It has taken Barbara Odanaka, 52, four years to feel better. In the beginning, lifting a mug of coffee stressed the tendons in her wrist and caused excruciating pain. Gripping her cellphone for 10 or 15 seconds risked a burning sensation, as if lava were flowing beneath her skin. She couldn’t lift her cat or open jars or, on bad days, squeeze toothpaste from a tube. Walking, she says, felt as if shards were cutting her feet. The pain was cyclical, at times striking her biceps, knees and Achilles tendons.
Odanaka had — and still does, to some degree — fluoroquinolone toxicity, a disorder of the musculoskeletal system. Simply put, Odanaka says, a drug poisoned her.
She was hospitalized and deathly ill with pneumonia when her doctor prescribed levofloxacin, known by the brand name Levaquin. It is an antibiotic in the fluoroquinolone drug class that is used to treat nasty bacterial infections. What was not explained, she says, were the drug’s potential side effects: It can damage tendons, cartilage, bone and muscle, and affect the cardiovascular and central nervous systems. No one can predict who is vulnerable.
“Right away, within 24 hours, I started feeling like I had carpal tunnel,” Odanaka says. “I had crazy, burning pain.”
She is a children's book author, a former Los Angeles Times sports reporter who once was an athlete. She surfed the waves near her home in Laguna Beach, Calif. She founded the International Society of Skateboarding Moms. After enduring so much uncertainty and pain, she hopes the good days will last.
Fingers crossed, she is back on her skateboard, even though a bad fall could re-injure her tendons. “I’m not going to let this thing steal my whole life from me,” she says.
Odanaka’s story illustrates the risks that can accompany drugs, risks that can range from temporary discomfort to injury, disability and even death.
Levofloxacin ranked third and another fluoroquinolone, ciprofloxacin (often known by the brand name Cipro), ranked fifth in the number of serious adverse event reports submitted directly to the Food and Drug Administration in 2013, according to the nonprofit Institute for Safe Medication Practices. The blood thinners warfarin and rivaroxaban ranked first and second.
“Fluoroquinolones are near the top of this ranking year after year,” says Thomas Moore, a senior scientist at the institute. “We know that people are getting seriously injured. How well are we managing the risks of these drugs? Are there safer alternatives? These questions need to get asked and answered.”
The FDA declined to comment directly about fluoroquinolones, but it offered this statement: “We can assure you that the FDA takes concerns raised about the safety of approved drugs very seriously. Based on an evaluation of the potential safety concern, FDA may take regulatory action(s) to improve product safety and protect the public health, such as updating a product’s labeling information, restricting the use of the drug, communicating new safety information to the public, or, in rare cases, removing a product from the market.”
Beatrice Golomb, a professor of medicine at the University of California at San Diego, says that fluoroquinolones can be far more disabling than other antibiotics.
“It’s true that every antibiotic class has the potential for some problems, but in many cases they are curable,” Golomb says. “These people seem to be left with a life-altering situation from which many years out they haven’t recovered.”
She and colleagues at UCSD are enrolling volunteers in a large study of fluoroquinolone's effects. "The reason we should care is that many of these problems are needless sources of permanent, horrifying, life-altering effects that did not need to happen," says Golomb, referring to the inappropriate use of fluoroquinolones when safer treatments might work. Most worrisome is how symptoms progress, she says, describing how someone with a painful or ruptured tendon might later report neurological, psychiatric or intestinal problems.
“They continue to develop and accrue multiple disabling symptoms across many domains in a fashion that turns formerly high-functioning athletic and intellectual people into disabled people who can’t contribute to their family.”
Assessing the risk
There is no dispute that antibiotics save lives, but the Centers for Disease Control and Prevention estimates that up to 50 percent of prescriptions for these drugs may be unnecessary or ineffective because they are written for colds, flu or other viral conditions that do not respond to antibiotics.
In 2011, health-care providers prescribed 263 million courses of antibiotics, or 842 prescriptions for every 1,000 people seen in outpatient settings in the United States. Fluoroquinolones accounted for 11 percent of those prescriptions.
Several studies document fluoroquinolone misuse. One, reported in the journal BMC Infectious Diseases, found that almost a third of the 227 fluoroquinolone regimens given to patients at a Cleveland hospital were for urinary syndromes where antibiotics were not warranted. Half of the fluoroquinolone patients used the drug for longer than guidelines recommend. Of the regimens that were warranted, the study's authors said, most could have been replaced by a drug associated with fewer side effects.
As for Odanaka, she is just one statistic among thousands who claim injury by fluoroquinolones. RxISK.org, an independent Web site run by researchers who download data from the FDA's Adverse Reporting System, compiled a list of more than 80,000 adverse drug reactions, including about 1,000 deaths, that were possibly associated with levofloxacin in roughly the past 10 years. The FDA data comes from patients and health-care professionals — whose reports of adverse reactions are voluntary — and from drug manufacturers, which are required to report.
Tendon ruptures top the list. Also reported, although infrequently, are disorientation and convulsion, nervous system disorder, anxiety, ringing in the ears, burning and tingling sensations, gait disturbance, difficulty breathing, cognitive issues and weakness. Fluoroquinolone labeling required by the FDA warns of the potential for disabling peripheral neuropathy or permanent nerve damage to the arms and legs, eye disorders, psychiatric and nervous system disorders, and seizures.
The FDA has kept an eye on fluoroquinolones, and drug manufacturers have pulled several from the market in recent years.
Of those remaining, the most-prescribed is Cipro. Some know it as the drug given to U.S. troops during the 1991 Persian Gulf War to protect against an anticipated chemical weapon attack. During the anthrax scare of 2001, thousands of workers at the Postal Service, the Capitol and the White House were prescribed Cipro to counteract possible exposure.
Cipro is linked to 79,000 reports of adverse events, including 1,700 deaths during the last 10 years. (Such reports are not verified by the FDA, which notes that they "do not always contain enough detail" to be properly evaluated.) Less frequently prescribed is moxifloxacin, whose brand names include Avelox. It had 900 reported deaths during the same period.
According to data accessible at RxISK.org, reported adverse events for fluoroquinolones far exceed those for other antibiotics such as penicillins, macrolides (erythromycin), tetracyclines and trimethoprim-sulfamethoxazole.
Thanks to petitioning by the advocacy group Public Citizen, all fluoroquinolones began carrying a boxed warning about the risk of tendinitis and tendon rupture in 2008. A black border — the FDA's strongest warning of risk — frames the cautionary words in the drug prescribing information directed at doctors. Also in that box is an alert that warns of greater risk for people older than 60, for those taking corticosteroid drugs or steroids, and for anyone who has had a kidney, heart or lung transplant. People with myasthenia gravis or muscle weakness are advised not to take fluoroquinolones.
Manufacturers defend their products. In response to a request for comment on the safety of Levaquin, Janssen Pharmaceuticals of Johnson & Johnson said all medicines, Levaquin included, have benefits and risks.
“Levaquin (levofloxacin) is part of the important fluoroquinolone class of anti-infective prescription medications that have been used for more than 20 years to treat infections, including those that may be serious or life threatening,” the statement said. “We continually collect and monitor information on the safety and effectiveness of all our medicines, and, in cooperation with the U.S. FDA and other health authorities, we incorporate new data into our product labels so doctors and patients can make informed decisions.”
Bayer, the maker of Cipro and Avelox, said in a statement: “We have sympathy for anyone experiencing medical problems, regardless of the cause. We maintain accurate product labels that share information about the benefits and risks associated with fluoroquinolone use, and report all adverse events we learn about to the FDA.”
The scope of injuries is hard to capture, because only a fraction of reports may reach the FDA. Researchers in one study looking at the incidence of side effects from four drugs said that just 1 percent to 15 percent of adverse effects were reported.
The FDA says it can’t require doctors to report because it is the responsibility of state medical boards to regulate the practice of medicine. And if a patient is on several medications, it may not be clear to the doctor which one is causing a negative reaction.
“The vast majority of physicians don’t even know how to report side effects to the FDA. They don’t have a clue,” says David Flockhart, head of the Department of Clinical Pharmacology at the Medical School of Indiana University. “And there’s a psychological resistance to believing that what they’ve done has hurt.”
Such Facebook groups as Fluoroquinolone Toxicity and Fluoroquinolone Wall of Pain, and such Web sites as Floxiehope.com and Saferpills.org offer support to patients. Together, thousands of “floxies,” or “floxed,” as they call themselves, share a good deal of rage.
“The crime is heinous beyond imagination,” says Mark Girard, an activist in Ottawa, “destroying patients’ bodies and their minds and leaving them high and dry facing a medical community that laughs in their faces when we suggest these gold-standard drugs did all this harm.”
Several patient sites speak of those who have died. Among them is Chris Dannelly of Duluth, Ga., who took levofloxacin for flulike symptoms. Five days later he was dead of rhabdomyolysis, a condition that breaks down muscle tissue. The autopsy report listed “an adverse outcome to this drug” as a cause of death. Dannelly was 41 when he died in 2013.
Bob Grozier of Allentown, Pa., took ofloxacin. He followed that with Cipro along with Vioxx, a now-recalled nonsteroidal anti-inflammatory, or NSAID. He was unaware of an FDA warning that taking an NSAID with fluoroquinolones may increase the "risk of central nervous system effects and seizures." Grozier suffered a psychotic break after taking the drugs and lived for 12 years with brain damage, his mother says. He died last year at 55 from a host of medical problems she attributes to his downward spiral.
Journalist Stephen Fried wrote a book, "Bitter Pills," about the pharmaceutical industry and what happened to his wife, novelist Diane Ayres, who ended up in the emergency room after taking a single dose of fluoroquinolone for a urinary tract infection. She survived but suffered a maze of psychiatric symptoms.
Outpatient pharmacies are required by law to provide consumers with medication guides when they fill prescriptions for drugs that, according to the FDA, "pose a serious and significant public health concern." Tablet and injectable forms of fluoroquinolones are among those drugs. The FDA does not mandate that all hospitalized patients receive guides, so inpatients who do not request them may never hear about the risks of the drugs they are given.
The warning about tendon rupture and other effects is in the guides, which take the place of the package inserts that come with other prescriptions. The guides are required to be written in nontechnical language and do not have the black border, or box — although the warning is visible on DailyMed, the drug-labeling Web site managed by the National Institutes of Health. That graphic, which the FDA uses to flag drugs as high-risk, is intended for physicians.
But doctors don’t necessarily pay attention to boxed warnings, says Jeffrey Linder, an internist at Brigham and Women’s Hospital in Boston. “The reality is, we get so many of them that they wind up just getting ignored. It’s all just noise,” he says.
So how dangerous are fluoroquinolones? Flockhart and other experts say the risk of injury is low, and they point to the millions of prescriptions written for fluoroquinolones each year without incident.
In a large Italian study, researchers found that patients treated with fluoroquinolones were up to four times as likely to rupture an Achilles tendon as were those who did not get these drugs.
Some have sued. At least 3,400 cases, which were consolidated into two multi-district lawsuits, have been filed in federal and state court against Johnson & Johnson since 2006.
Plaintiffs claim that the company failed to adequately warn physicians of the risk of tendon injuries associated with Levaquin, a drug with about $1.3 billion in sales in the United States in 2010. Most cases have been settled or dismissed.
Separately, about 60 product liability cases are pending in federal court against Johnson & Johnson and against Bayer for Cipro and Avelox, alleging their products caused irreversible peripheral neuropathy or nerve damage and were sold without adequate warnings of risk. Helping coordinate the effort is the patient advocacy group Quinolone Vigilance Foundation.
Rachel Brummert, executive director of the foundation, says the pharmaceutical industry should do more to warn physicians of the risk of injury. “Doctors are largely in the dark,” she says. “The few patients who are warned are not told that these adverse reactions can be permanent.”
Most doctors rarely sit down with patients to discuss how effective or toxic a drug might be, says Flockhart, who has been treating fluoroquinolone victims since the 1990s. “It’s something doctors don’t get much training in,” he says.
“It’s true that quinolones have tremendously ignored side effects, but they’re tremendously valuable,” he says, adding that they have saved millions of lives. “In general, they should not be drugs of first choice for bacterial infections. That’s like using a machine gun when you need a peashooter.”
In written statements, the drug manufacturers said that the risks of injury are properly disclosed and that the cases are without merit. Janssen Pharmaceuticals of Johnson & Johnson said prescribing information for Levaquin has warned about the risk of tendon rupture and tendinitis since 1996 and about the risk of peripheral neuropathy for more than a decade.
Bayer said it added timely warnings about Cipro and Avelox side effects and issued warning letters to U.S. health-care providers in 2008 and 2011 to make sure they understood “that sensory or sensorimotor axonal polyneuropathy in patients receiving fluoroquinolones could be permanent.”
Barbara Odanaka, the California skateboarder, and others affected by fluoroquinolones want full disclosure. They want patients to expressly consent to treatment. They want doctors to prescribe the drugs judiciously and only for life-threatening infections where no other remedy exists. They want the FDA to warn doctors and consumers more aggressively about risks.
In Odanaka’s case, the Levaquin was warranted, she says. “The reality is, I was very sick and quite frankly I could be dead if I hadn’t had that drug. . . . It’s harder for me to feel as outraged as people who had their lives completely ruined because they got it for a sinus infection, and with no warnings at all.”
Davidson writes about health and is co-author of "Your Brain After Chemo: A Practical Guide to Lifting the Fog and Getting Back Your Focus."