In its July 8th Advisory, the FDA also asked - and continues to request - all health care professionals to report any such cases and other toxicities associated with the use of the three drugs to FDA’s MedWatch program (1-800-FDA-1088/fax 1-800-FDA-0178) or to the respective pharmaceutical manufacturers. Such reporting allows FDA to better determine the scope of this problem, to better work with the academic community and the manufacturers in determining the reason(s) for this problem, and to better determine the most appropriate regulatory response to this concern.

Thanks to the reporting of health care professionals, as of August 22, FDA has received reports of 82 cases (including Mayo’s 24 cases) of cardiac valvular disease in patients - two of whom were men - on combination fenfluramine and phentermine. These reports have been from 23 different states. Severity of the cardiac valvular disease was graded as moderate or severe in over three-fourths of the cases, and two of the reports described deterioration from no detectable heart murmur to need for a valve replacement within one-and-a-half years. Sixteen of these 82 patients required surgery to repair their heart valves. At least one of these patients died following surgery to repair the valves. (The agency’s findings, as of July 31, are described in more detail in the current issue of The New England Journal of Medicine, which also carries the Mayo study.)

Five additional reported cases of cardiac valvular disease were associated with exposure to fenfluramine followed by dexfenfluramine, both in combination with phentermine; and 1 additional case was associated with exposure to the combination of all 3 drugs given at the same time.

In addition, there have been reports of cardiac valvular problems associated with the use of fenfluramine alone (n=2) and dexfenfluramine alone (n=7). However, no reports have yet been received of these heart problems developing when fenfluramine or phentermine are used as single agents for the duration presently approved.

In addition, FDA is working with the Centers for Disease Control and Prevention, the National Institutes of Health, and the Mayo Clinic researchers to develop methods to investigate the scope and cause(s) of this problem. Some epidemiologic studies using on-going trials and various data bases are already underway. Other prospective studies are presently being designed.