Estrostep Fe (Norethindrone Acetate and Ethinyl Estradiol, USP and Ferrous Fumarate) - 2 indications

• Oral Contraceptive; approved October 1996
• Moderate Acne; July 2001

General Information

Estrostep FE (Norethindrone Acetate and Ethinyl Estradiol, USP and Ferrous Fumarate) is a combination of a progestogen and an estrogen. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen, are non-hormonal, and do not serve any therapeutic purpose. 

Estrostep FE is specifically indicated for the following:

• the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception
• the treatment of moderate acne vulgaris in females, ≥15 years of age, who have no known contraindications to oral contraceptive therapy, desire oral contraception, have achieved menarche, and are unresponsive to topical anti-acne medications

Estrostep FE is supplied as a tablet for oral administration. 

Dosage and Administration for 28-Day Dosage Regimen for use as both a contraceptive and for the treatment of acne:

To achieve maximum contraceptive effectiveness, Estrostep Fe should be taken exactly as directed and at intervals not exceeding 24 hours. Estrostep Fe provides a continuous administration regimen consisting of 21 white oral contraceptive tablets and seven brown non-hormone containing tablets of ferrous fumarate. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen and do not serve any therapeutic purpose. There is no need for the patient to count days between cycles because there are no “off-tablet days”. See the drug label for a Sunday-Start Regimen and a Day-1 Start Regimen.

Mechanism of Action

Estrostep FE is a graduated estrophasic oral contraceptive providing estrogen in a graduated sequence over a 21-day period with a constant dose of progestogen. Estrostep Fe provides for a continuous dosage regimen consisting of 21 oral contraceptive tablets and seven ferrous fumarate tablets. 

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). In vitro and animal studies have shown that norethindrone combines high progestational activity with low intrinsic androgenicity. In humans, norethindrone acetate in combination with ethinyl estradiol does not counteract estrogen-induced increases in sex hormone binding globulin (SHBG). Following multiple-dose administration of Estrostep Fe, serum SHBG concentrations increase two- to three-fold and free testosterone concentrations decrease by 47% to 64%, indicating minimal androgenic activity.

Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of norethindrone acetate and ethinyl estradiol increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. 

Side Effects

Most side effects of oral contraceptives are not serious. The following side effects have been reported with oral contraceptive use and are believed to be drug-related:

• Nausea
• Vomiting
• Bleeding between menstrual periods
• Weight gain
• Breast tenderness
• Difficulty wearing contact lenses
• Migraine
• Rash
• Mental depression
• Edema (fluid retention)

Although serious side effects occur infrequently, an increased risk of the following more severe conditions has been associated with the use of oral contraceptives:

• Blood clots in the legs and lungs
• Heart attack
• Hypertension
• Gallbladder disease
• Liver tumors
• Stroke

Indication 1 - oral contraceptive

Approved October 1996

Clinical Trial Results

Oral contraceptives are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. When they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. Typical failure rates are actually 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: Implant: <1% Injection: <1% IUD: <1 to 2% Diaphragm with spermicides: 20% Spermicides alone: 26% Vaginal Sponge: 20 to 40% Female sterilization: <1% Male sterilization: <1% Cervical Cap: 20 to 40% Condom alone (male): 14% Condom alone (female): 21% Periodic abstinence: 25% Withdrawal: 19% No method: 85%

Indication 2 - moderate acne

Approved July 2001

Clinical Trial Results

Estrostep Fe was evaluated for the treatment of acne vulgaris in two randomized, double blind, placebo-controlled, multicenter, Phase 3, six (28-day) cycle studies. A total of 296 patients received Estrostep Fe and 295 received placebo. Mean age at enrollment for both groups was 24 years. At six months each study demonstrated a statistically significant difference between Estrostep Fe and placebo for mean change from baseline in lesion counts. Each study also demonstrated overall treatment success in the investigator’s global evaluation. Patients with severe androgen excess were not studied.