Estradiol/Norethin-drone Acetate Transdermal Systems (CombiPatch)

By William T. Elliott, MD, and James Chan, PhD

The fda has approved the first combination estrogen and progestin transdermal system for hormone replacement therapy. CombiPatch is an estrogen/progestin transdermal patch that uses a matrix patch technology that was developed by Noven Pharmaceuticals and marketed by Rhone-Poulenc Rorer. This system delivers 50 mcg of 17-estradiol and 140 mcg or 250 mcg of norethindrone acetate per day through the intact skin.1 CombiPatch provides an alternative to oral estrogen and progestin or transdermal estrogen and oral progestin.


CombiPatch is indicated for the treatment of moderate-to-severe vasomotor symptoms associated with menopause, treatment of vulvar and vaginal atrophy, and treatment of hypoestrogenism due to hypogonadism, castration, or primary ovary failure.


CombiPatch is available as a transdermal system that delivers 50 mcg of 17-estradiol or 140 mcg (9 cm2) or 250 mcg (16 cm2) of norethindrone acetate. For continuous combined therapy: CombiPatch 50 mcg/140 mcg should be worn continuously for 28 days. A new system should be applied twice a week during the 28-day cycle.

For continuous sequential therapy: CombiPatch 50 mcg/140 mcg should be worn for the last 14 days of the 28-day cycle following a 14-day estrogen regimen. Should a greater progestin dose be desired, CombiPatch 50 mcg/250 mcg is available.

The system should be appled on a smooth (fold-free), clean, dry area of the skin on the lower abdomen. The sites must be rotated with an interval of at least one week between sites. The patch should not be applied to or near the breast, oily areas, or areas where clothing may rub the system or modify its delivery (e.g., waistline).1

Potential Advantages

CombiPatch provides an alternative to oral estrogen/progestin therapy. This transdermal system provides consistent delivery of 17-estradiol, estrone, and norethindrone over the application interval. Mean serum concentrations at steady-state with application of the 50 mcg/140 mcg patches are 45 pg/mL (27-71) for estrogen, 54 pg/mL (49-72) for estrone, and 489 pg/mL (386-617) for norethindrone. Twice-weekly administration may improve medication adherence. CombiPatch has been reported to reduce triglyceride levels by 4.6% to 14.1% from baseline when measured after one year.1 Oral hormone replacement therapy tends to increase triglyceride levels.2

Potential Disadvantages

Transdermal estradiol bypasses the first past metabolism seen with orally administered estrogens and appears to have less favorable effects on the liproprotein profiles. Reductions in total cholesterol and LDL-cholesterol are less than that reported for oral estrogens.1-3 CombiPatch also reduced HDL-cholesterol, although most of the decrease was attributed to the HDL3 subfraction—not the HDL2 subfraction.1 Oral hormone replacement tends to increase HDL-cholesterol levels.2 Application site reactions have been reported at a rate of up to 21%.1


CombiPatch is the first transdermal product to combine estrogen and a progestin in a single patch for hormone replacement therapy. It is the transdermal counterpart to Prempro tablets (conjugated estrogen and medroxyprogesterone acetate) marketed by American Home Products and the recently approved Activelle tablets (estrogen/norethindrone acetate) marketed by Novo Nordisk. Clinical study results indicated that the product reduced the number and daily intensity of hot flushes compared to placebo.1 Trial results also indicated that norethindrone acetate as formulated in CombiPatch was effective in reducing the incidence of estrogen-induced endometrial hyperplasia.1 Transdermal estrogen appears to be effective in preventing osteoporosis; however, its potential favorable effect on cardiovascular disease risk is less certain. CombiPatch is about $0.90 per day compared to $0.65 per day for oral therapy with Prempro.

Clinical Implications

Oral hormone regimens are generally considered as first-line therapy for most postmenopausal women. Transdermal formulations may be considered for women in whom oral estrogen therapy does not relieve symptoms, is not tolerated, or women who have hypertriglyceridemia. The benefits of hormone replacement therapy include symptomatic relief, prevention of osteoporosis, and reduction of cardiovascular events. The latter has been an important reason for postmenopausal women to initiate hormone replacement therapy. Recently, the role of hormone replacement therapy in secondary prevention of CAD events and death has been questioned.4 However, most women use hormone replacement in the role of primary prevention and data from observational studies tend to support this use. Randomized trials are underway to study the effect of estrogen replacement therapy and hormone replacement therapy both in secondary prevention and primary prevention. Results are expected in 2000-2005.5


1. CombiPatch Product Information. Rhone-Poulenc Rorer Pharmaceuticals Inc. August 1998.

2. The Writing Group for the PEPI Trial. JAMA 1995;273: 199-208.

3. Taskinen MR, et al. Arterioscler Throm Vasc Biol 1996; 16(10):1215-1221.

4. Hulley S, et al. JAMA 1998;280:605-613.

5. Petitti DB. JAMA 1998;280:650-651.