Redux® (dexfenfluramine) and Pondimin® (fenfluramine)
There is a huge unmet medical need for safe and effective obesity treatments. Massive consumer demand also exists for treatments to lose weight. The experience of drugs approved for weight loss, however, has so far been controversial, with several product withdrawals. The biggest disaster was the ‘fen–phen’ diet combination. This episode actually involved three prescription medicines. The ‘fen’ component of the combination was either fenfluramine (Pondimin), approved in the US in 1973, or its isomer dexfenfluramine (Redux), approved in 1996. Both drugs were marketed by American Home Products as appetite suppressants in the management of obesity. Dexfenfluramine had already been marketed in Europe for over a decade. The ‘phen’ component of the combination was the drug phentermine, approved as an appetite suppressant since 1959. Both of the older agents had received approval for short-term use only (a few weeks). When launched in 1996, the safety of Redux during one year had been studied in 500 patients. An influential earlier study of 121 obese patients, published in 1992, had suggested that combined use of fenfluramine and phentermine resulted in effective weight loss with lower doses and fewer side effects when taken over an extended period of time. Subsequently, the fen–phen combination became extremely popular. There was common off-label usage not approved by the FDA in three ways – use for extended periods, use in combination, and use for ‘cosmetic’ weight loss by people who were not obese.
In July 1997, the FDA issued a Public Health Advisory notice. The Mayo Clinic had reported 24 patients developing heart valve disease after taking the fen–phen combination, with a number showing unusual and distinctive features (Connolly et al., 1997). Following dissemination of these findings, the FDA received further reports of heart valve disease – including some for patients taking Pondimin or Redux alone. An evaluation also found that approximately 30 per cent of treated patients – a very high proportion – had abnormal echocardiograms even though they showed no symptoms. In September 1997, both Pondimin and Redux were withdrawn world-wide (FDA, 1997). Phentermine remained on the market because there were no cases reported when it was used alone.
Between one million and five million people in the US, mostly women under 60 years of age, were estimated to have taken Pondimin or Redux between 1995 and withdrawal in 1997 (CDC, 1997). All patients subsequently required examination. American Home Products, which became Wyeth in 2002, was reported to have set aside an enormous sum of over $21 billion to resolve lawsuits over Pondimin and Redux (Feeley, 2009, 2012; Lenzner and Maiello, 2006). This episode demonstrated the dangers of off-label use and drug interactions. In addition, the longer-term safety of these products for weight loss had not been established in large studies that were able to identify less common symptoms. The side effect was unusual and unexpected, so detection relied on the vigilance of the Mayo Clinic.
Regulatory authorities subsequently became very cautious about approving weight-loss treatments, particularly after further market withdrawals. The treatment benefits need to be compared against the safety risks arising from chronic use. Strong consumer demand also exists for cosmetic weight loss, often from an otherwise relatively healthy and young population, which means that the risk of misuse of obesity drugs can be relatively high.
The Victims, the Drug Companies, and the Dramatic Story behind the Battle over Fen-Phen
St. Martins Press, New York, 2001, 402 pp, $24.95 hardback
Alicia Mundys Dispensing with the Truth opens with the story of Mary Linnen, a 29-year-old woman from Hingham, MA, who announced her engagement on Memorial Day in 1996. Anxious to begin planning her wedding, she had already decided that she wanted a simple wedding gownnothing too frilly. Mary also wanted to lose weight just a dress size or twoso her doctor prescribed a popular diet drug called fen-phen about 10 days earlier. However, a few days later, she complained of shortness of breath and dizziness during a family golf outing. Mary stopped taking fen-phen after only 23 days and briefly felt better. But soon her symptoms grew worse. She felt dizzy, exhausted, and severely short of breath on a daily basis.
Mary couldnt understand what was happening to her. Although she was overweight, she was not obese and had never had these health problems before. Ironically, fen-phens maker, Wyeth-Ayerst (a division of American Home Products), had been receiving reports for years about patients like Mary who had similar problems after taking the diet pills for only a few days or months. Even worse, Mundy claims that the FDA was also aware of these effects but dismissed them as insignificant, in part under pressure from the pharmaceutical company.
Fen-phen is a combination of two drugs: fenfluramine (also known as Pondimin), which was sold by Wyeth-Ayerst, and phentermine, distributed by Fisons Corporation. Both were lackluster diet drugs that failed to attract much attention in the marketplace during the 1980s and early 1990s because one of their main side effects was intense drowsiness. Then in 1992, a study announced that the combination of the two drugs canceled out the sleepiness. What followed was a media frenzy touting fen-phen as an obesity wonder drug, including a 1995 profile in the womens magazine Allure. By 1997, between 6 and 7 million American women had taken fen-phen, along with its prescriptive sister Redux. And it was not just the obese who were gobbling these diet drugsthose who wanted to quickly shed 10 or 15 pounds begged their doctors for a prescription.
Seven months after she took her first dose of fen-phen, Mary found herself in the emergency room going through a battery of respiratory tests to find out what was wrong. She was referred to a specialist, who soon gave her his depressing diagnosis: primary pulmonary hypertension (PPH). Her capillaries were thickening and closing, and consequently, her lungs were not getting enough oxygen. She was quickly fitted with a chest tube and put on Flolan, a drug fed through the tube that makes the heart pump harder to transport oxygen to the lungs. But Flolanbought her only a few months. Although PPH survival rates can be around four years, Mary Linnen died on February 22, 1997, only 10 months after taking her first dose of fen-phen.
Before her death, Mary and her parents hired a young, ambitious attorney named Alex MacDonald, who had a history of successful medical malpractice trials. Initially, they just wanted fen-phen pulled from the shelves, but after the Mayo Clinic released studies linking the drug to PPH and heart valve damage, the Linnen case was swept up in what would become one of the largest mass tort lawsuits in U.S. legal history. Even MacDonald was not aware of what this case would become and what disgraceful behavior it would unearth.
Mundys exhaustive research and acute observations make Dispensing with the Truth not only a taut legal thriller brimming with suspense but also a heartbreaking tale of corporate greed and federal corruption that left hundreds, if not thousands, of innocent victims with deadly heart and lung conditions. She makes a case that claims that the FDA caved in to pressure from the pharmaceutical company to get fen-phen approved quickly and tells how Alex MacDonald and his team of lawyers stumbled upon a Wyeth-Ayerst report listing pulmonary-hypertension-connected fen-phen cases dating from the early 1990s (including 101 deaths). Other revelations include evidence that an American Home Products executive approved the removal or overwriting of 13 reports of fatal valve disease from a doctor in North Dakota. Finally, Mundy exposes a company memo condemning a potential warning label on fen-phen concerning heart and lung damage because it would cost Wyeth-Ayerst $800 million in revenue.
Dispensing with the Truth is a page-turning courtroom drama that never slows down, but it is also an unflinching account of a case in which it appears that profits were more important than patients.