FDA Safety Changes: Comtan, Stalevo, Tasmar, Symmetrel, Xenical, Casodex

Yael Waknine

April 22, 2009

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April 22, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the risk for uncontrollable urges in patients with Parkinson's disease receiving treatment with drugs that increase central dopaminergic tone, the potential increased risk for melanoma in patients with Parkinson's disease, drug interactions between orlistat and levothyroxine, and the potential for decreased glucose tolerance in patients receiving luteinizing hormone–releasing hormone therapy in combination with bicalutamide for metastatic prostate cancer.

Entacapone (Comtan), L-Dopa/Carbidopa/Entacapone (Stalevo), Tolcapone (Tasmar), and Amantadine (Symmetrel) Linked to Intense Urges

On February 2, the FDA approved safety labeling revisions for entacapone (Comtan tablets; Orion Corp), levodopa/carbidopa/entacapone (Stalevo tablets; Orion), tolcapone (Tasmar tablets; Valeant Pharmaceuticals, Inc), and amantadine HCl (Symmetrel syrup and tablets; Endo Pharmaceuticals) to provide information regarding the risks for the development of intense urges and melanoma.

There have been reports of patients experiencing uncontrollable sexual urges, urges to gamble, and other intense urges during treatment of Parkinson's disease with 1 or more agents that increase central dopaminergic tone, the agency warned.

Although the causal role for the medications remains unclear, clinicians are advised to ask patients regarding the development of new or increased urges during treatment. Dose reduction or discontinuation of therapy should be considered for patients experiencing these symptoms.

The FDA also warned that epidemiologic studies suggest a 2-fold to approximately 6-fold increased risk for melanoma in patients with Parkinson's disease vs the general population. Although the cause is unknown, factors may include the disease itself and medication use.

Clinicians and patients are advised to monitor for melanomas frequently and on a regular basis when using levodopa/carbidopa/entacapone tablets for any indication. Ideally, periodic skin examination should be performed by dermatologists or other appropriately qualified individuals.

Levodopa (L-dopa) is transformed to dopamine by dopa decarboxylase and is used to replenish neurotransmitter supplies diminished by Parkinson's disease. Carbidopa is a dopa decarboxylase inhibitor that serves to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons. L-dopa and carbidopa are generally given together in a combination product.

Tolcapone inhibits the catecholamine-O-methyltransferase enzyme that degrades dopamine, thereby prolonging the therapeutic effects of L-dopa. It is generally used with L-dopa and carbidopa to reduce symptom fluctuations. Entacapone is a catecholamine-O-methyltransferase inhibitor that has not been shown to cause the significant elevations in liver enzymes observed with tolcapone therapy.

Amantadine is an antiviral medication used for the prophylaxis and treatment of Parkinson's disease symptoms and drug-induced extrapyramidal reactions; its mechanism of action remains unclear. Amantadine may also be used for influenza A prophylaxis and treatment.

Orlistat (Xenical) Drug Interactions with Levothyroxine Sodium Linked to Hypothyroidism

On February 11, the FDA approved safety labeling revisions for orlistat (Xenical capsules; Hoffmann-LaRoche, Inc) to warn of drug interactions with levothyroxine sodium.

Postmarketing reports have revealed cases of hypothyroidism in patients treated concomitantly with orlistat and levothyroxine, the agency warned.

Clinicians are advised to administer levothyroxine and orlistat at least 4 hours apart and to perform regular evaluations of thyroid function.

Orlistat is indicated for management of obesity, including weight loss and management, when used in conjunction with a reduced-energy diet.

Levothyroxine is indicated as replacement or supplemental therapy for congenital or acquired hypothyroidism and to suppress thyroid-stimulating hormone in the treatment and prevention of euthyroid goiters.

LHRH Component of Bicalutamide (Casodex) Therapy Linked to Reports of Decreased Glucose Tolerance

On February 10, the FDA approved safety labeling revisions for bicalutamide (Casodex tablets; AstraZeneca) to warn of the potential for reduced glucose tolerance.

Bicalutamide is an oral nonsteroidal anti-androgen that is used with a luteinizing hormone–releasing hormone (LHRH) for the treatment of stage D2 metastatic carcinoma of the prostate.

According to the FDA, a decrease in glucose tolerance has been observed in men receiving LHRH agonists. The decrease may manifest as diabetes or as loss of diabetic glycemic control.

Clinicians are urged to consider blood glucose monitoring in patients receiving LHRH agonist therapy with bicalutamide.

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