Pills with consequences

The media has widely covered the Hydroxycut recalls issued by the FDA earlier this month, making it unnecessary to repeat the recall notices here in detail. JFS readers aren’t the customers for dietary supplements marketed as being for weight loss, as fat burners, as energy-enhancers, and as low-carb diet aids. But one aspect of the news story hasn’t caught the attention of media and may provide a helpful cautionary note for readers.

Background

On May 1st, the FDA issued a consumer release, warning consumers to immediately stop using Hydroxycut products by Iovate Health Sciences Inc., of Oakville, Ontario and distributed by Iovate Health Sciences USA Inc. of Blasdell, New York. After receiving 23 reports of serious health problems, including liver damage resulting even in the need for a liver transplant and one death from liver failure, associated with use of the dietary supplements, the FDA announced that Iovate had agreed to recall all of its Hydroxycut products, except for Hydroxycut Cleanse and Hoodia products. The FDA’s Hydroxycut website provides a list of the recalled products, the warning letter issued to Iovate, and updates.

In 2002, the FDA’s Center for Food Safety and Applied Nutrition’s adverse event monitoring system, CAERS, began receiving reports of liver-related problems in people also taking the dietary supplements. Some people have experienced liver complications after taking the supplement only a week. As MedWatch — FDA’s Safety Information and Adverse Event Reporting Program — noted, however, the agency hasn’t yet figured out which ingredients, doses or health-related factors may be associated with the problems being reported with Hydroxycut products. The FDA’s Health Hazard Evaluation (HHE) board noted that the products contain a wide variety of ingredients, including proprietary mixtures, making it hard to isolate the ingredient(s) that might be contributing to health problems.

The FDA’s job is made especially challenging because products sold as dietary supplements don’t have to be registered with the FDA or undergo safety evaluations before they can be sold; nor can the FDA validate a manufacturer’s claims or test supplements to make sure they contain what the labels say, are not contaminated and are safe. With the Dietary Supplement Health and Education Act (DSHEA) of 1994, it can only act to protect consumers after a product is already on the market and the FDA proves the product is unsafe or is putting consumers at undue risk. It has only voluntary adverse event reports, which are understandably incomplete, and other sources of information, such as the medical literature, to rely upon.

The labels on Hydroxycut products say they contain minerals and herbs, as well as extracts Garcinia cambogia, Guarana, gymnema sylvestre, Rhodiola rosea and Camellia sinensis [green tea], the HHE board said. These ingredients are popular with nutraceutical companies and are claimed to offer a range of wellness, energy and weight loss benefits… and have been subsequently issued fines by the FTC for deceptive advertising, and warning letters from the FDA.

No weight loss product on the market has evidence for safety and effectiveness. One natural ingredient marketed to the public for weight loss, for example, is Garcinia cambogia. Few consumers heard that this was shown to be ineffective in clinical trials more than a decade ago. A randomized, double-blind, placebo-controlled trial by Columbia University obesity researchers found that the herbal compound failed to produce any statistical weight loss or fat mass loss over that seen in the placebo group.

At first, the FDA believed that the reports of Hydroxycut-related liver injuries may have been due to ephedra or Ma Huang, alone or in combination with the other ingredients, in the products. However, since Hydroxycut became ephedra-free in 2004, the liver-related adverse events have continued. The products have also undergone numerous formulation changes, making it difficult for the FDA to identify the potentially hazardous ingredient(s). Another ingredient that’s been found in variable amounts in the supplements is caffeine and the HHE board said that the doses recommended on the product labels would give people two to three times the average consumption of caffeine. The FDA identified 46 reports in CAERS of cardiovascular-related complications associated with Hydroxycut products, 19 after 2004.

Given the available information on liver and heart problems, most medical professionals are echoing the FDA’s concerns, as the potential serious risks outweigh taking supplements that offer no demonstrated health benefits.

Another health problem included in the CAERS reports provides an opportunity to better understand a condition that most consumers know little about, even though many might wish to.

Rhabdomyolysis

The FDA’s HHE report noted a case report of rhabdomyolysis involving a 23-year-old man who had been taking Hydroxycut intermittently for eight months in 2002. “On the day of hospital admission, he had taken two tablets for energy prior to working out,” the FDA said. The board said it was also aware of another case report in the medical literature seen in an 18-year old male.

That case report had come from the Department of Pharmacy Services at the University of Utah in Salt Lake City and described a previously healthy patient diagnosed with rhabdomyolysis. “His medications before symptom onset included Hydroxycut four caplets by mouth daily, naproxen sodium 220 mg by mouth as needed for pain, dextroamphetamine saccharate-amphetamine salts (Adderall) 15 mg by mouth once five days prior for a school examination, and hydrocodone-acetaminophen and cyclobenzaprine for pain,” said the authors. His history also revealed a recent increase in his exercise regimen.

These two case reports likely raised a questioning eyebrow among many medical professionals. Do you know why?*

It's the same reason seen yesterday in the Los Angeles Times. As so often happens whenever a health complication is linked to a pill or medical treatment, it becomes a potential class action windfall for lawyers. Yesterday, a feature story appeared in the newspaper describing a former Army serviceman, 27 years old, who had been diagnosed with rhabdomyolysis after an intense physical training session under his sergeant in July 2007. When the FDA’s recall of Hydroxycut made the news as being linked to two cases of rhabdomyolysis, the young man reportedly told the paper he’d remembered taking the supplement for three months in 2007. He is now a plaintiff in a planned lawsuit against maker Iovate Health Sciences, according to the newspaper. The story goes on to report:

Tropea says he was "completely shocked": How could an herbal supplement he took to trim down do all that?... Because rhabdomyolysis is most often the result of crush injuries, heat stroke, alcoholism or drug use, doctors thought it was unusual to see the condition in a fit, active-duty serviceman who, according to his military records, drank alcohol very rarely, had regularly passed drug tests, and had no recent history of trauma. Fearing a potentially disastrous recurrence, Tropea's physicians have warned against physical exertion of any kind…

Hydroxycut, Tropea believes, has left his health — and his future — uncertain. Tropea, who still lives in Stuttgart, is among the first wave of plaintiffs in a planned lawsuit against Iovate Health Sciences Inc., the maker of Hydroxycut… Tropea had not even thought to inform his doctors that he had been taking Hydroxycut steadily for the three months leading up to his hospitalization, in an effort to boost his fitness level and get down to the weight limits set for active-duty soldiers.

This news story was sad and may sway a future jury pool and garner additional clients for personal liability lawyers, but it raised some eyebrows among medical professionals.

Here’s why. Rhabdomyolysis has been widely recognized in the medical literature and among medical professionals for the past century as induced by exercise and even occurring in young, healthy people. Military physicians and military officers are especially cognizant of this common complication seen in recruit training. Doctors would not have found it shocking or unusual to see it in fit military trainees.

For example, a 1994 issue of Annals of Emergency Medicine, the journal of the American College of Emergency Physicians, reported on 35 patients seen in a New York emergency room with rhabdomyolysis after a history of strenuous exercise. All of them were men, with an average age of 24.4 years, and all had no medical history of health problems. “Exercise-induced rhabdomyolysis accounted for 47% of our admissions for rhabdomyolysis but was not responsible for a single case of acute renal failure,” the ER doctors concluded.

As Dr. Richard Sinert, and colleagues explained, since the syndrome was first described in 1910:

[N]numerous case reports have linked rhabdomyolysis to such strenuous activities as military basic training and weight lifting. Knochel has termed exercise-induced rhabdomyolysis "white collar rhabdomyolysis" because of its high incidence in intelligent, well-educated professionals who can arrange their work schedules to allow for daily running… this syndrome also has been reported commonly in professional athletes during marathon races and ice skating competitions.

Rhabdomyolysis appears to be a relatively common sequela of strenuous exercise. In the largest screening to date, Olerud et al sampled blood for myoglobin in 337 military recruits during their first six days of conditioning and found approximately 40% to have some degree of rhabdomyolysis.

“Rhabdomyolysis is a relatively common complication of strenuous exercise, as evidenced by the military recruit data and the large number of reports of "white collar rhabdomyolysis,” said Dr. Sinert and colleagues. “Reports of exercise-induced rhabdomyolysis in professional athletes support our experience that neither the amount of exercise nor the level of training appears to be a reliable predictor for the development of rhabdomyolysis.”

Reports of rhabdomyolysis occurring after exercise continue to appear regularly in the medical literature. In fact, while believed to be underreported, cases are increasing, as more and more people exercise, according to a 2004 article in The Physician and Sports Medicine, and it can develop at any level of physical exertion. For example, the Centers for Disease Control and Prevention reported exercise-induced rhabdomyolysis and acute renal impairment among New York City Fire Department recruits during competitive physical fitness tests in June 1988, resulting in 32 hospitalizations and one death. A 2005 report in the British Journal of Sports Medicine described 119 cases in high school students after repetitive exercise outside in cold weather. And the current issue of Clinical Advisor, reports a young 25 year old woman developed rhabdomyolysis after an aerobic spinning class. This syndrome can occur at any age. Beginning an exercise program precipitated rhabdomyolysis in a 63-year old woman who had also been taking a statin and using saunas for years.

Take-home information

Rhabdomyolysis means: striated (rhabdo) muscle (myo) disintegration (lysis). It is a series of potentially life-threatening complications that occur after muscles break down or are injured due to a variety of causes. When muscle breaks down, it releases muscle cells’ components (potassium, phosphate, myoglobin, creatine kinase and urate) into the bloodstream, leading to more muscle breakdown, shock, metabolic acidosis and hyperkalemia, kidney failure and disseminated intravascular coagulation. It accounts for up to 15 percent of cases of acute renal failure in the United States and is fatal for about 5 percent of patients.

Patients can develop any number of symptoms but about half will have darkened urine, prolonged weakness or aching muscles, cramps, muscle tenderness, swelling, confusion, seizures, nausea and/or fever. If you develop these symptoms, it’s important to seek medical care right away.

Exercise-induced rhabdomyolysis is more prevalent when physical activity is accompanied by heat and humidity, exposure to cold, dehydration and not drinking enough fluids. Sports medicine and emergency room doctors advise people to exercise wisely and not increase workouts more than 10 percent a week, even less in hot and humid weather, and to drink plenty of fluids. Early and generous hydration is the quickest way emergency room physicians also treat the condition to help prevent potentially life-threatening complications.

There are two other categories of causes of rhabdomyolysis. Genetic conditions are associated with about 10 percent of all cases. But the largest category of risk factors, which can work alone or synergistically, includes trauma, injury (crush or burn), substance abuse, toxins (such as tetanus or snake venom), infections, electrolyte abnormalities, inflammatory processes and a wide range of drugs. In the last one, prescription drugs, is the most common cause, accounting for nearly half of all cases. With prescription drugs being prescribed in greater number than ever before, awareness of this serious complication is more important than ever, too.

Rhabdomyolysis is a side effect of Adderall, mentioned in that FDA case report. But the public has most heard of rhabdomyolysis in connection with statins. Just between November 1997 and March 2000, the FDA received 871 reports of statin-associated cases of rhabdomyolysis, representing 601 cases. As reported in the Annals of Pharmacotherapy, the cases were associated with each of these statins: simvastatin, 215 (35.8%); cerivastatin, 192 (31.9%); atorvastatin, 73 (12.2%); pravastatin, 71 (11.8%); lovastatin, 40 (6.7%); and fluvastatin, 10 (1.7%). “Statins were designated as the primary suspect in 72.0% of the cases. Death was listed as the outcome in 38 cases.”

The FDA has issued repeated Consumer Alerts and Public Health Advisories about rhabdomyolysis and statins over recent years, such as:

August 8, 2001: FDA announcement of the recall of Baycol

March 2, 2005: Crestor (rosuvastatin) advisory

August 8, 2008: FDA alert on Zocor (simvastatin), especially at doses over 20mg daily and taken with amiodarone.

The Health Canada Advisory provides consumers with especially helpful safety information on rhabdomyolysis. Its 2005 advisory said rhabdomyolysis is “a serious side effect of all cholesterol-lowering drugs known as statins” which include:

Crestor (rosuvastatin)

Lipitor (atorvastatin)

Zocor (simvastatin)

Mevacor (lovastatin)

Lescol and Lescol XL (fluvastatin)

Pravachol (pravastatin)

Its statin advisory gave specific guidance for people, noting conditions that appear to place people at special risk for rhabdomyolysis from statins, including people with: thyroid, kidney or liver problems; diabetes; taking other medications or taking other cholesterol-lowering medications such as fibrates or niacin, do physical exercise, have had surgery or other injury, or family history of muscular disorders.

The bottom line, is that the decision to take any pill — all-natural dietary supplement, over-the-counter, or prescription — should not be made lightly. The decision means carefully balancing the demonstrated health benefits in treating an actual medical problem with the potential side effects. All drugs have side effects. Popping a pill, any pill, isn’t recreation. It can have serious consequences.

© 2009 Sandy Szwarc

* Looking back to those two case reports cited by the FDA of rhabdomyolysis occurring in two young men — both following intense physical workouts of increased intensity and taking Hydroxycut supplements — the correlation alone makes it impossible to parse out with certainty if the cause was the exercise or the supplement, or both. Or, it could have been the Adderall? Or some combination?