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ADHD Drugs: Controversy over the Black Box Warning

An advisory panel to the US Food and Drug Administration (FDA) has recently recommended that Ritalin and other drugs used to treat attention-deficit hyperactivity disorder (ADHD) should display on their packaging a "black box" warning-the strongest possible warning-concerning cardiac risks.

Panel members voted 8-7, with one abstention, to add the warning. Fifteen panel members also voted to recommend that the drugs be dispensed with a patient-friendly guide explaining associated risks.

The recommendation followed a government report showing that 25 people died suddenly and another 54 people had serious cardiovascular events after taking drugs prescribed for ADHD during the period 1999-2003. Of those affected, children accounted for 19 of the deaths and 26 of the cases of non-fatal cardiovascular problems.

Drugs commonly used to treat ADHD include methylphenidates Ritalin, Concerta, Focalin, Methylin and Metadate and chemically similar amphetamines Adderall and Dexedrine; all are stimulants. Strattera is also used to treat ADHD but is not a stimulant.

Several panel members believe there is cause for concern, because amphetamines are known to raise blood pressure-often a precursor to severe heart problems whose symptoms include including chest pain, heart attack, stroke, irregular heart beat and fainting.

The FDA's Response

Black box warnings are usually reserved for risks clearly linked to a drug. The panel's recommendation to add the high-level warning is somewhat unusual, because the FDA had requested advice only on the feasibility and advisability of studying whether cardiac problems were related to the drugs.

"It doesn't astonish me that the committee wanted to weigh in on the virtues of revising the labeling, but that is not the primary matter we went to them for," said Dr Robert Temple, director of the FDA's Office of Medical Policy, according to HealthDay News. "We're going to consider what this committee said."

Although the FDA usually follows the recommendations of its advisory panels, during a news conference FDA officials expressed ambivalence about accepting the committee's recommendations immediately:

"I think it's important not to minimize the benefits of these drugs," said Dr. Thomas Laughren, director of the division of psychiatry products at the FDA's Center for Drug Evaluation and Research, according to HealthDay News.

"We put a black box on antidepressants for adolescents, but it did have an impact on prescribing and there's been a lot of negative feedback from the clinical community. It's important to recognize that something as dramatic as a black box can have a dramatic effect on prescribing."

Dr Temple reportedly added, "You don't want to over-scare people with data that aren't very solid."

This recommendation is only the latest in a series for drugs used to treat ADHD. In August 2004, the FDA required that a warning be added to Adderall packaging, advising people with structural heart abnormalities not to use the drug.

In February 2005, Health Canada ordered Adderall off the market, citing reports linking it with cardiac death in 20 people and several strokes-some among children. However, the FDA maintained that its evaluation of the same Adderall XR data did not warrant taking similar measures in the US.

Is ADHD Over-Diagnosed?

The cause of ADHD remains unknown, but scientists believe that both genetics and environment may contribute to the disorder. According to one research report, children of an adult with ADHD have an approximately 25% chance of having ADHD.

Effective treatment of ADHD depends on appropriate diagnosis based on a comprehensive medical evaluation that ideally includes input from parents and teachers, according to the National Institutes of Mental Health (NIMH), which cites literature stating that 3-5% of school-age children have ADHD. Other estimates show that about half of children with ADHD still have the condition in adulthood.

As prescription numbers for drugs such as Ritalin have soared in recent years, some health professionals question whether some children are being wrongly diagnosed with ADHD: Many health professionals argue that some types of unwanted behaviour may simply be a normal part of growing up.

Another concern is that Ritalin's widely publicized effectiveness in helping children with ADHD to concentrate and complete tasks in the classroom may prompt parents of children who are not performing well in school (for any reason) to seek prescriptions for Ritalin or other drugs for ADHD, believing the treatments will improve their children's grades.

In the US, doctors write about one million prescriptions for ADHD drugs for adults each month and about two million prescriptions for children, according to the FDA. Dr Steven Nissen, a member of the FDA advisory panel and a cardiologist at the Cleveland Clinic, said that many prescriptions were probably unnecessary, and he hoped that the new warning would deter some use, according to Reuters.

"I want to get people's hands to tremble a little bit before they write that [prescription]," Nissen reportedly said.

Benefits of ADHD Drug Therapy

Treatment of ADHD with stimulant drugs originated from the work of a Rhode Island pediatrician, who in 1937 reported that administering stimulants to hyperactive or inattentive children unexpectedly calmed them down.

For people with genuine ADHD, taking Ritalin or other appropriate drugs can offer tremendous benefit. Children and adults with ADHD have trouble concentrating and are prone to impulsive or hyperactive to the point that their condition interferes with their ability to perform in school or at work, and can negatively affect relationships.

According to the NIMH, research into ADHD has shown that:

  • Boys have ADHD about 2-3 times more often than girls;
  • Children with untreated ADHD have unusually high rates of injury;
  • ADHD often occurs alongside other problems, including depressive and anxiety disorders, conduct disorder, drug abuse or antisocial behavior;
  • Symptoms usually arise in preschool or early elementary years;
  • ADHD frequently persists into adolescence and occasionally into adulthood.

Left untreated, ADHD can have long-term effects on a child's ability to make friends or have success in school or at work. Children with ADHD may develop depression, poor self-esteem and other emotional problems.

In contrast, treatment can significantly improve the quality of life for people with ADHD. Studies show that combination treatment-with drugs and behavior therapy-often produces the best outcomes for people with ADHD. Moreover, children who receive combined treatment are often able to reduce their medication dosage, compared with children who receive medication only.

Drug Manufacturers' Views

Most drugs commonly used to treat ADHD are stimulants within the methylphenidate (Ritalin, Concerta, Focalin, Methylin and Metadate) and amphetamine (Adderall and Dexedrine) classes. Strattera, another drug used to treat ADHD, is not classified as a stimulant.

After the panel's statement, it remained unclear whether the recommended cardiac warning should be placed on Strattera also, Dr Gerald Dal Pan, director of the FDA's drug safety office, reportedly said.

"It's our understanding that the committee excluded Strattera from the recommendations," said Eli Lilly spokeswoman Jennifer Bunselmeyer, according to Reuters.

Spokesman Matthew Cabrey of Shire, who manufacture Adderall, said the company was open to revising Adderall's label, which already displays a black box warning that misuse of amphetamines may lead to serious cardiovascular events or sudden death.

Johnson & Johnson, manufacturer of Concerta, "supports FDA efforts to ensure appropriate labeling for all medicines to treat ADHD," company spokeswoman Bonnie Jacobs reportedly said.

The FDA is expected to make a decision about the panel's recommendation in the near future.

More Information

To find out more about the diagnosis and treatment of ADHD, visit these websites:

US Advisers Urge Heart Risk Warning on ADHD Drugs, Reuters, February 10, 2006.
FDA panel calls for strongest warning on ADHD drugs, HealthDay News (Medline Plus), February 9, 2006.
Canada Orders ADHD Drug Off Market,, February 10, 2005.

Posted: February 2006