FDA Safety Labeling Changes: Lupron, Tikosyn, Cuprimine

Yael Waknine

December 29, 2004

Dec. 29, 2004 -- The U.S. Food and Drug Administration (FDA) approved in October revisions to safety labeling to advise healthcare professionals of the following changes: leuprolide acetate is associated with transient testosterone-related exacerbations of prostate cancer symptoms; use of leuprolide acetate by pregnant women is associated with fetal harm; use of dofetilide is contraindicated in patients receiving hydrochlorothiazide due to significantly increased dofetilide plasma levels and resulting QT interval prolongation; use of penicillamine in pregnant women may result in fetal harm.

Leuprolide Acetate (Lupron) Associated with Transient Testosterone-Related Adverse Events

On Oct. 16, the FDA approved revisions to the safety labeling for leuprolide acetate (Lupron injection, made by Tap Pharmaceuticals), advising of contraindications and warnings associated with its use.

Use of leuprolide injection is contraindicated in patients with known hypersensitivities to gonadotropin-releasing hormone (GnRH), GNRH-agonist analogs, or any constituents of the formulation. Anaphylactic reactions to synthetic GnRH or GnRH-agonist analogs have been reported in the medical literature.

Leuprolide injection is likewise contraindicated in women who are or may become pregnant during therapy, as it may cause fetal harm.

As with other LH-RH agonists, treatment with leuprolide acetate causes initial increases in serum testosterone levels that may lead to the transient development or worsening of signs and symptoms of prostate cancer within the first few weeks of therapy. Temporary worsening of bone pain may occur and should be managed symptomatically. Isolated cases of ureteral obstruction and spinal cord compression have been observed that may contribute to paralysis with or without fatal complications.

The FDA recommends periodic monitoring of testosterone and prostate-specific antigen (PSA) levels during leuprolide therapy, particularly in patients not achieving expected biochemical or clinical responses. Results of testosterone assays may vary with method type and precision, and the FDA emphasizes the importance of considering this factor when making appropriate clinical and therapeutic decisions.

Leuprolide acetate is indicated for the palliative treatment of advanced prostate cancer.

Hydrochlorothiazide Increases Dofetilide (Tikosyn) Concentrations, Prolongs QT Interval

On Oct. 22, the FDA approved revisions to the safety labeling for dofetilide (Tikosyn capsules, made by Pfizer), advising of its contraindication in patients receiving hydrochlorothiazide and the importance of maintaining normal-range potassium levels during therapy.

Concomitant use of hydrochlorothiazide (alone or in combination with other drugs such as triamterene) in patients receiving dofetilide is contraindicated due to significant elevation of dofetilide plasma concentration and QT interval prolongation.

The FDA notes that use of dofetilide in conjunction with other drugs that may prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, and certain fluoroquinolones.

The risk of torsade de pointes has been shown to increase with dofetilide dose. As potassium-depleting diuretics may cause hypokalemia or hypomagnesemia and thereby increase the potential for torsade de pointes, the FDA advises maintenance of normal-range potassium levels prior to and during the course of dofetilide therapy.

Dofetilide is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm. It is also indicated for the conversionof atrial fibrillation and atrial flutter to normal sinus rhythm.

Use of Penicillamine (Cuprimine) During Pregnancy Associated with Risk of Fetal Harm

On Oct. 26, the FDA approved revisions to the safety labeling for penicillamine (Cuprimine capsules, made by Merck), warning of the risk of fetal harm associated with its use during pregnancy (Pregnancy category D).

Penicillamine has been shown to be teratogenic in rats administered doses 6 times higher than the highest dose recommended for human use, resulting in skeletal defects, cleft palates and fetal toxicity (resorptions).

Although there are no controlled studies of penicillamine use in pregnant women, characteristic congenital cutis laxa and associated birth defects have been reported in infants whose mothers used the drug during pregnancy.

The FDA recommends that penicillamine be used in women of childbearing potential only when the expected benefits outweigh the potential hazards. Women of childbearing potential should be advised of this risk, and instructed to promptly report missed menstrual periods or other indications of possible pregnancy to their physician.

Women using penicillamine during pregnancy or who become pregnant during therapy should be advised of the potential hazard to the fetus.

Penicillamine is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy.

Reviewed by Gary D. Vogin, MD


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