FDA Safety Labeling Changes: Activella, Duramorph PF, Nutropin

Yael Waknine

September 07, 2005

Sept. 7, 2005 — The U.S. Food and Drug Administration (FDA) approved in June revisions to safety labeling to advise that use of estradiol/norethindrone acetate tablets is associated with increased risks of cardiovascular events, breast and endometrial cancer in postmenopausal women, and probable dementia in those aged 65 years and older; morphine sulfate preservative-free injection may cause severe hypotension in individuals with a compromised ability to maintain blood pressure; and somatropin [rDNA origin] injection may only be used for the long-term treatment of Prader-Willi syndrome in pediatric patients also diagnosed with growth hormone deficiency.

Estradiol/Norethindrone (Activella) Linked to Increased Risk of CV Events and More

On June 30, the FDA approved revisions to the safety labeling for estradiol/norethindrone acetate (Activella, made by Novo Nordisk, Inc.) to advise that use of the tablets is associated with increased risks of cardiovascular events, breast and endometrial cancer in postmenopausal women, and probable dementia in those aged 65 years and older.

Results of the five-year Women's Health Initiative (WHI) study have linked use of oral conjugated estrogens (CE) to increased risks of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women aged 50 to 79 years. Treatment should be discontinued if any of these occur or are suspected.

During treatment, risk factors for arterial vascular disease (eg, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (eg, personal or family history, obesity, and systemic lupus erythematosus) should be managed appropriately.

Results of the CE/medroxyprogesterone acetate (MPA) substudy of the WHI also revealed an increased risk of breast cancer that increased with duration of use over a mean follow-up of 5.6 years. Observational studies suggest that the risk is greater and becomes apparent earlier with use of estrogen/progestin therapy compared with estrogen alone. The risk appears to return to baseline five years after treatment has ended.

In contrast, concurrent use of a progestin with estrogen therapy has been shown to reduce the risk of endometrial hyperplasia that may lead to endometrial cancer. Adequate diagnostic measures such as endometrial sampling are recommended to rule out malignancy in women with an intact uterus who experience persistent or recurrent abnormal vaginal bleeding.

The FDA also warned that use of CE/MPA in postmenopausal women aged 65 years and older may be associated with an increased risk of developing probable dementia. Results of the Memory substudy of the WHI showed that after four years of treatment, the number of women diagnosed with probable dementia was significantly higher in the CE/MPA group compared with the placebo group (1.8% vs 0.9%; probable risk, 2.05; absolute risk per 10,000 women-years, 45 vs 22 cases).

The FDA notes that it is unknown whether the warning applies to younger postmenopausal women or to those taking estrogen-only therapy.

Estradiol/norethindrone acetate is indicated for the treatment of moderate to severe symptoms of vulvovaginal atrophy associated with menopause and for the prevention of postmenopausal osteoporosis.

Morphine Sulfate Preservative-Free Injection (Duramorph PF) May Cause Severe Hypotension in At-Risk Patients

On June 6, the FDA approved revisions to the safety labeling for morphine sulfate preservative-free injection (Duramorph PF, made by Baxter Healthcare Corp.) to advise that as with other opioid analgesics, its use may cause severe hypotension in individuals whose ability to maintain blood pressure has already been compromised by a depleted blood volume or concurrent administration of drugs such as phenothiazines or general anesthetics.

Morphine sulfate preservative-free injection is indicated for intravenous, epidural, or intrathecal administration in the management of pain not adequately managed by nonnarcotic analgesics. Epidural or intrathecal administration provides pain relief for extended periods without attendant loss of motor, sensory, or sympathetic function.

Somatropin Injection (Nutropin, Nutropin AQ) Contraindicated in Prader-Willi Patients Without GH Deficiency

On June 28, the FDA approved revisions to the safety labeling for somatropin [rDNA origin] injection (Nutropin, Nutropin AQ, made by Genentech, Inc.) to warn that it may only be used for the long-term treatment of genetically confirmed Prader-Willi syndrome in pediatric patients also diagnosed with growth hormone (GH) deficiency.

Nutropin and Nutropin AQ injections are indicated for the long-term treatment of growth failure due to a lack of adequate endogenous GH secretion, and short stature associated with Turner syndrome; and for the treatment of growth failure associated with chronic renal insufficiency prior to transplantation.

Nutropin AQ is also indicated for the long-term treatment of idiopathic short stature in pediatric patients whose epiphyses are not closed.

Reviewed by Gary D. Vogin, MD

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