Can CV Monitoring Warnings or REMS Restrictions Save Meridia?

In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.

However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.

“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.

Three-Month Decision Point

Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.

Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.

The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.

Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.

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