In 2013 a primary-care doctor suggested to a 43-year old man that he take Seroquel (quetiapine) to help him sleep. He was told that at low doses, Seroquel works like an antihistamine with mild sedation. He thought it was a good idea, as he had suffered from insomnia since his childhood. Despite working out, he gained 40 pounds. He also became pre-diabetic, started on blood-pressure medication and was seeing a cardiologist for an irregular heart beat. After a few years went by, he said: “I knew I had to get off of this drug.”

When he tried to slowly taper his dosage, his symptoms periodically seemed to worsen. “They say it’s not addictive, but your whole body gets used to it.” He said he was back and forth to the hospital 25-30 times with anxiety and heart palpitations. It took him a year to taper down from 200 milligrams to 25. His insomnia returned and if he took a pill to help him sleep, he’d wake up with his heart pounding. He was throwing up; he had cold sweats and itching all over his body. “Coming off, you’re seriously worse. I was struggling through, day by day.” This person’s experience was described in an article in The Washington Post, highlighting the issues with the off-label use of Seroquel (quetiapine).

Back in 2006, the FDA informed AstraZeneca, the parent company for Seroquel, that its marketing information false and misleading “because it minimizes the risk of hyperglycemia and diabetes mellitus and fails to communicate important information regarding neuroleptic malignant syndrome, tardive dyskinesia, and the bolded cataracts precaution.”

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.

Within the Justice Department’s announcement of its 2010 settlement with AstraZeneca was the following:

According to the settlement agreement, AstraZeneca targeted its illegal marketing of the antipsychotic Seroquel towards doctors who do not typically treat schizophrenia or bipolar disorder, such as physicians who treat the elderly, primary care physicians, pediatric and adolescent physicians, and in long-term care facilities and prisons.

Despite the lawsuits, some of which are still ongoing, AstraZeneca annual reports showed $3.6 billion in Seroquel sales from 2014 to 2016. Beside insomnia, Seroquel has been prescribed off-label for PTSD and agitation with dementia patients. Medical experts have expressed concern that many of the doctors prescribing it off-label have minimal training in psychiatry and little knowledge of its adverse effects. British psychiatrist David Healy said: “The range of problems it causes in terms of deteriorating quality of life makes it not worth it.”

Recent court rulings have said pharmaceutical companies have a First Amendment right to commercial free speech, raising questions about the extent the FDA can regulate the off-label marketing of medications. The FDA remains silent about its review process of its policies and regulations for “manufacturer communications” about unapproved, off-label uses of medical products. The review has been ongoing since the Obama administration. The current FDA Commissioner has previously advocated for allowing manufacturers to promote their products for off-label uses. An FDA spokesperson said: “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.”

The Washington Post did an analysis of data from the FDA’s Adverse Event Reporting System through the first quarter of 2017. They found that “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 reported deaths where Seroquel or quetiapine was listed as the primary and 2,309 reported deaths where 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 Chicago Tribune wrote about an ongoing whistleblower lawsuit against AstraZeneca. In 2009 one of its sales representatives was told by a doctor in New York City outpatient clinic that a methadone patient died while taking Seroquel. Soon afterwards two other doctors told her that as many as 10 patients at New York methadone clinics had died while taking Seroquel and methadone together. She reported the deaths to her company, “but that it continued to aggressively market the blockbuster drug, even to methadone clinics.” Alarmed at the company’s failure to take action, she quit AstraZeneca and filed a whistleblower lawsuit, alleging the company “concealed the true cardiac risks of Seroquel when taken with certain other medications.”

Her lawsuit, which seems to be still in talks regarding a settlement, charged the company withheld safety information from two FDA advisory panels and failed to alert patients, doctors and pharmacists about Seroquel’s heart risks. She claims AstraZeneca “directs and incentivized” its sales representatives to sell to doctors “whom it knew prescribed Seroquel with methadone and other drugs that might trigger a dangerous reaction.” According to court filings, in 2010 AstraZeneca made revised prescribing information to advise “caution” when using the drug with certain medications. Then in 2011 the FDA requested the language be strengthened to say Seroquel “should be avoided” with those drugs.

The Chicago Tribune said according to the whistleblower lawsuit, when Seroquel came to market in 1997, it failed to warn against taking the drug with medications known to lengthen the QT interval (a measure of the time between when the heart starts squeezing to when it finishes relaxing and prepares to beat again) “even though there were such warnings on Seroquel’s label in the United Kingdom.”  After a 2000 study by Pfizer found evidence that Seroquel did indeed increase the QT interval, an internal AstraZeneca document described a plan to “defend against potential FDA label lawsuits” related to QT prolongation. The heart problem referred to here, QT prolongation, can trigger a potentially fatal arrhythmia.

Dozens of medications, including methadone, have been shown to cause a long QT interval and the dangerous arrhythmia, but no one knows how many people have died. Unless a person is connected to an EKG monitor at the time of death, it is difficult to prove that an abnormal heart rhythm was the culprit. Perhaps even more difficult to determine is whether a drug combination caused the death.

The company was privately concerned about the drug’s heart risks and addressed the issue in an internal safety meeting in April of 2009. The lawsuit states AstraZeneca decided to strengthen Seroquel’s “core data sheet,” to use caution when prescribing Seroquel with QT-prolonging medications. This should have dictated changes to the prescribing information worldwide. But AstraZeneca delayed that action. A week after the internal safety meeting reached its decision, AstraZeneca officials went before an FDA advisory panel that was considering the company’s requests to expand the use of the drug. “According to the suit, the drugmaker said there were no cardiac safety issues associated with Seroquel, and the company did not disclose it had changed the core data sheet.”

In June of 2009 the FDA advisory panel convened to consider AstraZeneca’s applications. Again, AstraZeneca failed to disclose its decision to toughen Seroquel’s label. In December of 2009 the FDA approved three of the five requests to broaden the use of Seroquel; one of those applications was to use Seroquel with children. “According to the suit, a month later, in January 2010, AstraZeneca amended Seroquel’s warning label, advising ‘caution’ when the drug is used with QT-prolonging medications.” The financial incentive of the company for delaying its notification of the FDA is seen the company reportedly made $28 billion in Seroquel sales between 2007 and 2013.

The Canadian newspaper, the National Post, published an article documenting the concerns some Canadian physicians have with the off-label use of Seroquel. It began by relating the tweet of Dr. David Juurlink lamenting the patients prescribed Seroquel for sleep in his hospital. Despite drug safety experts growing concerns of its use to treat insomnia, there was a ten-fold increase of quetiapine (Seroquel) prescription for sleep problems in Canada between 2005 and 2012. Juurlink noted his experience with seeing several patients over a ten-year period who “had had quetiapine as part of, or one of the contributing causes to NMS [neuroleptic malignant syndrome].”

He went on to say he’s seen people diagnosed with Parkinson’s disease that he was confident was caused by quetiapine. “It’s getting to the point now where, when I admit a patient with Parkinson’s, I reflexively look at their other medications to see, ‘are they on quetiapine?’” According to a drug research firm, 25% of the 33 million prescriptions dispensed by Canadian retail drug stores for “tranquilizers” were for quetiapine. Low doses of the drug are used for sleep—25 mg tablets instead of the 150 to 800 mg per day recommended dose range for approved disorders. Dr. Ian Mitchell said: It’s popping up as a patient’s typical medication for insomnia all the time.”

AstraZeneca seems to have been illegally and immorally marketing Seroquel off-label for insomnia despite having knowledge of its serious, potential adverse effects. The company also appears to have withheld that information in order to maximize its chances of FDA approval for broader uses of Seroquel. It stragetically follows the time-honored drug- company method of trying to settle lawsuits out of court whenever it can, so there is no court record of corporate wrongdoing. And the profits from drug sales appears to make such an approach worthwhile. But for consumers, the off-label use of Seroquel as a sleep aide is simply not worth the risk.