FDA Safety Labeling Changes: CombiPatch, Efudex, Percodan, and Axert

Yael Waknine

September 08, 2004

Sept. 8, 2004 — The U.S. Food and Drug Administration (FDA) approved in June revisions to safety labeling to advise healthcare professionals of the following changes: estradiol/norethindrone patches are contraindicated in patients with cardiovascular disorders and venous thromboembolism, fluorouracil topical cream is contraindicated in patients with dihydropyrimidine dehydrogenase enzyme deficiency, oxycodone/aspirin tablets have multiple contraindications, and almotriptan malate may be associated with serious cardiac adverse events and fatalities.

Estradiol/Norethindrone Acetate Transdermal System (CombiPatch) Contraindicated in Cardiovascular Disorders and Venous Thromboembolism

On June 18, the FDA approved revisions to the safety labeling for the estradiol/norethindrone acetate transdermal system (CombiPatch, made by Novartis) to reflect additional contraindications for use.

Combination estrogen/progestins are contraindicated in women with known, suspected, or a history of breast cancer and in those with active deep vein thrombosis, pulmonary embolism, or a history of these conditions. Women who have active arterial thromboembolic disease or have had a thromboembolic event such as stroke or myocardial infarction within the past year should not use the patch.

The estradiol/norethindrone patch is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy associated with menopause. It is also indicated for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

Fluorouracil Topical Cream (Efudex) Contraindicated in DPD Enzyme Deficiency

On June 24, the FDA approved revisions to the safety labeling for fluorouracil topical cream (Efudex, made by Valeant Pharmaceuticals International) to reflect its contraindication in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.

Intravenous administration of fluorouracil in patients with DPD enzyme deficiency has resulted in rare reports of life-threatening toxicities including stomatitis, diarrhea, neutropenia, and neurotoxicity. One such case has been reported with topical use of fluorouracil cream 5%. It is unknown whether patients with profound DPD enzyme deficiency can develop systemic toxicity with lower concentrations of topically applied fluorouracil.

The FDA advises discontinuation of fluorouracil topical cream therapy in patients who develop symptoms of DPD enzyme deficiency.

Fluorouracil topical cream is indicated for the treatment of multiple actinic or solar keratoses and superficial basal cell carcinomas when conventional methods are impractical.

Oxycodone/Aspirin Tablets (Percodan, Percodan-Demi) Contraindicated in NSAID Allergies, More

On June 6, the FDA approved revisions to the safety labeling for oxycodone and aspirin tablets (Percodan and Percodan-Demi, made by Endo Pharmaceuticals) to reflect additional contraindications for use.

The oxycodone/aspirin combination is contraindicated in children or teenagers with viral infection with or without fever due to the risk of Reye's syndrome associated with use of aspirin in certain viral illnesses. Its use is also contraindicated in patients with allergic reactions to nonsteroidal anti-inflammatory drugs and in those with the syndrome of asthma, rhinitis, and nasal polyps because it can cause severe urticaria, angioedema, and bronchospasm.

Oxycodone/aspirin tablets are also contraindicated in patients with known oxycodone sensitivity. Oxycodone should not be used in patients with significant respiratory depression in unmonitored settings or in the absence of resuscitative equipment. It is also contraindicated in patients with acute or severe bronchial asthma or hypercapnia and in the setting of suspected or known paralytic ileus.

Oxycodone/aspirin tablets are indicated for the treatment of moderate to moderately severe pain.

Almotriptan (Axert) Linked With Serious Adverse Cardiac Events, Fatalities

On June 1, the FDA approved revisions to the safety labeling for almotriptan malate tablets (Axert, made by Janssen Ortho), to include reports of serious adverse cardiac events, including acute myocardial infarction, that have occurred within a few hours after almotriptan administration.

Almotriptan is known to cause coronary vasospasm. The FDA has received at least one report of vasospasm in a patient with no cardiac history and having a documented absence of coronary disease.

Due to the close proximity of these events to use of almotriptan, a causal relationship cannot be excluded. According to the FDA, the uncontrolled nature of postmarketing surveillance makes it difficult to ascertain the proportion of reported cases caused by almotriptan and attribute causation to almotriptan use in individual cases.

Almotriptan is indicated for the treatment of acute migraine with or without aura in adults.

Reviewed by Gary D. Vogin, MD

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