Warner-Lambert announces market availability of the first new class of oral contraceptives in 10 years called Estrophasic

Business Wire, March 27, 1997

MORRIS PLAINS, N.J.--(BUSINESS WIRE)--March 27, 1997--

Estrostep(R) (norethindrone acetate and ethinyl estradiol tablets, USP) from Parke-Davis offers healthcare providers and women a new approach to low estrogen dosing

Warner-Lambert Co. announced today the availability of Estrostep(R), the first oral contraceptive (OC) in a new class called "Estrophasic(TM)." The Estrophasic OC phases in estrogen in gradually increasing doses over the course of a women's cycle. Estrophasic is the first new class of OCs to be marketed in more than 10 years. Estrostep works by providing low, gradually increasing amounts of estrogen (20,30,35 mcg ethinyl estradiol) with a low, constant dose of progestin (one mg norethindrone acetate).

Since the earliest days of OCs, side effects such as nausea, break-through bleeding, breast tenderness, and amenorrhea, have been a concern for patients and physicians, especially for women first starting an OC. Recently, a national survey by the Association of Reproductive Health Professionals (ARHP) of current and recent OC users found that side effects were a key reason for women quitting the pill, second only to stopping OC use to become pregnant.

Estrostep was found to be well-tolerated in a clinical study involving 1,200 patients (769 receiving Estrostep), with a low overall drop-out rate due to side effects. Each of the following common OC side effects had drop-out rates of less than 1%.

Low ESTROSTEP Dropout Rates(a)

Unwanted Effect Dropout Rate(%) Number of drop-outs

n=769 patients

Nausea/vomiting 0.7 5 patients

Simple headache 0.7 5 patients

Amenorrhea 0.5 4 patients

Break-through bleeding 0.3 2 patients

Breast pain 0.3 2 patients

Weight gain 0.1 1 patient

Acne 0.1 1 patient

(a) Estrostep product insert. Data on file, Parke-Davis,

Morris Plains, N.J.

Estrogen's role in cycle control is to stabilize the endometrium therby helping to avert irregular shedding and break-through bleeding. In clinical studies, Estrostep demonstrated cycle control comparable to a 30 mcg monophasic OC.

"Our theory in developing a graduated estrogen OC was that it would expose women to relatively low doses of estrogen at the beginning of the cycle, and thus, would be well tolerated," explained Leon Speroff, MD, professor of Obstetrics and Gynecology at Oregon Health Sciences University in Portland, and one of the early researchers on this class of OCs.

Graduated Estrogen Dosing

Monophasic birth control pills contain a constant dose of estrogen and progestin. Triphasics change the dose of progestin throughout the cycle while keeping the estrogen dose constant or increasing then decreasing the estrogen dose. This is the first OC that gradually phases in the estrogen component of the pill in increasing doses. With Estrostep, low doses of estrogen are phased into the woman's body in three graduated steps during the menstrual cycle: 20 micrograms (mcg) of estrogen (ethinyl estradiol) for the first five days, 30 mcg for the next seven days, and 35 mcg for the last nine days, for a total of 21 days. Estrogen and progestin are stopped for the remaining seven days of the cycle, resulting in a woman's monthly menstrual period. The 28-day pill pack will contain seven inactive tablets to help women maintain their regimen. When used as directed, Estrostep is greater than 99% effective in preventing pregnancy, as are all other combination OCs.

Hormonal Content of ESTROSTEP and Various Other Currently Marketed OCs

OC Brand Ethinyl estradiol (mcg) Progestin (mg)

LOESTRIN(R) 1/20 20 1 (1 mg norethindrone acetate and 20 mcg ethinyl estradiol tablets, USP)

ESTROSTEP(R) 20, 30, 35 1 (20, 30, 35 mcg ethinyl estradiol and 1 mg. norethindrone acetate, USP)

LOESTRIN(R) 1.5/30 30 1.5 (1.5 mg norethindrone acetate and 30 mcg ethinyl estradiol tablets, USP)

Triphasil(R)(b) 30, 40, 30 0.05, 0.075, .125

Ortho Tri-Cyclen(R)(b) 35, 35, 35 .180, .215, .25

Ortho-Novum(R) 7/7/7(b) 35, 35, 35 0.5, 0.75, 1.0

Ortho-Cyclen(R)(b) 35 .25

(b) Physicians' Desk Reference(R) 51st ed. Montvale, N.J.; Medical Economics Co.; 1997

The most common pill prescribed today contains a constant 35 mcg estrogen dose. Early generation pills contained doses of estrogen as high as 150 mcg. Studies linking high doses of the hormone to adverse effects have resulted in a progressive reduction of estrogen content, leading to today's low-dose pills.

"Side effects are always a concern when they limit a women's birth control options," said Dennis Barbour, J.D., president of ARHP. "Women responding to our survey told us that they would like to see new OC formulations."