Public Citizen's Health Research Group's Petition to Ban Diet Drug Sibutramine (MERIDIA)

On March 19, 2002, Public Citizen’s Health Research Group petitioned Department of Health and Human Services (DHHS) Secretary Tommy Thompson to immediately ban the dangerous diet drug sibutramine (MERIDIA). As long ago as April 1998, we listed sibutramine as a Do Not Use drug in Worst Pills, Best Pills News. This drug is now sold by Abbott Laboratories.

The petition can be found on the web at www.citizen.org/publications/release.cfm?ID=7160 or by writing to the Health Research Group at 1600 20th Street, NW, Washington, DC 20009.

Since the drug’s availability in early 1998, the Food and Drug Administration (FDA) has had reports of 29 deaths including 19 from cardiovascular adverse effects in people using this minimally effective drug. In mid-March of this year, sibutramine’s use was suspended in Italy because of two cardiovascular deaths, and its safety is currently under review in other European countries where, in the United Kingdom (UK) and France alone, there have been a total of 103 serious adverse reaction reports in people using the drug including two deaths in the U.K.

Prior to sibutramine’s approval in 1997, an FDA advisory committee voted 5-4 that the benefits of sibutramine did not outweigh its risks. The FDA medical officer who reviewed the drug wrote that “sibutramine has an unsatisfactory risk-benefit ratio and therefore this reviewer recommends non-approval of the original submission [the application to market sibutramine].”

The concerns of both the advisory committee and the FDA medical officer were based on the fact that sibutramine significantly increases blood pressure and heart rate in many people. When announcing its seriously mistaken approval of sibutramine in November 1997, the FDA stated that the average weight loss in obese people taking the drug for one year—beyond the weight loss in those getting a placebo—was only 6 1/2 pounds in the group taking 10 milligrams of the drug.

This is the fifth petition we have filed with the FDA or DHHS to ban a drug since 1996. The last four were: (1) the diet drug dexfenfluramine (REDUX) banned in September 1997 after our April 1996 petition; (2) troglitazone (REZULIN), a diabetes drug banned in March 2000, one year and eight months after our July 1998 petition was filed; (3) the fluoroquinolone antibiotic trovafloxacin (TROVAN) which was severely restricted in the U.S. and banned in Europe in June 1999 after our earlier June 1999 petition; and (4) alosetron (LOTRONEX), a drug for irritable bowel syndrome that was banned in November 2000, three months after our August 2000 petition. For all of these drugs, including sibutramine, there was clear evidence of danger before their FDA approvals.

The effect of sibutramine in promoting weight loss is meager at best and it is not known if this drug, or any diet drug for that matter, can be taken safely for a long enough period of time to reduce the illness and death associated with chronic obesity. The editors of the highly respected independent American source of drug information, The Medical Letter on Drugs and Therapeutics, written for physicians and pharmacists, concluded in their review of sibutramine: “Medical Letter consultants advise against using the drug.” More recently, the French medical journal, Prescrire International, concluded that “Sibutramine...has amphetamine-like side effects” and “In practice sibutramine currently has no place in the management of obesity.”

The FDA Medical Officer responsible for coordinating the review of sibutramine was unequivocal in his concern about this drug’s safety, holding that its risks outweigh its benefits and that it should not be approved. In particular, his safety concerns centered on sibutramine’s paradoxical effect in significantly raising blood pressure even though patients taking the drug were losing weight.

The following are pertinent comments taken from the FDA’s review of clinical trials on sibutramine:

“To date, there have been eight reported cerebrovascular accidents [strokes]: Seven of these subjects were taking sibutramine and one was receiving placebo.”

“. . . the safety data indicate a possible to probable drug-related risk for several serious adverse events cardiac arrhythmia, cerebrovascular accident, acute interstitial nephritis, thrombocytopenia, and bleeding disorders. Furthermore, the safety data highlight the paradoxical increase in blood pressure despite weight loss in sibutramine-treated patients.”

”Sibutramine’s most worrisome safety issue centers on its effects on the major obesity-related co-morbidities [illnesses related to obesity], particularly blood pressure. A disturbing result of the dose-ranging study BPI 852, and its open-label extension 852X, was the paradoxical increase in blood pressure despite weight loss. Although the subjects in BPI 852 and 852X were normotensive [had normal blood pressures] at baseline, one would expect a reduction in blood pressure following weight loss in obese individuals.”

In his summary, before recommending that the drug not be approved, the Medical Officer said:

“. . . the 10 and 15 mg doses of sibutramine satisfy the minimum weight-loss criteria and duration of study as defined in the Guidance, however, sibutramine does not improve, and in some cases it aggravates major obesity-related co-morbidities.”

The Medical Officer was also concerned about sibutramine’s ability to alter a normal electrocardiogram (EKG or ECG). The manufacturer had determined, in clinical trials conducted before the drug was approved, that 31 ECGs from 2,473 patients had clinically significant changes from their respective baseline ECGs. Twenty-eight of the 31 abnormalities were from subjects taking sibutramine and three were from placebo patients.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee met on September 26, 1996 to discuss sibutramine. As mentioned above, when asked the question “Do the benefits of sibutramine outweigh the risks?” the committee voted five to four that they did not. Of the nine committee members, there were only two wholly unqualified votes that the benefits of sibutramine outweigh the risks. In response to the question “Is the pressor [high blood pressure-causing] effect of sibutramine clinically important?,”the committee voted 8 to 0 that it was.

Sibutramine was approved on November 22, 1997 and was on pharmacy shelves in February 1998. Using the Freedom of Information Act (FOIA), Public Citizen obtained a computerized version of all reports of serious adverse drug reactions associated with the use of the drug through September 30, 2001.

In this period there were 397 reports of people with serious adverse reactions, of whom 152 were hospitalized and an additional 29 patients died, 19 of cardiovascular causes such as heart attacks. Included in the 19 cardiac deaths were 10 people who were 50 or younger, including three women under the age of 30. There were also 143 patients in whom an arrhythmia was reported.

A dangerously low approval standard has led to needless deaths and injuries from sibutramine and other diet drugs. Over 30 years ago, in June 1968, FDA Medical Officer Dr. Robert O. Knox refused to approve the New Drug Application (NDA) for a diet drug. This disapproval touched off a dispute between the FDA and the drug’s manufacturer, A.H. Robbins, that eventually led to the drug’s approval and Dr. Knox’s transfer to another area within the agency. His reason for recommending against approval was: obesity is a chronic disease and there is no evidence that these drugs affect the course of the disease over the long term.

The drug Dr. Knox refused to approve was fenfluramine (PONDIMIN), a drug that ultimately became the “fen” portion of the notorious “fen/phen” combination, that was removed from the market on September 15, 1997, because it caused heart valve damage and a potentially fatal adverse reaction of the lungs known as primary pulmonary hypertension.

Thirty years’ experience with diet drugs has clearly vindicated Dr. Knox. If his recommendation had been heeded in 1968, and the FDA had adopted a standard that required the demonstration of a health benefit from these drugs, hundreds of millions of dollars would have been saved and an immeasurable number of patients would have been spared serious harm or death.

The known serious risks of sibutramine might be acceptable if there were evidence that it prevented one stroke or heart attack or prolonged the life of a single patient. Such evidence is lacking for sibutramine as well as for other diet drugs, leaving patients with only the risk of injury from their use and expensive drug bills. This disproportionate risk compared to any known therapeutic benefit of sibutramine was seen by the FDA medical officer and the members of the Endocrinologic and Metabolic Drugs Advisory Committee who recommended against its approval.

Sibutramine is a drug that should never have been approved, and in the interest of the safety of the American public it must come off the market now. Congress and the FDA must reexamine the episode of Dr. Knox and fenfluramine and reject an approval standard for diet drugs that requires only short term studies which demonstrate the statistical superiority of a drug over a placebo.

What You Can Do

The best advice we can give about obesity is that prevention may be the best course. Our advice about losing weight and diet pills has remained the same for 20 years: eat less, exercise more. This approach to losing weight is slow but effective. The only one who profits from it is you. That’s why it isn’t sold.