The Washington PostDemocracy Dies in Darkness

One of America’s most popular drugs — first aimed at schizophrenia — reveals the issues of ‘off-label’ use

Seroquel sits on a shelf at a Massachusetts pharmacy for this 2007 illustration. (JB Reed/Bloomberg News)

The first warning came a dozen years ago, when the Food and Drug Administration accused the drug company AstraZeneca of “false or misleading” information about health risks in the marketing material for its blockbuster medication Seroquel, an antipsychotic developed to treat schizophrenia but increasingly prescribed “off label” for insomnia.

What followed was an onslaught of litigation by state attorneys general, who charged AstraZeneca with fraudulently promoting Seroquel for unapproved uses, and by individual patients, who claimed that it had failed to alert consumers about some of the drug’s most pernicious side effects. Although the company never admitted wrongdoing, by the end of 2011 it had paid out more than $1 billion to settle many of the cases.

Another product might have been derailed, but not Seroquel. Despite generic competition and lingering lawsuits, AstraZeneca’s annual reports show Seroquel remained a blockbuster, with $3.6 billion in sales from 2014 to 2016. In the drug’s titanic success and its strong link to off-label prescribing lies a cautionary tale — about the sometimes conflicting forces within health care, the relationship between medications and marketing, and the limits of regulatory protections.

These days, the powerful antipsychotic is used for an expansive array of ills, including insomnia, post-traumatic stress disorder and agitation in patients with dementia. Many of the doctors who turn to it for off-label uses are physicians with minimal training in psychiatry and, medical experts say, too little understanding of the potential downsides. And while the FDA is responsible for oversight of safety issues, it lacks a mandatory reporting system for adverse events that could reveal a more complete picture of problems with a drug.

Adding to the agency’s constraints are recent court rulings that pharmaceutical companies have a First Amendment right to commercial free speech — rulings that raise questions about how much authority the FDA has to regulate off-label marketing of medications.

FDA Commissioner Scott Gottlieb, who has led the agency since May, previously advocated allowing manufacturers to promote uses of their products that the agency had not approved. Spokeswoman Stephanie Caccomo did not respond to questions about Gottlieb’s current position or concerns he might have about the off-label use of antipsychotics such as Seroquel. Nor would she say when the FDA will finish reviewing its policies and regulations for “manufacturer communications” about unapproved uses of approved medical products. The review began during the Obama administration; a public comment period was reopened for three months last year.

“The FDA continues to examine our rules and policies . . . as part of our efforts to make sure our authorities and policies best protect and promote the public health and are informed by ongoing scientific and legal developments,” Caccomo said in an email.

In the meantime, a pill that medical experts say can cause diabetes, heart arrhythmia and potentially irreversible movement disorders continues to be prescribed to many Americans who are only seeking a good night’s sleep or less anxiety by day. Many are probably not aware that it is a drug originally aimed at the delusions and paranoia of schizophrenia.

“The range of problems it causes in terms of deteriorating quality of life makes it not worth it,” said David Healy, a British psychiatrist who has written books on psychopharmacology. Healy says he prescribes Seroquel only for his most seriously ill patients “to be able to function.”

A Washington Post analysis of more than four years of the most recent data from the FDA’s Adverse Event Reporting System — through the first quarter of 2017 — found about 20,000 cases where Seroquel or its generic equivalent, quetiapine, was listed as the primary or secondary suspect in an adverse event. That included 1,754 deaths in which they were the primary suspect plus 2,309 deaths in which they were a secondary suspect. Overall, 93 percent were apparently the result of off-label prescribing of the drug.

Earlier data, analyzed by the nonprofit Institute for Safe Medication Practices, looked at adverse events by category of quetiapine use and found that off-label prescribing accounted for more than a quarter of 5,657 cases from 2004 through September 2010. More than half of the off-label cases were for insomnia and sleep disorders.

The numbers could actually be a significant undercount, too, although that’s impossible to determine because the FDA’s voluntary system depends on someone notifying the agency of a complication or death. A drug manufacturer is required to alert the FDA only when a health-care professional or consumer reports an injury directly to the company.

Paul Pennock, a New York City lawyer whose practice focuses on defective drugs and devices, has spoken with dozens of people who alleged their lives were harmed by Seroquel. Along with a group of other lawyers, he represented 2,200 plaintiffs who were diagnosed with Type 2 diabetes and other related disorders, and who became part of a nationwide, $520 million civil settlement joined by the federal government. The case involved allegations of illegal marketing and payments to doctors; AstraZeneca denied any improper actions.

“Off-label use was the mountain where the billions were made,” Pennock said. “That was the problem with Seroquel.”

Some lawsuits are still pending. The Texas attorney general filed suit in 2014, alleging that AstraZeneca defrauded the state’s Medicaid program by having its sales team urge doctors to prescribe the drug for unapproved uses, especially among children. Bloomberg News reported last November that the state and the company were in settlement talks and quoted an AstraZeneca spokeswoman as saying the allegations were “without merit” and that “all applicable laws were followed.”

AstraZeneca declined an interview request. Nearly a decade after that initial FDA warning prompted the drugmaker to revise Seroquel’s warning label, a company statement stressed that it “is committed to acting responsibly and sharing information about the safety and efficacy of its medicines.”

Both Seroquel and its extended-release version, Seroquel XR, “have been studied and granted several approved indications by the FDA,” the statement continued. “AstraZeneca provided appropriate clinical trial information to the FDA to support those approvals. These are important medicines to help people suffering with medical conditions such as schizophrenia and bipolar disorder, which are serious mental illnesses that can take devastating tolls on the lives of individuals and families.”

David Conley, 43, wasn’t thinking about any possible harm when his primary-care doctor suggested in 2013 that he take Seroquel. Seroquel works like an antihistamine at low doses, with mild sedation as a side effect. That sounded good to Conley, who couldn’t remember when he’d last had a full night’s sleep.

In fact, insomnia had been a constant nearly all his life, as far back as his childhood in the Midwest. Restless, his mind always “on,” he slept a fitful couple of hours a night, every night, even through his college years, when he played linebacker on a Division 1 football team. Conley was proud of maintaining his fitness after graduating and visited the gym almost daily. But lack of sleep made him increasingly miserable.

An internist first prescribed 100 milligrams of Seroquel, a moderate dose to be taken at bedtime. Conley says the doctor never told him it was an antipsychotic drug.

The pill “knocked me out,” he recounted from his home in the Phoenix area, where he works in human resources for a local nonprofit. “I’d never slept like that.” Yet within weeks, he began gaining weight and his blood-sugar level started to climb. “My hands were swelling at night. . . . I’m taking 200 milligrams two years in, and I notice heart palpitations, pools of sweat at night, stabbing pain in my feet and arms.”

Despite working out, Conley gained 40 pounds. He became pre-diabetic and began taking blood-pressure medication. He was also seeing more doctors, including a cardiologist for an irregular heartbeat that once frightened him so much he called 911 from a gas station.

“I knew I had to get off this drug,” he said.

As he tried to slowly taper his dosage, however, the symptoms sometimes seemed to worsen. “They say it’s not addictive, but your whole body gets used to it,” Conley said. “I was back and forth to the hospital . . . 25, 30 times with anxiety attacks and heart palpitations.”

When he asked the internist in 2015 why he had prescribed the drug given all the side effects, he remembers being told, “Because you needed to sleep.”

Even with physicians’ greater awareness of the side effects, they wrote nearly 9 million prescriptions of Seroquel and its generic versions in 2015, the latest year for which data are available through the federal Medical Expenditure Panel Survey. (The survey does not reflect Seroquel use by members of the military or Americans in institutional settings such as psychiatric facilities and nursing homes.) Many doctors turned to the drug for reasons other than its FDA-approved uses, which have expanded to bipolar disorder and as an adjunct to the treatment of major depression.

A Post review of data provided last year by SERMO, a social network for physicians, found that of 764 non-psychiatrists who said they had prescribed Seroquel or quetiapine, 84 percent did so for off-label uses. Insomnia was one of the top reasons cited, despite the lack of clinical studies on its efficacy. Other reasons doctors cited for giving patients Seroquel ran the gamut: obsessive compulsive disorder and autism, nausea and poor appetite, even erectile dysfunction.

Critics such as Aaron Kesselheim of Harvard Medical School, an expert on pharmaceutical development and policy, raise a host of concerns about the proliferation of off-label use generally and about the issues surrounding Seroquel specifically.

“It has to do with pharmaceutical promotion, not enough data, not enough research into the comparative effectiveness of the drugs already approved,” Kesselheim said of Seroquel’s popularity. “I think there are physicians who are cavalier about products they can use. And there are patients who are demanding and expecting medication.”

Initially, Seroquel seemed to have few side effects or complications, making it appealing as an alternative to the highly addictive benzodiazepines approved for insomnia and anxiety, among other conditions. But expert opinion has shifted.

“The risks are far greater than I think has been represented,” said Mark Olfson, a research psychiatrist at Columbia University and the New York State Psychiatric Institute.

Facebook, Instagram, message boards and blogs are replete with warnings from people who described serious side effects after they started taking Seroquel or its generic equivalent. And though the website rates the average patient opinion of Seroquel as “satisfied” across a range of FDA-approved and nonapproved uses — “This is the only medication that has ever truly helped me sleep,” a 42-year-old woman posted in 2016 — many other comments reveal distress sometimes bordering on despair.

●From a 58-year-old man, after taking Seroquel for four months for insomnia: “Severe ringing in the ears, raised cholesterol, blood pressure, heart rate, and sugar levels. Serious memory loss.”

●From a 29-year-old woman, after taking Seroquel for one year for anxiety: “Memory loss, shortness of breath, unbeatable fatigue, twitches.”

●From a 36-year-old man, after taking Seroquel for 10 years for insomnia and anxiety: “Was told by psychiatrists for 10 years that 100 mg Seroquel would never cause tardive dyskinesia [a severe movement disorder.] . . . Well, I’m walking around smacking my lips, puckering my lips like a fish and repetitively licking my lower lip.”

Off-label uses of medication carries an inherently higher risk of adverse reaction. A 2016 study by researchers at Canada’s McGill University, Brigham and Women’s Hospital in Boston and the Massachusetts College of Pharmacy and Health Sciences found a 50 percent higher incidence than for FDA-approved uses.

Yet it’s impossible to know exactly how big a problem adverse events present — for Seroquel or any other drug — since the FDA’s reporting system is voluntary for health-care professionals. And while the system is accessible to the public, it includes only raw data that are difficult to navigate.

In a statement to the Post, the FDA said it was “aware that there is substantial variation in the completeness and quality of adverse event reports” and that it “wants to ensure that it is broadly aware of public concerns about the safety of the drugs and biologics it regulates.”

The agency continues “to actively monitor the safety” of antipsychotics such as Seroquel and to update product labeling and medication guides as new information is learned, its spokeswoman noted via email. “The agency promotes and protects the public health by helping to ensure that these products are safe and effective for their intended uses.”

At the same time, the statement acknowledged the FDA’s “perspective” that once a drug is approved, “health care providers generally may prescribe or use it for unapproved uses when they judge that the unapproved use is medically appropriate for an individual patient.”

In Arizona, Conley keeps trying to rid himself of Seroquel. After he began reducing the dosage, it took him a year to go from 200 milligrams to 25. He held firm even when the insomnia returned.

“Coming off, you’re seriously worse. I was struggling through, day by day,” he said. “You’re throwing up, shaking, cold sweats, itching all over my body.”

The man who once took pride in being fit long after his college football career now despairs of getting his health back. Every time he gave in and took a pill — to steal a few hours of sleep — he knew he’d wake in the morning with his heart pounding. And on the nights he didn’t take Seroquel, he would lie in bed and try to force his body to release, praying for a slumber that rarely came.

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