the black box warning a weak response to Avandia’s safety issues and have requested Avandia be pulled from the market.

Avandia breaks down the body’s resistance to insulin but has long been known to cause fluid retention, a major risk factor for congestive heart failure. Evidence does not indicate Avandia and other oral anti-diabetes drugs-thiazolidinediones-prevent cardiovascular risk as a result of reducing blood sugar.

The American Diabetes Association and the European Association for the Study of Diabetes released a revised consensus statement stating that emerging information suggests additional hazards associated with thiazolidedione and rosiglitazone (Avandia) and may result in increased risk of myocardial infarctions. In October, the US Department of Veterans Affairs (VA) announced it was dropping Avandia from its prescription drug formulary stating their review concluded that, in some, Avandia did not afford the same margin of safety as other diabetes medications. The VA accounted for nearly 10-percent of Avandia’s US sales.

In November, Health Canada sent a letter to Canadian health professionals advising Avandia could no longer be prescribed as monotherapy for type 2 diabetes or in combination with sulfonylurea. In May, research based on 42 Avandia studies confirmed a 43-percent increased risk of heart attack among patients taking the drug. In August, Avandia’s warning label was changed to warn that Avandia and others in its class might worsen heart failure.

A Congressional Committee Report found that company executives made a concerted effort to intimidate a diabetes expert into keeping quiet about Avandia’s safety problems, alleging that Glaxo Chief Executive Jean-Pierre Garnier and former research chief Tachi Yamada were involved. An internal government memo dated July 16, 2002 analyzed 47 early FDA reports of patients who went into heart failure and required hospitalization while taking Avandia. The report contained warnings from Federal investigators that Avandia might cause heart failure.

Over six million Americans have used the drug to treat adult-onset, or type 2, diabetes and the concern about Avandia is nothing new. The association between Avandia and increased heart failure risk has been known since 1999 when the drug was first approved.

Avandia was Glaxo’s second most popular drug in 2006, with sales of $3.3 billion. Sales have plummeted since publication of evidence linking Avandia with increased risk of heart attack and failure.

November 29th, 2007 by Staff with NewsInferno.com

SOURCE: Avandia Recall › Avandia heart attack controversy results in black box warning

Methods We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes.

Results Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06).

Conclusions Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.

June 14th, 2007 by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. with The New England Journal of Medicine

SOURCE: Avandia Recall › Avandia on the risk of heart attack and death from cardiovascular causes

In a floor statement placed in the Senate record, Sen. Charles Grassley also said that safety watchdogs within the federal Food and Drug Administration “several months ago” recommended a “black box” on the drug’s label, the strongest possible warning.It is the first confirmation that the FDA’s own analysis of Avandia shows a similar magnitude of heart attack risks, dangers that were first publicly raised in a medical journal report published earlier this week.

Grassley complained that FDA higher-ups have said they want to wait for results of an ongoing study that will not be available for two more years before making a decision.

“That’s a long time from now when you have millions of Americans taking this drug,” said the statement by the Iowa Republican. “Those numbers seem like a high enough threshold to me for the FDA to warn the American people of the possibility of a problem.”

The FDA has been under fire since Monday’s report came out, attacked by consumer advocates for dropping the ball on drug safety and for taking no stronger action in light of the new warning signs.

Avandia, sold by the British company GlaxoSmithKline PLC, is a blockbuster medication used to treat Type 2 diabetes, the most common form of the disease. More than 6 million people worldwide have taken the drug, whose U.S. sales topped $2.2 billion last year.

On Monday, an analysis led by Cleveland Clinic cardiology chief Dr. Steven Nissen of 42 separate studies on Avandia concluded that it raised the risk of heart attacks by 43 percent, compared to the rates among people taking no or other diabetes drugs. The analysis also indicated that Avandia might increase the risk of heart-related deaths.

GlaxoSmithKline strongly disputes the conclusions. Company officials said that while their own similar analysis suggested a 31 percent greater risk _ information it shared with the FDA as early as 2005 _ more rigorous, albeit smaller, individual studies did not show that.

Critics have accused the FDA of being lax in monitoring drug safety, and some members of Congress scheduled hearings and have subpoenaed key people to appear.

Grassley’s staff has been meeting with FDA staffers and others and gathering documents all week to investigate the issue, said Jill Kozeny, press officer for the Senate Finance Committee, of which Grassley is ranking member.

FDA spokeswoman Julie Zawisza confirmed Thursday the internal analysis that Grassley’s statement revealed, but added, “we have conflicting data” from individual studies, and therefore “are continuing to review the results of GSK’s ongoing trial to determine the actual risk.”

She said she could not discuss “ongoing regulatory matters” like the black box warning that Grassley’s statement says was urged months ago by the FDA’s Division of Drug Risk Evaluation.

As for the number of heart attacks possibly linked to the drug _ as many as 20 a day, Grassley contends _ Zawisza said: “A relationship between the drug and these deaths has not been established. We don’t have data to support such a conclusion.”

Any increase in heart attack risk is especially worrisome for diabetics because two-thirds of them die of heart problems.

About 1 million Americans are currently taking Avandia, which costs from $90 to $170 for a one-month supply. The FDA and diabetes experts are advising users of the medication to talk to their doctors and not to immediately discontinue the drug, which helps keep blood-sugar levels under control.

May 24th, 2007 by Marilynn Marchione with The Associated Press

SOURCE: Avandia Recall › FDA study said to show Avandia risk