In late February, the US Food and Drug Administration (FDA) directed the manufacturers of all ADHD drugs to include special inserts warning patients of cardio-vascular risks and new psychiatric symptoms.
These so-called 'Patient Medica-tion Guides'-handouts given to the patient or his parents by the pharmacist when the drug is prescribed-warn patients of serious 'cardiovascular events' when taking the drug at the usual prescription levels, and attempt to offer FDA-approved advice on how to prevent these problems from happening.
Drug manufacturers have been told that they must create the handouts within the next month.
Nevertheless, the FDA has stopped short of taking the drugs off the market.
The FDA's move resulted from its review of reports of serious cardio-vascular adverse events in patients taking ADHD drugs. The reports revealed cases of sudden death in patients with underlying heart problems, and heart attack or stroke among adults with certain risk factors.
So far, the agency has received 27 reports of sudden cardiovascular-related deaths linked to ADHD-drug use among patients aged under 18, according to Tom Laughren, director of the FDA's Division of Psychiatry Products.
Nevertheless, Laughren refused to blame the drugs, declaring that some of the patients may have had underlying heart problems, and all had been taking the drugs for years.
The agency's review discovered new psychiatric problems with the drugs as well. Their review showed that one in a thousand patients taking the drugs suffered psychiatric episodes such as hearing voices, becoming paranoid or suspicious without good reason and even cases of mania. These side-effects have shown up in patients with no history of psychiatric problems, but those with conditions such as bipolar illness find that their preexistent problem becomes worse.
The suggested medication guide for Ritalin, for instance, suggests that a child be tested for heart, blood pressure and heart-rate problems before being prescribed the drug, and that he then be monitored while taking it. As for psychiatric illness, patients are advised to report any mental problems in the child or in the family-particularly bipolar disorder, suicide or depression.
The FDA's actions now appear to be swift and decisive-drug manu-facturers are being told they have
30 days to comply and are being urged to adopt the language of guidelines drafted by the agency for each drug in question. Nevertheless, the history of this decision reveals that the agency dragged its heels for months, and left the responsibility for tightened warnings in the hands of the manufacturers themselves.
A year ago, the FDA held two advisory meetings about this issue and, last May, asked drug makers to include clear warnings of the risks of heart-related events and psychiatric problems in patients taking ADHD drugs. However, the agency kept the decision from public view, placing it on an obscure area in its website, and only made piecemeal public announcements regarding the issue.
Even more damning, many of the psychiatric problems had already shown up in the results of clinical and post-marketing trials testing the various drugs.
But in spite of this, the FDA rejected the decision of its own Drug Safety and Risk Management Advisory Committee, which voted on 9 February 2006 for a black-box warning-the agency's most strongly worded warnings-to be included in product package inserts.
Instead, the agency based its decision on the advice offered by the Pediatric Advisory Committee. This led the agency to direct manu-facturers last May to simply revise their product labeling to reflect the new concerns. The FDA, however, did not take it one step further and make it mandatory to pass the information on to the patients who have to take the drugs. Thus, it allows the information to be buried in the general-warning sections of the drug sheets.
In his press announcements, Laughren said that the agency had been "very careful" to word the medication guides "in a way that is not intended to scare patients, families, or clinicians".
Shire's amphetamines Adderall and Adderall XR, and Glaxo-SmithKline's dextroamphetamine sulphate Dexedrine are the only ADHD drugs that have been asked to carry black-box warnings con-cerning the risk of cardiovascular-related sudden deaths. However, the warnings concern misuse, and fail to highlight the potential risks of developing heart problems with the normal, recommended use.
There's also a box on the Ritalin sheet with a warning that it is a "federally controlled substance" that can lead to dependency.
As for the psychiatric risks, only atomoxetine makes use of a black box to warn patients of the increase in risk of suicidal thoughts and behaviour associated with taking the drug.
Yet, the 22 March 2006 advisory meeting disclosed that the FDA has received hundreds of reports of psychosis or mania, particularly hallucinations, associated with the use of ADHD-medication in children.
No doubt the sanguine handling of the ADHD affair has much to do with the huge numbers of children now taking the drug.
Some six million children in the US have been prescribed Ritalin or its close cousins for ADHD. In the UK, monthly prescriptions for Ritalin have increased from 4000 in 1994 to 359,000 in 2004.
As for the new guidelines, the phrase 'closing the barn door . . .' seems particularly apt.