Levaquin causes tendon rupture

Was it too lucrative for its makers to warn patients?

The experimental pill contained half the molecular structure of ofloxacin, a heavy-duty antibiotic used to treat pneumonia and severe infections. In Japan, the drug had been on the commercial market for two years.

Under the microscope, ofloxacin resembled a butterfly, with left and right halves mirroring one another. The researchers had simply lopped off the left side—called the L-isomer—and the six men ingested it in pill form.

Blood drawn from the six volunteers yielded a promising result: It appeared that the left wing of the butterfly behaved almost identically to the joined pair.

Over the next several years, scientists in Japan performed dozens of tests, experimenting with the new drug on mice, rats, monkeys, dogs, chicken cells, and, eventually, people. Most of the tests were paid for by Daiichi Pharmaceuticals, the Tokyo-based firm that held the patent for the parent drug.

Daiichi was already making millions from sales of the older medication. So was Aventis, its distribution company in Europe, and Ortho-McNeil-Janssen Pharmaceuticals, the division of Johnson & Johnson distributing the drug in the United States.

But if the new drug worked, all three companies stood to make a small fortune.

"Ortho-McNeil realized that all the chemical activity was coming from the L-isomer," says John C. Rotschafer, a professor of experimental and clinical pharmacology at the University of Minnesota. "It probably would extend the patent of the product."

Japanese-funded scientists confirmed the work of the Germans. They also discovered more exciting results: Not only did the new drug behave like its parent, it appeared to reduce problems in the central nervous system the older drug caused when taken with drugs like aspirin.

In 1993, Daiichi introduced the new drug—its scientific name is levofloxacin—to the market. The Japanese company reached agreements with Aventis and Johnson & Johnson to distribute overseas. There were plans to expand to Finland, Argentina, and South Africa.

Johnson & Johnson dubbed its product "Levaquin" and saw it as a potential cash cow. Internal company documents reveal that the firm's strategists set an ambitious vision for their product: "To be the number one Anti-Infective in total sales by 2005."

  

JUST OFF HIGHWAY 202 in Raritan, New Jersey, a short road curves toward a thick wall of trees. Behind this curtain of green lies a million-square-foot compound: the headquarters of Ortho-McNeil-Janssen Pharmaceuticals.

In early January 1997, Katie Rielly-Gauvin stood in the sales training area and practiced her speech. A chemistry grad with an MBA, Rielly-Gauvin had worked on the Levaquin clinical trials. Now she was helping with the American launch of the drug. Soon she'd be in Palm Desert as part of a team explaining Levaquin's benefits to a roomful of sales reps.

Over the course of several days, Rielly-Gauvin rehearsed her presentation three times, according to court documents. The company was betting $46.5 million—75 percent of Ortho-McNeil's marketing budget—on Levaquin.

"Levaquin is an exciting new addition to our great product line," an inter-office memo proclaimed to Rielly-Gauvin. "You are a vital part of successfully introducing Levaquin to our field staff."

Together, marketing and sales carefully crafted their take-home message to doctors: Levaquin was proven to be safe. After years on the Japanese market plus the American clinical trials, 63 million people had tried the drug with no side effect more severe than diarrhea or nausea, marketing claimed, according to court documents.

The message resonated, and in its first year, Levaquin sales hit a jaw-dropping $135.9 million, quickly becoming Ortho-McNeil's most lucrative product. By 2000, sales were seven times that, topping $1 billion.

Even for a new drug, this was a rocket's pace. Bayer A.G.'s Cipro, Levaquin's toughest competitor, had taken more than a decade to reach the same mark.

When Rielly-Gauvin's tireless promotion was recognized with a prestigious sales award and a big promotion, she knew whom to thank for making Levaquin's success possible: Dr. Chuen L. Yee.

An Ivy League-educated physician, Yee was responsible for monitoring drug safety and suggesting a response to senior management. She communicated often with the company's global partners, Aventis and Daiichi, who created an international reporting database so that each company would be notified of any adverse event within one week.

Around the same time that Levaquin became Ortho-McNeil's top drug, a troublesome study emerged from the Netherlands.

The report concluded that the most toxic of the fluoroquinolones—the class of medications that included Levaquin—was none other than Levaquin's parent drug.

This could potentially be a big problem. In its initial application to the FDA, Johnson & Johnson had claimed Levaquin was just like its parent. Now the latest research said the parent drug was the most dangerous to tendons of any drug in its class.

"The noise level about spontaneous tendon rupture started to increase," says Rotschafer, the experimental and clinical pharmacology professor at the U.

Though the original labeling for Levaquin mentioned the possibility of tendon rupture, the information was in tiny print on the third page of the label, at the end of a long list of potential hazards.

In June 2001, an email arrived in Yee's in-box bearing some disturbing news: French regulators were launching a national safety inquiry. Only eight months after the drug—known as Tavanic in Europe—had debuted on the French market, 33 people had ruptured their tendons. The French wanted Aventis to investigate why.

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