FDA approves first generic drugs for schizophrenia

From FOX News:

The Food and Drug Administration has approved the first generic versions of a drug used to treat schizophrenia, the government organization announced Wednesday.

People who suffer from schizophrenia now have the option of treating their symptoms with the generic version of Seroquel (quetiapine) tablets. Quetiapine is also used to treat or prevent episodes of mania or depression in patients with bipolar disorder.

According to the FDA, the generic tablets are expected to be manufactured in several different strengths.

Posted: 4/12/2012 12:53:00 PM

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More Antipsychotics Approved for Pediatric Use

From Psychiatric News:

Days before a Food and Drug Administration (FDA) advisory committee reviewed the safety concerns about antipsychotic drug use in pediatric patients, two additional antipsychotics, quetiapine and olanzapine, were approved by the agency for treating youth with schizophrenia and those with bipolar I disorder.

With these additions, four second-generation antipsychotics (SGAs) have been approved by the FDA for use in patients under age 18: risperidone, aripiprazole, quetiapine, and olanzapine. Indications are for the acute treatment of schizophrenia and bipolar I manic or mixed episodes based on three- to six-week clinical trials in pediatric and adolescent patients. Risperidone and aripiprazole have also been approved by the FDA to treat irritability associated with autistic disorders.

Other SGAs, including ziprasidone and paliperidone, and recently approved iloperidone and asenapine, are not approved for pediatric use but are sometimes prescribed off-label for children and adolescents.

In the past decade, mounting research evidence has linked SGAs to significant weight gain, increased blood glucose and cholesterol levels, and endocrine abnormalities in adult and underage patients.
At a public meeting held last December 8, representatives from the National Institute of Child Health and Human Development Antipsychotics Safety Therapeutic Working Group told the FDA's Pediatric Advisory Committee that the lack of knowledge about these drugs in the pediatric population is worrisome. A number of published epidemiological studies suggest that children may experience more dramatic weight gain and worse metabolic effects on SGAs compared with adults, the working group reported. Most recently, a study in the October 28, 2009, Journal of the American Medical Association showed that first-time SGA use was associated with a large increase in cardiometabolic risks in patients aged 4 to 19. The study found that average weight gain in youth taking SGAs ranged from 4.4 kg (aripiprazole) to 8.5 kg (olanzapine) after a median of 10.8 weeks.

The working group urged the FDA and National Institutes of Health to fund and conduct postmarketing studies, both retrospective and prospective, to clarify the long-term effectiveness and safety of SGAs in children and adolescents.

U.S. Fines Prompt Drug Makers to Police Off-Label Marketing

From The Wall Street Journal:

U.S. government fines have made big drug makers "more sensitive than we've ever been" about preventing illegal promotion of their drugs, the chief executive of AstraZeneca PLC said in an interview.

AstraZeneca in September reached a preliminary agreement to pay $520 million to settle a U.S. investigation into its marketing of the schizophrenia drug Seroquel, including allegations that the company promoted the drug for uses for which it isn't approved by the Food and Drug Administration. This practice, called "off-label marketing," is illegal.

AstraZeneca officials have declined to say whether the company will admit wrongdoing as part of the settlement, the terms of which are still under discussion. In an interview in London, chief executive David Brennan said: "We don't promote products off-label."

But he said off-label marketing has become "a much bigger issue in the last few years as a result of the government's position on this."

A number of drug companies, including Pfizer Inc. and Eli Lilly & Co., have reached large settlements in recent months with U.S. investigators probing marketing practices.

Doctors are free to prescribe drugs any way they see fit, but drug makers aren't allowed to promote them for unapproved uses.

Controversy has long dogged Seroquel. AstraZeneca is facing thousands of lawsuits filed by patients who allege that Seroquel caused them to develop health problems including diabetes.

Earlier this year, lawyers representing those plaintiffs released documents that they said showed that AstraZeneca executives discussed promoting the drug for unapproved uses. The documents cited plans to "broaden Seroquel use on and off-label," including among adolescents and patients with Parkinson's and Alzheimer's disease, at medical meetings, in sales calls and with patient-advocacy groups.

Posted: 12/22/2009 10:10:00 AM

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Big Weight Gain For Kids on Psych Drugs

From TIME:

Children on widely used psychiatric drugs can quickly gain an alarming amount of weight; many pack on nearly 20 pounds and become obese within just 11 weeks, a study found.

Weight gain is a known possible side effect of the anti-psychotic drugs which are prescribed for bipolar disorder and schizophrenia, but also increasingly for autism, attention deficit disorders and other behavior problems. The new study in mostly older children and teens suggests they may be more vulnerable to weight gain than adults.

The study also linked some of these drugs with worrisome increases in blood fats including cholesterol, also seen in adults. Researchers tie these changes to weight gain and worry that both may make children more prone to heart problems in adulthood.

The study authors said their results show that children on the drugs should be closely monitored for weight gain and other side effects, and that when possible, other medicines should be tried first.

The study appears in Wednesday's Journal of the American Medical Association. It involved 205 New York City-area children from 4 to 19 years old who had recently been prescribed one of the drugs; the average age was 14.

Depending on which of four study drugs children used, they gained between about 10 and 20 pounds on average in almost 11 weeks; from 10 percent to 36 percent became obese.

The drugs are Abilify, Risperdal, Seroquel and Zyprexa. Of the four, Seroquel and Zyprexa are not yet approved for children, and they had the worst effects on weight and cholesterol. However, a government advisory panel recently voted in favor of pediatric use for the two drugs, and the Food and Drug Administration often follows its advisers' recommendations.

The drugs' makers said these problems are known side effects but emphasized the drugs' benefits in helping patients cope with serious mental illness.

The four drugs have been considered safer than older anti-psychotic drugs, which can cause sometimes permanent involuntary muscle twitches and tics. That has contributed to widespread use of the newer drugs, including for less severe behavior problems, a JAMA editorial said.

The number of children using these drugs has soared to more than 2 million annually, according to one estimate.

Why these drugs cause weight gain is uncertain but there's some evidence that they increase appetite and they may affect how the body metabolizes sugar, said Jeff Bishop, a psychiatric pharmacist at the University of Illinois at Chicago. The drugs also can have a sedation effect that can make users less active.

Older schizophrenia drug safer than more widely prescribed ones

From Los Angeles Times:

Schizophrenics taking the first -- and cheapest -- of a new generation of antipsychotic medications, clozapine, were less likely to suffer premature death than patients taking the newer, costlier and more widely prescribed antipsychotic drugs Seroquel, Risperdal and Zyprexa, says a study published in the British medical journal Lancet.

Researchers in Finland, where clozapine is still widely prescribed for schizophrenia patients, found that users of the drug were less likely to die than those who took any one of three other second-generation (also called "atypical") antipsychotics -- Seroquel, Risperdal and Zyprexa -- or those who took the first generation schizophrenia medication pherphenazine (once marketed as Trilafon).

Clozapine, sold now as a generic medication but also marketed as Clozaril, is currently recommended for use only when a patient's schizophrenia symptoms -- most notably hallucinations, confused thinking and emotional reactions -- fail to improve with use oftwo other antipsychotic medications. Clozapine was briefly taken off the European market -- and has been the subject of strong warnings in the United States -- because its use raises a patient's risk of a potentially deadly blood disorder called agranulocytosis. Patients taking Clozaril are to undergo routine blood checks to ensure they do not develop the decrease in white blood cells.

Finnish researchers reviewed the 1996-2006 death records of 66,881 patients who had taken one of the studied antipsychotic drugs, and compared them withpatients taking pherphenazine, an older drug considered one of the safest of the first generation. Patients taking Seroquel (also known as quetiapine) were 41% more likely to die prematurely; those taking Risperdal (risperidone) were 34% more likely to die early; those taking Zyprexa (olanzapine) were 13% more likely to die early.

Patients on Clozaril were 26% less likely than those on pherphenazine to die an early death. That finding led the researchers to urge that physicians and drug-safety agencies reconsider their warnings against Clozaril's use as a first-line drug.

Sufferers of schizophrenia have long been known to die earlier than the general population, markedly more often by suicide and by complications of diabetes. They are far more likely to engage in behaviors that lead to earlier death as well, including tobacco use, substance abuse and sedentary lifestyles. The Lancet article found that a schizophrenia patient who took any of the studied medications for seven to 11 years was less likely to die prematurely. And the longer she took it, the less likely she was to die an early death.

American physicians have largely abandoned Clozaril, which has been on the U.S. market since 1989, in favor of Zyprexa, Seroquel, Risperdal and Abilify -- all newer drugs that have been aggressively marketed to doctors and patients as safer and more effective than the first-generation of antipsychotic drugs, including pherphenazine and haliperidol (better known by its commercial name, Haldol).

In 2008, 50 million prescriptions for antipsychotic drugs -- overwhelmingly the newer ones -- were filled. The FDA is now considering whether to allow Seroquel to be prescribed for treatment-resistant depression, and to older children diagnosed with schizophrenia or bipolar disorder. 

Posted: 7/15/2009 12:03:00 PM

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A Silenced Drug Study Creates An Uproar

From The Washington Post:

The study would come to be called "cursed," but it started out just as Study 15.

It was a long-term trial of the antipsychotic drug Seroquel. The common wisdom in psychiatric circles was that newer drugs were far better than older drugs, but Study 15's results suggested otherwise.

As a result, newly unearthed documents show, Study 15 suffered the same fate as many industry-sponsored trials that yield data drugmakers don't like: It got buried. It took eight years before a taxpayer-funded study rediscovered what Study 15 had found -- and raised serious concerns about an entire new class of expensive drugs.

Study 15 was silenced in 1997, the same year Seroquel was approved by the Food and Drug Administration to treat schizophrenia. The drug went on to be prescribed to hundreds of thousands of patients around the world and has earned billions for London-based AstraZeneca International -- including nearly $12 billion in the past three years.

The results of Study 15 were never published or shared with doctors, even as less rigorous studies that came up with positive results for Seroquel were published and used in marketing campaigns aimed at physicians and in television ads aimed at consumers. The results of Study 15 were provided only to the Food and Drug Administration -- and the agency has strenuously maintained that it does not have the authority to place such studies in the public domain.

AstraZeneca spokesman Tony Jewell defended the Seroquel research and said the company had disclosed the drug's risks. Since 1997, the drug's labeling has noted that weight gain and diabetes were seen in study patients, although the company says the data are not definitive. The label states that the metabolic disorders may be related to patients' underlying diseases.

The FDA, Jewell added, had access to Study 15 when it declared Seroquel safe and effective. The trial, which compared patients taking Seroquel and an older drug called Haldol, "did not identify any safety concerns," AstraZeneca said in an e-mail. Jewell added, "A large proportion of patients dropped out in both groups, which the company felt made the results difficult to interpret."

Details of Study 15 have emerged through lawsuits now playing out in courtrooms nationwide alleging that Seroquel caused weight gain, hyperglycemia and diabetes in thousands of patients. The Houston-based law firm Blizzard, McCarthy & Nabers, one of several that have filed about 9,210 lawsuits over Seroquel, publicized the documents, which show that the patients taking Seroquel in Study 15 gained an average of 11 pounds in a year -- alarming company scientists and marketing executives. A Washington Post analysis found that about four out of five patients quit taking the drug in less than a year, raising pointed doubts about its effectiveness.

An FDA report in 1997, moreover, said Study 15 did offer useful safety data. Mentioning few details, the FDA said the study showed that patients taking higher doses of the drug gained more weight.

In approving Seroquel, the agency said 23 percent of patients taking the drug in all studies available up to that point experienced significant weight increases, compared with 6 percent of control-group patients taking sugar pills. In 2006, FDA warned AstraZeneca against minimizing metabolic problems in its sales pitches.

In the years since, taxpayer-funded research has found that newer antipsychotic drugs such as Seroquel, which are 10 times as expensive, offer little advantage over older ones. The older drugs cause involuntary muscle movements known as tardive dyskinesia, and the newer ones have been linked to metabolic problems.

For practicing psychiatrists, Study 15 could have said a lot not just about safety but also effectiveness. Like all antipsychotics, Seroquel does not cure the diseases it has been approved to treat -- schizophrenia and bipolar disorder -- but controls symptoms such as agitation, hallucinations and delusions. When government scientists later decided to test the effectiveness of the class of drugs to which Seroquel belongs, they focused on a simple measure -- how long patients stayed on the drugs. Discontinuation rates, they decided, were the best measure of effectiveness.

Study 15 had three groups of about 90 patients each taking different Seroquel doses, according to an FDA document. Approximately 31 patients were on Haldol. The study showed that Seroquel failed to outperform Haldol in preventing psychotic relapses.

In disputing Study 15's weight-gain data, company officials said they were not reliable because only about 50 patients completed the year-long trial. But even without precise numbers, this suggests a high discontinuation rate among patients taking Seroquel. Even if every single patient taking Haldol dropped out, it appears that at a minimum about 220 patients -- or about 82 percent of patients on Seroquel -- dropped out.

Eight years after Study 15 was buried, an expensive taxpayer-funded study pitted Seroquel and other new drugs against another older antipsychotic drug. The study found that most patients getting the new and supposedly safer drugs stopped taking them because of intolerable side effects. The study also found that the new drugs had few advantages. As with older drugs, the new medications had very high discontinuation rates. The results caused consternation among doctors, who had been kept in the dark about trials such as Study 15.

The federal study also reported the number of Seroquel patients who discontinued the drug within 18 months: 82 percent.

Posted: 3/20/2009 2:04:00 PM

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AstraZeneca Warned Japanese Doctors of Diabetes Link

From Bloomberg.com:

AstraZeneca Plc pushed salespeople to tell U.S. doctors its antipsychotic drug Seroquel didn’t cause diabetes more than two years after warning physicians in Japan of possible links to the disease, internal documents show.

The London-based drugmaker issued a letter to Japanese physicians in November 2002 that said AstraZeneca had received 12 reports that Seroquel users were diagnosed with high blood-sugar levels over a 21-month period, according to company documents unsealed last week in connection with litigation over the drug.

“Since February 2001 when Seroquel started to be marketed, 12 serious cases (including 1 death) of hyperglycaemia, diabetic ketoacidosis and diabetic coma where causality with the drug could not be ruled out have been reported,” AstraZeneca officials said in the letter.

Almost three years later, AstraZeneca sales managers were instructing company representatives to tell U.S. physicians that “the available data has not established a causal link between diabetes and Seroquel,” according to a transcript of an August 2005 voice-mail unsealed last week.

More than 15,000 patients have sued AstraZeneca, claiming the company withheld information about links between diabetes and Seroquel use from doctors and patients. Many of the lawsuits also claim AstraZeneca promoted Seroquel, approved by the U.S. Food and Drug Administration for schizophrenia and bipolar disorder, for unapproved uses.

AstraZeneca has denied wrongdoing in its handling of the drug and is vowing to fight the lawsuits in court.

AstraZeneca officials said today they sent the letter to Japanese doctors at the request of that nation’s regulators.

“Every country has a different regulatory administration with different regulatory standards and requirements,” Tony Jewell, an AstraZeneca spokesman, said in an e-mailed statement. “AstraZeneca marketing companies are required to comply with the rules and regulations of the regulatory authorities in the country in which they operate.”

Sidney Wolfe, director of Washington-based Public Citizen’s health-research group and a member of the FDA’s drug safety committee, called AstraZeneca’s failure to make a similar disclosure to American doctors “irresponsible.”

Jewell noted that under U.S. law, drug company salespeople are required to use information from “the label approved by the FDA.” AstraZeneca officials contend that Seroquel’s warning label provided “adequate and appropriate information” about possible diabetes-related side effects.

“When first approved, the Seroquel labeling alerted physicians that diabetes mellitus, hyperglycemia, and weight gain had been observed in clinical trials,” Jewell said in his e- mail. “We have continued to update the label on these topics as the science has developed.”

AstraZeneca agreed to release more than 100 files with information about the drug last week after Bloomberg News filed a motion in federal court in Orlando, Florida, to unseal records in the case. All federal-court suits over the drug have been consolidated in Orlando. The letter to Japanese doctors became publicly available when it appeared on the court’s electronic docket on Feb. 27.

In the letter, AstraZeneca officials noted that the 12 diabetes-related cases emerged from 130,000 patients who had taken Seroquel through the end of September 2002. That means only 0.009 percent of those who had taken the drug reported any diabetes-related problems.

The company advised Japanese doctors not to prescribe the drug for diabetic patients and to ensure that users monitor their blood-sugar levels, according to the letter. Seroquel’s label didn’t advise U.S. doctors to monitor blood-glucose levels until January 2004, Jewell said.

In the 2005 voice-mail, AstraZeneca manager Christine Ney offered the company’s U.S. sales reps information that they could use to “neutralize customer objections to Seroquel’s weight and diabetes profile.”

Ney noted that while “hyperglycemia-related adverse events have been reported in patients taking atypical antipsychotics, including Seroquel, to date the available data has not established a causal link between Seroquel and diabetes,” according to the transcript.

Ney also suggested that salespeople “refocus” doctors away from questions about Seroquel’s links to diabetes to its “Trusted Tolerability profile,” according to the transcript.

Posted: 3/3/2009 1:50:00 PM

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