The U.S. Food and Drug Administration's ( FDA ) has denied Public Citizen's petition against Meridia ( Sibutramine ), but says it will closely monitor a European study designed to better assess the Sibutramine's heart risks.

FDA says that review of the NDA for Sibutramine followed standard procedures, and that the application met the statutory requirements for approval.

The NDA for Sibutramine ( Meridia ), a norepinephrine and serotonin reuptake inhibitor with sympathomimetic activity, was submitted to the FDA’s Division of Metabolic and Endocrine Drug Products in August 1995.

The sponsor was seeking approval of 5-mg,10-mg, 15-mg, 20-mg, and 30-mg once-daily doses of Sibutramine for the treatment of obesity.

During the initial regulatory review cycle, the primary medical reviewer expressed concern about Sibutramine’s effect on blood pressure and eventually concluded that this single risk would likely outweigh the documented benefits of the drug, which in addition to weight loss itself, at that time, included secondary improvementsin levels of HDL cholesterol and triglycerides.

Given that the primary reviewing division’s expertise did not include drugs that affect blood pressure, a consult on the Sibutramine blood pressure data was obtained from the FDA’s Division of Cardio-Renal Drug Products.

In a response dated September 11,1996, the consulting division acknowledged that Sibutramine did cause a small pressor effect, but concluded that: “ were Sibutramine’s effects on blood pressure the only basis for considering non-approval, such a decision would be a mistake, because potential long-term benefits of weight reduction could outweigh short-term risks of blood pressure elevation...”

John Flack, a blood pressure expert then at the Bowman Gray School of Medicine, was retained by FDA as a consultant and asked to review the Sibutramine blood pressure data. Flack agreed that the drug did increase blood pressure by an average of 1 to 3 mmHg, and while he did not comment on whether Sibutramine should be approved, he stressed that the balance of Sibutramine’s risks vs. benefits would probably be unfavorable only in obese patients with uncontrolled hypertension, coronary artery disease, congestive heart failure, stroke, or cardiac arrhythmias, as these conditions would heighten the odds for adverse cardiovascular outcomes related to the drug’s sympathomimetic activity.

On September 26, 1996, the Endocrinologic and Metabolic Drug’s Advisory Committee convened to publicly evaluate the data from the Sibutramine NDA.
Eight of the nine committee members agreed that the drug’s effect on blood pressure was clinically important; however, all also believed that Sibutramine was an effective weight loss drug, leading to a nearly evenly split vote on the question of whether the drug’s benefits outweighed its risks.

Following the advisory committee meeting, FDA staff met internally and with Knoll on a number of occasions to discuss the pending Sibutramine application.
Although a wide range of opinions were expressed about the relative merits and shortcomings of the drug, all FDA staff concluded that Sibutramine was an effective obesity agent, using the criteria in the Agency’s draft Guidance for the Clinical Evaluation of Weight-Control Drugs.

Furthermore, FDA staff agreed that the drug’s major risk was its effect on blood pressure.
Discussion therefore focused on whether it was possible to identify practical ways to manage the blood pressure risk such that the drug’s overall risk-benefit profile would prove favorable.

To this end, FDA requested that Knoll conduct additional, detailed analyses of the clinical trial blood pressure data, which would be considered during a second regulatory review cycle.
These analyses confirmed two important findings that were crucial to rendering a final regulatory decision on the Sibutramine NDA:

(1) the risk for important elevations in blood pressure increased notably with the 20-mg and 30-mg doses of Sibutramine, and

(2) the risk for substantial increases in blood pressure was confined to a relatively small percentage of patients who could be identified through regular blood pressure monitoring.

In summary, the 26-month regulatory review of Sibutramine was a deliberative, open, interactive, and admittedly complex process involving multiple FDA scientists from the Division of Metabolic and Endocrine Drug Products and the Division of Cardio-Renal Drug Products, a blood pressure expert from the Bowman Gray School of Medicine, and nine members of the advisory committee.
There were certainly differences of opinion regarding Sibutramine’s overall risk-benefit profile, but all viewpoints and available data were taken into consideration before rendering a final regulatory decision on the NDA.

While Sibutramine was not considered an appropriate drug for all obese patients, such as those with coronary artery disease FDA ultimately concluded that when used in accordance with the approved labeling, the benefits of the lower doses of Sibutramine would outweigh the potential increase of blood pressure which can be monitored and, if necessary treated, in appropriately selected obese patients.

The 5-mg, 10-mg, and 15-mg ( but not the 20-mg and 30-mg ) once-daily doses of Sibutramine were approved on November 22, 1997, for the management of obesity, including weight loss and maintenance of weight loss, in obese patients with an initial body mass index greater than or equal 30 kg/m2 or greater than or equal 27 kg/m2 in the presence of other risk factors ( e.g., hypertension, diabetes, dyslipidemia ).

The approved professional and patient labeling includes prominent warnings that Sibutramine substantially increases blood pressure in some patients and that regular monitoring of blood pressure is required when prescribing Meridia.
The labeling also clearly warns against the use of Sibutramine in patients with uncontrolled hypertension or histories of coronary artery disease, stroke, heart failure, or cardiac arrhythmia.

Source: FDA, 2005


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