FDA Safety Changes: Reglan and Prometrium

Yael Waknine

July 16, 2009

This activity is part of an ongoing CME/CE initiative to provide information on labeling changes reported by the FDA. Activities of this nature will be posted on Medscape on a weekly basis.

July 16, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the risk for metoclopramide-induced tardive dyskinesia; and the potential for adverse cardiovascular events, probable dementia, and breast cancer in patients receiving long-term estrogen-progestin therapy.

Metoclopramide (Reglan) Linked to Risk for Tardive Dyskinesia

On June 30, the FDA approved safety labeling revisions for metoclopramide tablets, orally disintegrating tablets, and injection (Reglan; Alaven Pharmaceuticals, LLC) to include a boxed warning regarding the risk for tardive dyskinesia (TD).

TD is a potentially irreversible and disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities.

The risk for the development of metoclopramide-induced TD and the likelihood that TD will become irreversible increase with duration of treatment and total cumulative dose; other factors may include older age, female sex, and the presence of diabetes mellitus.

In 1 published study, TD was reported at a prevalence of 20% among patients receiving metoclopramide for at least 12 weeks. Metoclopramide therapy should therefore be limited to a 3-month period unless its therapeutic benefit is thought to outweigh the risk for the development of TD.

Metoclopramide should be discontinued in patients in whom signs or symptoms of TD develop. Although there is no known treatment of the disorder, symptoms may lessen or resolve within several weeks to months after metoclopramide therapy is stopped.

The FDA notes that use of metoclopramide can also suppress signs of TD, thereby masking the underlying disease process. Metoclopramide should not be used for the symptomatic suppression of TD because its long-term effects are unknown.

Metoclopramide is indicated for the short-term (4 - 12 weeks) treatment of gastroesophageal reflux disease in patients in whom failure to respond to conventional therapy occurs, and for the treatment of symptoms of diabetic gastroparesis.

Progesterone Use With Estrogens Linked to Cardiovascular Risks

The FDA approved revisions to the safety labeling for progesterone capsules to reflect class labeling for progestin drug products when used in conjunction with estrogens. On June 30, the label for Prometrium (Solvay Pharmaceuticals, Inc) was updated.

Five-year results from the Women's Health Initiative (WHI) study of 27,000 postmenopausal women aged 50 to 79 years have linked daily use of conjugated estrogens plus the progestin medroxyprogesterone (CE/MPA) to increased risks vs placebo for coronary heart disease–related events (relative risk [RR], 1.29; 95% confidence interval [CI], 1.02 - 1.63), stroke (RR, 1.41; 95% CI, 1.07 - 1.85), deep vein thrombosis (RR, 2.07; 95% CI, 1.49 - 2.87), and pulmonary embolism (RR, 2.13; 95% CI, 1.39 - 3.25).

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. Treatment should be discontinued if cardiovascular events occur or are suspected.

The FDA also warned that daily use of CE/MPA in postmenopausal women 65 years and older may be associated with an increased risk for the development of probable dementia. Results of the Memory substudy of the WHI showed that after 4 years of treatment, the number of women diagnosed with probable dementia was significantly higher in the CE/MPA group vs the placebo group (1.8% vs 0.9%; probable risk, 2.05; absolute risk per 10,000 women-years, 45 vs 22 cases). It remains unclear whether this finding applies to younger postmenopausal women.

The WHI has also provided important new information regarding the risk for breast cancer in women receiving CE/MPA vs CE alone.

In the CE/MPA substudy, daily use of the drug combination was linked to an increased risk for invasive breast cancer relative to placebo at a mean follow-up of 5.6 years (RR, 1.24; 95% CI, 1.01 - 1.54; absolute risk, 41 vs 33 cases per 10,000 women-years).

The increase in risk was greater for women who reported prior use of hormone therapy vs those who did not (RR, 1.86 vs 1.09). In this substudy, invasive breast cancers were larger and were diagnosed at a more advanced stage in the CE/MPA group relative to placebo; metastatic disease was rare, with no apparent difference between groups.

In contrast, women taking 0.625 mg of CE daily in the WHI estrogen-alone substudy had no increased risk for invasive breast cancer at a mean follow-up of 7.1 years (RR, 0.80; 95% CI, 0.62 - 1.04).

The FDA notes that use of estrogens with or without progestin has been reported to yield an increase in abnormal results on mammograms requiring further evaluation. All women should undergo yearly breast examinations by a healthcare professional and perform monthly self-examinations. Mammography should be scheduled based on patient age, risk factors, and prior mammogram results.

Progesterone capsules are indicated for the prevention of endometrial hyperplasia in postmenopausal women with an intact uterus who are receiving CE tablets. They also are indicated for use in secondary amenorrhea.

FDA Safety Information

Prometrium Prescribing Information

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