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.[48333] [30960] [57588]

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.[48333] [30960] [57588]

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.[48333] [30960] [57588]

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.[24588] [24654] The risk is even greater in women with genetic predisposition or family history for venous thromboembolic disease.[24655] 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.[48333] [30960] [57588]

Anaphylactic shock/anaphylactoid reactions have been reported with norethindrone. Rash (unspecified), pruritus, melasma, and urticaria have also been reported.[48333]  [30960] [57588]

Like all hormonal contraceptives, norethindrone use does not protect against the transmission of human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.

In general, experts consider progestin-only contraceptives to be acceptable for use in most patients with liver disease.[48201] [70437] Norethindrone contraceptive use is considered contraindicated in those with acute hepatic disease or in patients with benign or malignant liver tumors (hepatocellular cancer). Advise patients to get medical help right away if they develop yellowing of the skin or eyes, especially with fever, tiredness, loss of appetite or dark-colored urine. Discontinue norgestrel if jaundice or acute disturbances of liver function develop. Do not resume use until markers of liver function return to normal and norgestrel causation has been excluded.[57588]

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.[23505]

Norethindrone is absolutely contraindicated for use during pregnancy or suspected pregnancy.[57588] [48333] There is no known indication for hormone replacement therapy with norethindrone during pregnancy.[48333] 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.[48333] [57588] 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.[57588]

Caution should be exercised when using norethindrone acetate for hormone replacement or other hormonal treatment in lactating women.[48333] 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.[57588] [48335] [48201] 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.[57588] [48333] 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.[48201]

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.[57588] [30960] 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.[48333] 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 is still substantially less than with combined hormonal 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.[48201] 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.[30960] [57588] [48333]

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 migraine. Progestins may exacerbate these conditions in some patients. Discontinue medication pending examination if there are focal neurologic signs or symptoms, such as a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. If a headache or a worsening migraine headache with a new pattern that is recurrent, persistent, or severe occurs, or if there are symptoms suggesting focal neurologic effects (e.g., diplopia, partial or complete vision loss, proptosis), this requires discontinuation of the hormone and medical evaluation of the cause.[57588] [30960] [48333]

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.[57588]

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.