FDA Approval of Risperdal for Children Attempts to Lift Liability for Manufacturers & Psychiatrists

"The FDA has approved Risperdal for treating schizophrenia in adolescents 13 to 17 and for the short-term [three-week] treatment of bipolar I disorder in children and adolescents 10 to 17," Dr. Thomas Laughren, director of the Division of Psychiatry Products at the agency's Center for Drug Evaluation and Research, told the press during a teleconference.

This approval is an example of FDA's slip shod safety review and approval process: FDA officials issued the approval during the quiet days of August, without convening an advisory committee to evaluate the risk / benefit for children.

FDA officials lent support to the expanded use of the drug in children without regard for the documented evidence of profound harm; without regard to the heated controversy surrounding the use of Risperdal and the other drugs in its class of neuroleptics (a.k.a. 'atypical antipsychotics') in children. [1] [2]

In contradiction to unsubstantiated marketing claims, these antipsychotics pose greater risks for patients' overall medical condition than the old-cheap-neuroleptics which they replace. The damage they produce has led to multi-billion dollar legal settlements. And it is the threat of more lawsuits that, we believe, prompted the FDA to take this action in an effort to lend the appearance of legitimacy for off-label prescribing of these drugs. The massive misprescribing was prompted by manufacturers' legally questionable marketing activities which are currently under multiple government investigations. [3]

FDA officials lent the U.S. government seal of approval for use of Risperdal in children even in the knowledge that Johnson & Johnson had withdrawn its U.K application for use of the drug in Autistic children in June 2006. In sharp contrast to FDA's back-door approval, in the U.K. the trial data was reviewed by the Committee on Safety in Medicine and the Pediatric Medicines Working Group. An expert risk/ benefit analysis resulted in "extensive recommendations which would improve the safety of the prescribing of risperidone."

The U.K. Medicines Authority required the following safety measures: Before risperidone is prescribed the child must be fully assessed for physical, psychological and social causes of the aggressive behaviour such as pain, Attention Deficit HyperactivityDisorder (ADHD), inappropriate environmental demands. Non-pharmacological methods should be tried before medication is resorted to.

Pre-treatment assessment and regular clinical monitoring should be performed. This should include: i) Measurement of height, weight and developmental status including sexual maturation. ii) Bowel habit should be monitored to avoid constipation. iii) Somnolence and other behavioural changes.* iv) Neurological examination for movement disorders, including tardive dyskinesia or motor complications. ** v) Cardiovascular assessment and initially blood pressure monitoring

*Deterioration in behaviour on risperidone should be carefully assessed as to whether this is due to a drug adverse event rather than a sign of inadequate dosage.

**A re-evaluation of the indication for treatment must be made by the specialist at each consultation in light of the tolerability and the results of the monitoring detailed above. See: [Link]

Documented evidence-including evidence submitted in litigation--shows that Risperdal has a propensity to abnormally raise prolactin levels causing boys to grow breasts requiring surgical removal.

Even company financed psychiatrists who promote the use of psychotropic drugs acknowledge that evidence links Risperdal and the other aypicals to severe, debilitating adverse side effects.

Dr. Charles Goodstein, a clinical professor of psychiatry at New York University Medical School, cautions: "This is a drug that has real value, but one has to exercise a degree of caution when using what amount to be heavy-duty medications in young children and adolescents."

He also acknowledged the unreliability of psychiatric diagnoses in children: "diagnosing children with these conditions is difficult, and that can lead to misdiagnosis and the prescribing of inappropriate medications. One has to very careful that this medication is not overused.. This is medication that should be used with great care, because it does have side effects, and too often diagnoses are made more readily than they should be made," he said. [See Forbes report below]

Indeed, as the sobering indisputable findings of the government sponsored CATIE (Clinical Antipsychotic Trials in Intervention Effectiveness) study demonstrated, the new antipsychotics such as Risperdal, Zyprexa, Seroquel, induce chronic side effects so severe, the physical and mental health of adult patients with schizophrenia is undermined. [4] Leading psychopharmacologists who had been avid promoters of antipsychotics acknowledged: "the side effect outcomes are staggering in their magnitude and extent and demonstrate the significant medication burden for persons with schizophrenia. Sky-high drug discontinuation rates were seen, suggesting rampant drug dissatisfaction and inefficacy." [5] [Link]

The CATIE findings were confirmed by a 15-year follow-up study that compared recovery outcomes in schizophrenia patients treated with antipsychotics and those untreated or treated without drugs: 40% of patients diagnosed with schizophrenia who were NOT on antipsychotic drugs showed periods of recovery and better global functioning compared to only 5% of patients taking antipsychotics (p=.001). [6]

Yet, despite the demonstrably poor clinical performance of the antipsychotics, off-label prescriptions for these drugs for child and adolescent use surged by 82% from 2001 to 2006. According to Medco Health Solutions, last year, 7 of every 1,000 patients age 19 and younger in the United States were prescribed an antipsychotic.

The driving force for such irresponsible unapproved prescribing is commercial, not clinical. And the driving force for FDA's unwarranted approval is to remove the liability for off-label prescribing of drugs that harm.

FDA's own MedWatch database includes evidence that children's lives are cut short by the action of these drugs. USA Today reported 45 deaths between 2000-2004. [2]
The consequences of psychiatry's reckless prescribing is encapsulated by four year old Rebecca Riley whose drugs prescribed by a child psychiatrist killed her. [7] [Link]

FDA's approval of Risperdal for children-on the basis of two short trials whose data has not even been disclosed--is but an effort to help manufacturers and their financially dependent psychiatrists stave off liability suits.

As we stated in June: More than any other drug safety scandal the case of the antipsychotics encapsulates FDA's irresponsible approval process, providing further confirmation that the FDA is an agency mired irrevocably in a culture that promotes alignment with an industry that has grown intoxicated by the pursuit of profits at the expense of patient safety. An industry-dominated culture of ineptitude and corruption has derailed the agency from meeting its primary mission of protecting the public health. FDA licenses are not evidence of drug safety or efficacy--they are the means for profits. [Link]

References :

1. See New York Times series, Troubled Children: October 22, 2006. [Link] GARDINER HARRIS, BENEDICT CAREY and JANET ROBERTS. Psychiatrists, Children and Drug Industry's Role THE NEW YORK TIMES May 10, 2007 [Link] [Link]
2. Marilyn Elias. New antipsychotic drugs carry risks for children, USA Today, May 2, 2006: [Link] [Link]
3. See Johnson & Johnson: [Link] [Link]
4. Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Joseph P. McEvoy, M.D., Marvin S. Swartz, M.D., Robert A. Rosenheck, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Sonia M. Davis, Dr.P.H., Clarence E. Davis, Ph.D., Barry D. Lebowitz, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D., for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia NEJM, September 22, 2005, Volume 353:1209-1223
5. Carol Tamminga MD, "Practical Treatment Information fore Schizophrenia" Editorial. American J of Psychiatry, April, 2006, vol 163:563-565
6. Martin Harrow, PhD, and Thomas H. Jobe, MD. Factors Involved in Outcome and Recovery in Schizophrenia Patients Not on Antipsychotic Medications: A 15-Year Multifollow-Up Study, The Journal of Nervous and Mental Disease, Vol. 195, No. 5, May 2007 [Link]
7. Carey Goldberg. Bipolar labels for children stir concern Hull case highlights debate on diagnosis, BOSTON GLOBE February 15, 2007 [Link]

THE BOSTON GLOBE
Risperdal use OK'd in treating children Pediatric study of antipsychotic drug considered rarity
By Diedtra Henderson August 23, 2007

WASHINGTON -- The Food and Drug Administration yesterday approved the antipsychotic drug Risperdal to treat children with schizophrenia and bipolar disorder.

The FDA allowed Risperdal as a treatment for adults with schizophrenia in 1993, but until now psychiatrists did not have an approved drug to treat schizophrenia in youths.

More than 2 million Americans have schizophrenia, a condition characterized by the inability to differentiate between real and unreal experiences, to think logically, or to behave normally in social situations. One in 100 Americans will be diagnosed with the disease, but the bulk of diagnoses occur between ages 15 and 25, said Jeffrey Lieberman, chairman of psychiatry at Columbia University.

Once the FDA approves a drug for adults, manufacturers seldom retest it in children. Physicians, however, frequently treat children with drugs approved for adults -- a practice called off-label prescribing -- without knowing the proper dosing or whether the therapies even work in children. Drug industry critics say companies should conduct more pediatric trials, a push reflected in legislation pending before Congress.

The FDA asked Risperdal's maker, Janssen LP, to study it in children. The Titusville, N.J., manufacturer complied within five years, a relatively speedy turnaround. Janssen, a subsidiary of Johnson & Johnson, conducted clinical trials involving nearly 600 children. Based on those results, the FDA approved the drug for use in children ages 13 to 17 with schizophrenia and agreed to its short-term use to treat manic or mixed episodes of bipolar I disorder in children ages 10 to 17.

Because newer antipsychotic drugs, such as Risperdal, carry serious -- and sometimes fatal -- side effects, the FDA considers the pediatric studies on its use significant, as does the American Psychiatric Association, whose 38,000 members diagnose, treat, and conduct research into mental disorders.

Because Risperdal is also in a class of drugs associated with weight gain that can lead to diabetes, Janssen, at the FDA's request, is conducting a longer-term trial to look at weight gain and any impact that earlier use of the drug may have on children's growth and development.

Still, the FDA's move, which was made without first airing scientific data publicly through an advisory committee hearing, is certain to stoke an already fierce debate about how frequently such drugs should be prescribed.

Antipsychotics, among the nation's top-selling pharmaceuticals last year, already generate $16 billion annually for drug makers. Last year, Risperdal was the second best-selling antipsychotic in the United States, with $2.6 billion in sales, according to IMS Health, a health information company.

Some argue that adults have been overprescribed such drugs, driven, in part, by aggressive advertising campaigns. They should not be prescribed to growing children, said Vera Hassner Sharav, founder of the Alliance for Human Research Protection, pointing to the drugs' link to such side effects as uncontrolled growth of breast tissue in boys that must be corrected by surgery.

FDA approval "helps to provide doctors cover," Sharav said. "These are dangerous, toxic drugs. Every piece of evidence points in that direction."

But Dr. Carolyn Robinowitz, president of the American Psychiatric Association, said medications are "an important part of a comprehensive treatment program."

Columbia's Lieberman agreed, with caveats. A study that he led, funded by the National Institutes of Health, found that older, cheaper drugs worked as well in treating adults with chronic schizophrenia as newer, second-generation drugs like Risperdal. The older therapies also cost one-10th the price.

FDA approval of Risperdal use among children is "great to know," Lieberman said. "Now, we can use it with a higher degree of confidence. The question is, with the cost of the newer medicines, do we think the older medicines would do as well? Are the newer medications, indeed, better?" A second, NIH-funded trial that aims to answer that question is complete, but its results have not yet been published, he said.

BLOOMBERG NEWS
J&J Wins U.S. Approval of Teen Schizophrenia Drug
By Lisa Rapaport

Aug. 22 (Bloomberg) -- Johnson & Johnson won U.S. approval of its antipsychotic Risperdal to treat schizophrenia in teens, beating Eli Lilly & Co. and Bristol-Myers Squibb Co. in a push to expand use of such medicines by younger patients.

The Food and Drug Administration cleared Risperdal for schizophrenia in patients 13 to 17, and for bipolar disorder in children 10 and older, the agency said today in a statement. Risperdal, J&J's top-seller, generated $4.2 billion last year, behind Lilly's Zyprexa with $4.4 billion.

The companies' efforts to win approval of medicines for teens have drawn criticism from some doctors concerned that side effects such as weight gain may be more pronounced in children than in adults. Approval for adolescents may help expand the $16 billion antipsychotic market. The FDA is reviewing Zyprexa and Bristol's pill Abilify for teens.

"We are concerned about the safety profile of these drugs, and we are very closely looking at post-marketing data for this drug and other drugs in pediatric patients," said Thomas Laughren, director of the FDA's division of psychiatry products, in a conference call today. The FDA finds it "reassuring" that the side effects in children seem to be "predictable" and similar to those in adults, he said.

Johnson & Johnson, based in New Brunswick, New Jersey, rose 34 cents to $62.01 at 4 p.m. in New York Stock Exchange composite trading. The stock has dropped 6 percent in 2007.

About 1 in 100 people have schizophrenia, which causes hallucinations and distorted thinking, and a third of them develop it in adolescence.

`Debilitating Disorders'

Vivek Kusumakar, global head of Risperdal development for J&J, said the drug's side effects must be weighed against the potentially fatal side effects of conditions it treats.

"These debilitating disorders have all sorts of side effects, including suicide," Kusumakar said today in a telephone interview. "Up to 15 percent of young people kill themselves, and many more of them make attempts and thankfully don't succeed."

Child and adolescent use of antipsychotic drugs, including Risperdal, Zyprexa and Abilify, surged 82 percent from 2001 to 2006, according to an analysis of prescription data by Medco Health Solutions Inc., the largest U.S. manager of drug benefits. Last year, 7 of every 1,000 patients age 19 and younger were prescribed an antipsychotic, Medco found.

Marketing to Doctors

Prescriptions of the drugs for teenagers were written mostly by psychiatrists as unapproved, or "off-label," uses, which is permissible. FDA approval lets J&J promote Risperdal as a medicine for teens in marketing to doctors and advertising to patients.

FDA clearance may encourage pediatricians and primary care physicians to prescribe the drugs as well, according to Mark Olfson, a professor at Columbia University. Use of Prozac and other antidepressants for younger patients soared after the FDA cleared those medicines for children.

"These antipsychotics will follow the same path as Prozac," Olfson said in an interview. "The FDA label gives physicians outside psychiatry some reassurance and confidence in prescribing these medications."

That prospect is opposed by some doctors, including Stefan Kruszewski, a child and adolescent psychiatrist in Harrisburg, Pennsylvania. FDA approval of antipsychotics will "benefit absolutely no one except the pharmaceutical manufacturers," Kruszewski said in a telephone interview today.

`Tenuous' Risks, Rewards

"The drugs are already available for doctors to prescribe," he said. "This is a license for a $16 billion-a- year market to grow larger with the same tenuous risk/reward ratio" as for adults.

Joseph Palumbo, global head of psychiatry research at J&J, said in an interview today that Risperdal should be used "in the context of the individual child's illness, and with the expert opinion of a child psychiatrist."

The American Psychiatric Association also urged in a statement that parents and physicians weigh risks and benefits in treating illnesses that the organization called "severely disabling to patients and devastating to their families."

In trials, 27 percent of those receiving the highest dosage of Risperdal had symptoms of neurological side effects that cause involuntary jerking or movements, compared with 5 percent of patients on placebos.

Weight Gain

Thirty-nine percent gained more than 7 percent of their body weight, compared with 16 percent of those receiving lower doses and 2 percent of patients taking placebos. Weight gain is often a precursor of type 2 diabetes, a common side effect of such drugs.

Forty-nine percent of patients had elevated levels of prolactin, a hormone that can cause growth of breast tissue and lactation, said the FDA's Laughren. Some children taking the medication have so much breast growth that they require mastectomies, according to Kruszewski.

Bristol-Myers asked the FDA to approve its antipsychotic drug Abilify for schizophrenia in teenagers on June 5. Abilify sales surged 41 percent to $1.3 billion last year, helped by studies showing the pill caused less weight gain than competitors.

A study found 4.8 percent of teens on a 10-milligram dose of Abilify and 6 percent on a 30-milligram dose gained 7 percent or more of their weight, compared with 1 percent with a placebo.

Lilly's Drug

Lilly in April received what is known as an approvable letter from the FDA on its Zyprexa application. The agency indicated regulators needed more time to consider whether to approve that drug for schizophrenia and bipolar disorder in teens. Zyprexa sales rose 3.8 percent to $4.4 billion last year.

In one study of Zyprexa, children ages 13 to 18 were more than twice as likely to have significant weight gain as adults taking the drug, with 65 percent of teens gaining 7 percent or more of their weight, compared with 36 percent of adults.

Atypical antipsychotics, the class of drugs that includes Abilify, Risperdal and Zyprexa, came on the market in the mid- 1990s. The products were promoted as causing fewer of the neurological side effects that made users of earlier medications, such as Haldol, tremble, doze off and jerk involuntarily.

To contact the reporter on this story: Lisa Rapaport in New York at

Last Updated: August 22, 2007 16:20 EDT

~~~~~~~~~~~~~ [Link] FORBES FDA Approves First Anti-Psychotic for Kids 08.22.07, 12:00 AM ET

WEDNESDAY, Aug. 22 (HealthDay News) -- The powerful anti-psychotic drug Risperdal was approved by the U.S. and Food Administration on Wednesday for use in children and adolescents who have schizophrenia or bipolar disorder. Until this point, the agency hadn't approved any drug for the treatment of adolescent schizophrenia. For bipolar disorder, only lithium is approved for use in adolescents aged 12 and older.

"The FDA has approved Risperdal for treating schizophrenia in adolescents 13 to 17 and for the short-term [three-week] treatment of bipolar I disorder in children and adolescents 10 to 17," Dr. Thomas Laughren, director of the Division of Psychiatry Products at the agency's Center for Drug Evaluation and Research, said during a midday teleconference.

One expert thinks the move is warranted. "This is a drug that has real value," said Dr. Charles Goodstein, a clinical professor of psychiatry at New York University Medical School. "But one has to exercise a degree of caution when using what amount to be heavy-duty medications in young children and adolescents."

Goodstein noted that diagnosing children with these conditions is difficult, and that can lead to misdiagnosis and the prescribing of inappropriate medications. "One has to very careful that this medication is not overused," he said.

"Bottom line, it's a valuable medication, one that can produce momentous changes in a person's functioning, but a medication that should be used with great care, because it does have side effects, and too often diagnoses are made more readily than they should be made," Goodstein said.

The agency first approved Risperdal (risperidone) in 1993 for treating schizophrenia in adults. It was approved subsequently for the short-term treatment of acute manic or mixed episodes of bipolar I disorder in adults and the treatment of irritability associated autism in children and adolescents aged 5 to 16, Laughren noted.

Risperdal brought in $2.3 billion in sales in 2005, according to the Associated Press.

Laughren said the medication belongs to a class of powerful drugs that do have side effects, but they are used to treat disabling conditions that fail to respond to other medications.

"Both of these disorders are commonly treated off-label in pediatric patients with Risperdal and other drugs that are approved for treating these conditions in adults," Laughren said.

The FDA based its approval for using the drug with schizophrenic adolescents on the results of two short-term trials. Patients taking the drug had fewer symptoms, including fewer hallucinations and less delusional thinking.

In terms of bipolar disorder, the agency relied on the outcome of a three-week trial among children and adolescents with bipolar I disorder. In this trial, patients taking Risperdal had fewer symptoms, including a reduction in elevated mood and hyperactivity, the agency noted.

Common side effects of Risperdal include drowsiness, fatigue, increased appetite, anxiety, nausea, dizziness, dry mouth, tremor and rash. "This adverse event profile is similar to what we have seen in adults who are treated with these medications," Laughren said.

However, Laughren noted Risperdal might also affect growth and development in adolescents, so the FDA has asked the drug's maker, Janssen, L.P., of Titusville, N.J., to begin a study to look a those potential problems.

Schizophrenia is a disabling psychiatric disorder with symptoms that can include hallucinations, delusions, and disorganized thinking. Bipolar disorder, also known as manic-depressive illness, causes shifts in mood, energy and ability to function.

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