Drug Profile

Latest update: In October 2010, thanks to eight years of relentless pressure from Public Citizen and others, the Food and Drug Administration (FDA) finally banned sibutramine (MERIDIA). The agency issued a public advisory stating that sibutramine will be voluntarily withdrawn from the U.S. market due to the increased risk of heart attack and stroke associated with its use.

Sibutramine is another on the long list of diet drugs that have never been shown to be safe when taken for long enough to reduce the morbidity and mortality associated with obesity.

In 1998, we told Worst Pills, Best Pills News readers to avoid this drug and had originally asked the FDA to ban the sibutramine in 2002, with a follow-up petition in December 2009.

Although this drug is no longer officially marketed in the U.S., we continue to provide information about it because people may obtain drug products containing sibutramine via the Internet.

Sibutramine received marketing approval from the FDA in November 1997 for weight loss and weight maintenance when used with a reduced-calorie diet in those who meet the medical definition of "overweight."

The drug was evaluated at the September 1996 meeting of the FDA Endocrinologic and Metabolic Drugs Advisory Committee. This committee voted 5-4 against approval of sibutramine on the grounds that its risks outweighed its benefits. Committee members were concerned about sibutramine’s potential to raise blood pressure and increase heart rate.[1] These adverse effects could make this a dangerous drug for people with high blood pressure, heart disease, blood vessel disease, congestive heart failure, stroke, heart rhythm disturbances and hyperthyroidism (high thyroid hormone levels).

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.”[2] 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. The FDA, against the advice of the advisory committee and the review of the medical officer, approved sibutramine.[3]

Public Citizen petitions to ban drug

In the April 1998 issue of Worst Pills, Best Pills News, we listed sibutramine as a "Do Not Use" drug because of its risks and the meager amount of weight loss seen in clinical trials.

On March 19, 2002, Public Citizen’s Health Research Group petitioned the FDA to immediately remove sibutramine from the market for safety reasons. Publicly available material obtained from the FDA showed that from the time it was introduced in February 1998 to Sept. 30, 2001, there were almost 400 serious adverse reactions in patients taking sibutramine. The adverse reactions involved 19 cardiac deaths, including 10 in people under the age of 50, three of whom were women under 30. The average yearly weight loss for patients taking the usual 10-milligram dose was only six and a half pounds more than the loss of weight in those taking a placebo.[4]

Due to a rising number of severe adverse drug reactions being reported with sibutramine and the failure of the FDA to take action, the Health Research Group amended the original 2002 petition with new information and resubmitted it to the FDA in September 2003. In the 18 months subsequent to the original petition, there had been an additional 30 reports of cardiovascular deaths in people using sibutramine, adding to a total of 49 cardiovascular deaths.[5] In August 2005, the FDA rejected Public Citizen’s petition, despite the fact that since March 2003 there had been even more deaths in patients taking this dangerous drug. The FDA also ignored a report in the peer-reviewed international medical journal Archives of Internal Medicine that failed to find conclusive evidence supporting a positive risk-benefit profile.[6]

A thorough review of published (and some unpublished) studies of people using sibutramine appeared in the Archives of Internal Medicine in 2004. The review found that the more favorable studies were more likely to be published than the less favorable ones. The other notable finding was that the authors were unable to establish that sibutramine reduced the occurrence of obesity-related illness or death.[7]

Adverse effects

Birth defects
An analysis of an adverse event not discussed in our original petition, fetal toxicity, was included in the petition we updated in September 2003. Our analysis of the FDA Adverse Event Reporting System database, using information from the date of the initial marketing of the drug through March 2003, yielded 54 reports with the phrase “complications of maternal exposure” or “maternal drugs affecting fetus” where sibutramine was listed as the primary suspect drug.

It was surprising to find so many reports involving birth defects, including reports on four babies with cardiovascular birth defects. These defects were: (1) bicuspid aortic valve with cardiac murmur, (2) cardiomegaly (enlarged heart), (3) congenital heart disease and (4) ventricular hypoplasia (underdeveloped heart chamber).

In addition to cardiovascular defects in infants, there are reports of spontaneous abortions, stillbirths and congenital malformations, including those of the central nervous system (hydrocephalus, Chiari malformation, brain neoplasm, spina bifida).

The FDA-approved professional product information for sibutramine contained a number of important warnings:

The long-term effects of Meridia on the morbidity and mortality associated with obesity have not been established. ... The safety and effectiveness of Meridia, as demonstrated in double-blind, placebo-controlled trials, have not been determined beyond one year at this time. ... Meridia is contraindicated in patients taking other centrally acting appetite suppressant drugs.

The FDA-approved product labeling for sibutramine also mentioned that the use of the drug was not recommended during pregnancy and that women of childbearing potential should employ adequate contraception while taking sibutramine.

Blood pressure
Sibutramine product labeling also carried the following warning in bold uppercase letters:

MERIDIA SUBSTANTIALLY INCREASES BLOOD PRESSURE IN SOME PATIENTS. REGULAR MONITORING OF BLOOD PRESSURE IS REQUIRED WHEN PRESCRIBING MERIDIA.[8]

Heart problems
In 2009, the FDA issued an early communication that it was reviewing information from a study suggesting that sibutramine use is associated with an increased risk of cardiovascular events.[9]

In follow-up to the 2009 communication, the FDA requested that the product labeling for sibutramine include information that it was not to be used in patients with a history of cardiovascular disease. This action was taken in response to additional data received by the FDA indicating that patients who had a history of cardiovascular disease and took sibutramine had an increased risk of heart attack and stroke.[10]

Public Citizen, based on the above-mentioned study, re-petitioned the FDA late in 2009 to ban sibutramine, and shortly thereafter, the European Medicines Authority (EMA) recommended that the drug be banned throughout Europe.

The FDA, however, waited until October 2010 to ban the drug, and between the time of the EMA ban and the FDA ban, there were more than 160,000 prescriptions filled for sibutramine in the U.S, needlessly exposing large numbers of people to the risks of heart attacks and strokes.[11]

Kidney problems
In 2005, the FDA revised the product labeling for sibutramine to incorporate additional information for patients with kidney impairment or kidney insufficiency.[8]

Memory problems
The World Health Organization’s international database contains 33 reports of amnesia associated with sibutramine. In 25 cases, sibutramine was the only drug suspected of causing the amnesia. Although amnesia is listed as a reported event during postmarketing surveillance of sibutramine in the U.S. product information, literature searches found no published reports of this adverse event.[12]

Serotonin syndrome
Sibutramine inhibits the reuptake of the brain transmitter serotonin, as do some of the antidepressant drugs known as selective serotonin reuptake inhibitors (SSRIs). These antidepressants include escitalopram (LEXAPRO), fluoxetine (PROZAC), fluvoxamine (LUVOX), paroxetine (PAXIL) and sertraline (ZOLOFT). A rare but serious condition called serotonin syndrome has been reported with the use of SSRIs, including sibutramine, in combination with drugs for migraine headache treatment, such as sumatriptan (IMITREX) and dihydroergotamine (D.H.E. 45); certain opioids, such as dextromethorphan (DELSYM), meperidine (DEMEROL), pentazocine (TALWIN), and fentanyl (DURAGESIC); lithium (LITHOBID, LITHONATE); and tryptophan. Serotonin syndrome also has been reported when two SSRIs are taken together.

Serotonin syndrome requires immediate medical attention and may include one or more of the following symptoms: excitement, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, weakness, tremor, incoordination, shivering, sweating, vomiting and rapid heartbeat.

Regulatory actions surrounding sibutramine

2002: In March, Public Citizen’s Health Research Group petitioned the FDA to ban sibutramine.

2003: Public Citizen amended the 2002 petition with new information and re-submitted it to the FDA.

2005: The FDA rejected Public Citizen’s petition but revised the sibutramine product label with information on kidney impairment and kidney insufficiency.

2009: In December, Public Citizen submitted a follow-up petition to ban sibutramine. The FDA requested that the sibutramine product label contain an advisory stating that the drug is not to be used in patients with a history of cardiovascular disease.

2010: The FDA finally banned sibutramine due to the increased risk of heart attack and stroke associated with its use.