Risks Potentially Outweigh Benefits with Avandia®

Risks Potentially Outweigh Benefits with Diabetes Drug Avandia®

Avandia®, manufactured by GlaxoSmithKline (GSK), was first approved by the FDA in 1999 for marketing on the basis of its ability to lower blood glucose and reduce insulin resistance. By 2006 the drug had become the top selling oral diabetes drug in the United States (13 million prescriptions, approximately 10, 000 daily, for Avandia(R) were filled in the U.S. in 2006).

Avandia®, or rosiglitazone, and a related drug Actos® (pioglitazone), belong to the drug class thiazolidinediones (TZDs). The first drug in this class, Rezulin® (troglitazone), was removed from the market in 2000 for causing liver failure and death.

TZDs have been prescribed alone or used with other hypoglycemic drugs to improve glycemic control in diabetic patients. Initially the long term effects of the drug, such as cardiovascular events, were unknown.

According to a story published in The New York Times, Dr. John B. Buse, a diabetes expert and early critic of Avandia®, was “intimidated” by the GSK. As early as 2000, Dr. Buse, closely associated with the American Diabetes Association, charged in a letter to the FDA that Glaxo had used “blatant selective manipulation of data” to overstate the benefits of Avandia® and understate its risks. GSK has denied Dr. Buse’s allegations.

In 2003 several groups and health professionals made an effort to alert the public to the dangerous link between Avandia® and an increased risk of congestive heart failure. In late 2006 the New England Journal of Medicine (NEJM) published a study that illustrated how serious this danger is.

In 2007 Drs. Bruce Psaty of the University of Washington and Curt Furberg of Wake Forest University, in the New England Journal of Medicine, said that “to the extent that the new analysis shows valid risks”, the drug "represents a major failure of the drug-use and drug-approval processes in the United States".

When the drug was approved, "evidence was at best mixed" on its benefit, wrote the two doctors. Both have criticized the FDA's failure to spot dangers in the general drug approval process. Other experts have expressed concern that Avandia® is another example of the FDA failing to detect safety problems early enough.

Because TZDs can cause fluid retention, Avandia® is not recommended for patients with symptomatic heart failure. So, in 2007 the FDA did request that both Avandia® and Actos® carry a stronger “black box” warning against use for people with heart failure.

Finally in late 2008, a working group composed of Public Citizen, the American Diabetes association and the European Association for the Study of Diabetes, unanimously advised against using Avandia® because of concerns about the drug's risks. They further support immediate action by the FDA to ban the drug because of risks that outweigh benefits along with death from liver failure and life-threatening cardiovascular events.

The FDA’s own Adverse Event Reporting System lists 14 cases of liver failure and 12 deaths associated with Avandia®.

Liver toxicity is a recently identified risk associated with Avandia®. It also increases the risk of Avandia heart attacks by almost 40 percent, doubles the risk of heart failure and bone fractures, and increases the risk of anemia. Visual problems and loss from macular edema, a swelling of the retina caused by fluids accumulating in the eye were increasingly reported with Avandia® (39 times more reports of macular edema per million prescriptions filled).

Dr. Robert Misbin, the FDA official who examined the data on Avandia® at the time of the drug’s approval, found a noticeable increase in the rate of a condition known as congestive heart failure (CHF) in the study participants. And the FDA reports that the drug may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy.

Dr. Stephen Nissen of the Cleveland Clinic, wrote in the New England Journal of Medicine, that Avandia® showed a disturbing trend toward increasing not only CHF, but heart attack and stroke. The data reviewed in 2007 by Nissen showed the increased risk of CHF to be about 700 percent, and about 50 percent for heart attack and stroke. Death rates increased by 64 percent.

Following on Congressional hearings into the drug’s safety in 2007, when officials asked both the FDA and GSK why Dr. Nissen’s findings were not reported sooner. As a result of these hearings and Nissen’s study, the FDA did begin its own studies, the findings of which are scheduled to be released in 2009. At the same time the agency ordered GSK to issue a public warning about the potential heart-related risks associated with Avandia®.

Associated side effects of Avandia® (rosiglitazone)

Increased weight gain
Diarrhea
Cause or worsen anemia
Increase cholesterol
Deplete chromium, a necessary nutrient for blood sugar regulation and carbohydrate metabolism
Cause water retention
Cause Congestive heart failure, pulmonary edema, pleural effusion, angina, heart attack and stroke
Cause headache and Upper respiratory infection
Cause an increase of injury, especially related with contact sports
Increase risk of hypoglycemia (low blood sugar) and metabolic acidosis when used in combination with other diabetes drugs
Decrease white blood cells
Increase the risk of anemia associated with reduced red blood cells, hemoglobin and hematocrit
Increased levels of total cholesterol, LDL, HDL, and reduced free fatty acids
Increased risk of fracture especially in women using the drug
May increase ovulation in pre-menopausal women (Avandia ® is not to be used by women who are nursing or plan to nurse their infants)
Increased risk of macular edema
May cause nutrient depletion especially when used in combination with other diabetes drugs

Since liver function problems may arise while using this drug for blood sugar control the following information should be considered: Liver enzymes should be measured prior to initiating treatment with AVANDIA®. Therapy with this drug should not be initiated if the patient exhibits clinical evidence of active liver disease or increased levels of ALT (serum transaminase greater than 2.5X the upper limit of normal at start of therapy). After initiation of AVANDIA®, liver enzymes should be monitored periodically by your healthcare professional.

Rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) detox pathway in the liver (Phase 1). The half-life of the drug may be as long as 153 hours and women show a lower ability to clear the drug.

If, while using this drug you have developed any symptom of liver (hepatic) problems, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia (loss of or no appetite) or dark colored urine, contact your health care provider immediately.

It is notable that GSK suggests that if adverse effects occur, when used in combination with other drugs, to cease competing drugs.

A number of Avandia lawsuits have been filed against the manufacturer of Avandia over failure to warn consumers of Avandia side effects .

Should you have questions about using Avandia®, or related medical concerns, contact your health care provider. If you have suffered an injury from taking Avandia and would like to learn about your legal rights, you can find information at www.ConsumerInjuryLawyers.com .

This article is part of a consumer health education series written by Gayle Eversole, DHom, PhD, MH, NP, ND, of Creating Health Institute, in collaboration with Bernstein Liebhard, LLP.

The views expressed in this article are solely those of the author, Gayle Eversole.

Laxative Colonoscopy Prep Products and Kidney Damage

Laxatives are one of the most commonly overused products sold to consumers, over-the-counter (OTC). These same products, and others available by prescription only, have caused serious side effects associated with kidney damage (nephropathy) and dehydration.

The products are particularly risky for the elderly and people with existing heart, kidney and some gastrointestinal problems.

Since colon cancer prevention and screening are important health concerns, consumers are encouraged to be educated about using these products.

Osmolar Phosphate Laxatives: Keeping Water in its Place

Osmolarity is a fancy word that refers to a basic rule of physics and biology and it is about how fluids - in this case it’s water – move in and out of cells based on the presence of electrolytes, most often sodium and potassium. Phosphorus and calcium are two other electrolytes that are important health and often work together.

Your body depends on a delicate balance of trace elements and enzyme reactions to keep humming like a top. When this balance is altered you run the risk of dehydration and problems with the way your kidneys work.

Simply put, when you ingest a large amount of sodium containing foods or liquids, the kidneys work to flush the excess sodium out of the body. It does this by removing fluid from inside the cells, from your tissues and organs and moves it through the kidneys or the gastrointestinal tract. This may lead to excessive urination and diarrhea. In the process you lose not only the water but your electrolyte balance is altered.

Phosphorus and calcium reactions with dehydration may lead to the formation of crystals or “stones” and reduction of kidney function.

Laxatives often become the culprit in these cases, especially for the elderly, those with heart failure, people with kidney problems, and people using prescription or over-the-counter (OTC) medication affecting kidney function (diuretics for example).

Oral Sulfur Phosphates as Preps for Screening for Colorectal Cancer

Currently colorectal cancer is the third most common cancer and it is the second leading cause of cancer related deaths, therefore screening and early detection have become an important public health issue.

Thorough bowel cleansing is an important part of preparation for this screening and it is crucial to find a product that is safe and easy use. The difficulty in getting more people to seek the screening may be increased because of concerns with the products.

One very popular laxative has been Fleet’s Phospho-Soda. The C.B. Fleet Co. of Lynchburg, VA recently, in a voluntary action, withdrew its oral, over-the-counter Fleet Phospho-Soda bowel cleansing solutions after FDA regulators warned of potential harm to the kidneys when the Phospho-Soda is used as a bowel cleanser.

While the FDA has not required a recall, Fleet also removed the EZ-Prep Bowel Cleansing System used to clear the bowels before a colonoscopy.

Information found urges anyone using Phospho-soda to review current FDA product information pages. They also state that it is important to follow your doctor’s guidelines and drink at least nine 8-ounce glasses of water daily to prevent dehydration.

The FDA is now moving to have these laxative products relabeled to include warnings and make them available only by prescription.

Other prescription products, Visicol and OsmoPrep, will add the new FDA required warning regarding potential kidney damage to their oral sodium phosphate products.

The concern at the FDA is that oral sodium phosphate products have been connected with kidney function problems such as acute phosphate nephropathy that can cause permanent damage and lifelong dialysis or death. In acute phosphate nephropathy, calcium-phosphate crystals deposit in the renal tubules inside each kidney.

When used as directed or at lower levels, the FDA stated there is no evidence that the OTC laxatives lead to kidney problems. The agency, however, started issuing alerts in 2006. Other data show that product lawsuits for oral sodium phosphate laxatives, including lawsuits where OSP product users developed acute phosphate nephropathy began appearing in 2003.

While Phospho-soda has been the bowel prep product used and recommended by physicians for decades, Fleet is not asking doctors to not recommend the Phospho-soda products.

Gastroenterologists and proctologists have recommended Fleet’s Phospho-soda products for years, especially in patient preparation for screening colonoscopy (a colon cancer screening examination). In a clinical trial the product achieved the highest patient acceptance scores, and cleansing was generally rated as excellent.
However, Fleet Phospho-soda should not be used in patients with congenital megacolon, bowel obstructions, ascites, congestive heart failure or kidney disease.
When problems do not exist, physicians believe the product is good because it is effective, easily tolerated by patients and affordable.

Generally most patients do not like bowel prep products. Some doctors, like Mark Wax MD, suggest the need for “virtual bowel prep”. He adds that “until that becomes an option, patients will have to undergo conventional preparation and that requires making informed decisions about available options.” Wax is associated with a company that offers virtual colonoscopy.

The company states that virtual colon screening is a minimally invasive, safe and more comfortable procedure. Recent studies have shown it to be comparable to conventional colonoscopy for finding polyps larger than one centimeter. The risk of cancer in smaller polyps is almost negligible. With virtual colonoscopy, 100% of the colon surface can be seen. It is estimated that physicians only see 70%-80% of the colon surface with conventional colonoscopy.

Should you have medical questions about using these products, contact your health care provider.

This article is part of a consumer health education series written by Gayle Eversole, DHom, PhD, MH, NP, ND, of Creating Health Institute, in collaboration with Bernstein Liebhard, LLP, who sponsors the consumer advocate website, www.ConsumerInjuryLawyers.com