estrogen and progestin
Alesse, Apri, Aviane, Brevicon, Cyclessa, Demulen 1/35, Demulen 1/50, Desogen, Enpresse, Estrostep 21, Estrostep Fe, Jenest-28, Kariva, Lessina, Levlen, Levlite, Levora, Loestrin 21 1/20, Loestrin 21 1.5/30, Loestrin Fe 1/20, Loestrin Fe 1.5/30, Lo/Ovral, Low-Ogestrel, Microgestin Fe 1.5/30, Microgestin Fe 1/20, Mircette, Modicon, Necon 0.5/35, Necon 1/35, Necon 1/50, Necon 10/11, Nordette, Norinyl 1+35, Norinyl 1+50, Nortrel 0.5/35, Nortrel 1/35, Ogestrel, Ortho-Cept, Ortho-Cyclen, Ortho-Novum 1/35, Ortho-Novum 1/50, Ortho-Novum 7/7/7, Ortho-Novum 10/11, Ortho Tri-Cyclen, Ovcon-35, Ovcon-50, Ovral-28, Tri-Levlen, Tri-Norinyl, Triphasil, Trivora-28, Zovia 1/35 E, Zovia 1/50 E

Available forms
Available by prescription only
Tablets-monophasic type
Mestranol 0.05 mg and norethindrone 1 mg
Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg
Ethinyl estradiol 0.02 mg and norethindrone acetate 1 mg
Ethinyl estradiol 0.03 mg and desogestrel 0.15 mg
Ethinyl estradiol 0.03 mg and norethindrone acetate 1.5 mg
Ethinyl estradiol 0.03 mg and norgestrel 0.3 mg
Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg
Ethinyl estradiol 0.035 mg and norethindrone 1 mg
Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg
Ethinyl estradiol 0.035 mg and norethindrone 0.4 mg
Ethinyl estradiol 0.035 mg and norgestimate 0.25 mg
Ethinyl estradiol 0.035 mg and ethynodiol diacetate 1 mg
Ethinyl estradiol 0.05 mg and ethynodiol diacetate 1 mg
Ethinyl estradiol 0.05 mg and norethindrone 1 mg
Ethinyl estradiol 0.05 mg and norgestrel 0.5 mg
Tablets-biphasic type
10 tablets ethinyl estradiol 0.035 mg and norethindrone 0.5 mg; 11 tablets ethinyl estradiol 0.035 mg and norethindrone 1 mg
21 tablets 0.02 mg ethinyl estradiol and 0.15 mg desogestrel; 5 tablets 0.01 mg ethinyl estradiol; 2 inert tablets
Tablets-triphasic type
7 tablets ethinyl estradiol 0.035 mg and norethindrone 0.5 mg; 9 tablets ethinyl estradiol 0.035 mg and norethindrone 1 mg; 5 tablets ethinyl estradiol 0.035 mg and norethindrone 0.5 mg
7 tablets ethinyl estradiol 0.035 mg and norethindrone 0.5 mg; 7 tablets ethinyl estradiol 0.035 mg and norethindrone 0.75 mg; 7 tablets ethinyl estradiol 0.035 mg and norethindrone 1 mg
6 tablets ethinyl estradiol 0.03 and levonorgestrel 0.05 mg; 5 tablets ethinyl estradiol 0.04 mg and levonorgestrel 0.075 mg; 10 tablets ethinyl estradiol 0.03 mg and levonorgestrel 0.125 mg
7 tablets 0.035 ethinyl estradiol and 0.18 mg norgestimate; 7 tablets 0.035 mg ethinyl estradiol and 0.215 norgestimate; 7 tablets 0.035 mg ethinyl estradiol and 0.25 mg norgestimate
5 tablets 0.02 mg ethinyl estradiol and 1 mg norethindrone acetate; 7 tablets 0.03 mg ethinyl estradiol and 1 mg norethindrone acetate; 9 tablets 0.035 mg ethinyl estradiol and 1 mg norethindrone acetate
0.1 mg desogestrel with 25 mcg ethinyl estradiol (7 tablets); 0.125 mg desogestrel with 25 mcg ethinyl estradiol (7 tablets); 0.15 mg desogestrel with 25 mcg ethinyl estradiol (7 tablets).

Indications and dosages
 Contraception.
Monophasic. Adults: One tablet P.O. daily, beginning on day 5 of menstrual cycle (first day of menstrual flow is day 1), or on the first Sunday after onset of menstruation, or on day 1 of menstrual cycle depending on specific contraceptive. With 20- and 21-tablet packages, new dosing cycle begins 7 days after last tablet taken. With 28-tablet packages, dosage is one tablet daily without interruption; extra tablets are placebos or contain iron. If next menstrual period doesn’t begin on schedule, rule out pregnancy before starting new dosing cycle. If menstrual period begins, start new dosing cycle 7 days after last tablet was taken. If all doses have been taken on schedule and one menstrual period is missed, continue dosing cycle. If two consecutive menstrual periods are missed, pregnancy test is required before new dosing cycle is started.
Biphasic. Adults: One color tablet P.O. daily (Necon 10/11, Ortho-Novum 10/11) for 10 days, then next color tablet for 11 days. Or one color tablet P.O. daily (Jenest-28) for 7 days, then next color tablet for 14 days. Or one white tablet P.O. daily for 21 days (Mircette), then 1 green (inert) tablet daily for 2 days and 1 yellow (active) tablet daily for 5 days.
Triphasic. Adults: One tablet P.O. daily (Cyclessa, Enpresse, Estrostep21, Estrostep Fe Ortho-Novum 7/7/7, Ortho Tri-Cyclen, Tri-Levlen, Tri-Norinyl, Triphasil, Trivora-28) in the sequence specified by the manufacturer.
 Treatment of women with moderate acne vulgaris with no contraindications to hormonal contraceptives, who desire hormonal contraception, achieved menarche, and don’t respond to topical antiacne medication. Women age 15 and older: (Estrostep, Ortho Tri-Cyclen) 1 tablet P.O. daily as directed.
 Hypermenorrhea. Adults: Use only high-dose combinations. Dosage is same as for contraception.
 Endometriosis.
Cyclic therapy. Adults: One 10-mg tablet P.O. daily (Ortho-Novum) for 20 days from day 5 to day 24 of menstrual cycle.
Suppressive therapy. Adults: One 5- or 10-mg tablet P.O. daily (Enovid) for 2 weeks, starting on day 5 of menstrual cycle. Continue without interruption for 6 to 9 months, increasing dose by 5 to 10 mg q 2 weeks, up to 20 mg daily. Up to 40 mg daily may be needed if breakthrough bleeding occurs.

Pharmacodynamics
Contraceptive action: Estrogen components of hormonal contraceptives inhibit the release of follicle-stimulating hormone, thereby stopping follicular development and suppressing ovulation.
 Progestin components of hormonal contraceptives inhibit the release of luteinizing hormone, preventing ovulation even in the event of incomplete suppression of follicular development. Progestins also change the endometrial environment to inhibit nidation (implantation of the fertilized egg into the endometrium) and cause thickening of the cervical mucus, blocking the upward migration of sperm.

Pharmacokinetics
Absorption: Most components of hormonal contraceptives are absorbed relatively well from the GI tract. Bioavailabilities range from 40% to 70%; considerable individual variation exists in extent of absorption.
Distribution: Protein-binding of the various drugs used in hormonal contraceptives is high, ranging from 80% to 98%. These agents are distributed extensively into virtually all body tissues.
Metabolism: These drugs undergo metabolic transformation before excretion; their rates of metabolism may thus be affected by agents that induce or inhibit metabolism.
Excretion: Very little, if any, is excreted unchanged in urine or feces. They appear primarily as sulfate and glucuronide conjugates.

Contraindications and precautions
Hormonal contraceptives are contraindicated in patients with thromboembolic disorders, cerebrovascular or coronary artery disease, or MI because of the well-known link between contraceptives and thromboembolic disease; in patients with known or suspected cancer of the breast or reproductive organs or with benign or malignant liver tumors because of the link between contraceptives and tumorigenesis; in patients with undiagnosed abnormal vaginal bleeding; in women known or suspected to be pregnant; in breast-feeding women; in adolescents with incomplete epiphyseal closure; and in women smokers older than age 35.
 Use hormonal contraceptives cautiously in patients with systemic lupus erythematosus, hypertension, mental depression, migraine, epilepsy, asthma, diabetes mellitus, amenorrhea, scanty or irregular periods, fibrocystic breast disease, family history (mother, grandmother, sister) of breast or genital tract cancer, or renal or gallbladder disease. Advise patient to report development or worsening of any of these conditions. Prolonged therapy may be inadvisable in women who plan to become pregnant.

Interactions
Drug-drug. Aminoglutethimide, ampicillin, antihistamines, barbiturates, carbamazepine, chloramphenicol, felbamate, griseofulvin, isoniazid, neomycin, nitrofurantoin, penicillin V, phenylbutazone, phenytoin, primidone, protease inhibitors, rifampin, sulfonamides, and tetracycline: Increase metabolism of hormonal contraceptives, resulting in reduced efficacy, breakthrough bleeding, and occasionally contraceptive failure. Monitor patient for drug effects.
Anticonvulsants, antihypertensives, beta blockers, corticosteroids, oral warfarin-type anticoagulants, tricyclic antidepressants: Hormonal contraceptives may interfere with hepatic metabolism of these drugs and cause toxicity or decreased effects. Monitor patient for toxicity and decreased effects.
Insulin, oral antidiabetics: May affect serum glucose level. Adjust dosage as needed.
Drug-herb. Red clover: May interfere with hormonal therapies. Discourage use together.
St. John’s wort: May decrease efficacy of hormonal contraceptive because of increased hepatic metabolism. Discourage use together. If use together can’t be avoided, encourage use of an additional method of contraception.
Drug-food. Caffeine: May increase serum caffeine levels. Discourage caffeine use.
Drug-lifestyle. Smoking: Increases risk of CV effects. Discourage smoking.

Adverse reactions
CNS: headache, dizziness, depression, lethargy, migraine.
CV: thromboembolism, hypertension, edema, increase in varicosities.
EENT: worsening of myopia or astigmatism, intolerance of contact lenses, unexplained loss of vision, optic neuritis, diplopia, retinal thrombosis, papilledema.
GI: nausea, vomiting, abdominal cramps, bloating, diarrhea, constipation, changes in appetite, weight gain, bowel ischemia.
GU: breakthrough bleeding, granulomatous colitis, dysmenorrhea, amenorrhea, cervical erosion or abnormal secretions, enlargement of uterine fibromas, vaginal candidiasis, urinary tract infections.
Hepatic: gallbladder disease, cholestatic jaundice, liver tumors.
Metabolic: hyperglycemia, hypercalcemia, increased sulfobromophthalein retention, thyroid-binding globulin.
Skin: rash, acne, seborrhea, oily skin, erythema multiforme, hyperpigmentation.
Other: breast tenderness, enlargement, or secretion, libido changes, congenital anomalies.

Effects on lab test results
• May increase levels of glucose, calcium, triglycerides, phospholipid, transcortin, corticosteroids, transferrin, prolactin, renin, vitamin A, plasminogen, fibrinogen, and clotting factors VII, VIII, IX, and X. May decrease antithrombin III, folic acid, metyrapone, zinc, and vitamin B₁₂ levels.
• May increase PT and norepinephrine-induced platelet aggregation. May decrease pregnanediol excretion, free T₃ resin uptake, and glucose tolerance.

Overdose and treatment
Serious toxicity hasn’t been reported. Nausea, vomiting, and withdrawal bleeding may occur.

Special considerations
• Astigmatic error and myopic refractive error may be increased twofold to threefold, usually after 6 months of hormonal contraceptive therapy.
• If patient becomes hypersensitive, discontinue drug.
• Changes in ocular contour and lubricant quality of tears may necessitate change in size and shape of contact lenses.
• Breakthrough bleeding in patients taking high-dose combinations of estrogen and progestin for menstrual disorders may necessitate dosage adjustment.
Pregnant patients
• Drug is contraindicated during pregnancy.
Breast-feeding patients
• Hormonal contraceptives are contraindicated in breast-feeding women.
Pediatric patients
• To avoid later fertility and menstrual problems, hormonal contraception isn’t advised for the adolescent until after at least 2 years of well-established menstrual cycles and completion of physiologic maturation. An estrogen-dominant agent is the best choice for the adolescent with scanty menses, moderate or severe acne, or candidiasis. A progestin-dominant agent is the best choice for the adolescent with dysmenorrhea, hypermenorrhea, fibrocystic breast disease, or cyclic premenstrual weight gain.

Patient education
• Advise patient of potential adverse reactions and inform her that these should diminish after 3 to 6 dosing cycles (months).
• Advise patient to use an additional method of birth control for the first week of administration in the initial cycle (unless using day-1 start).
• Instruct patient to take drug at the same time each day at 24-hour intervals for efficacy of medication, to keep tablets in original container, and to take them in correct (color-coded) sequence.
• Tell patient that night-time dosing may reduce nausea and headaches.
• Suggest taking drug with or immediately after food to reduce nausea.
• Stress importance of annual Papanicolaou smears and gynecologic examinations while taking combinations of estrogen and progestin.
• Advise patient of increased risks linked to simultaneous use of cigarettes and hormonal contraceptives, especially the risk of serious CV adverse effects. Strongly advise women who use hormonal contraceptives not to smoke.
• Instruct patient as follows regarding missed doses.
Monophasic or biphasic cycles
For 20-, 21-, or 24-day dosing schedule:
• If one regular dose is missed, take tablet as soon as possible; if remembered on the next day, take two tablets, then continue regular dosing schedule.
• If two consecutive days are missed, take two tablets a day for next 2 days, then resume regular dosing schedule.
• If 3 consecutive days are missed, discontinue drug and substitute other contraceptive method until period begins or pregnancy is ruled out. Then start new cycle of tablets.
For 28-day dosing schedule:
• Follow instructions for 21-day dosing schedule; if one of the last seven tablets is missed, be sure to take first tablet of next month’s cycle on regularly scheduled day.
Triphasic cycle
For 21-day dosing schedule:
• If 1 day is missed, take dose as soon as possible; if remembered on the next day, take two tablets, then continue regular dosing schedule while using additional method of contraception for remainder of cycle.
• If 2 consecutive days are missed, take two tablets daily for next 2 days, then continue regular schedule while using additional contraceptive method for remainder of cycle.
• If 3 consecutive days are missed, discontinue drug and use other contraceptive method until period begins or pregnancy is ruled out. Then start new cycle of tablets.
For 28-day dosing schedule:
• Follow instructions for 21-day dosing schedule; if one of the last seven tablets was missed, be sure to take first tablet of next month’s cycle on regularly scheduled day.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use