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Real-World Issues: Fen-Phen

What is now called the “fen-phen” issue refers to the combination of fenfluramine and phentermine. Both products had long been approved (in 1973 and 1959, respectively) by the U.S. Food and Drug Administration (FDA) as appetite suppressants.

Reports in the literature of pulmonary hypertension and fenfluramine appeared in the 1980s and 1990s. Reports of headache, insomnia, nervousness, irritability, palpitations, tachycardia, and elevations in blood pressure were seen with phentermine. Few long-term data were available for the use of these drugs at the time.

The combination of fenfluramine and phentermine was never approved by the FDA, and their use was “off-label.” However, millions of prescriptions for their use were written (Diet pills redux [editorial]. N Engl J Med. 1997;337:629–630).

After this increased use, reports of toxicity started to appear. One report cited the death of a 29-year-old woman after only 23 days of the combination (Mark, Patalas, Chang, et al., N Engl J Med. 1997;337:602–606). Also in 1997, the Mayo Clinic reported 24 women who developed valvular heart disease (mitral, aortic, and tricuspid, sometimes more than one valve) after a mean of 12 months of combination therapy (with one woman using the drugs for only 1 month). One third had pulmonary hypertension, and several required valve surgery (Connolly, Crary, McGoon, et al., N Engl J Med. 1997;337:635). Valvular disease with only fenfluramine or only dexfenfluramine was also reported.

By November 1997, the Centers for Disease Control and Prevention reported 144 spontaneous cases of fenfluramine or dexfenfluramine with or without phentermine producing valvular disease. Reports of abnormal echocardiograms in fen-phen or dexfen-phen patients were received by the FDA. They noted 30% abnormal echocardiograms in 291 asymptomatic screened patients, primarily with aortic regurgitation. Many of the patients were women.

Fenfluramine and dexfenfluramine were withdrawn from the market in late 1997. Phentermine was not withdrawn because no cases were reported to the FDA with this drug alone (as of September 1997).

The FDA noted in its Q&A of September 1997 (Web Resource 48-1) that because valve disease is not usually associated with drug use, it was not screened for in patients and no cases were detected in 500 patients in a 1-year clinical trial. It noted that the link between symptoms and drug use was not “obvious.” In addition, there were few animal data to suggest this toxicity, and early on most patients and physicians did not give too much thought to pulmonary toxicity with these drugs.

After this publicity, not surprisingly, many new cases were noted and lawsuits were filed. In October 1999, the manufacturer agreed to a class action settlement of up to $4.75 billion. A trust was established by the manufacturer by order of the U.S. District Court to administer the claims and payments of benefits to registered class members, providing for benefits including refunds for the costs of Pondimin and Redux, medical monitoring and some medical treatment or payment for monitoring and treatment, and compensation for specifically defined valvular heart conditions. Several safety lessons were learned:

• Untested combinations of approved products may be quite dangerous even if the individual products are not—and especially if the individual products are.
  
• Old products are not always “well known” or studied.
  
• Old safety lessons or safety clues may be minimized or forgotten.
  
• Unintended consequences (AEs) may occur at any time (see fialuridine, Chapter 52, and diethylstilbestrol, Chapter 6) in an unexpected organ system or patient.
  
• Dose matters. But sometimes it does not.
  
• “Absence of evidence is not evidence of absence.” That is, just because there is no finding of a particular AE or disease in clinical trials or patients treated with a drug does not mean that it was sought. And if it was sought, it might not have been sought in the right patients at the right time with the proper diagnostic tools and tests.
  
• Companies, physicians, and regulators should be very careful about off-label use, and better ways to monitor their effects need to be developed. There are many valid medical reasons for certain off-label uses, especially in oncology, but extreme care must be exercised, particularly when there is no clear clinical or scientific basis for such use.
  
• Intelligent and clever clinicians can still discover serious drug AEs in the course of their daily practice. Such serious AEs should indeed be reported to the health authority or company.
  
• Drug usage, when popular and extrapolated to the populations of North America, Europe, Japan, and elsewhere, can produce enormous benefits to individuals, healthcare practitioners, and society. It can also produce major disasters.

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