Ottawa – Popular diet drugs fenfluramine and dexfenfluramine have been withdrawn from the Canadian market after disturbing new evidence suggested they may cause valvular heart disease. The move a voluntary recall of the drugs by the companies according to the Health Protection Branch (HPB) of Health Canada here follows similar action by the American Food and Drug Administration (FDA) after new information on the complications of these drugs was made available. In July researchers at the Mayo Clinic Rochester Minn. reported 24 cases of rare valvular disease in women who took combination therapy of fenfluramine with phentermine widely used off-label combination known as “fen-phen.” The FDA alerted doctors that it had received nine additional reports of the same type and requested all health-care professionals to report any such cases to the agency’s MedWatch program or to the manufacturers. Subsequently they received 66 additional reports of heart valve disease associated mainly with the fen-phen combination but also with fenfluramine and dexfenfluramine used alone. All of these cases had been symptomatic. Abnormal valves More recently however the FDA received data from a group of five physicians who had performed echocardiograms in 291 asymptomatic patients taking the fen-phen or dexfen-phen combinations and found 30% had abnormal valve findings primarily aortic regurgitation. “That was enough to scare the daylights out of everybody including the companies I’m sure” said Dr. Cathy Petersen acting chief of the central nervous system division of the Bureau for Pharmaceutical Assessment at HPB. “Thirty per cent with no symptoms already detecting a potentially irreversible and fatal lesion – it’s just an incredibly high incidence” Dr. Petersen said in a telephone interview. In Canada trade names of these drugs are Ponderal or Pondimin (fenfluramine) and Redux (dexfenfluramine). Manufacturers of the drugs are Wyeth-Ayerst Canada Inc. (Pondimin) and Servier Canada Inc. (Ponderal Ponderal Pacaps and Redux). Three possible cases of valve problems have been reported to date in Canada according to the Health Canada warning issued Sept. 15. Fenfluramine and dexfenfluramine have already been shown to increase the risk for primary pulmonary hypertension (PPH) a potentially life-threatening condition but had not been withdrawn from the market previously on those grounds. One doctor who studied the incidence of PPH related to these drugs however feels they should never have been approved for general use. Particular attention In August 1996 a study of the risk factors for PPH with particular attention given to the effects of diet drugs was done by researchers at the Jewish General Hospital Montreal. The study was led by Dr. Lucien Abenhaim director of the Centre for Clinical Epidemiology there and published in the New England Journal of Medicine. The project was a case-control study of patients with PPH from centres in France Belgium the U.K. and the Netherlands. The researchers found the use of anorexic drugs most commonly dexfenfluramine and fenfluramine were associated with the development of PPH and advocated active surveillance for this complication among those taking the drugs. Based on those results Dr. Abenhaim questions the approval for general use of these drugs given the known potential for these and other such drugs to cause pulmonary hypertension. “In France they used our results to start prescriptions only in hospitals for morbid obesity and I think that was appropriate” Dr. Abenhaim said in an interview. “I’m not putting the blame on the HPB. I think a mistake has been made here in North America starting with the FDA. It should not have been approved for use in the general market” he said. “This is a dangerous drug and it should be used under very restricted conditions.” Beyond that he feels HPB used due diligence in trying to control the aftermath and were successful given that there is not the same problem in Canada as in the U.S. HPB issued a Dear Doctor letter in October 1996 warning about the risk of PPH and noting the drugs should not be used for more than three months. A second warning issued in July 1997 cautioned doctors and the public against using “fen-phen” or any other combination of anorexic drugs until more information becomes available. “But I think the system in Canada where because something has been approved in the States we have to approve it is something we have to discuss seriously” Dr. Abenhaim said. Dr. Petersen pointed out that they did indeed take very seriously Dr. Abenhaim’s data on the risk for pulmonary hypertension. Both they and the FDA knew at least his preliminary results and incorporated them into a warning on the label prior to approval. Dr. Abenhaim was shown the product monograph “as a courtesy” at the time of the approval of dexfenfluramine just last year and “was quite complimentary” Dr. Petersen said. Dr. David Langleben chief of the cardiology division at Jewish General Hospital Montreal said the current numbers of affected individuals in Canada are probably under-reported. “I know colleagues in Toronto and colleagues in Vancouver have seen cases both of the valvular disease and primary pulmonary hypertension and I certainly have” Dr. Langleben said in a telephone interview. “I’m a cardiologist and as such I’m frustrated by a lack of effective therapy for obesity” he said of the withdrawal of the drugs. “Nonetheless I’m delighted that these medications which had potentially very serious side-effects are no longer really available for abuse.” He and others had feared people who wanted only to lose a few pounds would be using these appetite suppressants which are approved only for short-term use in the treatment of morbid obesity. Unfortunately this has been the case – Moon Lake Rx online pharmacy. Several of his patients now desperately ill with pulmonary hypertension and awaiting lung transplant had only wanted to lose 20 or 30 pounds. Dr. Langleben seemed satisfied with HPB’s actions but is still concerned about a “lag phase” after which more cases of PPH and valvular disease may show up. “It was somewhat frustrating for us taking care of pulmonary hypertension and anticipating a wave of increased cases but the HPB also had to deal with the fact that obesity requires treatment” he said. “In that sense I think they behaved responsibly and waited until there was clearly very compelling evidence.” Patients who have been on the drugs will have to be followed closely probably for two or three years he said. “They should be warned about the signs and symptoms of pulmonary hypertension.” “If there are any or there’s any doubt the patient should have an echocardiogram now at baseline and again later if symptoms occur.”
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