FDA Safety Labeling Changes: June 30, 2004

Yael Waknine

June 30, 2004

June 30, 2004 -- The U.S. Food and Drug Administration (FDA) approved in April revisions to drug safety labeling to inform healthcare professionals of the following changes: cetrorelix acetate for injection is contraindicated in severe renal impairment, doxapram HCl injection is contraindicated in patients with mechanical disorders of ventilation, voriconazole adversely interacts with ritonavir and efavirenz, conjugated estrogens for injection are associated with malignant neoplasms, and vitamin D and its derivatives should not be coadministered with doxercalciferol.

Cetrorelix Acetate for Injection (Cetrotide) Contraindicated in Severe Renal Impairment

The FDA approved a revision on April 30 to the safety labeling for cetrorelix acetate for injection (Cetrotide, made by Serono), advising of its contraindication in severe renal impairment.

Cetrorelix is indicated for the inhibition of premature luteinizing hormone surges in women undergoing controlled ovarian stimulation.

Doxapram HCl Injection USP (Dopram Injection) Contraindicated in Patients with Mechanical Disorders of Ventilation

On April 16, the FDA approved a revision to the safety labeling for doxapram hydrochloride injection USP (Dopram Injection, made by Baxter), advising of its contraindication in patients with mechanical disorders of ventilation.

The warning extends to patients with mechanical obstruction, muscle paresis (including neuromuscular blockade), flail chest, pneumothorax, acute bronchial asthma, and pulmonary fibrosis and other conditions that result in restriction of the chest wall, muscles of respiration, or alveolar expansion.

Doxapram is used to stimulate respiration in drug-induced postanesthesia respiratory depression, drug-induced central nervous system depression, and chronic pulmonary disease associated with acute hypercapnia.

Voriconazole (Vfend) Adversely Interacts With Ritonavir and Efavirenz

On April 21, the FDA approved revisions to the safety labeling for voriconazole injection, oral suspension, and tablets (Vfend, made by Pfizer), indicating its contraindication in patients receiving ritonavir and efavirenz due to drug interactions.

Concurrent administration of voriconazole with ritonavir (400 mg every 12 hours) results in decreased plasma voriconazole concentrations in healthy patients. The effect of ritonavir given as 100 mg every 12 hours to inhibit the CYP3A liver enzyme and increase concentrations of other antiretroviral drugs has not been assessed.

Concurrent administration of voriconazole with efavirenz results in significantly decreased voriconazole plasma concentration, while that of efavirenz significantly increases.

Voriconazole is indicated for the treatment of invasive aspergillosis, esophageal candidiasis, and other susceptible serious fungal infections.

Conjugated Estrogen USP for Injection (Premarin Intravenous) Associated With Malignant Neoplasms

On April 20, the FDA approved extensive revisions to the safety labeling for conjugated estrogen USP for injection (Premarin Intravenous, made by Wyeth Pharmaceuticals Inc.). Use of conjugated estrogen in women with intact uteri is associated with an increased risk of endometrial cancer, the greatest risk occurring with prolonged use (15- to 24-fold increased risk for 5-10 years of use or more) and persisting for at least 8 to 15 years after discontinuation. There is no evidence that the use of "natural" estrogen results in a different risk profile than synthetic estrogen in equivalent doses.

Use of conjugated estrogen is also associated with an increased risk of breast cancer. Observational studies have not found significant variation in this risk among users of different estrogens, estrogen-progestin combinations, doses, or routes of administration. In these studies, the excess risk increased with duration of use and appeared to return to baseline during a five-year span after therapy.

Results of the Million Women Study in Europe showed an increased risk of mortality due to breast cancer among current users of estrogen alone or with progestin compared with therapy-naive patients. Results of the estrogen plus progestin substudy of the Women's Health Initiative showed no effect on breast cancer mortality after a mean follow-up of 5.6 years.

Conjugated estrogen should not be used during pregnancy, and nursing mothers should be warned that estrogen intake has been shown to decrease the quantity and quality of breast milk.

Adverse events reported in the labeling include enlargement of hepatic hemangiomas, pruritus, and dementia.

Conjugated estrogen for injection is indicated in the treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology. The drug is indicated for short-term use only, to provide a rapid and temporary increase in estrogen levels.

Vitamin D and Derivatives Should Not Be Administered Concurrently With Doxercalciferol (Hectorol)

On April 23, the FDA approved revisions to the safety labeling for doxercalciferol capsules (Hectorol, made by Bone Care) to include several precautions. Pharmacologic doses of vitamin D and its derivatives should not be administered concurrently with doxercalciferol because it is a precursor to a potent metabolite (1α, 25 (OH) 2D 2 ) of vitamin D 2, and additive effects as well as hypercalcemia may result. If hypercalcemia occurs, the dose of doxercalciferol and/or calcium-containing binders should be decreased.

Uncontrolled serum phosphorus exacerbates secondary hyperparathyroidism and can lessen the effectiveness of doxercalciferol in reducing blood parathyroid hormone levels. If hyperphosphatemia occurs, the dose of doxercalciferol should be decreased and/or the dose of phosphate binders increased.

Doxercalciferol is indicated for the treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease and those on dialysis.

Reviewed by Gary D. Vogin, MD

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