FDA Safety Labeling Changes: Doxil, Concerta, and Fuzeon

Yael Waknine

January 12, 2005

Jan. 12, 2005 — The U.S. Food and Drug Administration (FDA) approved in October 2004 revisions to safety labeling to advise healthcare professionals of the following changes: cumulative doses of doxorubicin HCI liposome injection (Doxil) approaching 550 mg/m2 are associated with an increased risk of cardiac toxicity and myocardial damage; use of methylphenidate HCl in children may suppress their growth, and use of methylphenidate may exacerbate underlying cardiovascular conditions; and enfuvirtide may cause local injection site and systemic hypersensitivity reactions.

Doxorubicin HCI Liposome Injection (Doxil) May Cause Cardiac Toxicity

On Oct. 27, the FDA approved revisions to the safety labeling for doxorubicin HCI liposome injection (Doxil), marketed in the U.S. by Tibotec Therapeutics, warning of the risks of myocardial damage and cardiac toxicity associated with its use.

A new boxed warning advises that myocardial damage leading to congestive heart failure may occur as the total cumulative dose of doxorubicin HCl liposome injection approaches 550 mg/m2. In a clinical study of 250 patients with metastatic breast cancer, use of doxorubicin HCI liposome injection was associated with an 11% risk of cardiac toxicity at cumulative doses of 450 to 550 mg/m2.

The FDA notes that cumulative dosing calculations should include prior anthracycline and anthracenedione therapy. Cardiac toxicity may also occur at lower cumulative doses in patients receiving concurrent therapy with potentially cardiotoxic agents such as cyclophosphamide, and in those having a history of mediastinal irradiation.

The FDA recommends careful monitoring of heart function in patients treated with doxorubicin HCI liposome injection, using methods such as endomyocardial biopsy, echocardiography, or multigated radionuclide scans. Therapy should be continued in patients with possible myocardial injury only if the potential benefits of doxorubicin HCI liposome injection outweigh the associated risks.

Doxorubicin HCI liposome injection is indicated for the treatment of metastatic ovarian cancer that is refractory to both paclitaxel- and platinum-based chemotherapy regimens, and for AIDS-related Kaposi's sarcoma that has progressed on prior combination chemotherapy. It may also be used in the treatment of Kaposi's sarcoma in patients intolerant of combination chemotherapy.

Methylphenidate (Concerta) May Suppress Growth, Exacerbate Cardiovascular Conditions

On Oct. 21, the FDA approved revisions to the safety labeling for methylphenidate HCl extended-release tablets (Concerta, made by Alza Corp.), warning of the potential risks of long-term growth suppression in children receiving the drug. Methylphenidate therapy may also exacerbate underlying cardiovascular conditions.

Inadequate data exist to determine whether chronic use of stimulants in children causes growth suppression. The FDA recommends careful monitoring of growth and weight gain in pediatric patients receiving methylphenidate. Therapy should be interrupted in those not achieving growth and weight gains as expected.

The FDA advises caution in administering methylphenidate to patients with underlying medical conditions that may be compromised by increases in blood pressure or heart rate, such as preexisting hypertension, heart failure, recent myocardial infarction, or hyperthyroidism.

Blood pressure should be monitored at appropriate intervals in all patients receiving methylphenidate and especially in those with hypertension.

Methylphenidate is indicated in the treatment of attention deficit hyperactivity disorder.

Enfuvirtide (Fuzeon) Injection May Cause Local and Systemic Reactions

On Oct. 15, the FDA approved revisions to the safety labeling for enfuvirtide injection (Fuzeon, made by Hoffman-La Roche, Inc.), warning of the risks of local injection site and systemic hypersensitivity reactions associated with its use.

In phase 3 clinical trials, 98% of patients receiving enfuvirtide experienced at least one local injection site reaction (ISR). ISRs were often present at more than one injection site and occurred throughout the 48-week treatment with an average duration of three to seven days in 41% of patients, and more than seven days in 24% of patients. Symptoms included pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis.

The FDA advises that patients be familiar with injection procedures and monitor carefully for signs or symptoms of cellulitis or local infection.

Enfuvirtide use has also been associated with systemic hypersensitivity reactions (< 1%) that may recur with rechallenge. Symptoms include combinations of rash, fever, nausea and vomiting, chills, rigors, hypotension, and/or elevated serum liver transaminase levels.

Enfuvirtide should be discontinued and not resumed in patients exhibiting systemic signs and symptoms of a hypersensitivity reaction.

Enfuvirtide in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

Reviewed by Gary D. Vogin, MD


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