Levaquin and Cipro Side Effects and the Drug Label Problem - The Atlantic
A few days ago, an unusual offer landed in my inbox. "Do you want to interview this man before he ends his life?" read the subject line of the message sent by Linda Martin, who, out of concerns for her safety, would tell me only that she is in her 60s and lives on the West Coast.
She said that John Fratti, a 50-year-old former pharmaceutical-sales representative, was "making plans to end his life in the next few weeks because he can no longer stand the pain caused by Fluoroquinolone Toxicity." That's the term Martin and others use to describe the side effects of fluoroquinolone antibiotics, a class of drugs that includes ciprofloxacin, sometimes called Cipro, and levofloxacin, or Levaquin, which are taken for severe bacterial infections. She added that Fratti had already obtained a powerful sedative that can be used in assisted suicide.
Martin herself took Levaquin multiple times for sinus infections more than a decade ago, and afterward, she said, she developed insomnia, panic attacks, brain fog, digestive problems, tendon issues, weakness, and pain in her arms. Walking and getting dressed became excruciating. She and others who have reported fluoroquinolone injuries call their experiences "getting floxed." More than 20,000 people—admittedly a small fraction of 1 percent of the millions who are prescribed fluoroquinolones—have reported some type of pain after taking the drugs Levaquin, Cipro, or Avelox (or their generics) since they came on the market, according to FDA data. And about 200 people killed themselves after taking the drugs, according to the agency's data, which rely on voluntary reporting by patients and doctors.
Beyond being difficult to ascribe to a single circumstance, suicide is a vanishingly rare outcome for people taking fluoroquinolones, which were until recently some of the most commonly prescribed antibiotics in the United States. No study has proved that taking fluoroquinolones causes people to kill themselves, and the number of fluoroquinolone-associated suicides that have been reported to the FDA is much lower than the U.S. suicide rate would lead one to expect. But in hundreds of cases in which people killed themselves after taking the drugs, either they or their family members blamed the fluoroquinolone at least partially for their death. And the FDA's numbers for post-fluoroquinolone suicides and pain are likely an undercount, since doctors and patients don't tell the agency about every problem patients experience after taking a drug.
Severe drug side effects, rare as they are, can be distressing and even disabling when they happen. For example, birth control containing drospirenone can increase the risk of blood clots compared to other types of contraceptives, but the risk is still fairly low, with only about a tenth of one percent of patients affected. And bupropion, a very common antidepressant, increases the risk of seizures, but other than at very high doses, the seizures occur in fewer than 1 percent of users. All these black swans—people who took a mostly innocuous drug and had a horrible experience—add up to a fairly substantial crowd of individuals who reacted poorly to common medications. You may not have developed scary side effects on Cipro, but it's quite possible that some drug, at some point, did something to you that you weren't expecting, and that, in retrospect, might not have been worth the cure.
[Read: Acne's Wonder Drug Is a Mental-Health Puzzle]
It's hard to say whether knowing about these rare side effects would change the number of patients who urge their doctors not to prescribe them a certain drug. But Martin and other floxed people say that if they had known about the possibility of these side effects, they would have never taken the antibiotics. Though patients currently do get some warnings about fluoroquinolones, she and others feel they aren't enough.
Some researchers have, in fact, proposed a better way for doctors to both understand the potential harms of medications and explain them to patients. But so far, the FDA hasn't been interested in pursuing it. Implementing this system might help all sorts of patients—not only those who have been floxed—better comprehend the relative harms and benefits of the drugs they're taking. And for a small number, it might help prevent the type of anguish that Martin and others experience every day.
The floxed are right about the severity of fluoroquinolone risks. The drugs have been tied to tendon rupture, aortic rupture, hypoglycemia, C. difficile infections, mental-health issues, heart-valve problems, and nerve damage, but in fewer than 1 percent of people who take them. In a 2015 meeting, FDA officials presented data showing that fluoroquinolones were more likely to be associated with disabling side effects than other types of antibiotics. For a very small number of the floxed, the medications seemingly prompt a temporary psychotic episode, during which they, say, step in front of a semitrailer or jump out of a window. In all, as of 2015, more than 60,000 people had reported "serious adverse events" associated with five fluoroquinolone antibiotics since the 1980s, when they were developed.
Until very recently, doctors prescribed fluoroquinolones far too often, seemingly unaware of the medications' dark side. A CDC study found that in 2014 doctors prescribed the drugs 31.5 million times, and about a quarter of the time either they were not the best antibiotics for the illness or no antibiotics should have been prescribed at all. Doctors overprescribe all sorts of antibiotics, of course, but few seem to cause the severe and prolonged side effects that fluoroquinolones do.
In response to pressure from patient advocates and nonprofits such as Public Citizen, the FDA has updated the black-box warning label for fluoroquinolones multiple times. In 2018, the agency expanded the warning to include the risk of mental-health problems and the possibility of comas resulting from hypoglycemia. The FDA now says that fluoroquinolones should be used only when no other drugs will work.
While the rate at which fluoroquinolones are prescribed has dipped periodically, the drugs' opponents argue that it hasn't changed enough. In 2018, the same year the FDA added the mental-health warnings and the most recent year for which data are available, Cipro was prescribed 6.7 million times, and levofloxacin, the generic form of Levaquin, was prescribed 3.9 million times, according to ClinCalc.com. (Brand-name Levaquin was discontinued in 2017.)
And the floxed argue it's not just about the number of prescriptions—it's about making sure people really understand the drugs they're taking.
When I called John Fratti in Georgia, where he is staying with a friend, I was relieved to find that he was not imminently suicidal. Though his pain has led him to think about ending his life on occasion, he is now looking forward to getting a spinal-cord stimulator and trying something called an exosome treatment.
After taking Levaquin in 2005 for testicle inflammation, Fratti developed seizures, insomnia, vision damage, panic attacks, head pressure, numbness, and, most importantly, chronic pain, which for 15 years has stubbornly broken through his pain medication. When we finished talking, Fratti handed the phone to Judi Cohen, the 74-year-old woman he's staying with, who said she had also been floxed. Four months after she took Levaquin for bronchitis in 2009, Cohen developed tendon ruptures in both her shoulders. "I felt like someone had poured acid all over me," she said. "Probably the worst part," she added, is that "doctors laugh at us."
[Read: Sleepy, Stressed, or Sick?]
The makers of these drugs say they keep a close eye on side effects and diligently report them to doctors and the FDA. In an emailed statement, the former Levaquin manufacturer Janssen said, "Ever since it was first approved by the U.S. FDA in 1996, the United States Prescribing Information (USPI) has provided information to health care providers on the risks and benefits associated with [Levaquin], including warnings and precautions." Bayer, which makes Cipro and Avelox, said, "The current FDA-approved product labeling of both Cipro and Avelox reflects the benefit-risk profile of these drugs in their approved indications, including information about the potential side effects."
For its part, the FDA said that pharmacies are required to give patients a "medication guide" with information about the risks associated with fluoroquinolones when they receive a prescription. "The labeling for systemic fluoroquinolones also includes a boxed warning that states that fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together," Chanapa Tantibanchachai, an agency spokesperson, said. She also pointed out that a special section in the boxed warning talks about how the drugs could affect the central nervous system, alerting patients that "attempted or completed suicide have been reported, especially in patients with a medical history of depression, or an underlying risk factor for depression."
People like Martin want an even more aggressive approach, arguing that the various warnings haven't stopped doctors from overprescribing fluoroquinolones. They want doctors to be required to make patients sign a consent form detailing all the risks before they prescribe fluoroquinolones, similar to the process for the acne drug Accutane. "It would require more time between the doctor and the patient," says Charles Bennett, a hematologist at the University of South Carolina and the director of the Southern Oncology Network on Adverse Reactions, a pharmaceutical-safety watchdog. "The doctor is gonna think twice before he prescribes it—does this patient really need this drug?"
Several years ago, a similar idea for adding clearer information about side effects to all sorts of drugs percolated through the public-health space and even made it all the way to the FDA, where it ultimately died. Steven Woloshin and his late wife, Lisa M. Schwartz, both professors of medicine at the Dartmouth Institute, thought that drug ads presented information about medications in a confusing and incomplete way. "We thought it would be really good and helpful for consumers if the FDA required the ads to present benefit and harm information in a transparent way," Woloshin told me, "so people could make better decisions."
They developed what Woloshin calls a "drug-facts box"—a one-page sheet that doctors would give to patients or pull up via a website or app. In clear, simple language, the box describes exactly what the drug is for, how much it helps people, what the side effects are, and how often they occur. A sample box he sent me, for the insomnia drug Lunesta, shows that Lunesta helps people fall asleep about 15 minutes faster, but its users are about four times as likely to experience an aftertaste than those who took a placebo. Woloshin envisioned it as a nutrition label, but for prescription drugs. "If they can do that for Cocoa Krispies, why can't you do it for Lipitor?" Woloshin said.
The way Woloshin sees it, a doctor would show a patient the drug-facts box before prescribing a drug, so the doctor and patient together could decide whether the benefit of taking the medication outweighs the possible harms. With fluoroquinolones, for example, it's not quite appropriate to say that the drugs are unsafe for all patients, because although the side effects are horrifying, they occur in just a small number of people who take the medications. ("Unsafe" is a personal designation, not a medical one.) Psychotic reactions occur in fewer than 1 percent of people who take Cipro, but the drug is used to treat anthrax and plague. It's worth knowing what the alternative to not taking Cipro is in your situation too.
Woloshin's drug-facts box may even work better than the patient-consent form Martin and Bennett want, since a patient could just skim the form and sign it in a moment of desperation. And some patient-consent systems, such as the one used to avoid fetal exposure to Accutane, are so onerous that they prompt some people to unnecessarily avoid using a drug, which isn't healthy either.
The box would also be different from standard FDA black-box warnings, which can be hard for laypeople to understand. In studies that Woloshin and Schwartz conducted (using drugs that weren't antibiotics), people who saw the drug-facts box were better able to understand the benefits and side effects than people who saw a standard magazine drug ad, and they chose the objectively more effective drug to hypothetically take.
Woloshin and Schwartz presented the fact-box idea to the FDA in 2009, but the agency decided not to create the boxes, determining "that the inclusion of such quantitative information in a standardized format cannot be readily applied to many drugs." In an email to me, Woloshin was still aghast at this decision, saying, "We thought that made no sense. There are few drugs where a box would not provide useful information, even if it just highlighted a lack of available data! And why not do them for drugs where the info is readily applicable?"
[Read: Why Women Get So Many Autoimmune Diseases ]
"I think they did everything right," says Baruch Fischhoff, a public-policy professor at Carnegie Mellon University, who is a fan of the fact-box idea. "I think it's a shame that the FDA wasn't able to adopt it."
Beyond antibiotics, a fact box could be useful in all sorts of situations in which people are confused by or suspicious of medications. Vaccine fact boxes, for instance, could help reduce hesitancy by showing just how rare vaccine injury is, as well as by highlighting the fact that vaccines have no correlation with autism. The opioid crisis, which has only grown worse throughout the pandemic, might have been mitigated if patients and doctors had known from the outset that the drugs don't work well for, say, pain caused by depression, a use that the FDA has never condoned. "One of the issues with the opioid crisis was that there was massive off-label prescribing," Woloshin said. "With drug boxes, it's very clear what the drug was approved for."
Woloshin admitted that the drug-facts box might not resolve all prescribing quandaries, including those involving fluoroquinolones. Just like FDA labels, which in the case of fluoroquinolones have changed so often that doctors find it hard to keep track, the boxes would have to be updated with the latest research. Some patients will balk at a .01 percent chance of a side effect even if they really, really need to take a drug; others will take on the risks and regret it later. But for those who feel robbed of control over their body's response to medications, better drug information may offer a feeling of empowerment. The drug-facts box, or something like it, could help patients feel more fully in charge of their medical destiny.
When I asked Martin if the drug-facts box would be a good solution for the floxed community, she said she'd have to think about it. The current system isn't working, but she doesn't trust the FDA to come up with a new system. As countless doctors have learned the hard way, patients' trust, once destroyed, is hard to regain.
Comments
Post a Comment