Levaquin causes tendon rupture

Was it too lucrative for its makers to warn patients?

In the moment just before it happened, John "Bob" Schedin was sitting calmly in his Edina living room, reading the paper just as he had for 50 years.

But this time, when he went to stand up, an excruciating pain ripped through the back of his ankle.

Bob fell back onto the sofa. It felt like a knife was sawing into his left Achilles tendon.

"I can't get up," he hollered to his wife.

Vicki walked into the room. Her 77-year-old husband never complained, so she knew something must be seriously amiss.

"What's wrong?" she said.

"I can't stand up."

"You better call the Medica nurse hotline," she urged.

Bob punched in the number and reached a nurse named Sally.

"Can I help you?" Sally asked.

Bob explained his sudden ankle pain.

"Are you taking any medication?" Sally asked.

Bob told her he was taking Levaquin and a steroid, which his doctor had prescribed three days earlier for a pesky upper respiratory tract infection.

"Hold on a moment, please," Sally said.

After several minutes, she returned to the line.

"Stop taking Levaquin," she said. "It can rupture your tendons. And call the doctor in the morning."

Bob stopped taking the drug. But over the next several days, the pain didn't go away. So he called for another appointment.

When the physician saw Bob's tender, painful ankles, he prescribed physical therapy. But after four sessions, Bob didn't feel any better.

This time, the physician said, he would need an MRI.

The images revealed that the damage was far worse than Bob had anticipated. His right Achilles tendon was shredded to half its natural thickness, and the left one was hanging together by just a few fibers.

Bob's tendons never fully healed and he must constantly wear a brace just to get around.

"I used to walk two miles a day in Southdale in the winter," Bob recalls wistfully. "Now I'd love to walk 30 feet."

  

HOLDING ALOFT A medicine bottle, Congressman Edolphus Towns of Brooklyn, New York, leveled his complaint.

"Every time we give our children or grandchildren medicine like this bottle of children's Tylenol that was included in the recall, we expect it to be safe, and we expect it to help the children get better—not create problems for them," he said.

It was May 2010, and Johnson & Johnson was before a House investigatory panel, defending itself against increasing evidence that the company's safety controls were in shambles. The House had convened the special hearing after the medicine maker recalled more than 136 million bottles of liquid children's Tylenol, Motrin, Benadryl, and Zyrtec amid suspicions that they were contaminated.

Worse yet, it looked like the pharmaceutical company had delayed reporting the problems to the FDA. In one case, Johnson & Johnson hired a private contractor to quietly pull Motrin from store shelves—effectively launching a secret recall. Now, the FDA was considering fines.

The May hearings were just the beginning of the company's publicity woes. In August, it announced a recall of millions of one-day contact lenses from store shelves in Asia and Europe after consumers in Japan complained of stinging eye pain. Two days later, the firm disclosed that it was pulling two popular hip implants after discovering the devices had an unacceptably high failure rate, requiring a second surgery.

This year, the pharmaceutical giant is facing allegations that it paid nursing homes to boost sales of its anti-dementia drug, which was later shown to speed death. And it confessed to bribing doctors in Europe and paying kickbacks to the regime of Saddam Hussein, for which the company had to pay $70 million in fines.

In 1886, Johnson & Johnson set out on a mission to make the world a more sanitary, healthy place with the first commercially available sterile bandages in the United States. Over the years, the company built an image of trust with products designed for children, like No More Tears baby shampoo, and Tylenol, the first prescription aspirin-free painkiller. The corporation gave Americans dental floss, Listerine, and haloperidol, an early medication to treat schizophrenia.

Today, the bandage maker from New Brunswick, New Jersey, has ballooned into a Fortune 500 company with revenue of $61.6 billion and 250 subsidiaries in 60 countries.

But a lawsuit in Minnesota threatens to further tarnish the company's once-pure reputation.

The case alleges that Johnson & Johnson understood that Levaquin was more likely to cause tendon rupture than other drugs, and that the company did not adequately warn doctors. Hundreds whose lives have been devastated by ruptured tendons have joined the suit.

"Johnson & Johnson has been a company that has long been the gold standard of ethics for many, many years," says Bill Trombetta, a professor of pharmaceutical marketing at Saint Joseph's University in Philadelphia. "It looks they stubbed their toe on this one."

   

INSIDE A MASSIVE red brick industrial complex along the bank of a tributary of the Rhine that runs through Frankfurt, six healthy men lay inert.

It was January 1987, and the scientists of Hoechst AG were performing an important experiment. The men—all employees of the pharmaceutical company—had signed up to be subjects in a clinical trial that had the potential to generate millions.

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.

Yee immediately responded, copying her colleagues at Daiichi in Japan. What happened in France could have a ripple effect on the entire continent and possibly trigger a safety inquiry by the Americans at the FDA. The three firms scheduled an emergency meeting in New York to discuss how to handle it.

  

THE KITANO HOTEL on Park Avenue in New York offered an East meets West atmosphere that formed the perfect backdrop for a meeting of scientific minds from Europe, the United States, and Japan.

But in July 2001, there was little time for soaking up the ambiance. The top drug safety executives from Daiichi, Aventis, and Ortho-McNeil had urgent matters to address.

Dr. Céline Melcion, head of global regulatory approval for Aventis, spelled out the timeline: The companies had a scant two and a half months to convince French regulators that the drug was safe. Great Britain and Belgium had also entered the fray, asking Aventis to compare the risks of its product with similar antibiotics. If the companies failed to make a strong case, Europe might restrict the drug—or ban it entirely—as soon as October.

But Aventis had a plan. Since the drug had been on the international market for many years, the company proposed an epidemiological study quantifying the medication's link to tendon problems. Researchers could simply crunch data from the millions of people who'd already taken the drug.

"The ability for retrospective studies—once a drug is on a market—can be very useful, in terms of ongoing assessment of value," says Stephen Beckman, president and general manager of the North American division of Pharmaxis, an Australian pharmaceutical company.

There was just one small problem: The databases in Europe were too small to produce conclusive results.

So Aventis planned to use data from the United States. When the Johnson & Johnson scientists heard that idea, they quickly objected. If Aventis's study yielded a connection between Levaquin and tendon rupture, the American market would be ruined.

The emergency session ended in a holding pattern. Aventis agreed to come up with a proposal for the epidemiological study and distribute it to the Americans and the Japanese for review. Billons in sales were riding on the outcome, so all the companies wanted a say in the final decision.

Two days later, Yee met with her colleagues—physicians, drug safety officers, and business development execs—back in New Jersey to plot a takeover. There was no way Johnson & Johnson was letting Aventis run this important study. According to the internal minutes from the company's defensive huddle, the study "if not conducted by J&J might be inappropriately designed, with consequences in the U.S. This will need to be managed."

By August, an Aventis epidemiologist named Drew Griffin Levy sent out a draft of the study protocol. The plan was simple enough: Levy suggested first taking a look at fluoroquinolones—the overall class of drugs that included Levaquin—and then evaluating how dangerous Levaquin was compared to the rest.

But Johnson & Johnson didn't like the Aventis proposal.

"We need to assure ourselves and Daiichi that the design of any such study is entirely appropriate, and that it will answer the question that needs answering," wrote Dr. Neil Minton, one of Yee's colleagues, "and that it will cause no harm to the product by asking the wrong questions."

Ortho-McNeil hired Ingenix, an Eden Prairie firm, to come up with an alternate study proposal. Ingenix suggested using the United Health Care database to find medical records indicating tendon repair, and to use that information to figure out the risk factors for tendon rupture among patients using the drug.

The scientists from the American company convinced their European partners that this study design was superior. They even agreed to pay for the contractor to do the work, even though the results would be used primarily in Europe.

In mid-September, as the contractors worked on their proposal, Kendall Qualls, the product director for Ortho-McNeil's line of anti-infectives, sent out an email to his colleagues. He explained that because of the French situation, the company was adding a sentence to Levaquin's FDA label that acknowledged the increased risk of tendon rupture while taking steroids.

Despite the label change, there would be no formal announcement to the employees peddling the drug, nor any alteration to the package insert, or P.I.

"There is no need to conduct teleconferences with the Field Sales Force regarding this issue," Qualls wrote. "Verbal communication to make the sales force aware will suffice. We will update the P.I. once inventories are depleted."

By late October, the Ingenix proposal was ready. Aventis used it to convince the regulators to wait for the final results before scaring European doctors with possibly unnecessary warnings.

While Ingenix worked feverishly to complete the study, Tavanic was under siege in Europe. French regulators sent a letter to doctors warning them that it could lead to cases of tendonitis and even tendon rupture. Italy mailed a similar note. And Belgium told doctors the drug should be used only for battling community-acquired pneumonia in patients who were allergic to other types of antibiotics.

Meanwhile, the firm's international database of adverse events was building a private record of the factors that led to tendon rupture. By the end of the year, Johnson & Johnson quietly added the sentence to the Levaquin label noting that the risk might be elevated in people taking steroids, especially the elderly.

In May 2002, Great Britain's version of the FDA, the Medicines Control Agency, proposed changing the drug's label to say that it was more damaging to tendons than other drugs in its class. If that happened, no British doctor in her right mind would continue prescribing it.

Aventis convinced the regulators to hold off just a bit longer—long enough to see the results of the American study.

Two months later, Ingenix completed an interim study report and handed over the findings. They turned out to be quite fortuitous for companies selling the antibiotic, revealing no greater risk in taking it than with any other drug in its class. In fact, compared to the rest, Levaquin's parent drug—which was supposedly nearly identical to Levaquin—was the drug least likely to cause tendon problems, according to the report.

With this tentative conclusion in hand, Aventis got the European regulators off its back.

Almost a year later, Ortho-McNeil sent its near-final report to its partners for review. The response from Aventis was more shock than pleasure.

"I was surprised and puzzled by the results of this report and by some of the conclusions derived from the findings," wrote one of the Aventis reviewers.

Nonetheless, Tavanic had managed to avoid having to add a warning to its label. The final report of the Medicines Control Agency recommended "[n]o further action given the rarity and non-lethality of adverse reaction."

Triumphant, Johnson & Johnson prepared its research for publication in a lauded peer-reviewed journal. The company submitted an explanatory poster to a noted microbiology conference in the nation's capital, and it created a press guide to be sure journalists got the story straight.

"There is enormous commercial risk if these presentations are misunderstood," wrote David Grewcock, director of marketing for Levaquin, in an email to his colleagues. "We need to clearly explain everything from why the studies were conducted to what the results mean."

  

AT THE BOTTOM of a document printed on official letterhead, Drs. Arnold Widen and Babs Waldman penned their names.

It was May 2005, and the two physicians were urging the FDA to require a black box warning for drugs like Levaquin.

As medical directors for the Illinois Attorney General's Office, they knew they had a strong case against Levaquin. For months, they'd been hearing complaints from patients who'd suffered ruptured tendons while taking the drug.

"On behalf of the Office of the Illinois Attorney General, we are writing to you to request action by your agency in regard to a medication side effect, which although already recognized, is not well-known by practicing physicians and other health care professionals," the doctors wrote. "We are referring to the condition of fluoroquinolone-induced tendonopathy, including actual tendon ruptures, which can be multiple, can cause severe and protracted disability, and can require surgical correction."

The evidence against fluoroquinolones was stacking up. One case study described an 80-year-old man in France whose left Achilles, right rotator cuff, and left biceps tendons all ruptured after he took Tavanic. Another report confirmed the significant risk of rupture in patients taking drugs like Tavanic with steroids, especially the elderly.

Meanwhile, Ortho-McNeil was targeting a lofty list of publications for its Ingenix study, including the New England Journal of Medicine, The Lancet, and JAMA.

But the best journals turned the paper down.

Finally, in June 2005, the less prestigious Pharmacoepidemiology and Drug Safety agreed to publish the Ingenix findings. But the editors told the authors to acknowledge what might be a major shortcoming in the study's design.

A common problem with using insurance databases for epidemiological studies is that the medical codes that doctors write in patient charts do not always reflect the final diagnosis. A physician might jot down the code for tendon rupture in the chart of a patient who has only a sprained ankle, for example, because the doctor wants to rule out tendon rupture with an X-ray.

The only way to be sure that the code mirrors the diagnosis is to review each chart by hand. But Ortho-McNeil didn't have time to do this.

Instead, the Ingenix team created an algorithm that was supposed to accurately predict which records in the database were real tendon ruptures, and which were false reports.

The algorithm was based on the company's review of a random sample of 328 of the medical records. For each chart, the researchers visited doctor's offices and pulled the hard copy, carefully confirming the diagnosis.

They found out that only 58 percent of the sample records were the kinds of Achilles tendon rupture they wanted to count. The rest were mostly rule-outs and ruptures due to trauma—weekend warriors wrenching their heels.

The results from the sample helped Ingenix craft an algorithm it then applied to the rest of the records. But as the journal editors noticed, this approach comes with a potential flaw: It could make the connection between tendon problems and drugs like Levaquin appear smaller than it actually is.

The final version of the study found that people taking drugs like Levaquin were 1.2 times (or 20 percent) more likely to rupture their Achilles tendons than people not taking such drugs. But if the flaw that the journal editors flagged was indeed present, that rate could be a gross undercount.

"In other words, the weak association of 1.2 could be stronger and point to the drug as a risk factor for Achilles tendon rupture," says DeAnn Lazovich, a professor of epidemiology and community health at the University of Minnesota, "but we cannot know for sure because the observed association is fairly weak."

There was another, more serious problem with the study results.

In research, every study is assigned a "power," which describes the study's ability to compare groups and draw significant conclusions. This is calculated by a number of factors, including sample size. If a study's power is low, then it can't properly measure what it purports to track—its results could be nothing more than random noise. The Ingenix study's power was low.

A second measure of a study's reliability is its confidence interval, a numerical range that represents the trustworthiness of the results. The confidence interval is written as two numbers, with a dash between. If the range between the numbers is small, researchers consider the study results reliable. If the range is broad, the results are less certain.

In the Johnson & Johnson study, the confidence interval was 0.9-1.7. Statistically speaking, that's a gap the size of the Grand Canyon. But more importantly, the range includes the number 1.

"Any test where the confidence interval includes 1.0 is generally considered non-significant," explains Russell Luepker, a Mayo Professor of Public Health at the U, "whether from inadequate power or the lack of a real difference."

The greatest criticisms of the study came directly from Aventis, and they had to do with the study's design, which systematically eliminated the elderly—precisely the population most at risk.

"The elderly population is under-represented," wrote Carla Canabarro, one of the doctors at Aventis. "Regarding age distribution, the Ingenix research database population does not reflect the elderly age group as per the United States 2000 census population."

The study algorithm had also eliminated tendon ruptures in old people at a higher rate than the overall group.

By January 2008, with no substantial response to the petition for a black box warning from the doctors at the Illinois Attorney General's Office, consumer watchdog advocacy group Public Citizen sued the FDA, demanding that it mandate the warning.

"These stronger warnings to doctors and patients could lead to earlier intervention to stop tendon pain from progressing to frank tendon rupture by changing to other antibiotics," the lawsuit read. "Therefore, to protect public safety and prevent needless injury, Public Citizen seeks a declaration that FDA has acted unlawfully by withholding action."

By the end of the year, the FDA required Johnson & Johnson—and all makers of antibiotics like Levaquin—to add a black box warning to its label.

Vicki Schedin was watching television one day when a commercial caught her ear. A lawyer was looking for people who'd taken Levaquin and ruptured their tendons.

"Give us a call," the television voice intoned.

Vicki rushed to tell her husband.

A few days later, Bob phoned the hotline from the TV. He reached a receptionist who was working for Lewis J. Saul, an attorney in Portland, Maine, who had been prescribed Levaquin and suffered tendon problems himself. Saul was suing Johnson & Johnson.

Last fall, Schedin, now 83, was the first plaintiff in a series of lawsuits in the massive case against the drug maker. The jury awarded him $700,000 in compensatory damages plus $1.1 million in punitive damages.

Next week, another trial begins in federal court in Minneapolis before Judge John Tunheim. It is the second of six cases slated to be tried as part of the complex litigation.

The central issue at trial is whether Johnson & Johnson adequately warned doctors about the risks of taking Levaquin. The company argues that the warning was sufficient.

"We want to make clear that ever since it was first approved by the FDA in 1996, the LEVAQUIN label, in addition to the labels for the wider class of fluoroquinolone antibiotics, has included warnings about tendonitis and tendon ruptures," William Foster, a Johnson & Johnson spokesman, told City Pages in an emailed statement. "This risk was well known to prescribers."

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