Sept. 4 (Bloomberg) -- Arthritis and autoimmune drugs marketed by Amgen Inc., Wyeth and Johnson & Johnson must carry stronger warnings about fungal infections tied to more than 45 deaths, U.S. regulators said.

The new cautions, posted today on the Food and Drug Administration's Web site, also apply to Abbott Laboratories' Humira and UCB SA's Cimzia. Market-leading Enbrel, sold by Amgen and Wyeth, J&J's Remicade, and Humira were among the 25 biggest drugs worldwide last year, with $13.5 billion in combined sales, according to data compiled by Bloomberg. They are usually used to treat rheumatoid arthritis.

At least 241 patients have developed histoplasmosis, an infection caused by a fungus found in the Ohio and Mississippi river valleys, in the decade since the first drugs were approved, the FDA said. Forty-five died, including 12 whose doctors didn't recognize the infection and delayed treatment, the agency said. More deaths were reported from other fungal infections, though the FDA wouldn't say how many.

``These infections need to be identified early enough so treatment is not delayed,'' said Jeffrey Siegel, a clinical team leader in the FDA's Division of Anesthesia, Analgesia and Rheumatology Products, on a conference call today with reporters.

The FDA ordered the companies to strengthen existing cautions in a black box in the drugs' prescribing information, the agency's strictest form of caution. They also must educate doctors about the risks and the symptoms of fungal infections. The drugmakers all said in separate statements that they are working with the agency to make the required changes.

Helping Doctors

Highlighting the risks in prescribing information and in communications with doctors will help them ``be more vigilant in watching for these adverse events and better assess the various benefits and risks for their patients,'' New Brunswick, New Jersey-based J&J said in an e-mailed statement.

The new warnings won't hurt demand, because the risks were already known, said analyst Alex To, who covers Thousand Oaks, California-based Amgen for Natixis Bleichroeder.

``We do not think this will specifically impact the sales trajectory of Enbrel, since it is already known that the drug is associated with increasing various infections such as bacterial sepsis and tuberculosis,'' To said today in a note to clients. He recommends buying Amgen shares and doesn't own any.

All of the companies' shares fell amid a broad decline in U.S. stocks. Amgen fell $2.22, or 3.5 percent, to $60.88 in Nasdaq Stock Market composite trading at 4 p.m. On the New York Stock Exchange, Wyeth, of Madison, New Jersey, declined $1.54, or 3.6 percent, to $41.05, and J&J dropped $1.06, or 1.5 percent, to $70.45. J&J's Remicade partner Schering-Plough Corp., of Kenilworth, New Jersey, lost 20 cents, or 1 percent, to $19.16.

Abbott, UCB Fall

Abbott, of Abbott Park, Illinois, fell $1.36, or 2.4 percent, to $56.57. UCB lost 56 cents, or 2.1 percent, to 26.19 euros in trading in its hometown of Brussels before the FDA announcement.

The medicines are approved to treat a variety of conditions, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and Crohn's disease. They work by blocking the inflammatory protein called tumor necrosis factor-alpha, or TNF-alpha. This ``is a double-edged sword,'' Siegel said, since suppressing the immune system also leaves patients at risk for infections.

An estimated 46.4 million people in the U.S. have some form of arthritis, according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Rheumatoid arthritis, the most disabling form of the disease, affects about 1.3 million Americans.

TNF Blockers

Enbrel was the top-seller last year, with $5.28 billion in worldwide sales, while Remicade had $5.21 billion. Both drugs were approved in 1998. Humira, cleared in 2002, brought in $3.06 billion. Cimzia was approved in April for Crohn's disease.

This isn't the first safety warning from the FDA over the so-called TNF blockers. The agency said in June that it was investigating a possible link between the drugs and an increased risk of cancer in children and young adults. That review is still in progress.

To contact the reporter on this story: Catherine Larkin in Washington at clarkin4@bloomberg.net.

Last Updated: September 4, 2008 16:57 EDT