A Deadly Drug Cocktail Shines a Light on an AstraZeneca Blockbuster
The last time John Nebinger spoke to his son Bradley was about thirty minutes after midnight on March 15, 2010.
Twenty-four-year-old Bradley said he couldn’t sleep—a frequent complaint. His father went to bed.
“I found him dead the next day,” Nebinger, who lives near Seattle, said in an interview. His son was in his underwear in an untidy room littered with prescription bottles. “He didn’t overdose. It was just those two drugs that mixed together and led him to die.”
Bradley struggled with substance abuse and had been taking methadone for a week to treat pain from a knee injury. A year earlier, he’d been prescribed the antipsychotic Seroquel for sleep problems and anxiety. An autopsy and subsequent review found the combination led to Bradley’s sudden cardiac death.
At the time, Seroquel was approved by U.S. regulators to treat schizophrenia and bipolar disorder, though it was also popular with doctors, who are free to prescribe medicines as they see fit, as a treatment for insomnia and anxiety.
Seroquel’s maker, AstraZeneca Plc, knew for years that taking the drug with methadone could lead to abnormal heart rhythm but didn’t add a warning to its U.S. label until January 2010, a whistleblower lawsuit in federal court in Brooklyn alleges.
The U.K. pharmaceutical giant played down the risk of deaths from the drugs’ interaction, according to former New York sales representative Allison Zayas, who’s suing AstraZeneca on behalf of the U.S. government, 27 states, Washington, D.C., and the city of Chicago. Neither Nebinger nor his family is part of the lawsuit.
AstraZeneca spokeswoman Abigail Bozarth said in a statement that the company acted responsibly in giving data to the U.S. Food and Drug Administration before the drug’s approval and after it had come to market, “to inform appropriate labeling to assist physicians in making informed benefit-risk decisions for individual patients.”
AstraZeneca has paid more than $1 billion in settlements over side effects and marketing of Seroquel, once one of the world’s best-selling drugs. The company hasn’t admitted any wrongdoing.
Zayas claims that AstraZeneca targeted pain clinics and addiction centers to sell Seroquel as it battled for share in a competitive market for such drugs. Salespeople were directed to call on clinic doctors and paid bonuses based on sales to the facilities, she alleges in the suit, which seeks reimbursement for costs to government health programs and fines.
The drugmaker and Zayas have reached a settlement in principle, according to a Nov. 14 filing in federal court in Brooklyn, and an update on the status of the agreement is expected on Dec. 18.
Bozarth said AstraZeneca believes that all applicable laws were followed and the allegations in the suit are without merit.
James Pepper, Zayas’s lawyer, declined to comment on the lawsuit or settlement discussions.
The lawsuit alleges that the interaction of Seroquel and methadone played a role in 10 patient deaths at Staten Island University Hospital, the largest hospital in the New York City borough. The century-old, 714-bed facility has a comprehensive alcohol-and-drug rehabilitation center and methadone program.
Methadone has long been prescribed to treat pain as well as addiction to heroin and prescription medications. The drug is highly regulated and patients must take it under the care of a medical professional.
The alleged deaths in Staten Island came as methadone use and deaths from drug overdoses were skyrocketing in the U.S., according to the lawsuit, amid a wider opioid-abuse epidemic.
Hospital spokeswoman Arleen Ryback did not confirm or deny that 10 patients had died as described in the lawsuit. Employees contacted by Bloomberg News said they did not recall the patient deaths or interacting with Zayas, the whistleblower.
“The person in question is a whistleblower and until there is validated testimony and court evidence it is premature to pursue additional comments,” Ryback said.
The hospital’s acting chair of behavioral health, Timothy B. Sullivan, said in an email that “there seems to be a lack of clinical/research evidence confirming a connection between Seroquel and methadone deaths.”
Seroquel, sold in generic form as quetiapine, was approved in the U.S. in 1997 for schizophrenia, and cleared to treat some types of bipolar depression in 2004. By 2010, sales reached $5.3 billion—roughly 16 percent of AstraZeneca’s revenue. An extended-release version, Seroquel XR, was approved in 2007.
AstraZeneca agreed to pay $520 million in 2010 to settle U.S. Department of Justice allegations that it promoted Seroquel for numerous off-label uses, though it didn’t admit wrongdoing. A Texas lawsuit alleges the drugmaker violated the terms of that pact; AstraZeneca has said the allegations in the suit are without merit. Talks on a settlement in the case are underway, according to court filings.
As it sought to promote Seroquel to pain clinics and physicians, AstraZeneca allegedly directed its sales force to doctors who also prescribe methadone at Staten Island University Hospital, according to the whistleblower’s lawsuit.
“People have been aware of Seroquel being overused by folks with substance abuse disorders for several years but this combination being problematic is not well known,” said Marvin D. Seppala, chief medical officer of the Hazelden Betty Ford Foundation, an addiction treatment nonprofit.
In December 2009, Swarnamba Mani, a doctor at the hospital, told Zayas that Seroquel “played a role” in the death of a male patient who was also taking methadone, according to the lawsuit. The patient wasn’t being treated by Mani, the suit says.
Zayas reported the death to her manager, according to an email included in court filings. The manager said she would follow up with Mani, though it’s unclear if she did.
Mani said in a phone interview she could not recall interacting with Zayas and didn’t remember people at the hospital dying from the combination of Seroquel and methadone.
In July 2010, Zayas said that she was told by Robert Schaer, a hospital social worker, of 10 patients taking methadone and Seroquel who died unexpectedly in the previous year. On July 6, Zayas reported the deaths to AstraZeneca, according to the lawsuit.
Schaer, who retired from the hospital in September, said in an interview that he did not recall the deaths or the conversation with Zayas.
Two other doctors, Eileen Sweeney and Robert Walter, believed Seroquel played a role in the deaths, according to the lawsuit. Walter’s concerns led him to petition the hospital to remove Seroquel from its formulary, the suit says.
Sweeney said in an interview she did not recall whether there had been 10 deaths in the hospital at the time and had never heard of Zayas. Walter did not respond to requests for comment.
Zayas’s sales partner circulated a petition to keep Seroquel on the hospital’s formulary. It did, with some warnings, according to the lawsuit.
In August 2010, Zayas met with her supervisors at a hotel near New York’s LaGuardia Airport to express her concern about the deaths. Her bosses told her to continue to sell Seroquel to doctors the company knew prescribed it with methadone, according to the lawsuit, including those at Staten Island University Hospital.
From January 2008 to August 2009, AstraZeneca representatives in New York, New Jersey, and Connecticut called on specialists in pain or addiction 800 times and left 4,614 Seroquel XR samples, and the doctors wrote 1,181 new prescriptions, the suit claims.
One of those doctors was Richard DeWorsop, a now-retired psychiatrist in Toms River, New Jersey. In a phone interview, he couldn’t recall any AstraZeneca representatives mentioning the risk of possible death from Seroquel interacting with methadone.
DeWorsop wrote 107 new Seroquel XR prescriptions in that period and received 488 samples, according to the lawsuit.
“They didn’t caution us about that,” DeWorsop said. “I don’t remember the rep ever talking to me about anything related to methadone.”
“AstraZeneca’s policy is to promote its medicines in accordance with FDA-approved labeling and FDA regulations—our employees are required to follow our compliance policies,” said Bozarth, the company spokeswoman.
Seroquel first carried a warning label about drug interactions in the U.K. in 1997. Six years later, regulators in the European Union required similar labeling. In June 2011, the FDA told AstraZeneca to enhance the U.S. warning by advising doctors that use of Seroquel with drugs like methadone should be avoided.
The combination with methadone remains a concern among doctors, particularly because the heart risk isn’t well known, according to physicians who treat patients with addiction issues.
Detox facilities found Seroquel helped treat withdrawal symptoms in patients who had abused opioids. But people addicted to opioids also sometimes take the drug for its euphoric feelings.
“The problem is that some patients have learned that if they use more Seroquel than is prescribed, it can sedate them, it can numb their emotions,” said Stephen Delisi, a psychiatrist at Hazelden. He said he wouldn’t prescribe the drug unless all other alternatives failed.
The Kings County Medical Examiner listed acute combined methadone and quetiapine intoxication as the primary cause of Bradley Nebinger’s death, concluding it was an “accident.” A review commissioned by the family found that the doses he was prescribed were within a reasonable range and that there appeared to be no signs of intentional overdose.
The 269-pound Bradley suffered from knee pain for several years, and had searched for doctors who would prescribe him medications, his father said, a practice known as “doctor shopping.”
“He was a charmer. He could talk people into things,” said his father.
John Nebinger said his son’s life had brightened before he died. He hadn’t had a drink in two months and was about to graduate from community college. “Things were looking up.”
“Unfortunately, he always thought a pill was the answer,” Nebinger said.
—With assistance from Margaret Cronin Fisk.