Norethindrone - Drug Monograph

Introduction

Norethindrone (also known as norethisterone) is a first-generation synthetic progestin medication that has been widely used in clinical practice since the 1950s. As a progesterone receptor agonist, it is structurally derived from 19-nortestosterone and serves as a cornerstone in hormonal contraception and menstrual cycle regulation. Norethindrone is available in various formulations including oral tablets, combination oral contraceptives, and long-acting injectable preparations.

Mechanism of Action

Norethindrone exerts its pharmacological effects primarily through binding to intracellular progesterone receptors in target tissues. Its mechanisms include:

• Inhibition of gonadotropin secretion from the pituitary gland, preventing follicular maturation and ovulation
• Transformation of endometrial tissue to a decidualized state, making it less receptive to implantation
• Thickening of cervical mucus, creating a barrier to sperm penetration
• Competitive binding to androgen receptors with weak androgenic activity (approximately 1/50th the potency of methyltestosterone)

Indications

• Prevention of pregnancy (as progestin-only oral contraceptive)
• Treatment of amenorrhea and abnormal uterine bleeding due to hormonal imbalance
• Endometriosis management
• Management of secondary amenorrhea

• Luteal phase support in assisted reproductive technology
• Hormone replacement therapy in combination with estrogen
• Treatment of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD)
• Management of menstrual migraines

Dosage and Administration

• 0.35 mg orally once daily at the same time each day
• Initiation: First day of menstruation or immediately postpartum if not breastfeeding

• 2.5-10 mg orally daily for 5-10 days during the second half of menstrual cycle
• Withdrawal bleeding typically occurs 3-7 days after discontinuation

• 5 mg orally daily for 14 days, increasing by 2.5 mg daily every 2 weeks up to 15 mg daily
• Treatment duration typically 6-9 months

• Renal impairment: Use with caution; no specific dosage adjustment recommended
• Hepatic impairment: Contraindicated in severe impairment; use caution in mild-moderate impairment
• Geriatric patients: Not indicated in postmenopausal women
• Pediatrics: Safety and efficacy not established for most indications

Pharmacokinetics

Contraindications

• Known or suspected pregnancy
• Current or history of thromboembolic disorders
• Cerebrovascular disease
• Known or suspected hormone-dependent neoplasia
• Undiagnosed abnormal genital bleeding
• Severe hepatic impairment or disease
• Cholestatic jaundice with prior hormone use
• Benign or malignant liver tumors
• Hypersensitivity to norethindrone or any component

Warnings and Precautions

Drug Interactions

• Rifampin, carbamazepine, phenytoin, St. John's wort: May decrease norethindrone efficacy

• Ketoconazole, itraconazole, clarithromycin: May increase norethindrone levels

• Warfarin: May alter anticoagulant effect

• Insulin, oral hypoglycemics: May require dosage adjustment

• May increase thyroid-binding globulin, requiring thyroid hormone dosage adjustment

Adverse Effects

• Menstrual irregularities (breakthrough bleeding, amenorrhea)
• Headache
• Nausea
• Breast tenderness
• Weight changes
• Acne
• Mood changes

• Thromboembolic events (DVT, PE, stroke)
• Hepatic adenomas
• Gallbladder disease
• Hypertension
• Optic neuritis
• Anaphylactic reactions
• Ectopic pregnancy

Monitoring Parameters

• Pregnancy test
• Blood pressure
• Lipid profile
• Liver function tests
• Fasting blood glucose
• Personal and family medical history

• Blood pressure every 6-12 months
• Annual clinical breast exam
• Signs/symptoms of thromboembolism
• Menstrual pattern changes
• Mood changes
• Weight changes
• Visual disturbances

• Bone mineral density with prolonged use (>2 years)
• Regular breast cancer screening per guidelines
• Liver function if symptomatic

Patient Education

• Take at the same time daily for contraceptive efficacy
• Use backup contraception if dose is >3 hours late
• Report sudden severe headache, chest pain, leg pain, or visual changes immediately
• Understand that menstrual patterns may change significantly
• Notify healthcare provider if pregnancy is suspected
• Regular self-breast exams recommended
• Do not smoke while taking norethindrone
• Potential decreased efficacy with certain antibiotics and anticonvulsants
• May take with food to reduce nausea
• Store at room temperature away from moisture

• <3 hours late: Take immediately and next dose at regular time
• >3 hours late: Take as soon as remembered and use backup contraception for 48 hours

References

1. Curtis MG, Teal SJ. Progestin-Only Contraceptives: A Comprehensive Review. J Reprod Med. 2021;66(3-4):129-142. 2. FDA Prescribing Information: Norethindrone Tablets. Revised 2022. 3. Nelson AL. Progestin-Only Oral Contraceptives. In: Hatcher RA, et al., eds. Contraceptive Technology. 21st ed. 2018:173-188. 4. Kaunitz AM. Progestin-Only Contraception: Injectables and Implants. Best Pract Res Clin Obstet Gynaecol. 2020;66:67-77. 5. Stanczyk FZ, et al. Ethinyl estradiol and norethindrone pharmacokinetics with a multiphasic oral contraceptive: a randomized crossover study. Contraception. 2020;101(2):109-115. 6. Practice Bulletin No. 206: Use of Hormonal Contraception in Women with Coexisting Medical Conditions. Obstet Gynecol. 2019;133(2):e128-e150. 7. Lobo RA. Hormone therapy for postmenopausal women: a comprehensive review. Climacteric. 2020;23(2):115-124. 8. Tepper NK, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep. 2016;65(3):1-104.