Note: Norethindrone (NET) is used for progestin-only contraception. Norethindrone acetate (NETA) is a prodrug of norethindrone used in treatment of abnormal uterine bleeding, amenorrhea, and endometriosis. In addition, norethindrone (NET) and norethindrone acetate (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: Oral: Norethindrone acetate (NETA): 2.5 to 10 mg/day for 5 to 10 days. 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 (NETA).
Heavy menstrual bleeding, acute (off-label dosing): Oral: Norethindrone acetate (NETA): 5 to 10 mg every 6 hours in patients who cannot tolerate or have contraindications to estrogen. Once bleeding has stopped, decrease dose to 5 to 15 mg/day to suppress menstruation (ACOG 2019). Additional dosing regimens have been reported (Ramalho 2021).
Amenorrhea (secondary): Oral: Norethindrone acetate (NETA): 2.5 to 10 mg/day for 5 to 10 days. 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 (NETA).
Functional hypothalamic amenorrhea: Oral: Norethindrone acetate (NETA): 5 mg/day for a 5- to 10-day course; used as a diagnostic test to assess endometrial estrogen exposure and/or outflow tract integrity. Use of the shorter 5-day course may be considered in patients who do not tolerate treatment. May repeat in a few weeks if withdrawal bleeding does not occur (ES [Gordon 2017]).
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 (CDC [Curtis 2016a]):
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.
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 (Kliegman 2011; Kliegman 2016). 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 (CDC [Curtis 2016a]):
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 (Kaser 2012): 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Camila: 0.35 mg [DSC]
Camila: 0.35 mg [contains corn starch, fd&c red #40 aluminum lake]
Deblitane: 0.35 mg [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #10 aluminum lake, soybean lecithin]
Errin: 0.35 mg [contains corn starch, fd&c yellow #10 aluminum lake]
Heather: 0.35 mg [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]
Incassia: 0.35 mg [contains corn starch, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]
Jencycla: 0.35 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]
Jolivette: 0.35 mg [DSC]
Lyleq: 0.35 mg [contains corn starch, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]
Lyza: 0.35 mg [contains corn starch, fd&c yellow #10 (quinoline yellow)]
Nora-BE: 0.35 mg
Norlyda: 0.35 mg
Norlyroc: 0.35 mg
Ortho Micronor: 0.35 mg [DSC] [contains corn starch, fd&c yellow #10 aluminum lake]
Sharobel: 0.35 mg [contains fd&c blue #1 aluminum lake, fd&c yellow #6 aluminum lake, soybean lecithin]
Tulana: 0.35 mg [contains corn starch, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]
Generic: 0.35 mg
Tablet, Oral, as acetate:
Aygestin: 5 mg [scored]
Generic: 5 mg
Yes
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 aluminum lake, fd&c yellow #10 aluminum lake]
Micronor: 0.35 mg [DSC] [contains fd&c yellow #10 (quinoline yellow)]
Movisse: 0.35 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]
Tablet, Oral, as acetate:
Norlutate: 5 mg [contains corn starch, fd&c yellow #10 (quinoline yellow)]
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 (CDC [Curtis 2016a]).
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 (CDC 2013).
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016).
Abnormal uterine bleeding (norethindrone acetate [NETA]): Treatment of abnormal uterine bleeding due to hormonal imbalance in absence of organic pathology, such as submucous fibroids or uterine cancer.
Amenorrhea, secondary (norethindrone acetate [NETA]): Treatment of secondary amenorrhea.
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.
Limitations of use:
Norethindrone acetate (NETA) is not indicated for use with estrogen therapy in postmenopausal patients for endometrial protection.
Menstrual suppression
Micronor may be confused with miconazole, Micronase
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined.
Cardiovascular: Cerebral embolism, cerebral thrombosis, deep vein thrombosis, edema, pulmonary embolism, retinal thrombosis
Central nervous system: Depression, dizziness, fatigue, headache, insomnia, migraine, emotional lability, nervousness
Dermatologic: Acne vulgaris, alopecia, chloasma, pruritus, skin rash, urticaria
Endocrine & metabolic: Amenorrhea, hirsutism, hypermenorrhea, menstrual disease, weight gain
Gastrointestinal: Abdominal pain, nausea, vomiting
Genitourinary: Breakthrough bleeding, breast hypertrophy, breast tenderness, cervical erosion, change in cervical secretions, decreased lactation, genital discharge, mastalgia, spotting, vaginal hemorrhage
Hypersensitivity: Anaphylaxis, hypersensitivity
Hepatic: Cholestatic jaundice, hepatitis, abnormal hepatic function tests
Neuromuscular & skeletal: Arm pain, leg pain
Ophthalmic: Optic neuritis (with or without vision loss)
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:
• Bleeding irregularities: Irregular menstrual bleeding patterns are common with progestin-only contraceptives; nonpharmacologic causes of abnormal bleeding should be ruled out.
• 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). Risk factors should be managed 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 progestin than contained in estrogen/progestin–combined contraceptives. Risks associated with estrogen/progestin 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.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Albiglutide: Norethindrone may diminish the therapeutic effect of Albiglutide. Albiglutide may increase the serum concentration of Norethindrone. 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
Asunaprevir: May decrease the serum concentration of Hormonal Contraceptives. Management: Use of a high-dose oral contraceptive (at least 30 mcg of ethinyl estradiol combined with norethindrone) is recommended when combined with asunaprevir. Consider an additional barrier method when other forms of contraception are used with asunaprevir. 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
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
Cladribine: May diminish the therapeutic effect of Hormonal Contraceptives. Management: In females of reproductive potential using systemically acting hormonal contraceptives, add a barrier method during cladribine dosing and for at least 4 weeks after the last dose in each treatment course Risk D: Consider therapy modification
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
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
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 increase the serum concentration of Hormonal Contraceptives. Specifically, concentrations of ethinyl estradiol may be increased with elagolix therapy. Elagolix may decrease the serum concentration of Hormonal Contraceptives. Specifically, concentrations of progestins may be decreased 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
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
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). Risk X: Avoid combination
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
LamoTRIgine: May decrease the serum concentration of Progestins (Oral Contraceptive [mini-pill]). Risk C: Monitor therapy
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
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
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
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
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
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
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: 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
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
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
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.
Information related to the presence of norethindrone in breast milk is 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).
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 of norethindrone (NET) recommends breastfeeding 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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