FDA Staff Suggests Pediatric Warnings For Zyprexa
10 CommentsBy Ed Silverman // November 17th, 2008 // 7:31 am
Agency staffers believe that labeling for the Lilly antipsychotic should include info about the risk of children gaining weight, developing hyperglycemia or experiencing other metabolic effects in briefing documents prepared for a Pediatric Advisory Committee being held on Tuesday. FDA reviewers also suggest that Lamisil, a Novartis fungus med, should be watched for potential psychiatric side effects in children.
“No new safety signals emerged as part of this review; however, it has made us aware that the pediatric population is not spared from the adverse events caused by (Zyprexa),” FDA reviewers wrote on page 12 of the briefing documents. “The potential risks…should be weighed against the potential benefit when choosing to initiate therapy.”
Zyprexa is currently approved for anyone 18 years or older, although prescriptions are increasingly written for children (take a look). Lilly, meanwhile, is seeking FDA approval to market the antipsychotic to children between 13 and 17 years old (back story).
The committee meeting is being held to comply with the Best Pharmaceuticals for Children Act of 2002 for all drugs recently tested in children (see letter). Eleven drug safety reviews will take place at the meeting, including nine new meds and two others recommended for follow-up at previous committee meetings.
Lilly, you will recall, has been accused of failing to properly warn states and healthcare providers that Zyprexa could result in weight gain, high blood sugar and diabetes. Documents from a lawsuit in Alaska, which Lilly settled for $15 million, revealed that Lilly’s research showed some patients gained as much as 80 pounds and the incidence of high blood sugar at diabetes levels was 3.5 times higher than for placebos (back story). The drugmaker took a $1.4 billion charge in the third quarter to settle federal and state investigations into Zyprexa marketing.
Daniel Haszard
Lilly Zyprexa ‘ Chemical Straitjacket’ Use by Children.
Zyprexa,as well as the other atypical antipsychotics, are being prescribed for children, even though this is an unapproved, off-label use. Eli Lilly has been charged in allegedly pushing the drug for children in more than one state.
A report by Dr. Cooper at Vanderbilt University states that 2.5 million children are now taking atypical antipsychotics. Over half are being given them for Attention Deficit Hyperactivity Disorder. Perhaps it is statistics like these that caused the FDA to finally require warnings on the labels of the ADHD drugs.
The use of atypical antipsychotics for children should be banned. St. Petersburg Times Reports on Zyprexa A risky drug may get wider marketThe FDA may approve Zyprexa for kids, despite its significant side effects in adult use. By ROBERT FARLEY, Times Staff …
http://www.youtube.com/watch?v=uuK1t474ei4
Daniel Haszard http://www.zyprexa-victims.com
Lisa Van S
Hey Ed, Promoting Zyprexa for NJ Infants and Toddlers? Just ask this group, maybe they’d like to offer up a finacial disclosure?
http://www.njaimh.org
Dan A.
“The FDA suggests…..”
Thought they were suppose to ‘regulate’
Salmon
No. FDA employees may no longer use any words like shall or should it’s against the rules and you can get reprimanded for not following the rules.
Slow progressive additions of minimal warnings, and class warnings (like last June 16th) that are worthless as they hid the real culprit are standard FDA tactics to drag out the evaluation of a major safety issue that has been identified as long as possible so as to have minimal finacia inpact on the company.
Look at the history of Troglitazone, Vioxx/Bextra/ Retin A / Antidepressants and suicidality. The list goes on.
Meg
As it stands, the FDA is useless. Perhaps there will be a change under a new president. This drug, which killed my son, was judged the worst in the CATIE study done by NIH. Why would anyone in their right mind give it to children? Couple of answers: 1. greed 2. Have to give something, and now that the SSRIs finally got a black box, the doctor’s black bag has fewer choices.
Salmon
It appears that the recommendation for Zyprexa will be that it’s already pretty much adequately labeled and to just continue to monitor.
The following is what I have gleaned from the briefing documents.
Zyprexa accounts for about 15% of all US antipsychotic sales. Usage of Seroquel is greatest at 36%, then risperidone at 26%, followed by aripiprazole and Zyprexa each at around 15%.
Approximately 5% of all Zyprexa usage is in children and 40% of this is in children less than 12 years old.
Usage appears mainly for outpatient long term use, yet Zyprexa was only studied for acute inpatient use and there is virtually no safety data in children beyond 6 months.
Most prescriptions are written by adult psychiatrists.
The top pediatric uses were for off label uses and/or in age groups that the drug is not approved for.
The primary uses in children 0 to 12 years of age are anxiety states” (ICD-9 300.0) and “early child psychoses, NEC” (ICD-9 299.8) for patients aged 13 to 17 years the primary use was for “depressive disorder, NEC” (ICD-9 311.0).
Sales for Zyprexa have been falling but instead appear to be shifting to quietiapine (Seroquel) an antipsychotic that is considered to be even worse than Zyprexa as to cardiac toxicity.
The pharmacokinetic review indicates that doses should be adjusted by both weight and gender to prevent overexposure, yet this in not adequately addressed in the labeling.
On May 25, 2006. a review of cases of myocarditis and cardiomyopathy associated with the use of olanzapine and quetiapine was conducted. The review recommended that both cardiomyopathy and myocarditis be added to the Adverse Events section of both olanzapine and quetiapine labels as well as continued monitoring of cardiac adverse events associated with the two drug products. In particular, pediatric cases and fatal cases with hypertrophic cardiomyopathy associated with these two drug products should undergo heightened monitoring.
Around 3% of serious adverse events and 3% of deaths occurred in children, with lower rates reported in the US. Since US pediatric sales are 5% this may be a result of underreporting and/or the fact that serious toxicities and death are cumulative and time dependent and may not be fully appreciated yet. The median duration of pediatric use is 88 days (half of patients on Zyprexa on less than 88 days and half more. The average duration is 261 with a maximum of 2095 days, indicating that the majority of patients have received Zyprexa for less than 9 months. Thus long term cardiac toxicities similar to phen-fen are not likely to have become apparent yet as data from Vioxx and other drugs show that the increased death rate in the elderly only begins to become demonstrable after 1 year of use. The documented duration of exposure to Zyprexa in children is much less and children in general have less cumulative natural cardiovascular damage and thus cardiac, vascular and pulmonary toxicities in the majority are not expected to become apparent until after much longer durations of use as compared with Vioxx.
12 of the 44 deaths were in neonates and infants, 4 of the 12 deaths had symptoms suggestive of cardiac or pulmonary involvement, and thus may be due to in utero exposure. Most cases were complicated by other factors however, one was born full term with cardiomegaly, and macrosomia due to olanzapine induced gestational diabetes, two died from SIDS, and another due to heart and kidney complications. Two others died with kidney problems. Other serious AEs reported due to 11 cases of in utero exposure include 1 case each of atrial septal defect, and patent ductus arteriosus.
Of the remaining 32 deaths in older children 6 were suicides, 5 due to diabetes, and 4 were cardiac effects. Of the others there were a number of cases of pulmonary or cardiac involvement.
Thus of the 44 pediatric deaths approximately 1 in 5 had cardiac or pulmonary involvement. If my hypothesis that Zyprexa (the 7-OH or related metabolites) causes a phen-fen like cardio-pulmonary toxicity. Then the current duration of use is too short and we should see an explosion of cases over the next several years, and possibly even more if quetiapine causes cardiac toxicity by a similar mechanism due to the much greater sales of quetiapine due to shunting of sales secondary to the metabolic concerns with Zyprexa.
Salmon
Raptor
Take a look at the black box warning on cardiac and PULMONARY deaths in the elderly with atypical antipsychotics. Just look up the labeling for any atypical antipsychotic.
It’s interesting to speculate. If concerns about long term toxicities were raised at FDA, especially in children, one way to dismiss them would be to wait until after this postmarketing safety report and then say see nothing was seen, the concern isn’t valid.
Salmon
Another interesting fact is that the category with the most number of pediatric deaths with Zyprexa is suicide. Yet the main reasons for using it is anxiety disorders and depression.
Does this mean that Zyprexa via effects on serotonin receptors causes suicide just like SSRI’s? Maybe this is the real reason for the increase in teenage suicides. After all suicides in kids began to go up even before the warnings about suicidality due to antidepressants was made public, and if you look at the background documents for this meeting on Zyprexa the use of Zyprexa in children appears to have skyrocketed in 2003, which would be just at the right time.
Salmon
Meg
Salmon, thank you for your information which I will certainly share. It has long been my belief that the SSRI black box warning caused a thundering herd of doctors to switch children over to atypical antipsychotics. After all, the doc can’t just sit there - and psychiatrists have nothing else to do but prescribe lethal meds. It is my understanding that adult suicide from Zyprexa and the other atypicals has also been underrated - if no toxicology work is done, which it often is not with the atypicals - the cause of death is never known. And interesting that some of the pediatric causes of death mirror those of seniors with dementia.
Could you tell me where you found this information? Thank you.
Salmon
Meg,
The information is in the background documents that FDA released for yesterday’s pediatric advisory committee meeting.
Even though Zyprexa was discussed at 9 AM yesterday morning, the background documents were also not released until yesterday. Thus I didn’t even find them until after the advisory committee discussion on Zyprexa had begun.
Since the ability of the public to comment has to be requested (including what is to be discussed) and approved by FDA and since these requests have to be submitted in advance, there was no possible way for the public to have had any opportunity to comment.
Not only that but the background documents were not linked to the announcement under the upcoming meetings page (http://www.fda.gov/opacom/hpmeetings.html) which is the what you get if you do a google search, even though the announcement stated that they would be linked when available. The page has since been updated to remove yesterday’s meeting so you can’t check this any longer.
Instead you need to go to the FDA advisory committee web page (http://www.fda.gov/oc/advisory/) even though they used to be linked under the meeting as listed on the calendar instead you now have to look to the side and click on a link for 2008 Meeting Documents and then try to find the specific advisory committee meeting and also keep checking back to see if the documents have changed prior to the meeting. Plus it’s not unde the list for the center for drugs but you have to go all the way down to the office of the commissioner. (http://www.fda.gov/ohrms/dockets/ac/08acdocs.htm)
I have seen in the past that meetings for specialized FDA meetings , e.g. the manufacturing policy changes, have been reported in the Federal Register as required, but then a day or two before the meetings a correction is published in the Federal Register changing the venue but it doesn’t discuss regarding what and only gives a cross reference to the original Federal Register announcement. This is common shell game tactic that FDA repeatedly uses.
The reason I say the use of Zyprexa in kids skyrocketed in 2003 is because there is a sharp spike in the reporting of AEs in children in 2003. This tends to coincide with increased usage and then they go back down to background rates.
Salmon