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Uses

Norethindrone acetate is used for the treatment of secondary amenorrhea and for the treatment of abnormal uterine bleeding caused by hormonal imbalance in patients without underlying organic pathology such as fibroids or uterine cancer. The drug also is used for the treatment of endometriosis.

For the use of low-dose norethindrone as a progestin-only oral contraceptive, . For the use of norethindrone or norethindrone acetate in combination with estrogens as an oral contraceptive,

Dosage and Administration

Administration

Norethindrone acetate is administered orally.

Dosage

Amenorrhea and Uterine Bleeding

In establishing the dosage cycle for the treatment of secondary amenorrhea or abnormal uterine bleeding, the menstrual cycle is considered to be 28 days. The first day of bleeding is counted as the first day of the cycle. For the treatment of secondary amenorrhea or abnormal uterine bleeding, the usual oral dosage of norethindrone acetate is 2.5-10 mg daily for 5-10 days, beginning during the assumed latter half of the menstrual cycle to produce an optimum secretory transformation of an endometrium that has been adequately primed with endogenous or exogenous estrogen. Progestin-induced withdrawal bleeding usually occurs within 3-7 days after discontinuing therapy with the drug. Patients with a history of recurrent episodes of uterine bleeding may benefit from planned cycling with the drug.

Endometriosis

For the treatment of endometriosis, the usual initial oral dosage of norethindrone acetate is 5 mg daily for 14 consecutive days. Norethindrone acetate therapy may be increased by 2.5 mg daily at 14-day intervals until a maximum dosage of 15 mg daily is reached. Daily therapy may then be continued consecutively (no cyclic drug-free periods) for 6-9 months; if annoying breakthrough bleeding occurs, therapy should be temporarily discontinued.

Cautions

Adverse Effects

Norethindrone, like other progestins, may cause breakthrough bleeding, spotting, changes in menstrual flow, amenorrhea, changes in cervical erosion and secretions, edema, weight gain or loss, cholestatic jaundice, allergic rash with or without pruritus, melasma or chloasma, and mental depression.

An association between thrombophlebitis, pulmonary embolism, and cerebral thrombosis and embolism and use of estrogen-progestin combination preparations has been shown. The possibility that thromboembolic disorders may occur in patients receiving norethindrone should be considered and patients should be carefully observed for these effects during therapy with the drug. Although available evidence suggests that an association exists between neuro-ocular lesions such as optic neuritis or retinal thrombosis and use of estrogen-progestin combination preparations, such a relationship has been neither confirmed nor refuted. Increased blood pressure in susceptible individuals, premenstrual-like syndrome, changes in libido or appetite, cystitis-like syndrome, headache, nervousness, dizziness, fatigue, backache, hirsutism, loss of scalp hair, erythema multiforme or nodosum, hemorrhagic skin eruption, and itching have occurred in patients receiving estrogen-progestin combination preparations. Use of estrogen-progestin combinations has also been associated with increased levels of coagulation factors VII, VIII, IX, and X. The possibility that these effects may occur in patients receiving norethindrone should be considered and patients should be carefully observed for these effects during therapy with the drug.

Precautions and Contraindications

Norethindrone shares the toxic potentials of progestins, and the usual precautions of progestin therapy should be observed. Because oral contraceptive combinations contain progestins, the precautions associated with oral contraceptives should generally be considered in patients receiving progestins. Prior to initiation of therapy with norethindrone in women, a physical examination should be performed, including special attention to the breasts and pelvic organs and a Papanicolaou test (Pap smear). Women receiving norethindrone should be given a copy of the patient labeling for the drug.

Norethindrone should be used with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention (e.g., asthma, seizure disorders, migraine, or cardiac or renal dysfunction). The drug should also be used with caution in patients with a history of mental depression; norethindrone should be discontinued if depression recurs to a serious degree during therapy with the drug.

When breakthrough bleeding or irregular vaginal bleeding occurs during norethindrone therapy, nonfunctional causes should be considered. Adequate diagnostic procedures should be performed in patients with undiagnosed vaginal bleeding.

The manufacturers caution that the effect of long-term norethindrone therapy on pituitary, ovarian, adrenal, hepatic, or uterine function has not been determined. Diabetic patients should be carefully monitored during norethindrone therapy, since decreased glucose tolerance has been observed in women receiving estrogen-progestin combinations. Norethindrone may mask the onset of climacteric in women.

The clinician and the patient using norethindrone should be alert to the earliest signs and symptoms of thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis). The drug should be discontinued immediately when any of these disorders occurs or is suspected.

If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; retinal vascular lesions; or migraine occur during therapy with norethindrone, the drug should be discontinued and appropriate diagnostic and therapeutic measures instituted. Because steroidal hormones are metabolized in the liver, norethindrone should be used with caution in patients with impaired liver function.

Norethindrone is contraindicated in patients with thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a history of these conditions. The drug is also contraindicated in patients with undiagnosed vaginal bleeding, missed abortion, known sensitivity to the drug or any ingredient in the formulation, markedly impaired liver function or liver disease, or carcinoma of the breast or for use as a pregnancy test.

Mutagenicity and Carcinogenicity

The carcinogenic and mutagenic potentials of norethindrone have not been specifically determined.

Administration of medroxyprogesterone to beagles has been associated with the development of mammary nodules, some of which were malignant. Although nodules occasionally occurred in control beagles, they were intermittent in nature; nodules in drug-treated beagles were larger, more numerous, persistent, and occasionally malignant with metastases. The clinical relevance of these findings to humans has not been established. For additional information on the carcinogenic potential of progestins,

Pregnancy and Lactation

Pregnancy

Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion or to treat threatened abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses; however, there is evidence of potential adverse effects on the fetus when these drugs are administered during the first 4 months of pregnancy. In addition, in most women, the cause of abortion is a defective ovum, which progestins could not be expected to influence. Because of their uterine-relaxant effects, progestins may delay spontaneous abortion of fertilized defective ova. Masculinization of the female fetus has reportedly occurred when progestins were used during pregnancy. Clitoral hypertrophy and fusion of the labia have been reported in a few female neonates born to women who had received medroxyprogesterone during pregnancy; hypospadias in male neonates born to women receiving progestational agents occurs at approximately twice the rate of occurrence in male neonates born to women not receiving the drugs. An association between intrauterine exposure to female sex hormones and congenital anomalies, including cardiovascular and limb defects, has been suggested. Use of progestins, including norethindrone, is not recommended during the first 4 months of pregnancy. If a woman becomes pregnant while receiving norethindrone or is inadvertently exposed to the drug during the first 4 months of pregnancy, she should be advised of the potential risks to the fetus.

Norethindrone should not be used to induce withdrawal bleeding as a test for pregnancy.

Lactation

Progestins are reportedly distributed into milk. The manufacturers warn that the possible effects of progestins in milk on nursing infants have not been determined.