July 30

ADHD-Adderall Label Warnings Added Re: Cardiovascular, Psychosis

So far, Shire, manufacturer of Adderall, is the only stimulant drug manufacturer to add warnings to its drug label. In fact, Shire’s Adderall products, but not the other stimulant drugs, carry BLACK BOX warnings acknowledging their “high potential for abuse:” http://www.fda.gov/cder/foi/label/2006/011522s034s037,021303s013lbl.pdf:


Inasmuch as scientific evidence shows that amphetamines and methylphenidate are both addictive, [1] it is unclear why the FDA has not required Novartis, the maker of Ritalin (methylphenidate), and McNeil, the maker of Concerta to warn about the “high potential for abuse.”

The revised Adderall label now carries an additional warning in the Black Box:

The revised Adderall warning label warns about “treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by stimulants at usual doses.” 

Furthermore, Shire warns about treatment emergent aggression:
 “Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.”

It should be noted that that the makers of psychotropic drugs–including stimulants, antidepressants, and antipsychotics–have evaded monitoring and systematically recording, evidence of treatment-induced violent, aggressive and homicidal /suicidal behavior.  Thus, there is “no systematic evidence” for these drug-induced effects.

Shire notes that these alarming drug effects are linked interchangeably to amphetamines and methylphenidate.  Thus, questions must be raised about FDA’s indecisiveness about requiring the other manufacturers of these drugs to also carry Black Box warnings.

It is difficult to find reasoned, rational, medical justification for exposing children to drugs whose prolonged use increases the likelihood of addiction; drugs that induce psychosis, mania, violence and aggression in children; drugs that increase the risk of “sudden death” from cardiovascular damage, not to mention that they suppress growth.

Why, are these drugs being prescribed for millions of children?
Early exposure to stimulants will likely condemn children to a life of drug dependence.

Children are “graduating” from stimulants to ever more toxic prescribed drugs. A Vanderbilt University analysis and MEDCO prescribing data confirm that 2.5 million children—some as young as 18 months–are being antipsychotic drugs. [2]

An investigative series by Marilyn Elis of USA TODAY reported in May, 2006 that a review of FDA’s Medwatch adverse event report database (from 2000 to 2004)  found "at least 45 deaths of children in which an atypical anti-psychotic was listed as the "primary suspect." One-fourth of the cases in the database did not list the patient’s age.  In addition, there were 1,328 reports of bad side effects, some of them life-threatening. [3]

FDA officials’ lack of concern for children’s safety is encapsulated by the response given by FDA’s director of the division of psychiatry products. When confronted by USA Today to evidence that at least 45 children prescribed antipsychotics off-label died as a result, Dr. Thomas Laughren stated:

"we haven’t been alerted to any particular or unusual concern. The effects (in kids) are similar to what we’re seeing in adults. We have not systematically looked at the data for children" because the drugs aren’t approved for them."

AHRP has urged the FDA to set in motion a risk minimization action plan for ALL classes of drugs that trigger psychosis / violence. See: https://ahrp.org/cms/content/view/113/28/

Isn’t it time the FDA put effort into protecting children’s lives from lethal effects of prescribed drugs?

1. Lambert, NM. and Hartsough, CS. 1998. Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-ADHD participants. Journal of Learning Disabilities 31:533-44.

  1. Cooper, et. al. Trends in Prescribing of Antipsychotic Medications for U.S. Children, Ambulatory Pediatrics, 2006;6:79–83.

  2. See Marilyn Elias investigative series in USA Today, May 2006:  https://ahrp.org/cms/content/view/158/52/

Contact: Vera Hassner Sharav
veracare@ahrp.org <mailto:veracare@ahrp.org>  

Cardiovascular, Psychiatric Warnings Strengthened on Adderall
FDA Seeks Stronger Warnings on All ADHD Drugs

BETHESDA, MD, 28 July 2006 — Shire has revised the labeling <http://www.fda.gov/cder/foi/label/2006/011522s034s037,021303s013lbl.pdf>  of its attention-deficit/hyperactivity disorder (ADHD) medications Adderall and Adderall XR to include stronger warnings about psychiatric and cardiovascular risks associated with use of the products.

FDA letters <http://www.fda.gov/cder/foi/appletter/2006/011522s034,%20037,%20021303s013LTR.pdf>  to Shire posted late yesterday on the agency’s Web site state that the changes are "class labeling revisions" requested by regulators on May 22.

The agency directed all makers of ADHD stimulants in May to strengthen the wording in the "Warnings" section of the labeling "with regard to serious cardiovascular events and psychiatric events," said FDA spokesperson Crystal Rice.

"To date, all sponsors of stimulant medications have replied and the responses are currently under review," she said in an e-mail response.

Rice could not confirm when revised labeling on other ADHD stimulants will be available. But she said, FDA "will review any ‘Changes Being Effected’ labeling supplements, as they come in to the agency."

Product labeling for Adderall and Adderall XR previously carried warnings alerting prescribers that children and adults with structural cardiac abnormalities should not be treated with amphetamine products.

The revised labeling includes additional warnings that stimulants should not be used in pediatric or adult patients with cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.

In addition, the revised labeling notes that adults have a greater likelihood than children of having serious structural cardiac abnormalities and warns that adults with coronary artery disease should not take stimulants.

On February 9, an FDA panel of drug safety advisers voted 8–7 to add a black-box warning to the labeling of stimulants used to treat ADHD to alert prescribers about cardiovascular risks associated with use of the drugs.

The Drug Safety and Risk Management Advisory Committee also voted in favor of requiring makers of ADHD stimulants to develop medication guides, which pharmacists would distribute when dispensing the medications, to inform patients about cardiovascular risks in ADHD medication use.

At a March 22 meeting, FDA’s Pediatric Advisory Committee supported the medication guide proposal, but rejected the idea of adding a black-box warning.
Shire’s Adderall products already carry a black-box warning alerting prescribers to the high potential for amphetamine abuse and warning that misuse of amphetamines may cause sudden death and serious cardiovascular adverse events.

But other stimulants, such as methylphenidate, marketed by Novartis as Ritalin and McNeil as Concerta, do not carry a similar black-box warning.

Methylphenidate products are the most frequently prescribed ADHD medications, according to FDA. About 1.5 million adults and 2.5 million children in the United States take ADHD medications.

Regulators have yet to decide whether to require a black-box warning in all ADHD labeling or to add medication guides, Rice said.

The revised labeling for Adderall and Adderall XR advises prescribers that children, adolescents, or adults who are being considered for treatment with stimulant medications should have their medical history carefully evaluated, including assessment for a family history of sudden death or ventricular arrhythmia and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation, like electrocardiogram or echocardiogram, if findings suggest cardiac disease.

Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation, the labeling warns.

Psychiatric warnings. Shire’s labeling for its Adderall products previously warned that amphetamines may exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.

But regulators in March said that ADHD medication labeling needed stronger warnings about psychiatric risks, specifically about risks of drug-induced signs or symptoms of psychosis or mania, including hallucinations, associated with use of the drugs.

FDA drug safety reviewers also stated that ADHD labeling did not clearly state the importance of stopping drug therapy in any patient who has hallucinations or other signs or symptoms of psychosis or mania during drug treatment of ADHD.

The updated labeling for Adderall and Adderall XR notes that stimulants at usual dosages can cause psychotic or manic symptoms, such as hallucinations, delusional thinking, or mania in children and adolescents.

"If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate," the revised labeling recommends.

Prescribers should be particularly cautious in using stimulants to treat ADHD patients with comorbid bipolar disorder "because of concern for possible induction of mixed/manic episode in such patients," the labeling warns.

Patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder before starting treatment with ADHD stimulants, the revised labeling advises, adding that the screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Patients beginning treatment for ADHD should be monitored for the appearance or worsening of aggressive behavior or hostility, the labeling counsels.

However, there is "no systematic evidence that stimulants cause aggressive behavior or hostility," Shire stated in the labeling. —Donna Young

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