Norethindrone (Monograph)

Brand name: Aygestin
Drug class: Progestins
ATC class: G03AC01
VA class: HS800
CAS number: 51-98-9

Introduction

Synthetic progestin.

Uses for Norethindrone

Amenorrhea

Treatment of secondary amenorrhea.

Endometriosis

Treatment of endometriosis.

Uterine Bleeding

Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology such as fibroids or uterine cancer.

Prevention of Endometrial Changes Associated with Estrogens

Not intended, recommended, or approved by FDA for the prevention of endometrial hyperplasia in postmenopausal women receiving estrogen replacement therapy.

Norethindrone Dosage and Administration

Administration

Oral Administration

Administer orally once daily.

Dosage

Available as norethindrone acetate; dosage expressed in terms of the salt.

Individualize dosage according to the condition being treated and the therapeutic response of the patient.

Adults

Amenorrhea or Uterine Bleeding

Oral

2.5–10 mg daily for 5–10 days.

To establish dosage cycle for the treatment of secondary amenorrhea or abnormal uterine bleeding, the menstrual cycle is usually considered to be 28 days. The first day of bleeding is counted as the first day of the cycle.

Begin norethindrone during the assumed latter half of the menstrual cycle to induce optimum secretory transformation of the endometrium that has been adequately primed with endogenous or exogenous estrogen.

Withdrawal bleeding usually occurs within 3–7 days after discontinuing therapy. Planned menstrual cycling may benefit patients with a history of recurrent episodes of uterine bleeding.

Endometriosis

Oral

Initially, 5 mg daily for 14 consecutive days. Increase dosage by 2.5 mg daily at 14-day intervals until a maximum dosage of 15 mg daily is reached. Continue to administer daily (no cyclic drug-free periods) for 6–9 months. Temporarily interrupt therapy for annoying breakthrough bleeding.

Prescribing Limits

Adults

Endometriosis

Oral

Maximum: 15 mg daily.

Cautions for Norethindrone

Contraindications

Known or suspected pregnancy. Not effective for any purpose during pregnancy.
Undiagnosed vaginal bleeding.
Known or suspected breast cancer; history of breast cancer.
Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.
Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI).
Liver disease or dysfunction.
Use as a pregnancy test.
Known hypersensitivity to norethindrone acetate or any ingredient in the formulation.

Warnings/Precautions

Warnings

Cardiovascular Disorders

Appropriately manage risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity) and/or venous thromboembolism (e.g., personal or family history of venous thromboembolism, obesity, systemic lupus erythematosus). (See Contraindications under Cautions.)

Ocular Effects

If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; migraine; or retinal vascular lesions occur, discontinue and initiate appropriate diagnostic and therapeutic measures. Do not reinitiate therapy if ocular examination reveals evidence of papilledema or retinal vascular lesions.

Fetal/Neonatal Morbidity and Mortality

Potential adverse effects on the fetus when administered within the first 4 months of pregnancy (masculinization of the female fetus, hypospadias in male neonates, low birth weight). (See Contraindications under Cautions.)

General Precautions

Fluid Retention

May cause some degree of fluid retention. Use with caution and careful monitoring in patients with conditions (e.g., asthma, seizure disorders, migraine headache, cardiac or renal impairment) that might be aggravated by fluid retention.

Bleeding Irregularities

Possible breakthrough or irregular vaginal bleeding. Perform adequate diagnostic tests in patients with undiagnosed vaginal bleeding.

Depression

Possible depression. Exercise caution in women with a history of depression; discontinue if severe depression recurs during use.

Physical Examination and Follow-up

Physical examination prior to initiation of therapy advised. Physical examination should include special attention to the breasts and pelvic organs and should include a Papanicolaou test (Pap smear) and relevant laboratory tests.

Metabolic Effects

Possible adverse effects on carbohydrate and lipid metabolism. Choice of progestin, dosage, and regimen may minimize metabolic adverse effects; further study needed to clarify this issue. Monitor patients with hyperlipidemia or diabetes mellitus carefully.

Estrogen Therapy

When used in combination with an estrogen, consider the cautions, precautions, and contraindications associated with estrogens.

Specific Populations

Pregnancy

Category X. (See Contraindications and also Fetal/Neonatal Morbidity and Mortality, under Cautions.)

Lactation

Progestins are distributed into milk; caution advised.

Pediatric Use

Safety and efficacy not established.

Hepatic Impairment

Contraindicated in patients with liver disease or dysfunction.

Common Adverse Effects

Menstrual abnormalities (amenorrhea; frequent, irregular, prolonged, or infrequent bleeding), nausea, weight changes, breast changes (tenderness, enlargement, secretion), headache.

Drug Interactions

Changes in the pharmacokinetics of norethindrone reported with some HIV protease inhibitors.

Norethindrone Pharmacokinetics

Absorption

Bioavailability

Rapidly deacetylated to norethindrone. Peak plasma concentration of norethindrone achieved in 2 hours.

Distribution

Extent

Distributed into human milk.

Plasma Protein Binding

61% to albumin and 36% to sex hormone binding globulin (SHBG).

Elimination

Metabolism

Metabolized by reduction, followed by glucuronide and sulfate conjugation.

Elimination Route

Excreted in urine and feces, mainly as metabolites.

Half-life

Single dose: 8.51 hours.

Stability

Storage

Oral

Tablets

20–25°C.

Actions

Some estrogenic, androgenic, and anabolic activity.
Transforms a proliferative endometrium into a secretory one.
Inhibits the secretion of pituitary gonadotropins at usual dosages, thereby preventing follicular maturation and ovulation.

Advice to Patients

Importance of reading the manufacturer’s patient information.
Importance of advising patients of anticipated menstrual effects.
Importance of discontinuing therapy and contacting clinician if sudden partial or complete vision loss, blurred vision, bulging of the eyes, double vision, or migraine occurs.
Importance of discontinuing therapy and contacting clinician if any symptoms of thromboembolic and thrombotic disorders occur.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name