Professional Information

Estrogens and Progestins (Ovarian Hormone Therapy Systemic)

This monograph includes information on the following:

1) 17 beta–Estradiol and Norgestimate
2) Ethinyl Estradiol and Norethindrone Acetate

INN:
Ethinyl Estradiol—Ethinylestradiol
Norethindrone—Norethisterone
^{11}
BAN:
Ethinyl estradiol—Ethinyloestradiol
Norethindrone—Norethisterone
^{11}

JAN:
Ethinyl Estradiol—Ethinylestradiol
Norethindrone—Norethisterone
^{11}
VA CLASSIFICATION
Primary: HS105

Commonly used brand name(s): Activella³; Ortho-Prefest¹; femhrt 1/5².

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Estrogen-progestin—17 beta-Estradiol and norgestimate tablets; Ethinyl estradiol and norethindrone tablets;

Ovarian hormone therapy agent— 17 beta-Estradiol and norgestimate tablets; Ethinyl estradiol and norethindrone tablets;

Osteoporosis prophylactic— 17 beta-Estradiol and norgestimate tablets; Ethinyl estradiol and norethindrone tablets;

Indications

Accepted

Menopause, vasomotor symptoms of (treatment) or
Vaginal atrophy (treatment) or
Vulvar atrophy (treatment)—17 beta-Estradiol and norgestimate tablets and estradiol and norethindrone tablets are indicated in the treatment of vaginal or vulvar atrophy, and moderate to severe vasomotor symptoms associated with menopause^{01}^{15}. Ethinyl estradiol and norethindrone tablets are indicated in the treatment of moderate to severe vasomotor symptoms associated with menopause^{02}.

Osteoporosis, postmenopausal (prophylaxis)—17 beta-Estradiol and norgestimate tablets, ethinyl estradiol and norethindrone tablets, and estradiol and norethindrone tablets are indicated in postmenopausal women to retard bone loss and estrogen deficiency–induced osteoporosis. Replacing estrogen can reduce the rate of bone loss and fractures in postmenopausal women. Proper diet, elemental calcium supplementation, and weight bearing exercise should also be encouraged along with estrogen replacement.^{01}^{02}

Unaccepted
The use of estrogens and progestins to reduce postpartum breast engorgement is not recommended.^{01}

The use of estrogen and progestin combinations in hysterectomized women is not recommended.^{01}^{02}

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—

Estrogens:
    17 beta-estradiol^{01}
    Ethinyl estradiol^{02}
    Estradiol (E₂)^{15}

Progestins, 19-nortestosterone derivatives:
    Norethindrone acetate^{02}^{15}
    Norgestimate^{01}

Molecular weight—
    17 beta-estradiol: 272.39^{01}
    Ethinyl estradiol: 296.41^{02}
    Estradiol (E₂): 281.4^{15}
    Norethindrone acetate: 340.47^{02}^{15}
    Norgestimate: 369.50^{01}

Mechanism of action/Effect:

At the cellular level, estrogens increase the synthesis of DNA, RNA, and various proteins in target tissues^{03} including the breasts and genitourinary structures.

For treatment of genitourinary atrophy and vasomotor symptoms:

In healthy females, estrogens maintain genitourinary function and vasomotor stability. By direct action, they cause growth and development of reproductive organs and help to maintain the tone and elasticity of the urogenital tract. Circulating estrogens regulate pituitary secretion of gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone (FSH) via a negative feedback loop^{01}. Progestins counter estrogenic effects by decreasing the number of estrogen receptors^{01}^{15}, suppressing epithelial DNA synthesis in endometrial tissue ^{01}, increasing local metabolism of estrogen to less active metabolites^{02}^{15}, and inducing gene products that blunt cellular responses to estrogen^{15}.

For prevention of postmenopausal osteoporosis:

During periods of estrogen deficiency, the rate of bone resorption by osteoclasts greatly exceeds the rate of bone formation by osteoblasts ^{04} ^{05}. Replacing estrogen prevents this accelerated bone loss by inhibiting bone resorption to a level where the near equilibrium between bone resorption and formation is restored ^{04}^{05}^{06} ^{07} ^{08} . However, estrogens do not replace previously lost bone or significantly increase total bone mass ^{04}.

Absorption:

Both estrogen and progestin components are rapidly and well absorbed.^{01}^{02}^{15}

Ethinyl estradiol and norethindrone—Absolute bioavailability is 55% and 64%, respectively; both components undergo first-pass metabolism^{15}. Ethinyl estradiol may also undergo enterohepatic recirculation.^{02}

Distribution:

Widely distributed throughout the body; concentrations generally higher in the sex hormone target organs
^{01}^{15}
.

Ethinyl estradiol and norethindrone: Volume of distribution (Vol _D)—2 to 4 L per kg of body weight. ^{02}

Protein binding:

17 beta-estradiol and norgestimate—estradiol binds to albumin and sex hormone binding globulin (SHBG) while 17–deacetylnorgestimate (the primary active metabolite of norgestimate) binds with high affinity (99%) to serum proteins but not to SHBG.^{01}

Ethinyl estradiol and norethindrone— High (> 95%); ethinyl estradiol binds to albumin only, whereas norethindrone binds to both albumin and SHBG.^{02}

Estradiol and norethindrone—Very high (90% or more); estradiol binds to albumin (61%) and sex hormone binding globulin (SHBG) (37%) while norethindrone binds to albumin (61%) and SHBBG (36%) to a similar extent^{15}.

Biotransformation:

In the liver, many estrogens are interconverted to various forms. Estrogens may be glucuronidated or sulfated via enterohepatic recirculation. These compounds are secreted into the intestines, then hydrolized and reabsorbed^{01}^{02}^{15}. Estradiol is reversibly converted to estrone; both compounds can be converted to estriol^{15}. Norgestimate is metabolized to 17–deacetylnorgestimate via first pass mechanisms in the gastrointestinal tract and liver. ^{01}Norethindrone is reduced, then undergoes sulfate and glucuronide conjugation.^{02}

Elimination

17 beta-estradiol—16 hours^{01}

17–deacetylnorgestimate—37 hours^{01}

Ethinyl estradiol—24 hours^{02}

Estradiol—12 to 14 hours^{15}.

Norethindrone—8 to 13 hours^{02}^{15}

Time to peak concentration:

17 beta-estradiol—7 hours^{01}

17–deacetylnorgestimate—2 hours^{01}

Ethinyl estradiol—1 to 2 hours^{02}

Estradiol—7 hours^{15}

Norethindrone—1 to 2 hours^{02}^{15}

Peak steady state concentration—

17 beta-estradiol—49.7 pg per mL ^{01}

17–deacetylnorgestimate—643 pg per mL^{01}

Ethinyl estradiol—38.3 ng per mL^{02}

Estradiol—33 to 47% above levels following single dose administration (34.6 pg per mL)^{15}

Norethindrone—7.5 ng per mL^{15}

Elimination:
    Primarily renal, as metabolites, glucuronide and sulfate conjugates;^{01}^{02}^{15}some fecal ^{01}^{02}.
        Ethinyl estradiol—

• Renal: 22 to 58%. ^{12} ^{13}

• Fecal: 30 to 53%. ^{12} ^{13}

• Biliary: 26 to 43% ^{12} ^{13}.

        Norethindrone—

• Renal: 37 to 87%, of which 3% is unchanged, and 40% is excreted as glucuronide and 15% as sulfate conjugates. ^{12}

• Fecal: Up to 40%. ^{12}

        Norgestimate—

• Renal: 45 to 49% ^{12}.

• Fecal: 16 to 49% ^{12}.

Precautions to Consider

Carcinogenicity/Tumorigenicity

The risk of endometrial cancer in unopposed estrogen users, which appears to depend on duration of treatment and dose, is about 2 to 12 times greater than in nonusers. The risk increases to 15 to 24–fold when the duration of use increases to five to ten or more years, and persists for at least 8 to 15 years after discontinuation of therapy. Risk reduction occurs when estrogen therapy is opposed with progestins^{01}^{02}^{15}.

Whether the use of systemic estrogens increases the incidence of breast cancer in some postmenopausal women is unresolved. Some studies have reported relative risks of 1.3 to 2.0 for breast cancer in patients taking high doses and patients taking lower doses over long periods of time (e.g. greater than 10 years)^{02}^{15}. Other studies have reported breast cancer rates similar to the background rate for women not on hormone replacement therapy.^{01} Progestin therapy appears to impart no benefits in terms of decreasing the risk of breast cancer development^{01}^{02}^{15}.

Continuous, long-term administration of estrogens in certain animal species resulted in increases in the incidence of carcinomas of the breast, cervix, liver, testis, uterus and vagina^{01}^{02}^{15}.

Pregnancy/Reproduction

Pregnancy—
Estrogen/progestin combinations should be avoided during pregnancy^{01}^{02}^{15}.Risk-benefit must be carefully considered.

FDA Pregnancy Category X^{01}^{02}^{15}

Breast-feeding

Estrogens and progestins are distributed into breast milk^{02}^{09}^{15}. The effect of this on the nursing infant has not been determined. Decreases in milk quantity and quality have been observed in nursing mothers who took estrogens^{01}^{02}^{15}. Estrogens are not indicated for the prevention of postpartum breast engorgement^{14}.

Pediatrics

Estrogen/progestin combinations are not indicated for children^{01}^{02}^{15}.

Geriatrics

Appropriate studies on the relationship of age to the effects of estrogens and progestins have not been performed in the geriatric population ^{01}^{02}^{15}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen or
Ascorbic acid or
Atorvastatin    (plasma concentrations of ethinyl estradiol may be increased^{02})

Acetaminophen or
Aspirin or
Clofibric acid or
Morphine or
Temazepam    (decreased plasma concentrations or increased clearance of these drugs may occur when given concomitantly with ethinyl estradiol^{02})

Anticonvulsants, such as
Carbamazepine or
Phenobarbital or
Phenytoin
Rifampin    (plasma concentrations of ethinyl estradiol may be decreased^{02})

» Cyclosporine or
Prednisolone or
Theophylline    (metabolism of these drugs may be inhibited by ethinyl estradiol; increased plasma concentrations have been reported^{02})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Glucose tolerance test^{01}^{02}^{15}    (may increase the glucose tolerance test results)

Metapyrone test    (reduced response^{01}^{02}^{15})

Thyroid function tests, such as
Thyroxine (T ₄) determinations
Triiodothyronine (T ₃) determinations    (total thyroid hormone, T₄, or T ₃ may be increased and values for the T ₃ uptake test may be decreased because of an increase in thyroid-binding globulin [TBG]; free T ₃ and thyroxine [T ₄] concentrations remain unaltered ^{01}^{02}^{15})

With physiology/laboratory test values
Anti-factor Xa and^{01}
Antithrombin III and^{01}^{15}
Factor VII and^{15}
Folate^{01}^{02}^{15}
Lipoproteins, low density (LDL) and^{01}^{02}^{15}
Plasminogen activator inhibitor-1^{15}    (serum concentrations may be decreased^{01}^{02}^{15})

Alpha-1–antitrypsin and ^{01}^{02}^{15}
Angiotensinogen/renin substrate and^{01}^{02}^{15}
Ceruloplasmin and ^{01}^{02}^{15}
Clotting factors II, VII, VIII, IX, X and XII and ^{01}
Corticosteroid binding globulin (CBG) and^{01} ^{02}^{15}
Fibrinogen and^{01}
Glucose—especially in diabetic or prediabetic patients taking larger doses of estrogens, and ^{01} ^{02}
Lipoproteins, high density (HDL) and ^{01}^{02}^{15}
Plasminogen antigen and^{01}
Platelets and ^{01}
Sex-hormone binding globulin (SHBG) and^{01}^{02}^{15}
Triglycerides ^{01} ^{02}^{15}     (serum concentrations may be increased ^{01} ^{02} )

» Calcium ^{01} ^{02}^{15}     (increased serum concentrations, especially for patients with bone cancer or metastatic breast cancer ^{01} ^{02})

Partial thromboplastin time^{01}
Platelet aggregation time^{01}
Prothrombin time^{01}     (may be increased ^{01} ^{02})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Breast cancer, known or suspected^{01} ^{02}^{15}    (possible promotion of tumor growth may occur)

» Genital or uterine bleeding, abnormal and undiagnosed ^{01} ^{02}^{15}
» Hypersensitivity reactions^{01} ^{02}^{15}
» Neoplasia, estrogen-dependent, known or suspected^{01} ^{02}^{15}    (possible promotion of tumor growth may occur)

» Pregnancy, known or suspected^{01} ^{02}^{15}
» Thrombophlebitis or thromboembolic disorders, active or past history^{01} ^{02}^{15}    (estrogens should be discontinued if thromboembolic events occur )

Risk-benefit should be considered when the following medical problems exist
Gallbladder disease, or history of^{01}^{02}^{15}
Hepatic function impairment^{01}^{02}^{15}
» Hypercalcemia associated with bone or metastatic breast cancer ^{01} ^{02}^{15}     (severe hypercalcemia may occur in patients with bone cancer or metastatic breast cancer who are treated with estrogens ^{01}^{02}^{15} )

» Hyperlipoproteinemia, familial or ^{01}^{02}^{15}
» Pancreatitis^{01}^{02}^{15}    (increased triglycerides may lead to or exacerbate pancreatitis in susceptible individuals)

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure determinations and
Breast examination or
Mammogram and
Papanicolaou (Pap) test and
Physical examinations    (recommended as determined by physician—generally every 12 months. Special attention should be given to breast, liver, and pelvic area in the physical examination and patient should be taught to perform periodic self-examination of breasts )

    (^{01} ^{02}^{15})

Endometrial biopsy^{01} ^{02}^{15}    (should be considered periodically as necessary in patients with an intact uterus; patients with a uterus should be monitored for signs of endometrial cancer and malignancy should be ruled out in cases of persistent or abnormal vaginal bleeding ^{01} ^{02}^{15}; there is no risk of endometrial cancer in patients who have undergone a hysterectomy )

Hepatic function determinations ^{01} ^{02}^{15}    (recommended at regular intervals, especially during therapy in patients who have or are suspected of having hepatic disease)

Lipid profile, serum and
Lipoprotein profile, serum    (recommended in patients with familial defects of lipoprotein metabolism^{02}^{15})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Breast pain or tenderness^{01}^{02}^{15}

hypertension^{01}^{02}^{15} (dizziness or light-headedness; headache)

peripheral edema^{01}^{02}^{15} (swelling of feet and lower legs; rapid weight gain)

upper respiratory tract infection^{15} (cough, fever, sneezing, or sore throat)

vaginal bleeding^{01}^{02}^{15}

Incidence less frequent or rare

Breast tumors^{01}^{02}^{15} (breast lumps; discharge from nipple)

endometrial hyperplasia^{01}^{02}^{15} (change in vaginal discharge; pain or feeling of pressure in pelvis; vaginal bleeding)

gallbladder obstruction,
liver dysfunction, or
pancreatitis^{01}^{02}^{15} (nausea and vomiting ; pains in stomach, side, or abdomen; yellow eyes or skin)

thrombus formation^{01}^{02}^{15} (severe or sudden headache; sudden loss of coordination; pains in chest, groin, or leg, especially calf; sudden and unexplained shortness of breath ; sudden slurred speech; sudden vision changes ; weakness or numbness in arm or leg )

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Back pain^{01}^{02}^{15}

dizziness^{01}^{02}^{15}

fatigue^{01}^{02}^{15} (general feeling of tiredness)

flatulence^{01}^{02}^{15} (bloating or gas )

flu-like symptoms^{01}^{02}^{15}

headache^{01}^{02}^{15}

insomnia^{15} ( sleeplessness)

mental depression^{01}^{02}^{15}

muscle aches^{01}^{02}^{15}

nausea^{01}^{02}^{15}

vaginitis^{01}^{02}^{15}

Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
No serious ill effects have been reported following acute ingestion of large doses of estrogen/progestin-containing oral contraceptives by young children. The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Nausea or vomiting

withdrawal bleeding
^{01}^{02}^{15}
Treatment of overdose
Treatment of overdose is symptomatic.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Estrogens and Progestins (Ovarian Hormone Therapy) (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance)

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to estrogens or progestins

Carcinogenicity—
Increased risk of endometrial cancer for patients with intact uteri placed on unopposed estrogen therapy; decreased risk occurs when used with a progestin; continuous, long-term estrogen use in animal studies increased frequency of cancers of the breast, cervix, and liver

Pregnancy— Not recommended for use during pregnancy

Breast-feeding—Estrogens and progestins are distributed into breast milk
Other medications, especially cyclosporine
Other medical problems, especially abnormal or undiagnosed genital or uterine bleeding; active thrombophlebitis or thromboembolic disorders; estrogen-dependent neoplasia; history of estrogen-induced thrombophlebitis, thrombosis, or thromboembolic disorders; or hypercalcemia associated with bone cancer or metastatic breast cancer

Proper use of this medication
» Reading patient package insert carefully

» Compliance with therapy

» Proper dosing
Taking or using as soon as possible; not using if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician every year, or more often, as determined by physician

» Checking breast by self-examination regularly and having clinical examination and mammography as required by physician; reporting unusual breast lumps or discharge

» Understanding that menstrual bleeding may begin again; checking with doctor immediately if uterine bleeding is unusual or continuous

If scheduled for laboratory tests, telling physician about taking estrogens; certain blood tests are affected

Side/adverse effects
Irregular vaginal bleeding or spotting may occur in many postmenopausal patients with an intact uterus who are placed on continuous estrogen therapy with a progestin

Signs of potential side effects, especially breast pain or tenderness, enlargement of breasts in females, peripheral edema, amenorrhea, breakthrough bleeding, menorrhagia, or spotting; breast tumors; gallbladder obstruction, hepatitis, or pancreatitis;

General Dosing Information
It is recommended that the patient package insert be given to patients.

In general, combination estrogen/progestin therapy should be administered at the lowest effective dosage. The recommended dose may not be the lowest effective dose for treatment of vulvar and vaginal atrophy or for the prevention of osteoporosis^{01}. Patients should be reevaluated at three- to six-month intervals to determine if treatment is still necessary for symptoms.^{01}^{02}^{15}

17 beta-estradiol and Norgestimate

Oral Dosage Forms

17 BETA-ESTRADIOL AND NORGESTIMATE TABLETS

Usual adult dose
Menopause, vasomotor symptoms of (treatment) or
Vaginal atrophy (treatment) or
Vulvar atrophy (treatment)
Oral, 1 mg estradiol for three days followed by 1 mg of estradiol combined with 0.09 mg of norgestimate for three days. The regimen is repeated continuously without interruption.

Osteoporosis, postmenopausal (prophylaxis)
Oral, 1 mg estradiol for three days followed by 1 mg of estradiol combined with 0.09 mg of norgestimate for three days. The regimen is repeated continuously without interruption.

Strength(s) usually available
U.S.—

Intermittent formulation^{14}

1 mg estradiol (three days) followed by 1 mg estradiol and 0.09 mg norgestimate (three days) (Rx) [Ortho-Prefest (croscarmellose sodium ) (microcrystalline cellulose) ( magnesium stearate) (ferric oxide red) (lactose monohydrate)]

Note: Product is packaged as 30 tablets (15 of each type) encased in a blister card, with weekly schedule stickers which are to be placed on the card by the patient.

Packaging and storage:
Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F)

Note: Include patient package inserts (PPIs) when dispensing.

Ethinyl Estradiol and Norethindrone

Oral Dosage Forms

ETHINYL ESTRADIOL AND NORETHINDRONE TABLETS

Usual adult dose
Menopause, vasomotor symptoms of (treatment)
Oral, 5 mcg (0.05 mg) ethinyl estradiol and 1 mg norethindrone once daily.

Osteoporosis, postmenopausal (prophylaxis)
Oral, 5 mcg (0.05 mg) ethinyl estradiol and 1 mg norethindrone once daily.

Strength(s) usually available
U.S.—

Continuous formulation^{14}

5 mcg (0.05 mg) ethinyl estradiol and 1 mg norethindrone (Rx) [femhrt 1/5 (calcium stearate) (lactose monohydrate ) (microcrystalline cellulose) ( cornstarch)]

Packaging and storage:
Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F)

Note: Include patient package inserts (PPIs) when dispensing.

Estradiol and Norethindrone

Oral Dosage Forms

ESTRADIOL (E₂) AND NORETHINDRONE TABLETS

Usual adult dose
Menopause, vasomotor symptoms of (treatment) or
Vaginal atrophy (treatment) or
Vulvular atrophy (treatment)
Oral, 1 mg estradiol and 0.5 mg norethindrone once daily.

Osteoporosis, postmenopausal (prophylaxis)
Oral, 1 mg estradiol and 0.5 mg norethindrone a day.

Strength(s) usually available
U.S.—

Continuous formulation^{14}

1 mg estradiol and 0.5 mg norethindrone (Rx) [Activella (lactose monohydrate) (cornstarch) ( copovidone) (talc) (magnesium stearate) (hydroxypropylmethylcellulose) (triacetin)]

Packaging and storage:
Store in a dry place protected from light at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F)

Note: Include patient package inserts (PPIs) when dispensing.

Developed: 04/10/2000
Revised: 08/08/2000

References

Product Information: Ortho-Prefest, 17 beta-estradiol and norgestimate. Ortho-McNeil Pharmaceutical, Raritan, NJ, (PI revised 12/99) reviewed 1/2000.

Product Information: femhrt, norethindrone acetate and ethinyl estradiol. Parke-Davis, Morris Plains, NJ, (PI revised 10/99) reviewed 1/2000.

Mullins PM, Pugh MC, and Moore AO: Hormone replacement therapy. In: DiPiro JT, Talbert RL, Yee GC et al (eds). Pharmacotherapy: A Pathophysiologic Approach, 3rd ed. Appleton & Lange, Stamford, CT; 1997:1635–1646

Ettinger B. Prevention of osteoporosis: treatment of estradiol deficiency. Obstet Gynecol 1988; 72(5): 12S-17S.

Bauwens SF, Drinka PJ, Boh LE. Pathogenesis and management of primary osteoporosis. Clin Pharm 1986; 5: 639-59.

Alden JC. Osteoporosis—a review. Clin Ther 1989; 11(1): 3-14.

Bergkvist L, Adami HO, Persson I, et al. The risk of breast cancer after estrogen-progestin replacement. N Engl J Med 1989; 321(5): 293-7.

Lufkin EG, et al. Estrogen replacement therapy: current recommendations. Mayo Clin Proc 1988; 63: 453-60.

Briggs GG, Freeman RK, Yaffe SJ. A reference guide to fetal and neonatal risk: Drugs in pregnancy and lactation. 4th ed. Baltimore: Williams & Wilkins; 1994. p. 281, 339, 340.

Pernoll ML, Benson RC, editors. Current obstetric and gynecologic diagnosis and treatment. 6th ed. Norwalk, CT: Appleton & Lange; 1987. p. 115-9, 947-8.

Canada JR, editor. The USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 288, 519, 520.

Goldzieher JW. Pharmacokinetics and metabolism of ethynyl estrogens. In: Goldzieher JW, editor. Pharmacology of the contraceptive steroids. New York: Raven Press; 1994. p. 127-51.

Fotherby K, Akpoviroro J, Abdel-Rahman HA, et al. Pharmacokinetics of ethynyloestradiol in women from different populations. Contraception 1981; 23(5): 487-97.

Manufacturer comment, 5/2000.

Product Information: Activella, estradiol/norethindrone acetate. Pharmacia & Upjohn Company, Kalamazoo, MI, (PI revised 2/2000) reviewed 7/2000.

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