Version October 2024
Note: Norethindrone (NET) is used for progestin-only contraception. Norethindrone acetate (NETA) is a prodrug of NET used in treatment of abnormal uterine bleeding, amenorrhea, and endometriosis. NET and NETA have different dosing, warnings, and precautions; confirm appropriate formulation before prescribing. International considerations: Different preparations (with different dosing and indications) are available outside of the United States.
Abnormal uterine bleeding, acute (off-label use):
Note: Hemodynamically unstable patients should generally be managed with surgical interventions (Ref). Typically used for hemodynamically stable patients with anovulatory bleeding and a thickened endometrium (Ref).
Oral: Norethindrone acetate (NETA): 5 to 10 mg 1 to 4 times a day for 5 to 10 days (Ref). Note: Transition to maintenance dosing after resolution of acute bleeding (refer to dosing for “Abnormal uterine bleeding, nonacute”) or to another type of progestin (eg, levonorgestrel IUD) (Ref).
Abnormal uterine bleeding, nonacute (alternative agent): Note: Dosing not intended for management of acute abnormal bleeding (ie, excessively heavy or prolonged bleeding that requires urgent evaluation). Alternative for patients who cannot or choose not to use preferred agents (eg, estrogen-progestin contraceptives, levonorgestrel IUD) (Ref).
Oral: Norethindrone acetate (NETA): 5 to 15 mg per day in 1 to 3 divided doses; adjust dose at 1- to 3-month intervals within this range to the lowest effective dose to control bleeding and minimize adverse reactions (Ref). Note: Continuous therapy is preferred in most patients due to increased efficacy and patient adherence; however, for patients who do not desire contraception, cyclic therapy (eg, administration only on days 5 to 26 of the menstrual cycle) may be preferred (Ref).
Contraception: Oral: Norethindrone (NET): 0.35 mg once daily in the order presented in the blister pack (no missed days).
Initial dose: Start on first day of menstrual period or the day after a miscarriage or abortion. If switching from a combined oral contraceptive, begin the day after finishing the last active combined tablet.
Missed dose: Take as soon as remembered. A back up method of contraception should be used for 48 hours if dose is taken ≥3 hours late.
Additional contraception dosing considerations (Ref):
Initiation of therapy: May be started at any time in the menstrual cycle once it is determined that the patient is not pregnant. Back-up contraception is not needed if started within 5 days of onset of menstruation. If started >5 days after the onset of menstruation or at any time in a patient experiencing amenorrhea (not postpartum), back up contraception should be used for 2 days.
Switching from a different contraceptive to a progestin-only contraceptive: May be started at any time if it is determined that the patient is not pregnant. Unless the patient abstains from sexual intercourse, a backup method of contraception is needed if it has been >5 days since menstrual bleeding has begun. When an additional method of contraception is needed, consider continuing the patient's previous method for 2 days after starting the progestin-only contraceptive.
Switching from an IUD to a progestin-only contraceptive: Continue the IUD for at least 2 days after the progestin-only contraceptive is started or advise the patient to abstain from sexual intercourse or use a barrier contraceptive for 7 days before removing the IUD. Alternately, an emergency contraceptive may be used at the time of IUD removal.
Endometriosis: Oral: Norethindrone acetate (NETA): 5 mg/day for 14 days; increase at increments of 2.5 mg/day every 2 weeks to reach 15 mg/day; continue for 6 to 9 months or until breakthrough bleeding demands temporary termination.
Estrogen therapy-associated endometrial hyperplasia, prevention (alternative agent):
Note: Indicated in patients with a uterus receiving estrogen therapy (eg, for secondary amenorrhea) (Ref). Discontinue when estrogen therapy is discontinued.
Oral: Norethindrone acetate (NETA): 5 to 10 mg/day for 10 to 14 days (Ref).
Secondary amenorrhea, diagnostic aid ("progestin challenge") (alternative agent): Oral: Norethindrone acetate (NETA): 5 mg daily for 5 to 10 days (Ref). Note: Withdrawal bleeding may be expected during therapy or within 3 to 7 days after cessation of therapy; absence of withdrawal bleeding suggests low endometrial estrogen exposure and/or uterine or outflow tract abnormality (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling. However, use is contraindicated in patients with hepatic tumors or impairment.
(For additional information see "Norethindrone: Pediatric drug information")
Abnormal uterine bleeding and amenorrhea (secondary): Postmenarche females: Limited data in postmenarche children: Norethindrone acetate: Oral: 2.5 to 10 mg once daily for 5 to 12 days each month; most pediatric experts suggest 5 mg once daily for 12 days per month (Ref). Secretory transformation of the endometrium will occur when adequately primed with endogenous or exogenous estrogen. Withdrawal bleeding may be expected within 3 to 7 days after discontinuing norethindrone acetate.
Contraception: Postmenarche adolescent females: Norethindrone: Oral: 0.35 mg once daily every day (no missed days)
Initial dose: Start on first day of menstrual period or the day after a miscarriage or abortion. If switching from a combined oral contraceptive, begin the day after finishing the last active combined tablet.
Missed dose: Take as soon as remembered. A back-up method of contraception should be used for 48 hours if dose is taken ≥3 hours late.
Additional contraception dosing considerations (Ref):
Initiation of therapy: May be started at any time in the menstrual cycle once it is determined that the female is not pregnant. Back-up contraception is not needed if started within 5 days of onset of menstruation. If started >5 days after the onset of menstruation or at any time in a female experiencing amenorrhea (not postpartum), back up contraception should be used for 2 days.
Switching from a different contraceptive to a progestin-only contraceptive: May be started at any time if it is determined that the female is not pregnant. Unless the female abstains from sexual intercourse, a back-up method of contraception is needed if it has been >5 days since menstrual bleeding has begun. When an additional method of contraception is needed, consider continuing the woman’s previous method for 2 days after starting the progestin-only contraceptive.
Switching from an IUD to a progestin-only contraceptive: Continue the IUD for at least 2 days after the progestin-only contraceptive is started or advise the female to abstain from sexual intercourse or use a barrier contraceptive for 7 days before removing the IUD. Alternately, an emergency contraceptive may be used at the time of IUD removal.
Endometriosis: Postmenarche females ≥10 years: Limited data in children 10 to 12 years (Ref): Norethindrone acetate: Oral: 5 mg once daily for 14 days; increase at increments of 2.5 mg/day every 2 weeks to reach target maintenance of 15 mg/day; continue for 6 to 9 months or until breakthrough bleeding demands temporary termination
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling; however, use is contraindicated in patients with hepatic tumors or impairment.
Norethindrone may cause menstrual bleeding irregularities (change in menstrual flow), including shortened or prolonged menstrual cycles, amenorrhea, and/or spotting (Ref). Menstrual bleeding irregularities are the most common reason for drug discontinuation (Ref). Menstrual bleeding irregularities may be experienced by up to 50% of users with 10% experiencing amenorrhea (Ref). Consistent medication administration minimizes changes in bleeding patterns, as variances of 2 to 3 hours in administration may cause menstrual bleeding irregularities (Ref).
Mechanism: Dose-related; short half-life and weak suppression of the hypothalamic-pituitary-ovarian axis (Ref).
Onset: Varied; menstrual bleeding irregularities are most likely experienced in the first 3 months of therapy. However, daily variations in dose administration may be a continued source of irregular patterns (Ref). One missed dose may cause withdrawal bleeding in 24 to 72 hours (Ref).
Risk factors:
• Inconsistent time of drug administration (Ref)
The following adverse drug reactions are derived from product labeling unless otherwise specified. Reactions listed are based on reports for other agents in this same pharmacologic class and may not be specifically reported for norethindrone.
Frequency not defined.
Cardiovascular: Deep vein thrombosis, edema, pulmonary embolism
Dermatologic: Acne vulgaris, alopecia, chloasma, pruritus, skin rash, urticaria
Endocrine & metabolic: Decreased HDL cholesterol, heavy menstrual bleeding, hirsutism, spotting, weight gain, weight loss
Gastrointestinal: Abdominal pain, nausea, vomiting
Genitourinary: Breakthrough bleeding, breast hypertrophy, breast tenderness, cervical erosion, change in cervical secretions, genital discharge, infrequent uterine bleeding, lactation insufficiency, mastalgia, vaginal hemorrhage
Hepatic: Abnormal hepatic function tests, cholestatic jaundice, hepatitis
Hypersensitivity: Anaphylaxis, hypersensitivity reaction, nonimmune anaphylaxis
Nervous system: Cerebral artery embolism, cerebral thrombosis, depression, dizziness, emotional lability, fatigue, headache, insomnia, migraine, nervousness
Neuromuscular & skeletal: Limb pain
Ophthalmic: Optic neuritis (with or without vision loss), retinal thrombosis
Postmarketing: Endocrine & metabolic: Amenorrhea (Santos 2014), change in menstrual flow (Santos 2014)
Hypersensitivity to norethindrone or any component of the formulation; breast cancer (known, suspected, or history of); undiagnosed abnormal genital bleeding; pregnancy.
Norethindrone (NET): Additional contraindications: Benign or malignant liver tumors; acute liver disease.
Norethindrone acetate (NETA):
Additional contraindications: Deep vein thrombosis or pulmonary embolism (current or history of); active or recent history of arterial thromboembolic disease (eg, stroke, myocardial infarction); hepatic impairment or disease; as a diagnostic test for pregnancy.
Additional contraindications in Canadian labeling: Estrogen or progestin dependent malignant tumor; partial or complete vision loss due to ophthalmic vascular disease; missed abortion.
Concerns related to adverse effects:
• Delayed follicular atresia/ovarian cysts: If follicular development occurs following use for contraception, follicles may grow and enlarge beyond the size attained in a normal cycle. May be asymptomatic or can be associated with mild abdominal pain; surgical intervention is rarely required.
• Ectopic pregnancy: The possibility of ectopic pregnancy following use of a progestin-only contraceptive should be considered in patients with lower abdominal pain.
• Hepatic adenomas or carcinomas: Use of combination hormonal contraceptives is associated with hepatic adenomas (rare); rupture may cause fatal intra-abdominal hemorrhage. Long-term use may be associated with an increased risk of hepatocellular carcinoma (rare). Data are insufficient to determine if progestin-only contraceptives also increase this risk.
• Lipid effects: May have adverse effects on lipid metabolism; use caution in patients with hyperlipidemias.
• Visual abnormalities: Norethindrone acetate (NETA): Discontinue if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
Disease-related concerns:
• Breast cancer: In patients at risk for breast cancer due to family history or susceptibility genes (BRCA1, BRCA2), it is unclear if combination hormonal contraceptives increase the risk for breast cancer and there are insufficient data specific to progestin-only contraceptives. However, breast cancer is a hormonal-sensitive tumor and the prognosis for patients with a current or recent history of breast cancer may be worse with hormonal contraceptive use (CDC [Curtis 2016b]; SGO/ASRM [Chen 2019]).
• Cardiovascular disease: Norethindrone acetate (NETA): Risk factors for cardiovascular disorders include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Manage risk factors appropriately.
• Depression: Norethindrone acetate (NETA): Use with caution in patients with depression. Progestin-only contraceptive tablets may be used in patients with depression (CDC [Curtis 2016b]).
• Diabetes: May have adverse effects on glucose tolerance; use caution in patients with diabetes. Progestin-only contraceptive tablets may be used in patients with diabetes (CDC [Curtis 2016b]).
• Diseases exacerbated by fluid retention: Norethindrone acetate (NETA): Use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, epilepsy, or cardiac or renal dysfunction.
• Migraine: Use with caution in patients with a history of migraine. Progestin-only contraceptive tablets may be used in patients with a history of headache or migraine; new headaches or changes in headaches should be evaluated (CDC [Curtis 2016b]).
Special populations:
• Smoking: Progestin-only contraceptives may be used in patients who smoke (CDC [Curtis 2016b]). Because of an increased risk of cardiovascular disease, patients using oral contraceptives should be strongly advised not to smoke.
Other warnings/precautions:
• Appropriate use: Norethindrone (NET): Progestin-only contraceptives contain less progestogen than contained in estrogen/progestogen–combined contraceptives. Risks associated with estrogen/progestogen contraceptives should be considered for progestin-only products.
• HIV infection protection: Progestin-only contraceptives do not protect against HIV infection or other sexually transmitted diseases.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Camila: 0.35 mg [contains corn starch, fd&c red #40(allura red ac)aluminum lake]
Deblitane: 0.35 mg [contains fd&c blue #2 (indigo carm) aluminum lake, fd&c red #40(allura red ac)aluminum lake, quinoline (d&c yellow #10) aluminum lake, soybean lecithin]
Emzahh: 0.35 mg [contains corn starch, quinoline (d&c yellow #10) aluminum lake]
Errin: 0.35 mg [contains corn starch, quinoline (d&c yellow #10) aluminum lake]
Heather: 0.35 mg [contains fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]
Incassia: 0.35 mg [contains corn starch, fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]
Jencycla: 0.35 mg [contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]
Lyleq: 0.35 mg [contains corn starch, fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]
Lyza: 0.35 mg [contains corn starch, quinoline yellow (d&c yellow #10)]
Nora-BE: 0.35 mg
Norlyda: 0.35 mg [DSC]
Norlyroc: 0.35 mg
Ortho Micronor: 0.35 mg [DSC] [contains corn starch, quinoline (d&c yellow #10) aluminum lake]
Sharobel: 0.35 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c yellow #6(sunset yellow)alumin lake, soybean lecithin]
Tulana: 0.35 mg [DSC] [contains corn starch, fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]
Generic: 0.35 mg
Tablet, Oral, as acetate:
Aygestin: 5 mg [DSC] [scored]
Generic: 5 mg
Yes
Tablets (Camila Oral)
0.35 mg (per each): $1.32
Tablets (Deblitane Oral)
0.35 mg (per each): $1.32
Tablets (Emzahh Oral)
0.35 mg (per each): $0.44
Tablets (Errin Oral)
0.35 mg (per each): $1.32
Tablets (Heather Oral)
0.35 mg (per each): $1.32
Tablets (Incassia Oral)
0.35 mg (per each): $1.32
Tablets (Jencycla Oral)
0.35 mg (per each): $1.32
Tablets (Lyleq Oral)
0.35 mg (per each): $1.32
Tablets (Lyza Oral)
0.35 mg (per each): $1.32
Tablets (Nora-BE Oral)
0.35 mg (per each): $1.32
Tablets (Norethindrone Acetate Oral)
5 mg (per each): $2.65
Tablets (Norethindrone Oral)
0.35 mg (per each): $1.32
Tablets (Norlyroc Oral)
0.35 mg (per each): $3.96
Tablets (Sharobel Oral)
0.35 mg (per each): $1.32
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Jencycla: 0.35 mg [contains fd&c blue #1 (brill blue) aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Maeve: 0.35 mg [contains corn starch, quinoline yellow (d&c yellow #10)]
Micronor: 0.35 mg [DSC] [contains quinoline yellow (d&c yellow #10)]
Movisse: 0.35 mg [contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]
Tablet, Oral, as acetate:
Norlutate: 5 mg [contains corn starch, quinoline yellow (d&c yellow #10)]
Ora l: For oral administration. Administer at the same time each day.
When used for the prevention of pregnancy, a backup method of contraception should be used for 48 hours if dose is missed or taken ≥3 hours late. If vomiting or severe diarrhea occur within 3 hours of taking a dose, take another dose as soon as possible, then continue taking one dose daily and use a backup method of contraception (or avoid sexual intercourse) until 2 days after vomiting or diarrhea have resolved. Emergency contraception should be considered in the event of unprotected intercourse (Ref).
Oral: Administer at the same time each day
When used for the prevention of pregnancy, a back-up method of contraception should be used for 48 hours if dose is missed or taken ≥3 hours late. If vomiting or severe diarrhea occur within 3 hours of taking a dose, take another dose as soon as possible, then continue taking one dose daily and use a backup method of contraception (or avoid sexual intercourse) until 2 days after vomiting or diarrhea have resolved. Emergency contraception should be considered in the event of unprotected intercourse (Ref).
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Abnormal uterine bleeding, nonacute (norethindrone acetate [NETA]): Treatment of nonacute abnormal uterine bleeding due to hormonal imbalance in absence of organic pathology, such as submucous fibroids or uterine cancer.
Contraception (norethindrone [NET]): For the prevention of pregnancy.
Limitations of use: For use in patients who may become pregnant; not for use prior to menarche or post menopause. Norethindrone (NET) is not indicated for emergency contraception.
Endometriosis (norethindrone acetate [NETA]): Treatment of endometriosis.
Estrogen therapy-associated endometrial hyperplasia, prevention: Prevention of endometrial hyperplasia in patients with a uterus receiving estrogen therapy for secondary amenorrhea.
Limitations of use: Norethindrone acetate (NETA) is not indicated for prevention of estrogen therapy-associated endometrial hyperplasia in patients who are postmenopausal.
Secondary amenorrhea, diagnostic aid ("progestin challenge") (norethindrone acetate [NETA]): For use as a diagnostic aid to determine endometrial estrogen exposure and/or uterine or outflow tract abnormality.
Abnormal uterine bleeding, acute; Menstrual suppression
Micronor may be confused with miconazole, Micronase
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (contraindicated in pregnancy) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).
Norethindrone (NET) and norethindrone acetate (NETA) may both be available as 5 mg tablets outside of the United States; these products are not equivalent and have different dosing and indications; confirm appropriate formulation before prescribing.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Adalimumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Aprepitant: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration with aprepitant, and to continue back-up contraception for 28 days after discontinuing aprepitant to ensure contraceptive reliability. Risk D: Consider therapy modification
Asparaginase Products: Hormonal Contraceptives may enhance the thrombogenic effect of Asparaginase Products. Management: Consider discontinuing hormonal contraceptives and using an alternative contraceptive method in patients treated with asparaginase products. Risk D: Consider therapy modification
Atazanavir: May decrease the serum concentration of Hormonal Contraceptives. Specifically, atazanavir/ritonavir may decrease concentrations of estrogens. Atazanavir may increase the serum concentration of Hormonal Contraceptives. Specifically, atazanavir alone may increase concentrations of estrogens and atazanavir alone or boosted may increase concentrations of progestins. Management: Dose adjustment of hormonal contraceptives or use of alternative or additional nonhormonal contraceptive may be needed when combined with atazanavir. See full interact monograph for details. Atazanavir/cobicistat with drospirenone is contraindicated. Risk D: Consider therapy modification
Bimekizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Brigatinib: May decrease the serum concentration of Hormonal Contraceptives. Management: Use a non-hormonal contraceptive during brigatinib use and for at least 4 months after the last brigatinib dose. Males with partners of reproductive potential should use contraception during treatment with brigatinib and for 3 months after brigatinib use. Risk D: Consider therapy modification
Carfilzomib: Hormonal Contraceptives may enhance the thrombogenic effect of Carfilzomib. Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib, especially patients using carfilzomib in combination with dexamethasone, lenalidomide plus dexamethasone, or daratumumab plus dexamethasone. Risk D: Consider therapy modification
Chlorprothixene: Progestins may enhance the adverse/toxic effect of Chlorprothixene. Progestins may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Cobicistat: May decrease the serum concentration of Hormonal Contraceptives. Specifically, cobicistat may decrease serum concentrations of estrogens. Cobicistat may increase the serum concentration of Hormonal Contraceptives. Specifically, cobicistat may increase serum concentrations of progestins. Management: Use alternative or additional nonhormonal forms of contraception when estrogen-containing hormonal contraceptives are combined with cobicistat. Progestin-only contraceptives can be used without back up, but monitor for progestin toxicities. Risk D: Consider therapy modification
Colchicine: May enhance the adverse/toxic effect of Hormonal Contraceptives. Risk C: Monitor therapy
Colesevelam: May decrease the serum concentration of Norethindrone. Management: Oral contraceptives containing ethinyl estradiol and norethindrone should be administered at least 4 hours before colesevelam. Risk D: Consider therapy modification
CycloSPORINE (Systemic): Norethindrone may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a strong CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
CYP3A4 Inducers (Weak): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Hormonal Contraceptives. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Efavirenz: May decrease the serum concentration of Hormonal Contraceptives. Management: Use a back-up method during coadministration, and to continue back-up contraception for 12 weeks after stopping efavirenz to ensure contraceptive reliability. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Risk D: Consider therapy modification
Elagolix: Hormonal Contraceptives may diminish the therapeutic effect of Elagolix. Specifically, estrogen-containing hormonal contraceptives may diminish the therapeutic effects of elagolix. Elagolix may decrease the serum concentration of Hormonal Contraceptives. Specifically, concentrations of progestins may be decreased with elagolix therapy. Elagolix may increase the serum concentration of Hormonal Contraceptives. Specifically, concentrations of ethinyl estradiol may be increased with elagolix therapy. Management: Use an alternative, nonhormonal contraceptive during treatment with elagolix and for at least 28 days following discontinuation of elagolix treatment. Use of elagolix 200 mg twice daily with an estrogen-containing hormonal contraceptive is not recommended Risk D: Consider therapy modification
Elexacaftor, Tezacaftor, and Ivacaftor: Hormonal Contraceptives may enhance the adverse/toxic effect of Elexacaftor, Tezacaftor, and Ivacaftor. Specifically, the risk for rash may be increased. Risk C: Monitor therapy
Encorafenib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
Etravirine: May decrease the serum concentration of Hormonal Contraceptives. Specifically, progestin concentrations may decrease. Etravirine may increase the serum concentration of Hormonal Contraceptives. Specifically, estrogen concentrations may increase. Risk C: Monitor therapy
Exenatide: Hormonal Contraceptives may diminish the therapeutic effect of Exenatide. Exenatide may decrease the serum concentration of Hormonal Contraceptives. Management: Administer oral hormonal contraceptives at least one hour prior to exenatide. Monitor blood glucose more frequently when patients treated with exenatide initiate therapy with a hormonal contraceptive. Increases in exenatide doses may be needed. Risk D: Consider therapy modification
Felbamate: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing felbamate to ensure contraceptive reliability. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flibanserin: Hormonal Contraceptives may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Fosaprepitant: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration with fosaprepitant, and to continue back-up contraception for 28 days after discontinuing fosaprepitant to ensure contraceptive reliability. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification
Griseofulvin: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing griseofulvin to ensure contraceptive reliability. Risk D: Consider therapy modification
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Ivosidenib: May decrease the serum concentration of Hormonal Contraceptives. Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib. Risk D: Consider therapy modification
Ixazomib: May decrease the serum concentration of Hormonal Contraceptives. More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of hormonal contraceptives. Management: Patients of reproductive potential should use a non-hormonal contraceptive method during treatment with ixazomib and for at least 90 days after the last ixazomib dose. Risk D: Consider therapy modification
Lixisenatide: Hormonal Contraceptives may diminish the therapeutic effect of Lixisenatide. Lixisenatide may decrease the serum concentration of Hormonal Contraceptives. Management: Administer oral hormonal contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Additionally, monitor blood glucose more frequently when patients treated with lixisenatide initiate therapy with a hormonal contraceptive. Risk D: Consider therapy modification
Mavacamten: May decrease the serum concentration of Hormonal Contraceptives. Management: Use with ethinyl estradiol/norethindrone is permitted. With other hormonal contraceptives, use a back-up method (eg, condoms) during coadministration, and to continue back-up contraception for 4 months after stopping mavacamten. Risk D: Consider therapy modification
MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification
MiFEPRIStone: May diminish the therapeutic effect of Hormonal Contraceptives. Management: Nonhormonal contraception should be used during, and for 4 weeks following, mifepristone treatment for hyperglycemia due to Cushing syndrome. If used for pregnancy termination, hormonal contraceptives can be used after pregnancy expulsion is confirmed. Risk D: Consider therapy modification
Mitotane: May decrease the serum concentration of Hormonal Contraceptives. Management: Effective nonhormonal contraception is recommended for those of reproductive potential during treatment with mitotane as well as after discontinuation of mitotane for as long as mitotane plasma levels are detectable. Risk X: Avoid combination
Mobocertinib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
Mycophenolate: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients of childbearing potential who are taking hormonal contraceptives should use an additional form of barrier contraception during treatment with mycophenolate and for 6 weeks after mycophenolate discontinuation. Risk D: Consider therapy modification
Nirmatrelvir and Ritonavir: May decrease the serum concentration of Hormonal Contraceptives. Specifically, nirmatrelvir and ritonavir may decrease concentrations of estrogens. Nirmatrelvir and Ritonavir may increase the serum concentration of Hormonal Contraceptives. Specifically, nirmatrelvir and ritonavir may increase concentrations of progestins. Management: Use additional nonhormonal forms of contraception (back-up method) when estrogen-containing hormonal contraceptives are combined with nirmatrelvir/ritonavir. Progestin-only contraceptives can be used without back-up, but monitor for progestin toxicities. Risk D: Consider therapy modification
Octreotide: May decrease the serum concentration of Hormonal Contraceptives. Management: Women should use an alternative non-hormonal method of contraception or a back-up method when octreotide is combined with hormonal contraceptives. Risk D: Consider therapy modification
Olutasidenib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Avoid use of olutasidenib with sensitive or narrow therapeutic index CYP3A4 substrates when possible. If concurrent use with olutasidenib is unavoidable, monitor closely for evidence of decreased concentrations of the CYP3A4 substrates. Risk D: Consider therapy modification
Omaveloxolone: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
OXcarbazepine: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing oxcarbazepine to ensure contraceptive reliability. Risk D: Consider therapy modification
Perampanel: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients should use an alternative, nonhormonal-based form of contraception during the concurrent use of perampanel and for 1 month after discontinuing perampanel. Risk D: Consider therapy modification
Pexidartinib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
Pitolisant: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuation of pitolisant treatment. Risk D: Consider therapy modification
Protease Inhibitors: May decrease the serum concentration of Hormonal Contraceptives. Specifically, protease inhibitors may decrease concentrations of estrogens. Protease Inhibitors may increase the serum concentration of Hormonal Contraceptives. Specifically, protease inhibitors may increase concentrations of progestins. Management: Use alternative or additional nonhormonal forms of contraception when estrogen-containing hormonal contraceptives are combined with protease inhibitors. Progestin-only contraceptives can be used without back up, but monitor for progestin toxicities. Risk D: Consider therapy modification
Repotrectinib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
Retinoic Acid Derivatives: May diminish the therapeutic effect of Progestins (Contraceptive). Retinoic Acid Derivatives may decrease the serum concentration of Progestins (Contraceptive). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Microdosed progesterone-only preparations (ie, minipills that do not contain estrogen) are considered an inadequate method of contraception. Risk D: Consider therapy modification
Sugammadex: May diminish the therapeutic effect of Hormonal Contraceptives. Management: Patients receiving any hormonal contraceptive (oral or non-oral) should use an additional, nonhormonal contraceptive method during and for 7 days following sugammadex treatment. Risk D: Consider therapy modification
Taurursodiol: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk X: Avoid combination
Tazemetostat: May decrease the serum concentration of Hormonal Contraceptives. Management: Individuals of childbearing potential should use a non-hormonal contraceptive method during treatment with tazemetostat and for 6 months after. Males with partners of childbearing potential should use contraception during treatment and for 3 months after. Risk D: Consider therapy modification
Tetrahydrocannabinol and Cannabidiol: May decrease the serum concentration of Hormonal Contraceptives. Management: Product labeling recommends that patients taking hormonal contraceptives should use an additional, non-hormonal contraceptive or reliable barrier method during treatment with tetrahydrocannabinol and cannabidiol buccal spray. Risk D: Consider therapy modification
Thalidomide: Hormonal Contraceptives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Tirzepatide: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients using oral hormonal contraceptives should switch to a non-oral contraceptive method, or add a barrier method of contraception, for 4 weeks after initiation of tirzepatide and for 4 weeks after each dose escalation of tirzepatide. Risk D: Consider therapy modification
Topiramate: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing topiramate to ensure contraceptive reliability. Risk D: Consider therapy modification
Tovorafenib: May decrease the serum concentration of Hormonal Contraceptives. Management: Avoid concurrent use when possible. If combined use is unavoidable, use of an additional nonhormonal method of contraception is recommended during combined use and for 28 days after stopping tovorafenib. Risk D: Consider therapy modification
Tranexamic Acid: Hormonal Contraceptives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Ustekinumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Vaborbactam: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing meropenem/vaborbactam to ensure contraceptive reliability. Risk D: Consider therapy modification
Vedolizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Hormonal Contraceptives may increase the serum concentration of Vitamin K Antagonists. Hormonal Contraceptives may decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Voriconazole: Hormonal Contraceptives may increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Hormonal Contraceptives. Risk C: Monitor therapy
Norethindrone (NET): Progestin-only contraceptives may be started immediately postpartum (CDC [Curtis 2016a]; CDC [Curtis 2016b]). A rapid return to fertility occurs when progestin-only contraceptives are discontinued.
All available forms of contraception, including norethindrone (NET), can be considered for patients on gender affirming testosterone therapy after evaluating patient preferences and medical conditions (eg, risk for venous thromboembolism) (Bonnington 2020; Krempasky 2020).
Norethindrone acetate (NETA): The contraceptive dose of norethindrone acetate is not known. Barrier contraception is recommended to prevent unintended pregnancy (eg, when treating endometriosis) (Kaser 2012). Pregnancy should be excluded prior to inducing withdrawal bleeding with norethindrone acetate (NETA) when evaluating patients for secondary amenorrhea (ES [Gordon 2017]).
First trimester exposure of progestins may cause genital abnormalities including hypospadias in male infants and mild virilization of external female genitalia. Changes in external genitalia have been reported in female infants exposed to norethindrone acetate (NETA) (Fine 1963). Significant adverse events related to growth and development have not been observed following use of oral progestins in contraceptive doses (limited studies). Use is contraindicated during pregnancy.
Norethindrone is present in breast milk.
Data related to the presence of norethindrone in breast milk are available following maternal administration of oral norethindrone (NET) 0.35 mg to 5 women within 1 month of delivery (Saxena 1977):
Maternal milk concentrations were measured over 24 hours on the first day of treatment and peak milk concentrations occurred 2 hours after the maternal dose.
Using the highest breast milk concentration reported in the study (1,364 pg/mL), the relative infant dose (RID) of norethindrone is 4.1% compared to a weight-adjusted maternal dose of 0.35 mg/day, providing an estimated daily infant dose via breast milk of 0.205 mcg/kg/day.
In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
Actual milk concentrations varied widely between women and were about one-tenth of the concentrations in maternal plasma (Saxena 1977).
Breast milk concentrations vary in studies conducted with higher norethindrone doses used in combination with estrogen (Betrabet 1987; Sahlberg 1987; Toddywalla 1980) or norethindrone delivered by different routes (Bhaskar 1979; Fotherby 1983; Koetsawang 1982).
Isolated reports of decreased milk production and very rare reports of jaundice in breastfeeding infants have been noted. In general, adverse events related to infant growth and development have not been reported.
The manufacturer of norethindrone acetate (NETA) recommends that caution be used if administered to a breastfeeding patient.
When used for contraception, the manufacturer recommends norethindrone (NET) not be initiated for 6 weeks after delivery (if fully breastfeeding) or 3 weeks after delivery (if partially breastfeeding). However, available guidelines state norethindrone (NET) may be started at any time postpartum in breastfeeding patients (CDC [Curtis 2016a]; CDC [Curtis 2016b]).
Norethindrone (NET): Contraception: Assessment of pregnancy status (prior to therapy); weight (optional; BMI at baseline may be helpful to monitor changes during therapy); assess potential health status changes at routine visits (CDC [Curtis 2016a]). Evaluate pregnancy status if 2 consecutive menstrual cycles are missed, or if the menstrual cycle is delayed and ≥1 pill was taken late or missed in a cycle in which intercourse occurred without a back-up method of contraception.
Norethindrone acetate (NETA): Monitor patient for vision changes; signs or symptoms of depression; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias.
Regardless of indication, adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. Pathologist should be informed of therapy when submitting endometrial tissue for histologic evaluation.
Once absorbed, systemic disposition of norethindrone acetate (NETA) and norethindrone (NET) is the same.
NET is used in preparations for progestin-only contraception. NET suppresses ovulation, thickens cervical mucus (which inhibits sperm penetration), alters follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations, slows the movement of ovum through the fallopian tubes, and alters the endometrium.
Progestogens, such as NETA in the doses used for abnormal uterine bleeding, amenorrhea, and endometriosis, lead to atrophy of the endometrial tissue. They may also suppress new growth and implantation. Pain associated with endometriosis is decreased. When treating endometriosis, NETA may be used in combination with gonadotropin-releasing hormone agonists to decrease side effects from hypoestrogenism (ASRM 2014).
Absorption: Oral: Rapidly absorbed
Distribution: Vd: 4 L/kg
Protein binding: 61% to albumin; 36% to sex hormone-binding globulin (SHBG); SHBG capacity affected by plasma ethinyl estradiol levels (Orme 1983)
Metabolism: Oral: Norethindrone acetate (NETA) is deacetylated to norethindrone; norethindrone undergoes hepatic reduction and conjugation; orally administered norethindrone is subject to first-pass effect (Orme 1983). In addition to forming glucuronide and sulfide conjugates, norethindrone is also metabolized to ethinyl estradiol (Kuhnz 1997; Orme 1983).
Bioavailability: 64% (Orme 1983)
Half-life elimination: ~8 to 9 hours
Time to peak: ~2 hours (varies by dose and use of concomitant estrogen (Orme 1983)
Excretion: Urine (>50% as metabolites); feces (20% to 40% as metabolites)
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