‘Black-Box Warnings’

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Don't Read Those Black-Box Drug Label Warnings, They Will Make You Sick

by Bill Sardi

Recently by Bill Sardi: Two Doctors Challenge the FDA Over the Public's Misunderstanding of What FDA-Approved Means

     

If you are taking pills for high blood pressure, high blood sugar or high cholesterol, and you are a bit jittery when reading about all those potential side effects associated with prescription drugs, you might want to avoid reading product inserts and black-box warnings altogether. The experience is like reading a Halloween horror story and the stress just might cause release of more cholesterol from your liver and raise your blood sugar, which in turn can elevate blood pressure.

There is no better example of how the FDA punts on safety issues and uses Black Box warnings to get drug manufacturers off the hook than Avandia. Safety concerns over Avandia (rosiglitazone), an anti-diabetic drug that was approved by the Food & Drug Administration (FDA) in 1999, didn't arise until 2007. By then sales of Avandia pills exceeded $3 billion a year.

Even with all the potential side effects including premature death listed in these warning boxes, one thing the FDA does not require of drug manufacturers or of itself is to assist consumers in determining the relative risks posed from one drug to another.

The FDA approves drugs on the basis of working better than an inactive placebo pill. Does the FDA have any obligation to educate consumers that the drugs it approves may not be as safe as other drugs in its class? Obviously, the FDA does not feel the need to inform the public of comparable risks between different drugs prescribed for the same purpose.

Two drugs, Avandia (rosiglitazone) and Actos (pioglitazone) serve as an example. The composite risk for strokes, heart attacks, heart failure and death is 68% higher for Avandia (rosiglitazone) than for pioglitazone. Avandia produces a harmful outcome in 1 of every 60 users over a period of 1 year.

Do diabetic patients understand the drug they are taking has become controversial in the US and has been suspended from use in Europe? Probably not.

The FDA's decision to maintain restricted availability of Avandia runs counter to the recommendation of a senior scientist, Dr. Gerald Dal Pan, who advised the agency to pull Avandia from the market altogether. Dal Pan heads the FDA's Office of Surveillance and Epidemiology, which oversees the safety of drugs that have previously been approved.

The FDA also ordered a halt to a study that would reveal how Avandia compared to another similar drug, Actos.

Investigators outside the US have called Avandia into question because it shows "a degree of toxicity that should not have allowed it to remain on the market for so long."

The FDA is pretending to do its diligence in demanding long-term safety studies after a drug is initially approved based upon data from relatively small groups, but pharmaceutical companies are dragging their feet before they finalize follow-up safety studies. That is why it took almost 8 years to discover side mortal risks associated with Avandia.

Another example is Meridia (sibutramine). A safety trial of Meridia, a weight loss drug, was committed to in 2002, began in January 2003, completed in 2009 and published in September 2010, 3 years after the drug had been approved. It is no longer being marketed.

In an article entitled "Why The Avandia Scandal Proves Big Pharma Needs Stronger Ethical Standards" (Bioethics, Oct 2010), researchers argue that  "for-profit pharmaceutical companies have a moral obligation to warn patients of any data that indicates risks associated with their product." But Avandia's manufacturer intentionally left out some reports of adverse events when it presented data to the FDA. Some bioethicists advocate large financial penalties be imposed upon companies that may attempt to hide any negative data and if pharmaceutical companies cannot act in good conscience, they should set up bioethics committees to provide them with one. Forget the fines, the drug makers build that into the price. How about prison time?

Avandia is a synthetic drug prescribed to improve insulin resistance among patients with adult-onset diabetes. It also exhibits beneficial properties for the heart and blood vessels, though inconsistently. There are some studies showing Avandia use results in more heart attacks and heart failure. However, the data is mixed and perplexing for this drug.

Even in Canada where Avandia had been restricted researchers believe limitations don't go far enough. Health Canada issued a letter advising doctors to restrict use of this drug to those patients for whom all other treatments to control their blood sugar have failed or are not appropriate. By comparison, the European Medicine Agency yanked rosiglitazone off the market. So the burden to ensure safety has been placed upon the physician.

The US FDA's Black Box warning issued in 2007 is another weak-kneed example. Rosiglitazone (Avandia) is not the first drug in its class to be withdrawn or recalled. Troglitazone's earlier downfall casts a dark shadow over this entire class of drugs. Some investigators call the FDA's Black Box warning a farce.

A Cleveland Clinic cardiologist said: "It's taken too long to stop the use of a drug that clearly was harming people. We've got to fix this system."

Paul Thacker, who as an investigator for Senator Charles Grassley (R-Iowa) and the Senate Finance Committee, accused the manufacturer of Avandia of burying negative information and said the FDA is being too timid. "When you look at all the evidence provided by Congress to the FDA about misconduct by the drug maker, and when you look at the numerous independent studies saying that the drug is harming patients, what evidence does the FDA want to have to make a decision that a drug needs to be yanked? What evidence do you need?"

Dr. Janet Woodcock, who heads the FDA division that evaluates medicines, said "There is still considerable uncertainty of the magnitude and existence of this cardiovascular risk." But why decide in favor of the drug rather than the patients. Drugs don't get approved because they "might" work.

A statement by Avandia's manufacturer said it still has faith in its product. "The company continues to believe that Avandia is an important treatment for patients with type 2 diabetes and is now working with the FDA to implement the required actions," said its chief medical officer.

But Time magazine reporters fully described the drug manufacturer's irresponsibility here. Time magazine's report entitled: "After Avandia: Does The FDA Have A Drug Problem?" said this:

Five days before a 2007 article in the New England Journal of Medicine showed that the diabetes drug Avandia was linked to a 43% increase in heart attacks compared with other medications or placebos, a group of scientists and executives from the drug’s maker, gathered in a conference room at the offices of the Food and Drug Administration in White Oak, Md. The goal: to convince regulators that the evidence that the company’s $3 billion-a-year blockbuster drug caused heart problems was inconclusive.

What the manufacturer didn’t tell the FDA was that on May 14, 2007, two days before the White Oak meeting, the drug maker's Global Safety Board had noted that a new assessment of Avandia studies “strengthens the [cardiac-risk] signal observed in the [previous] analysis.” Or that eight days earlier, the company’s head of research and development, had sent an e-mail to its chief medical officer saying Avandia patients showed an “increased risk of ischemic event ranging from 30% to 43%!” Or that the day before the meeting, the company had produced a preliminary draft report that showed patients on Avandia had a 46% greater likelihood of heart attack than those in a control group.

Over the past two decades, as drug after drug has been recalled after winning FDA approval, it has been hard not to wonder if FDA regulators have been captured by the drug industry. FDA critics and industry monitors charge that the drug-approval process is too easy for pharmaceutical companies to game. It is in some ways an unsurprising development. The FDA serves a public insatiably hungry for new medicines. Yet the agency does not have responsibility for performing safety testing. It relies on drug companies to perform all premarket testing on drugs for safety and efficacy.

Federal studies reveal that the FDA doesn’t have a complete or accurate list of prescription drugs on the market and is missing or has incomplete information on one-third of the drug-safety and efficacy trials under way.

Modern medicine also threw tomatoes at Avandia. The New England Journal of Medicine weighed in on the controversy.

So did the British Medical Journal, which said: "It was, as one Food and Drug Administration (FDA) adviser put it, a "perfect regulatory storm" — a combination of problematic data, uncertain clinical need, politics, and poor drug company behavior."

The FDA warning had an effect, but it was not enough. While the absolute number of filled prescriptions for rosiglitazone decreased from 1.3 million monthly at the peak (in January 2007) to slightly more than 317,000 in June 2009, a lot of Americans were still taking the drug.

A law group in Canada has gone so far as to file class-action lawsuits against Health Canada and the manufacturer of Avandia for not fully informing patients they faced an increased risk for serious medical events when taking this drug.

Why do we even have an FDA? Did anyone agree with the FDA's position on Avandia? Congress? Consumer watchdogs? Doctors groups?

Underlying mechanisms

For those diabetic patients who continue to take Avandia, avoidance of side effects is another aspect of drug information that the FDA skips over.

The problem with Avandia has been in determining the underlying cause of adverse events. Some researchers in Europe believe Avandia's problem may emanate from over-dosage or decreased elimination of the drug among patients at high-risk for heart and blood vessel disease. But over-dosage is a cop-out.

The underlying mechanisms behind heart side effects associated with Avandia (rosiglitazone) use may be linked to the selection of oils in the diet. When laboratory mice were fed a corn oil diet + rosiglitazone they were found to exhibit inflammation that stimulates heart enlargement which was prevented when animals were fed the drug + fish oil.

There appears to be an increased risk for bone fractures when taking this class of drugs, and that is a dire sign.

It is possible that the drug induces loss of calcium from bone which is then deposited in arteries, stiffening them and increasing the risk for adverse events like strokes and heart attacks.

Avandia apparently promotes calcification of arteries which is countered by an herbal supplement.

Bill Sardi [send him mail] is a frequent writer on health and political topics. His health writings can be found at www.naturalhealthlibrarian.com. His latest book is Downsizing Your Body.

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