November 29, 2006 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise that use of central nervous system stimulants may increase the risk for cardiovascular events and exacerbate psychotic symptoms in certain patients and that chronic use may cause temporary suppression of growth rate in children. Also, interferon-alfa-2a [recombinant] subcutaneous injection may be linked to potential risks for severe infection and pancreatitis.CNS Drugs May Potentiate Risk for Sudden Death
The FDA approved safety labeling revisions in August for dexmethylphenidate HCl tablets and extended-release capsules (Focalin and Focalin XR, made by Novartis Pharmaceuticals Corp), methylphenidate HCl extended-release capsules (Metadate CD, made by UCB Pharma, Inc), methylphenidate chewable tablets/oral solution (Methylin, made by Mallinckrodt), and methylphenidate tablets, sustained-release tablets, and extended-release capsules (Ritalin, Ritalin SR, and Ritalin LA, made by Novartis Pharmaceuticals Corp).
The revisions are associated with an FDA class-labeling initiative for all central nervous system (CNS) stimulants to warn about their potential use in patients with preexisting structural cardiac abnormalities and other serious heart conditions and their potential to exacerbate some preexisting psychiatric disorders. Use of these products is also linked to risks for treatment-emergent psychiatric effects and temporary growth suppression in children.
The first warning was based in part on reports of sudden death associated with use of CNS stimulants at normal doses in children and adolescents with structural cardiac abnormalities or other serious heart conditions. Stimulant therapy should be avoided in pediatric patients with these defects because of their potential increased vulnerability to sympathomimetic effects.
Serious cardiovascular events (eg, sudden death, stroke, and myocardial infarction) have also been reported in adults receiving stimulant drugs at usual doses. While a causative role for the drug remains unclear, the FDA notes that adults are more likely than children to have serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems. Therefore, use of CNS stimulants should be avoided in these settings.
The FDA advises obtaining a careful history (including family history of sudden death or ventricular arrhythmia) and physical assessment from patients for whom CNS stimulant therapy is being considered. Those with cardiac disease should be further evaluated via electrocardiogram and echocardiogram. Patients who develop symptoms suggestive of cardiac disease during treatment (eg, exertional chest pain or unexplained syncope) should be promptly evaluated.
During treatment, patients should be monitored for excessive changes in mean blood pressure and heart rate (usual mean increases, about 2 - 4 mm Hg and 3 - 6 bpm, respectively). Particular caution is advised when treating those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.
Pretreatment screening should also include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Stimulant therapy can exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorders and should be used with caution in patients with attention-deficit/hyperactive disorder and comorbid bipolar disorder.
However, treatment-emergent psychotic/manic symptoms (eg, hallucinations, delusional thinking, and mania) have also been reported in children and adolescents without prior history of these conditions receiving normal doses of CNS stimulants. Data from a pooled analysis of multiple short-term studies have revealed an increased incidence of these events in patients receiving methylphenidate or amphetamines for several weeks, relative to placebo (0.4% vs 0%). A potential causal role for the stimulant should be considered in patients who develop symptoms of psychosis or mania, and discontinuation of therapy may be indicated.
The FDA notes that although there is no systematic evidence that stimulants cause aggressive behavior or hostility, such symptoms are often observed in children and adolescents with attention-deficit/hyperactive disorder and have been reported in clinical trial and postmarketing data of some attention-deficit/hyperactive disorder drugs. Patients should therefore be monitored for the appearance of or worsening of aggressive behavior or hostility during initial therapy.
Growth rate monitoring is also advised for pediatric patients receiving chronic stimulant therapy. The measure is based on data from a careful follow-up of weight and height in children aged 7 to 10 years randomized to receive either methylphenidate or nonmedication treatment for 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated children aged 3 years or older to 10 or 13 years.
Study results suggested that children receiving chronic therapy every day for a year experience a temporary slowing in growth rate (mean, 2 cm less in growth height and 2.7 kg less in weight for 3 years) without evidence of growth rebound during this period. The FDA notes that interruption of therapy may be required in children who are not growing or gaining height or weight as expected.
Methylphenidate extended-release capsules and dexmethylphenidate tablets and extended-release capsules are indicated for the treatment of attention-deficit/hyperactive disorder. Methylphenidate tablets, sustained-release tablets, extended-release capsules, chewable tablets, and oral solution are indicated for the treatment of narcolepsy in addition to attention-deficit/hyperactive disorder.Severe Infections and Pancreatitis Reported During Interferon-Alfa-2a (Roferon A) Therapy
On August 29, the FDA approved safety labeling changes for interferon-alfa-2a [recombinant] subcutaneous injection (Roferon A, made by Hoffmann-La Roche, Inc) to warn of the potential risks for severe infection and pancreatitis.
According to the FDA, serious and severe infections (bacterial, viral, and fungal) have been reported during treatment with alpha-interferons, including interferon-alfa-2a. Although fever can be associated with the flu-like syndrome that commonly occurs during interferon therapy, other causes should be ruled out for high or persistent fever (particularly in neutropenic patients). Whereas infections should be treated appropriately, discontinuation of interferon therapy should also be considered.
The FDA also warned that cases of pancreatitis (some fatal) have been reported in patients receiving alpha-interferon therapy. Some of these have occurred in patients with markedly elevated triglyceride levels, a risk factor for pancreatitis. Although a causal role for interferon-alfa-2a has not been established, treatment should be suspended in patients who present with symptoms or signs suggestive of pancreatitis. Discontinuation of therapy should be considered for those subsequently diagnosed with the condition.
Interferon-alfa-2a is indicated for the treatment of chronic hepatitis C viral infection and hairy cell leukemia in adults aged 18 years and older. It may also be used in minimally pretreated patients with chronic phase, Philadelphia chromosome (Ph)–positive chronic myelogenous leukemia.