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Mechanism of Action
US Drug Names
2.5—10 mg PO once daily for 5—10 days. Withdrawal bleeding usually occurs within 3—7 days after discontinuing norethindrone acetate. The endometrium should be adequately primed with either endogenous or exogenous estrogen. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with norethindrone acetate.
Therapy is usually initiated on day 1 of menses. Take 0.35 mg (1 tablet) PO once daily at the same time of day as indicated by the pack, without interruption. Administration is continuous, with no interruption between pill packs. The interval between doses should not exceed 24 hours; missed doses greatly increase the risk of pregnancy. When 1 pill is missed (even if only 3 hours late), the patient should take the missed pill as soon as possible and continue taking a pill each day at the regular time (a backup method of birth control, like a condom or spermicide, should be used for the next 48 hours). Whenever more than 1 dose is missed, additional contraception should adopted for the rest of the cycle, until menses occurs. NOTE: If switching from combined oral contraceptive (OC), initiate norethindrone the day after the last active combined OC pill. Progestin-only pills can be started the day after a miscarriage or abortion. Women who are partially breastfeeding can initiate norethindrone as early as 3 weeks postpartum. If fully breastfeeding, may initiate at 6 weeks postpartum. 
Initially, 5 mg/day PO for 14 consecutive days then increase dose by 2.5 mg/day every 2 weeks until a maximum dose of 15 mg/day is reached. Continue for 6—9 months or until annoying breakthrough bleeding demands temporary termination. 
5 mg/day PO plus leuprolide 3.75 mg IM once monthly or 11.25 mg IM once every 3 months for 6 months for either initial treatment or retreatment for symptom recurrence. Greater than 1 retreatment period is not recommended and assessment of bone density is recommended before making the decision to re-treat.  
Continuous norethindrone acetate doses of 0.1 mg/day or 0.5 mg/day PO are effective at negating the risk for endometrial hyperplasia associated with unopposed, continuous estrogen (i.e., estradiol 1 mg/day PO) in postmenopausal women. Norethindrone acetate doses of 0.5 mg/day or 1 mg/day PO with continuous ethinyl estradiol (EE) (i.e., ethinyl estradiol 2.5 mcg/day or 5 mcg/day PO, respectively) are also effective. Norethindrone acetate single-agent dosage forms for this indication are not available in the U.S.; combination products for estradiol; norethindrone acetate and EE; norethindrone acetate are available.  
Dependent on product used and indication for therapy.
Not indicated in prepubescent females.
Norethindrone should generally be avoided in patients with hepatic dysfunction.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Norethindrone is a synthetic oral progestin. Norethindrone acetate is a prodrug that is rapidly converted to norethindrone in the body; on a weight basis, norethindrone acetate is twice as potent as norethindrone. Norethindrone is a first generation oral progestin with moderate androgenic and slight estrogenic activity relative to newer progestins. Norethindrone is known as norethisterone outside of the United States. Norethindrone is used for routine contraception and is available as either a progestin-only contraceptive or in combination hormonal contraceptive products with an estrogen. Progestin-only formulations or "mini-pills" of norethindrone are not widely used due to the higher risk of contraceptive failure and certain side effects such as spotting and breakthrough bleeding compared to combination hormonal contraceptives. However, progesin-only oral contraceptives may be appropriate choices when women have relative or absolute contraindications to the use of estrogen-based hormonal contraception. The choice of a routine hormonal contraceptive for any given patient is based on the individual's contraceptive needs, underlying medical conditions or risk factors for adverse effects, and individual preferences for use. The Centers for Disease Control's U.S. Medical Eligibility Criteria describe considerations for risk vs. benefits, including medical conditions or attributes that contraindicate use; these criteria can help prescribing practitioners in product selection for individual patients. Norethindrone acetate is found in some combination oral contraceptives. Single-agent norethindrone acetate products are primarily used to treat such conditions as secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. For endometriosis, norethindrone acetate is commonly used in combination with leuprolide. While norethindrone acetate is effective at preventing endometrial hyperplasia due to unopposed estrogen therapy in postmenopausal women, single-agent norethindrone products are not available for this indication in the U.S. Norethindrone was initially approved by the FDA in 1961.
For storage information, see the specific product information within the How Supplied section.
Instruct patient on risks and warnings associated with hormonal agents (see Patient Information).
Hazardous Drugs Classification
The most common adverse reactions of progestin-only oral contraceptives (OCs) include menstrual irregularity, menstrual flow changes, and dysmenorrhea or amenorrhea. These effects may be indistinguishable from pregnancy. Progestins may also cause spotting, breakthrough bleeding, menorrhagia, weight gain, nausea, vomiting, breast tenderness, mastalgia, and mild headache. These adverse effects occur less frequently with progestin-only OCs compared to combination OCs. Other reported adverse reactions during norethindrone therapy include dizziness, dermatitis, alopecia, acne vulgaris, anorexia, appetite stimulation, libido decrease, libido increase, breast discharge, lactation suppression, cervicitis, galactorrhea, weight loss, fatigue, musculoskeletal pain, hirsutism, abdominal pain, leukorrhea, insomnia, optic neuritis, hypercholesterolemia, and vaginitis.  
Fluid retention and/or edema may occur in patients receiving norethindrone. Patients with heart failure and/or renal disease may experience an exacerbation of their condition.  
Patients receiving norethindrone or other hormonal contraceptive can experience emotional lability. This adverse effect may be manifest as mental depression, anxiety, frustration, anger, or other emotional outbursts.  
Thromboembolic disease is more common in oral contraceptive users than in non-users. Previously, thromboembolic disease appeared to be more related to estrogen therapy than to progestin therapy, however, there is some evidence that different types of progestins are associated with differing rates of venous thromboembolism. At usual doses, women receiving third generation progestins (e.g., desogestrel or gestodene) appear to have an increased risk of venous thromboembolic disease compared to women receiving previous generation progestins.  The risk is even greater in women with genetic predisposition or family history for venous thromboembolic disease. Thromboembolism or thrombus formation has also been associated with high doses of progestins. Some of the thrombotic events include pulmonary embolism, and cerebral thrombosis. Other rare adverse reactions that may occur during norethindrone therapy may include retinal thrombosis, elevated blood pressure or hypertension, hepatoma, hepatitis (and elevated hepatic enzymes), biliary obstruction, cholestatic jaundice, and hyperglycemia.  
Anaphylactic shock/anaphylactoid reactions have been reported with norethindrone. Rash (unspecified), pruritus, melasma, and urticaria have also been reported.  
Norethindrone is contraindicated for use in patients with a known norethindrone hypersensitivity or hypersensitivity to any of the components within the drug product.
Like all hormonal contraceptives, norethindrone use does not protect against the transmission of human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.
Hormonal contraceptives have been associated with the development of hepatic tumors. Although this is believed to be an estrogen-mediated effect, progestins such as norethindrone are contraindicated in patients with hepatic disease or hepatic dysfunction.
Norethindrone is absolutely contraindicated in undiagnosed abnormal vaginal bleeding or incomplete abortion. Hormonal contraceptives can cause irregular menstrual bleeding in most women. In general, these irregularities diminish with continuing use. Women should be counseled regarding irregular menstrual bleeding.
Norethindrone is contraindicated in patients with pre-existing breast cancer, except as palliative therapy in selected patients. Although progestins reduce the risk of endometrial cancer in patients receiving estrogen replacement therapy, it is unclear whether progestins added to estrogen therapy reduce the risk of breast cancer in postmenopausal women.
Norethindrone is absolutely contraindicated for use during pregnancy or suspected pregnancy.  There is no known indication for hormone replacement therapy with norethindrone during pregnancy. Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and congenital abnormalities in male and female fetuses. Some progestational drugs induce mild virilization of the external genitalia of female fetuses. In studies of hormonal contraceptives, the continued use of the contraceptive inadvertently for a limited time in the early part of pregnancy prior to detection of the pregnancy has failed to find significant adverse effects on fetal or infant growth and development. No norethindrone product should be used in diagnostic tests for pregnancy.  The incidence of ectopic pregnancy during use of progestin-only oral contraceptives is 5 per 1,000 woman-years. Up to 10% of pregnancies reported in clinical studies of progestin-only oral contraceptive users are extrauterine. Although symptoms of ectopic pregnancy should be watched for, a history of ectopic pregnancy need not be considered a contraindication to use of this contraceptive method. Health providers should be alert to the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while taking norethindrone contraception.
Caution should be exercised when using norethindrone acetate for hormone replacement or other hormonal treatment in lactating women. Progestin-only contraceptives, including norethindrone, are generally considered to be compatible with breast-feeding; available evidence suggests that progestin-only contraceptives pills (POPs) are preferable to other hormonal contraceptives during lactation. Very rarely, adverse effects in the infant have been reported, including jaundice. In general, no adverse effects on breast-feeding performance or on the health, growth, or development of the infant have occurred with norethindrone POPs. Only rarely have there been isolated reports of decreased lactation.   Progestins pass into breast milk in low amounts, resulting in steroid levels in infant plasma of 1% to 6% of the levels of maternal plasma.  Monitoring of infant weight gain and growth can occur as per usual practices during maternal POP use. Medroxyprogesterone depot contraceptive injection is considered another acceptable progestin-only contraceptive option during lactation.
Norethindrone should be used cautiously in patients with diabetes mellitus. Although the effects appear to be minimal during therapy with progestins, altered glucose tolerance secondary to decreased insulin sensitivity has been reported during hormonal contraceptive therapy. In addition, diabetes mellitus, a risk factor for arterial disease, should be managed appropriately in patients taking norethindrone.
Norethindrone should be used cautiously in patients with hyperlipidemia. Although hyperlipidemia is associated with estrogen-progestin combinations, the effects of progestin-only oral contraceptives on serum lipids have not been studied. Serum lipoproteins (HDL and LDL) should be monitored during therapy with norethindrone. In addition, hyperlipidemia, a risk factor for arterial disease, should be managed appropriately in patients taking norethindrone.
Norethindrone progestin-only contraception products should be used cautiously in patients with active or a history of thrombophlebitis or thromboembolic disease.  Norethindrone acetate, used for hormonal replacement therapy (HRT) and for non-contraceptive hormonal indications, is contraindicated in patients with active or a history of thromboembolic disease, including cerebrovascular disease or stroke. Although thromboembolic disease is believed to be an estrogen-related effect, studies have shown that patients receiving combined hormonal contraceptives or hormonal replacement therapy (HRT) regimens containing progestins may have a higher risk of venous thromboembolic (VTE) disease. Patients with existing coronary artery disease or risk factors for arterial disease including hypertension, diabetes mellitus, hyperlipidemia, and obesity should be managed appropriately. Because of the higher risk of thromboembolic disease in tobacco smoking women, women should be advised not to smoke, particularly if they are over the age of 35 years. Despite the caution against use in patients with known thrombotic disease, progestin-only contraceptives are generally the hormonal contraceptives of choice in patients with a potential risk for thrombosis when reliable contraception must be ensured and the risks of hormonal therapy are acceptable; advantages of these methods usually outweigh proven or theoretical risks. When multiple thrombosis risk factors exist, the risk of thromboembolic disease may increase; determine risk vs. benefit for use of the progestin-only contraceptive. The increase in the risk of thrombosis from newer progestin-only contraceptives (e.g., etonogestrel implants) is still substantially less than with combined oral contraceptives containing both estrogen and progestin. For women who are at an increased risk of thromboembolism and have multiple-risk factors for thrombosis (e.g., tobacco smoking woman age 35 and older, diabetes, hypercoagulopathy, severe hypertension, etc.), consider an intrauterine device (IUD) or other estrogen-free contraceptive if appropriate. During use of norethindrone or norethindrone acetate in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, myocardial infarction, cerebrovascular disorder such as stroke or focal headache with symptoms consistent with cerebral ischemia, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, norethindrone therapy should be discontinued immediately.  
Norethindrone should be prescribed cautiously in patients with asthma and nephrotic syndrome or other renal disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions.
Norethindrone and norethindrone acetate should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients. If a patient develops focal migraine with symptoms consistent with cerebral ischemia, or, severe headache that may be due to cerebrovascular disease, consider discontinuing the drug.
Patients receiving norethindrone may develop an ovarian cyst if follicular development occurs; atresia of the follicle is sometimes delayed and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally these enlarged follicles disappear spontaneously. Often they are asymptomatic; in some cases patients may experience mild abdominal pain. Rarely, they may twist or rupture, requiring surgical intervention.
The safety and efficacy of norethindrone has only been established in females of reproductive age. Safety and efficacy of hormonal birth control is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older. Use of hormonal contraceptive products in female children before menarche is not indicated.
The primary contraceptive effect of progestins involves the suppression of the midcycle surge of luteinizing hormone (LH). The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Additional mechanisms may be involved. Other actions of norethindrone include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus. The administration of norethindrone to women with adequate estrogen production transforms the uterus from a proliferative to a secretory phase. Norethindrone has minimal estrogenic, androgenic, and anabolic activity. When there is perfect adherence to proper oral dosing, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills.
Norethindrone is administered orally. Pharmacokinetic parameters for norethindrone are poorly understood. Norethindrone is moderately bound to plasma proteins. It is hepatically metabolized and eliminated in both the urine and the feces. The elimination half-life of norethindrone is about 10 hours.
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