In addition to the well-publicized safety issues involving antidepressants, physicians who prescribe behavioral health products may have a new worry. Adderall, a psychostimulant for the treatment of persons with attention deficit hyperactivity disorder (ADHD), has been pulled from the Canadian market. On February 9, 2005, Health Canada (Canada’s equivalent of the FDA) suspended market authorization for Adderall XR. This means that no version of Adderall can be marketed in Canada, including the immediate-release form of Ad derall that was never available there. Health Canada is concerned about the sudden deaths, heart-related deaths, and strokes in children and adults taking usual recommended doses of Adderall and Adderall XR.
Health Canada cited results from a review of safety information provided by Shire US, the manufacturer, which indicated that there were 20 reports of sudden death in patients taking either Adderall or Adderall XR worldwide. None of the deaths occurred in Canada, nor were any deaths associated with overdose, misuse, or abuse of the medication. Fourteen of those who died were children. There were 12 reports of stroke, 2 of which occurred in children. The Canadian warning went on to say that a preliminary review of safety data for other stimulants used in the management of ADHD did not show as many serious adverse reactions leading to death as did Adderall and Adderall XR.
On the same day that Health Canada suspended market authorization for Adderall XR, the FDA chose to deliver a different message. Rather than suspending distribution of Adderall preparations, the FDA issued a warning that the products not be used in children or adults who have structural cardiac abnormalities. The FDA substantiated its position by reviewing all 12 cases of sudden death in pediatric patients who were being treated for ADHD with either form of Adderall. All cases reviewed were from the FDA’s Adverse Reporting System database for the years 1999 to 2003. During this period, approximately 30 million prescriptions for Adderall products were written. The 12 deaths were all of boys between the ages of 7 and 16, who had been treated from 1 day to 8 years with total daily doses ranging from 10 to 50 mg.
Cardiac Risk Factors
Significantly, autopsies in 5 of the 12 pediatric sudden death cases revealed underlying cardiac risk factors, including previously undiagnosed cardiac abnormalities (eg, aberrant origin of coronary artery, bicuspid aortic valve, and idiopathic hypertrophic subaortic stenosis). In one case, there was a family history of ventricular arrhythmia. Seven of the cases were complicated by other illnesses (eg, type 1 diabetes mellitus, fatty liver, and myocardial infarction) or heat exhaustion and rigorous exercise. Unusual and unexplained accumulation of drug, resulting in toxic levels during usual therapeutic dosing, also appears to have played a role in several deaths. The FDA commented that the number of cases of sudden death reported for Adderall is only slightly higher, per million prescriptions, than the number reported for methylphenidate products, which are also commonly used to treat children with ADHD.
Because it appeared that patients with underlying heart defects might be at increased risk for sudden death, the labeling was changed in August 2004 to warn that such patients should ordinarily not be treated with Adderall or Adderall XR. As amphetamines, both forms of Adderall already carried black-box warnings cautioning physicians against prescribing them for children or adults with cardiovascular disease or hypertension.
If the FDA were to follow Canada in banning Adderall, where would that leave us in terms of options for managing ADHD? According to the FDA, methylphenidate preparations may carry a similar risk of sudden death in users. What are the alternatives? We know that double-blind placebo-controlled studies of the effectiveness of bupropion and desipramine show that these antidepressants are more effective than placebo for treatment of ADHD, although possibly less effective than stimulants.
Atomoxetine (Strattera), a selective norepinephrine reuptake inhibitor, and thus similar to some antidepressants, is approved by the FDA for managing ADHD in children and adults. Results of several studies show good efficacy compared with placebo. However, we are still in the middle of the controversy about antidepressants and suicide risk.
In addition, on December 17, 2004, the FDA put out a new warning for Strattera. The labeling for that medication is being updated with a bold-type warning about the potential for severe liver injury after 2 reports. One case occurred in a teenager and the other in an adult, after they were treated with Strattera for several months. Both patients recovered, but the new labeling warns that severe liver injury may progress to liver failure resulting in death or the need for a liver transplant in a small percentage of persons. There were no signs of hepatotoxicity in the original clinical trials of atomoxetine. Since marketing began in 2002, some 2 million children and adults have been treated with the medication.
I think that the FDA is being prudent in not rushing to join Health Canada in banning Adderall and Adderall XR. There may be risks associated with all medications used in the treatment of ADHD, as well as great benefit. As usual, a careful clinical assessment is needed before these medications are prescribed, and patients should be carefully monitored thereafter. That is the position of the American Academy of Child and Adolescent Psychiatry, which has advised its members that it is safe to continue prescribing psychostimulants for patients with ADHD (including Adderall and Adderall XR) by using clinical practices that were already in place before the FDA’s latest warning.
It is interesting that the Adderall controversy does not involve a new medication, but one that has been on the market for years. Adderall, a mixture of 4 different amphetamine salts (dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate) was first developed for weight control 20 years ago by Rexar and marketed under the name Obetrol. Adderall was approved by the FDA for the treatment of ADHD in 1996.
Just as with the more substantiated and clear concerns about hormone replacement therapy in postmenopausal women, the increased risk of myocardial infarction for persons taking cyclooxygenase-2 inhibitors, and the increased risk of suicide associated with antidepressants that are prescribed for children and adolescents, it is not enough to determine safety and efficacy in short-term studies with a select population. Larger, ongoing studies with diverse populations may be required for both new and old medications to ensure that we really understand the safety/efficacy equation for each one.