FDA Issues Stronger Warnings for ADHD Stimulants; Warnings Don’t Go Far Enough

On August 21, the Food and Drug Administration (FDA) announced stronger warnings for drugs widely used to treat attention deficit hyperactivity disorder (ADHD).

The most serious change applies to amphetamine-containing ADHD drugs. There are two types of stimulant drugs used to treat ADHD: methylphenidates (CONCERTA, DAYTRANA, [dexmethylphenidate] FOCALIN, METADATE, METHYLIN, RITALIN) and amphetamines (ADDERALL, [detroamphetamine] DEXEDRINE).

The FDA now requires the manufacturers of amphentamine-containing ADHD drugs to include a black box warning, which is found in a drug’s professional product label (also known as a package insert), informing patients about the possibility of sudden death and serious cardiovascular problems associated with these drugs. The new black box warning for the drugs appears below.

A black box warning is the strongest type of warning that the FDA can request on a drug’s professional product label. However, the statement “misuse of amphetamines may cause sudden death and serious cardiovascular adverse events” is extremely misleading because it does not tell patients that the drugs can also cause sudden death in those using the medication properly. Sudden death has been reported in association with the use of stimulant ADHD drugs in the recommended doses in children, adolescents and adults with structural heart abnormalities or other serious heart problems, such as a heart murmur or abnormal heart rhythm — not just in those who misuse stimulants. The FDA should immediately take steps to change this statement to say that sudden death and serious complications can occur in a wide variety of people who are not misusing the drugs.

In addition to the new black box warning, the un-boxed warnings section of the labels for amphetamine-containing drugs now require that children, adolescents or adults who are being considered for treatment with stimulant drugs for ADHD have a careful medical history assessment, including assessment for a family history of sudden death or heart rhythm disturbance. Patients should undergo a physical examination to assess for the presence of heart disease.  Further evaluation could be necessary if the findings of an electrocardiogram and echocardiogram do suggest heart disease.

The FDA also has extensively strengthened the warnings section of the professional product labels for other stimulant ADHD drugs that contain methylphenidate to warn not only of sudden death and serious cardiovascular problems but also of psychiatric problems, stunted growth, seizures and visual disturbances. A summary of the new FDA warnings follows.

Sudden Death, Strokes and Heart Attacks
Sudden death has been reported in association with central nervous system stimulant treatment at usual doses in children and adolescents with structural heart abnormalities or other serious heart problems. Although some heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known structural heart abnormalities, disease of the heart muscle (cardiomyopathy), major rhythm disturbances or other serious heart problems that may place them at increased risk from a stimulant drug.

In adults, sudden death, stroke and heart attacks have been reported in those taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having structural heart abnormalities, cardiomyopathy, significant heart rhythm disturbances, coronary artery disease, or other serious heart problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.

Blood Pressure and Heart Rate
Stimulant medications cause increases in blood pressure and heart rate, and patients taking stimulants should be monitored for changes in these areas. Doctors should use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, for example, those with pre-existing high blood pressure, heart failure, recent heart attack or a rhythm disturbance of the large chambers of the heart (ventricular arrhythmia).

Doctors should monitor patients before treating them with stimulants
Children, adolescents or adults who are being considered for treatment with stimulant drugs should thoroughly review their medical history with their doctors, including an assessment to determine whether the patient’s family has a history of sudden death or ventricular arrhythmia, as well as a physical examination to assess for the presence of heart disease. A patient should receive further evaluation if the initial assessments suggest heart disease, for example, electrocardiogram and echocardiogram tests. Patients who develop symptoms such as chest pain, unexplained fainting or other symptoms suggestive of heart disease during stimulant treatment should undergo a prompt evaluation.

Psychiatric complications
Treatment with stimulants may make the symptoms of behavior disturbance and thought disorder worse in patients with a pre-existing psychotic disorder.

Bipolar illness — Particular care should be taken in using stimulants to treat ADHD in patients with bipolar disorder because of concern about possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.

New psychotic or manic symptoms — Treating patients with stimulants at usual doses can trigger psychotic or manic symptoms, such as hallucinations, delusional thinking or mania in children and adolescents without a prior history of such illnesses. In an analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1 percent of patients, or four patients out of the 3,482 who were exposed to average doses of methylphenidate or amphetamine for several weeks. If such symptoms occur, doctors should consider the possible role of the stimulant and look into discontinuing the treatment.

Aggression — Aggressive behavior or hostility is often observed in children and adolescents with ADHD. This behavior has also been reported in clinical trials and the post-marketing experience of some drugs used in the treatment of ADHD. 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.

Slowed growth in children
Careful follow-up of weight and height in children ages seven to 10 who were treated with either the stimulant methylphenidate or non-medication treatment over 14 months suggests that children who are treated every day have a height that is retarded by almost an inch and are about six pounds lighter. There is inadequate data to determine whether chronic use of amphetamines may cause a similar decrease in a child’s growth rate, but the drugs likely have the same effect. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Seizures
There is some evidence that stimulants increase the risk of seizure in patients with prior history of seizures, in patients with prior electroencephalogram (EEG) abnormalities who haven’t had seizures and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.

Vision problems
Difficulties with the automatic adjustment of the eye for seeing at different distances and blurring of vision have been reported with stimulant treatment.

Patients and their parents are left in the dark
Despite the fact the professional product labels for the stimulant ADHD drugs have been extensively revised to warn of the potential serious adverse drug reactions discussed above, patients treated with these drugs and their parents most likely will never see these new warnings. Professional product labels are not routinely distributed to patients at the time a prescription is filled. Rather, most patients receive a print-out at the pharmacy produced by unregulated commercial information vendors that have been shown to omit important risk information (see Worst Pills, Best Pills News August 2002).

The FDA has the regulatory authority to require that pharmacists distribute agency-approved written drug information, called medication guides, at the time a prescription is dispensed for drugs that present significant public health concerns. Of the thousands of prescription drugs on the market, there are only about 75 drugs that require the distribution of medication guides. Clearly, the FDA should require the distribution of a medication guide with each new and refill prescription of stimulant ADHD drugs because they present a serious public health concern.

What You Can Do
If you are considering treatment with a stimulant ADHD drug for yourself or your child, become familiar with the new warnings for these drugs that are presented in this article. If you have questions or concerns, you should discuss them thoroughly with the prescribing physician.