Prempro, Premarin Not Indicated For Coronary Heart Disease – Revised Label

Wyeth's Prempro/Premphase and Premarin are not indicated for the prevention of coronary heart disease, revised labeling for the hormone therapies says.

Bolded label warnings state that Prempro/Premphase (estrogens/medroxyprogesterone) and Premarin (conjugated estrogens) "are not indicated and should not be used to prevent coronary heart disease." Wyeth announced the changes Sept. 4 and outlined them in an Aug. 28 "Dear Doctor" letter to 500,000 physicians.

The changes reflect data from the National Institutes of Health-sponsored Women's Health Initiative, which show an increased risk of cardiovascular disease and breast cancer with Prempro (¹ (Also see "Prempro Cancer Risk Addressed In 550,000 Physician Letters, Label Review" - Pink Sheet, 15 Jul, 2002.), p. 11). The Prempro arm of the study was halted in July; the Premarin arm will continue until 2005.

Wyeth pursued a cardioprotective claim for Premarin for more than a decade. After the HERS II study failed to show a cardiac benefit, the program was put on hold pending WHI results. Although Wyeth has added the warning to Premarin labeling, the company may seek an indication if WHI produces a favorable outcome.

Wyeth made the labeling revisions through a "changes being effected" supplement rather than an FDA-approved sNDA after the agency expressed a desire to hold an advisory committee meeting on the hormone therapies before clearing any label changes.

The committee meeting, which Wyeth expects will be held in November, could lead to additional label changes. FDA may also consider whether the WHI findings could be extrapolated to other estrogen/progestin products (² (Also see "Wyeth Prempro Updated Label Submission Soon; HHS To Discuss WHI Results" - Pink Sheet, 19 Aug, 2002.), p. 11). NIH is planning a separate meeting on HRT Oct. 23-24 (³ 'The Pink Sheet' Aug. 26, In Brief).

The WHI study found seven more coronary heart disease events, eight more strokes, eight more pulmonary embolisms and eight more cases of invasive breast cancer in Prempro patients per 10,000 person-years, labeling says. "The absolute excess risk of events...was 19 per 10,000 person-years."

Prempro labeling also notes a two-fold greater rate of venous thromboembolism in estrogen/progestin patients: 34 per 10,000 woman-years compared to 16 per 10,000 in the placebo group. Premarin labeling notes an increase in VTE among estrogen patients in the WHI study, but adds that the "observations are preliminary and the study is continuing."

Both labels note a 26% increased risk of breast cancer with Prempro use, or 38 cases per 10,000 woman-years versus 30. Premarin labeling states that there was no increased breast cancer risk in the WHI estrogen arm, although the "observations are preliminary."

In light of WHI, revised labeling for Prempro and Premarin also suggests physicians consider other options before prescribing the drugs for osteoporosis prevention. "When used solely for the prevention of postmenopausal osteoporosis, alternative treatments should be carefully considered," bolded warnings state.

The indications for Prempro/Premphase and Premarin also limit use in osteoporosis prevention to postmenopausal women; previous labeling did not specify a patient group.

In light of the WHI results, the bolded warnings recommend shortening the duration of use. Use of estrogen alone or in combination with progestin "should be limited to the shortest duration consistent with treatment goals and risks for the individual woman, and should be periodically reevaluated."

The revised Prempro and Premarin warnings sections also cite an increased risk of ovarian cancer based on a separate NIH survey. "Two large cohort studies suggested an increased risk of ovarian cancer associated with long-term postmenopausal estrogen-only therapy, particularly for 10 or more years of use."

"In one of these studies, the baseline incidence among untreated postmenopausal women was reported to be 4.4 cases per 10,000 woman-years, compared to 6.5 cases per 10,000 woman-years among women using postmenopausal estrogen therapy."

"Other epidemiologic studies of postmenopausal estrogen therapy and ovarian cancer did not show a significant association," labeling notes. "Data are insufficient to determine whether there is an increased risk with postmenopausal estrogen/progestin therapy."

Wyeth does not expect WHI to result in a major impact on Premarin prescriptions; Prempro scripts fell 25% in the two weeks following the announcement (⁴ (Also see "Wyeth Sees Premarin Emerging Unscathed From WHI; Prempro Rxs Down 25%" - Pink Sheet, 29 Jul, 2002.), p. 34).