Fen-phen caused heart damage in 20% of users — American Home Products paid $13B

Fenfluramine was developed in the 1960s and approved by the FDA in 1973 as an appetite suppressant. In 1984, a combination of fenfluramine and phentermine — fen-phen — became a wildly popular off-label weight loss regimen. By the mid-1990s, approximately 5 million Americans were taking fenfluramine or its sister drug dexfenfluramine, with tens of millions more across Europe. The drug was marketed by American Home Products, later renamed Wyeth, under the brand names Pondimin and Redux.

In 1997, a Mayo Clinic study linked fen-phen to valvular heart disease. A subsequent study of 5,743 former users found that 20% of women and 12% of men had heart valve damage — a sevenfold increase in the need for valve surgery. The mechanism was traced to the active metabolite norfenfluramine, which overstimulates 5-HT2B receptors on heart valves, causing uncontrolled cell growth. Fen-phen users were also at elevated risk for primary pulmonary hypertension, a fatal condition.

The FDA requested withdrawal in September 1997. More than 50,000 product liability lawsuits followed. In 1999, American Home Products began settling, and by 2005 the company had set aside $21.1 billion, with total payouts estimated at $13 billion — the largest pharmaceutical settlement in history at the time. The company also faced criminal charges, pleading guilty in 2004 to misbranding the drug. The fen-phen disaster permanently changed how the FDA monitors post-market drug safety.