FDA Safety Labeling Changes: Sustiva, Adderall XR, Hepsera, Amicar

Yael Waknine

November 03, 2004

Nov. 3, 2004 — The U.S. Food and Drug Administration (FDA) approved in August revisions to safety labeling to advise healthcare professionals of the following changes: efavirenz use is contraindicated with concurrent voriconazole therapy, and it has been associated with psychiatric and nervous system adverse events; unusual doses of amphetamine therapy in patients with cardiac structural abnormalities are linked to sudden death and serious cardiovascular adverse events; the discontinuation of adefovir dipivoxil therapy may result in serious hepatitis B virus exacerbations, resulting in the need for longer-term clinical and laboratory monitoring; and the benzyl alcohol preservative in aminocaproic acid is associated with "gasping syndrome" in premature neonates.

Efavirenz (Sustiva) Contraindicated With Voriconazole Therapy and Associated with Psychiatric and Nervous System Adverse Events

On Aug. 13, the FDA approved revisions to the safety labeling for efavirenz (Sustiva capsules and tablets, made by Bristol-Myers Squibb) to warn of its contraindication in combination with voriconazole therapy, and of psychiatric and nervous system adverse events associated with its use.

Efavirenz has been shown to significantly decrease voriconazole plasma concentrations, and its use is contraindicated in patients receiving voriconazole therapy.

The FDA has also received reports of serious psychiatric adverse events in patients receiving efavirenz. According to the long-term results of a study (Study 006) comparing efavirenz-containing regimens (n = 1008; 1.6 years) with control regimens (n = 635; 1.3 years), patients receiving efavirenz regimens experienced higher incidences of severe depression (1.6% vs 0.6%), suicidal ideation (0.6% vs 0.3%), nonfatal suicide attempts (0.4% vs 0%), aggressive behavior (0.4% vs 0.3%), paranoid reactions (0.4% vs 0.3%), and manic behavior (0.1% vs 0%) compared with control subjects.

Factors associated with increased risk of psychiatric symptoms included history of injection drug use, psychiatric history, and psychiatric medication use at study entry.

Study results also showed a significantly higher rate of nervous system symptoms in patients receiving efavirenz compared with control subjects (53% vs 25%). Symptoms included (but were not limited to) dizziness (28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%).

After six months of therapy, incidence rates of new-onset nervous system symptoms were similar between the efavirenz and control groups.

Efavirenz is indicated for use in combination with other antiretroviral therapies in the treatment of HIV-1 infection.

Amphetamine (Adderall XR) Misuse Associated With Sudden Death, Cardiovascular Adverse Events in Patients With Structural Cardiac Abnormalities

On Aug. 11, the FDA approved changes to the safety labeling for mixed salts of a single-entity amphetamine product made up of amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate (Adderall XR, made by Shire Laboratories), warning that its misuse is associated with serious cardiovascular adverse events and may cause sudden death in patients with preexisting cardiac structural abnormalities.

The FDA has received reports of sudden death associated with unusual amphetamine dosing in children with structural cardiac abnormalities. The FDA does not recommend general use of amphetamines in children or adults with structural cardiac abnormalities.

Mixed salts of a single-entity amphetamine product are indicated in the treatment of attention deficit hyperactivity disorder.

Adefovir Dipivoxil (Hepsera): Discontinuation Warrants Longer-Term Monitoring

On Aug. 19, the FDA approved changes to the safety labeling for adefovir dipivoxil (Hepsera tablets, made by Gilead), warning that because of acute exacerbations of hepatitis B virus (HBV) associated with its discontinuation, both clinical and laboratory follow-up for at least several months is warranted.

The FDA has received reports of severe acute exacerbations of HBV in patients discontinuing therapy, including adefovir dipivoxil. The FDA recommends that hepatic function be monitored with clinical and laboratory follow-up for a minimum of several months in these patients. Resumption of therapy may be warranted in some cases.

Adefovir dipivoxil is indicated in the treatment of chronic HBV infection in adults with evidence of active viral replication, and either persistent elevations in serum aminotransferase levels (AST, ALT) or histologically active disease.

Preservative in Aminocaproic acid (Amicar) Associated With Fatal "Gasping Syndrome"

On Aug. 24, the FDA approved revisions to the safety labeling for aminocaproic acid (Amicar tablets, injection, and syrup; made by Xanodyne Pharmaceuticals), warning of a fatal adverse event related to its preservative component benzyl alcohol.

According to the FDA, medications containing benzyl alcohol as a preservative have been associated with "gasping syndrome" in premature neonates.

Aminocaproic acid is useful in enhancing hemostasis when fibrinolysis contributes to bleeding.

Reviewed by Gary D. Vogin, MD

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