MedPath

Norethisterone Advanced Drug Monograph

Published:Aug 18, 2025

Generic Name

Norethisterone

Brand Names

Activella 1/0.5 28 Day, Activelle, Alyacen 1/35, Alyacen 7/7/7, Amabelz 0.5/0.1 28 Day, Aranelle 28, Aurovela, Aurovela Fe, Aygestin, Balziva 28 Day, Blisovi 21 Fe 1.5/30 28 Day Pack, Blisovi 21 Fe 1/20 28 Day Pack, Blisovi 24 Fe 1/20 28 Day, Brevicon, Briellyn 28 Day, Camila 28 Day, Charlotte 24 Fe Chewable 28 Day, Combipatch, Cyclafem 1/35 28 Day, Cyclafem 7/7/7 28 Day, Cyonanz 28 Day, Dasetta 1/35 28 Day, Dasetta 7/7/7 28 Day, Deblitane 28 Day, Emzahh 28 Day, Errin 28 Day, Estalis, Etyqa 0.5/0.1 28 Day, Femcon Fe 28 Day, Femhrt 0.5/2.5 28 Day, Finzala 24 Fe Chewable 28 Day, Fyavolv, Gemmily 28 Day, Hailey 1.5/30 21 Day, Hailey 24 Fe 28 Day, Hailey Fe 1.5/30 28 Day, Hailey Fe 1/20 28 Day, Heather 28 Day, Incassia, Jencycla 28 Day, Jinteli, Junel 1.5/30 21 Day, Junel 1/20 21 Day, Junel Fe 1.5/30 28 Day, Junel Fe 1/20 28 Day, Junel Fe 24 1/20 28 Day, Kaitlib Fe 28 Day, Larin 1.5/30, Larin 1/20, Larin 24 Fe 1/20, Larin Fe 1.5/30, Larin Fe 1/20, Layolis Fe 28, Leena 28 Day, Lo Loestrin Fe 28 Day, Loestrin 1.5/30 21 Day, Loestrin 24 Fe 28 Day, Loestrin Fe 1/20 28 Day, Lolo, Lomedia 24 Fe, Lopreeza 1/0.5 28 Day, Lupaneta Pack 1-month, Lyleq 28 Day, Lyza, Melodetta 24 Fe Chewable 28 Day, Merzee 28 Day, Mibelas 24 Fe Chewable 28 Day, Microgestin 1.5/30 21 Day, Microgestin 1/20 21 Day, Microgestin 24 Fe 28 Day, Microgestin Fe 1.5/30 28 Day, Microgestin Fe 1/20 28 Day, Mimvey, Minastrin 24 Fe Chewable 28 Day, Myfembree, Necon 0.5/35 28 Day, Necon 1/35 28 Day, Necon 7/7/7 28 Day, Nexesta Fe 28 Day, Nora-BE 28 Day, Norlutate, Norlyda 28 Day, Norlyroc 28 Day, Nortrel 1/35 21 Day, Nortrel 1/35 28 Day, Nortrel 7/7/7 28 Day, Nylia 1/35 28 Day, Nylia 7/7/7 28 Day, Oriahnn 28 Day Kit, Ortho Micronor, Ortho Micronor 28 Day, Ortho-novum 7/7/7 28 Day, Philith 28 Day, Pirmella 1/35 28 Day, Pirmella 7/7/7 28 Day, Rhuzdah 28 Day, Select, Sharobel 28 Day, Synphasic, Tarina 24 Fe 1/20 28 Day, Tarina Fe 1/20 28 Day, Taysofy 28 Day, Taytulla 28 Day, Tilia Fe, Tri-legest 28 Day, Tulana 28 Day, Vyfemla 28 Day, Wera 28 Day, Wymzya Fe 28 Day, Zenchent, Ryeqo

Drug Type

Small Molecule

Chemical Formula

C20H26O2

CAS Number

68-22-4

Associated Conditions

Endometriosis related pain, Heavy Menstrual Bleeding, Moderate to Severe Vasomotor Symptoms, Osteoporosis, Postmenopausal Osteoporosis, Severe Pain, Vulvo Vaginal Atrophy, Hypoestrogenism, Moderate, severe, Vasomotor Symptoms caused by Menopause

A Comprehensive Monograph on Norethisterone (DB00717)

Executive Summary

Norethisterone, also known as norethindrone, is a synthetic small molecule progestin that has served as a cornerstone of gynecological and endocrine pharmacotherapy for over seven decades. First synthesized in 1951, its development marked a pivotal moment in medicine by providing the first orally active and potent progestational agent, a critical step that enabled the creation of hormonal contraceptives. Chemically classified as a second-generation, 19-nortestosterone (estrane) derivative, its structure confers high progestational activity and oral bioavailability, but also accounts for its secondary hormonal effects.

The primary mechanism of action of Norethisterone is potent agonism of the progesterone receptor (PR), with a binding affinity approximately 150% that of endogenous progesterone. This activity underlies its therapeutic effects, including ovulation inhibition, endometrial transformation, and stabilization of the uterine lining. Pharmacodynamically, Norethisterone exhibits a complex profile; it is also a weak agonist of the androgen receptor (AR) and possesses indirect estrogenic activity through hepatic metabolism to the potent estrogen, ethinylestradiol. This metabolic conversion is a key determinant of its dose-dependent effects, with the drug acting as a pure progestin at low contraceptive doses and as a de facto combination hormone therapy at higher therapeutic doses, a distinction with significant clinical implications for its safety profile.

Pharmacokinetically, Norethisterone is characterized by rapid oral absorption and extensive hepatic metabolism, with a mean elimination half-life of approximately 8 hours. Notably, there is significant inter-individual variability in its bioavailability and clearance, which can influence both efficacy and the incidence of side effects.

The clinical utility of Norethisterone is exceptionally broad. It is a key component in progestogen-only and combined oral contraceptives, a primary treatment for abnormal uterine bleeding, endometriosis, and secondary amenorrhea, and a component of menopausal hormone replacement therapy. It is also used in high doses for the palliative treatment of breast cancer and is widely used off-label for the short-term postponement of menstruation.

The safety profile of Norethisterone is well-characterized and is contingent upon dose, formulation, and patient-specific risk factors. Common side effects include menstrual irregularities, headache, and nausea. The most significant serious risk, particularly at higher doses or in combination with estrogens, is venous thromboembolism (VTE). Combination products containing Norethisterone carry a boxed warning regarding cigarette smoking and the increased risk of serious cardiovascular events in women over 35. While classified as "reasonably anticipated to be a human carcinogen" based on animal data, decades of widespread clinical use have not established a strong causal link in humans.

Regulatory approval for Norethisterone spans the globe, with a history dating back to the late 1950s. Its remarkable longevity is underscored by its continued inclusion in novel, multi-component therapies and innovative drug delivery systems, such as the recently approved orally disintegrating tablet, confirming its enduring relevance in modern women's healthcare.

Introduction: A Foundational Progestin

Historical Context and Discovery

The discovery of Norethisterone represents a landmark achievement in 20th-century medicinal chemistry and a turning point in reproductive medicine. In 1951, a team of researchers at Syntex S.A. in Mexico City, led by Carl Djerassi, synthesized the molecule, which would become the first orally active and highly potent synthetic progestin.[1] This breakthrough was not merely a chemical feat but a solution to a long-standing pharmacological problem: the clinical utility of natural progesterone was severely limited by its poor oral bioavailability due to rapid first-pass metabolism in the liver. The Syntex team, building on earlier work that identified a method to synthesize steroids from diosgenin, a compound extracted from Mexican wild yams, successfully created a molecule that could withstand hepatic degradation and exert powerful progestational effects when taken orally.[2]

The availability of an effective oral progestin was the critical missing component for the development of hormonal contraception. The work on Norethisterone paved the way for the "pill," a development that had profound and lasting impacts on women's health, reproductive autonomy, and societal structure. The drug was first introduced for medical use as a standalone therapy in 1957 for the treatment of gynecological disorders such as irregular menstruation and endometriosis.[3] Its role expanded dramatically in the early 1960s when it was incorporated, in combination with an estrogen, into the first generation of combined oral contraceptive pills, solidifying its place in medical history.[3]

Chemical Classification and Structural Significance

Norethisterone is classified as a synthetic progestin, a term for a synthetic progestogen, and belongs to the 19-nortestosterone (or estrane) class of steroids.[1] Its chemical structure is derived from testosterone, but with two crucial modifications that define its pharmacological profile. First, the methyl group normally found at the carbon-19 (C19) position of the steroid nucleus is removed, hence the prefix "19-nor." This alteration significantly enhances progestational activity while reducing androgenic activity relative to its parent compound. Second, an ethynyl group (

−C≡CH) is added at the C17α position. This modification sterically hinders the enzymatic oxidation of the 17β-hydroxyl group in the liver, thereby preventing rapid inactivation and conferring the molecule's essential oral bioavailability.[3]

This structural heritage is a direct predictor of Norethisterone's secondary hormonal activities. While the "19-nor" modification attenuates androgenicity, the underlying testosterone framework is not entirely masked. This explains the residual affinity for the androgen receptor and the potential for androgenic side effects observed clinically. Within the landscape of synthetic progestins, Norethisterone is considered a "second-generation" progestin, a group that also includes levonorgestrel.[1] Furthermore, it serves as the biologically active form for several other progestin prodrugs, including norethynodrel and lynestrenol, which are metabolized to Norethisterone in the body.[1]

Physicochemical Profile

The precise identification and characterization of a drug's physical and chemical properties are fundamental to its development, formulation, and regulatory assessment. Norethisterone is a well-defined small molecule with established properties.

Identification, Nomenclature, and Formulae

Norethisterone is known by several names and identifiers across different regions and scientific disciplines. Its primary non-proprietary name is Norethisterone, while in the United States, it is predominantly referred to as Norethindrone.[5] Its systematic IUPAC name provides an unambiguous description of its stereochemistry and structure.

Table 1: Key Identifiers and Physicochemical Properties of Norethisterone

PropertyValueSource(s)
Primary NameNorethisterone5
Alternative NameNorethindrone5
IUPAC Name(8R,9S,10R,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one3
CAS Registry Number68-22-47
DrugBank IDDB007171
PubChem CID62303
SynonymsNSC-9564, SC-4640, 17α-Ethynyl-19-nortestosterone1
Molecular FormulaC20​H26​O2​3
Molecular Weight298.42 g/mol7
Physical DescriptionWhite to off-white, odorless, crystalline powder3
Melting Point202-208 °C3
Water Solubility7.04 mg/L at 25 °C (Practically insoluble)10
SolubilitySoluble in chloroform, dioxane, DMSO; slightly soluble in ethanol12
StabilityStable in air; light-sensitive10

Physical Properties and Solubility Characteristics

Norethisterone exists as a white to off-white crystalline powder that is odorless and possesses a slightly bitter taste.[3] Its high melting point, consistently reported in the range of 202-208 °C, is indicative of a stable crystalline structure.[3] As a lipophilic steroid hormone, it is practically insoluble in water, a characteristic that influences its formulation and absorption kinetics.[11] It is, however, soluble in various organic solvents, including chloroform and dioxane.[12] The molecule is known to be sensitive to light, requiring appropriate storage and handling precautions to prevent degradation.[10]

Comprehensive Pharmacological Profile

The clinical effects of Norethisterone are a direct result of its interactions with hormonal receptors and its subsequent journey through the body. A detailed understanding of its pharmacodynamics and pharmacokinetics is essential for its safe and effective use.

Pharmacodynamics: Mechanisms of Action and Receptor Interactions

Norethisterone exerts its effects through a multi-faceted interaction with the body's steroid hormone receptor systems. While its primary activity is progestogenic, its residual androgenic and indirect estrogenic properties are clinically significant.

Progesterone Receptor (PR) Agonism and Progestogenic Potency

The principal mechanism of action of Norethisterone is its function as a potent agonist at the progesterone receptor (PR).[5] It binds to the PR with an affinity that is approximately 1.5 times greater than that of endogenous progesterone, making it a highly potent progestin.[5] This high-affinity binding activates the receptor, which then acts as a ligand-activated transcription factor to modulate the expression of target genes in tissues such as the uterus, cervix, pituitary gland, and hypothalamus.[15] The clinical consequences of this PR agonism are the classic progestogenic effects: transformation of the estrogen-primed endometrium from a proliferative to a secretory state, which is essential for treating uterine bleeding disorders; thickening of the cervical mucus, which impedes sperm transport and contributes to its contraceptive effect; and suppression of the mid-cycle luteinizing hormone (LH) surge, which inhibits ovulation.[5]

Androgen Receptor (AR) and Estrogenic Receptor (ER) Activity

Norethisterone's hormonal activity is not limited to the progesterone receptor. Its structural relationship to testosterone results in clinically relevant off-target effects.

  • Androgenic Effects: Norethisterone is a weak agonist of the androgen receptor (AR), demonstrating approximately 15% of the binding affinity of the potent synthetic androgen metribolone.[5] This residual androgenicity can manifest clinically, particularly at higher therapeutic doses, as side effects such as acne, hirsutism (increased hair growth), and changes in lipid profiles.[5]
  • Estrogenic Effects: The estrogenic activity of Norethisterone is indirect and complex. The parent molecule has negligible affinity for the estrogen receptor (ER).[5] However, Norethisterone undergoes biotransformation in the liver, where a small fraction (approximately 0.35%) is metabolized by the aromatase enzyme into ethinylestradiol (EE), a very potent synthetic estrogen.[5] The clinical significance of this conversion is highly dose-dependent. At low contraceptive doses (e.g., 0.35 mg/day), the amount of EE produced is minimal and likely clinically irrelevant. In contrast, at higher therapeutic doses used for gynecological disorders (e.g., 5-15 mg/day), the resulting systemic levels of EE can be equivalent to those achieved by taking a low-dose oral estrogen pill (30-60 µg of EE).[5] This metabolic pathway means that at higher doses, Norethisterone functions not as a pure progestin, but as a combination hormonal agent, which has profound implications for its safety profile, particularly concerning the risk of estrogen-related adverse events like venous thromboembolism.

The Role of Active Metabolites

The pharmacological profile of Norethisterone is further complicated by its active metabolites. The principal metabolite, 5α-dihydronorethisterone (5α-DHNET), is formed by the action of the 5α-reductase enzyme.[5] 5α-DHNET exhibits a unique and complex activity profile; it retains progestogenic activity but has also been found to possess marked

antiprogestogenic properties.[5] Its affinity for the PR is significantly reduced to about 25% of that of Norethisterone. While 5α-DHNET binds to the androgen receptor more strongly than its parent compound, its androgenic

potency in bioassays is almost completely abolished. This loss of androgenic effect upon 5α-reduction is a distinctive feature of ethisterone derivatives (like Norethisterone) and is attributed to the presence of the C17α-ethynyl group.[5] Further metabolic reduction leads to various tetrahydronorethisterone isomers, which are largely considered inactive.[1]

Table 2: Receptor Binding Affinity Profile of Norethisterone and Key Metabolites

CompoundReceptorRelative Binding Affinity (%)Primary Source(s)
NorethisteroneProgesterone (PR)67–755
Androgen (AR)155
Estrogen (ER)05
Glucocorticoid (GR)0–15
Mineralocorticoid (MR)0–35
5α-DihydronorethisteroneProgesterone (PR)255
Androgen (AR)275
Estrogen (ER)05
Ethinylestradiol (Metabolite)Estrogen (ER)1125

Note: Affinities are expressed as percentages relative to reference ligands (e.g., promegestone for PR, metribolone for AR, estradiol for ER).

Antigonadotropic Effects and Ovulation Inhibition

A key therapeutic action of Norethisterone, central to its contraceptive efficacy, is its antigonadotropic effect. By acting on progesterone receptors in the hypothalamus and pituitary gland, it exerts powerful negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis.[5] This action suppresses the pulsatile release of Gonadotropin-Releasing Hormone (GnRH) from the hypothalamus, which in turn blunts the pre-ovulatory surge of luteinizing hormone (LH) from the pituitary gland.[5] Without the LH surge, follicular maturation is arrested and ovulation is prevented. At higher doses, the estrogenic activity from its metabolism to EE also contributes to this HPG axis suppression.[5]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Norethisterone describes its movement into, through, and out of the body, which dictates its dosing regimen and duration of action. A notable feature of its pharmacokinetics is the substantial variability observed between individuals, which can have significant clinical consequences.

Oral Bioavailability and Absorption

Following oral administration, Norethisterone is rapidly and completely absorbed from the gastrointestinal tract.[5] Peak plasma concentrations (

Cmax​) are typically achieved within 1 to 3 hours (Tmax​).[6] Despite complete absorption, the absolute oral bioavailability is variable, with a mean of 64% and a range of 47% to 73%.[5] This incomplete bioavailability is due to significant pre-systemic, or first-pass, metabolism in the intestinal wall and liver.[6]

Plasma Protein Binding and Distribution

Once in the systemic circulation, Norethisterone is extensively bound to plasma proteins, with approximately 97% of the drug bound.[5] It binds primarily to albumin (~61%) and, with higher affinity, to sex hormone-binding globulin (SHBG) (~36%).[5] Only a small fraction (~3%) circulates as free, unbound drug, which is the pharmacologically active portion. It has a large apparent volume of distribution (

Vd​) of approximately 4 L/kg, indicating extensive distribution into tissues.[6]

Hepatic Metabolism

Norethisterone undergoes extensive metabolism, predominantly in the liver.[5] The metabolic pathways are complex and involve several key transformations:

  1. A-Ring Reduction: The primary metabolic route involves the reduction of the Δ4 double bond and the C3 keto group, mediated by 5α- and 5β-reductases, to form various dihydro- and tetrahydronorethisterone metabolites.[5]
  2. Aromatization: A minor but clinically important pathway is the conversion of a small fraction of the dose to the potent estrogen ethinylestradiol, catalyzed by the aromatase enzyme (a member of the cytochrome P450 family).[5]
  3. Hydroxylation: Norethisterone is also a substrate for oxidative metabolism, primarily mediated by the cytochrome P450 enzyme CYP3A4.[1]
  4. Conjugation: The parent drug and its various metabolites are subsequently conjugated with sulfate and glucuronic acid to form water-soluble compounds that can be readily excreted.[1]

Elimination Half-Life and Excretion

The elimination of Norethisterone from the plasma is relatively rapid, with a mean elimination half-life (t1/2​) of approximately 8.0 hours, though studies report a range from 5.2 to 12.8 hours.[5] The drug and its metabolites are eliminated from the body through both renal and fecal routes. Approximately 50% to 81% of an administered dose is excreted in the urine, and 20% to 43% is excreted in the feces, primarily as conjugated metabolites.[1]

A critical aspect of Norethisterone's pharmacokinetics is the high degree of inter-subject variability. Studies have demonstrated up to a 3-fold variation in elimination half-life and a 5-fold variation in overall drug exposure (bioavailability as measured by area under the curve) among individuals receiving the same dose.[19] This variability is likely a key factor in determining why some individuals experience contraceptive failure or breakthrough bleeding (indicative of low exposure), while others experience more pronounced side effects (indicative of high exposure).[19] This underscores that a standardized dose may not yield a uniform clinical response across all patients.

Table 3: Summary of Norethisterone Pharmacokinetic Parameters

ParameterMean Value / RangeSource(s)
Time to Peak (Tmax​)1–3 hours6
Peak Concentration (Cmax​)4.63 ng/mL (for 1 mg dose)19
Oral Bioavailability64% (Range: 47–73%)5
Plasma Protein Binding~97% (61% Albumin, 36% SHBG)5
Volume of Distribution (Vd​)~4 L/kg6
Elimination Half-Life (t1/2​)8.0 hours (Range: 5.2–12.8 hours)5
Clearance~0.4 L/hr/kg1
Route of EliminationUrine (50–81%), Feces (20–43%)1

Clinical Applications and Therapeutic Efficacy

Norethisterone's potent progestogenic activity has led to its application across a wide spectrum of gynecological conditions, from contraception and menstrual regulation to hormone replacement and oncology. Its efficacy in these areas is well-established through decades of clinical use and formal clinical trials.

Approved Gynecological and Contraceptive Indications

  • Hormonal Contraception: Norethisterone is a mainstay of hormonal contraception. It is formulated as a progestogen-only pill (POP or "mini-pill"), typically at a dose of 0.35 mg, for women who cannot or should not take estrogen.[5] More commonly, it is a component of combined oral contraceptives (COCs), where it is paired with an estrogen like ethinylestradiol.[1] Multiple completed Phase 3 clinical trials, such as NCT00391807 and NCT00477633, have confirmed the safety and efficacy of these combinations for pregnancy prevention.[21]
  • Management of Abnormal Uterine Bleeding (AUB) and Menstrual Disorders: Norethisterone is a first-line therapy for various menstrual disturbances. It is indicated for the treatment of dysfunctional uterine bleeding, including heavy menstrual bleeding (menorrhagia) and excessively frequent periods (polymenorrhea).[22] By converting the endometrium to a secretory state and then allowing for a coordinated, predictable withdrawal bleed upon cessation, it helps to regulate the menstrual cycle and reduce blood loss.[16] It is also effective for treating painful periods (dysmenorrhea), with Phase 3 trials like NCT00212342 demonstrating its efficacy in this indication.[24]
  • Treatment of Endometriosis: The drug is indicated for the management of endometriosis, a condition characterized by the growth of endometrial-like tissue outside the uterus.[5] Norethisterone alleviates the associated pelvic pain by inducing a state of pseudo-pregnancy, which causes the ectopic endometrial tissue to atrophy.[5] It is sometimes used as an "add-back" therapy in combination with GnRH agonists like leuprolide to mitigate the hypoestrogenic side effects of the GnRH agonist while still treating the endometriosis.[1]
  • Secondary Amenorrhea: For women who have previously menstruated but have stopped having periods (and are not pregnant or menopausal), Norethisterone is used to induce a withdrawal bleed.[17] This is typically done after ensuring the endometrium has been adequately primed by endogenous or exogenous estrogen.
  • Hormone Replacement Therapy (HRT): In postmenopausal women with an intact uterus who are taking estrogen for symptomatic relief, a progestin is required to protect the endometrium from the proliferative effects of unopposed estrogen, which can lead to endometrial hyperplasia and cancer. Norethisterone is frequently used for this purpose in continuous combined HRT regimens.[1]
  • Premenstrual Tension (PMT): In some jurisdictions, Norethisterone is approved for alleviating the physical and psychological symptoms of premenstrual tension.[23]

Oncological Applications

  • Breast Cancer: At high doses (e.g., 40-60 mg per day), Norethisterone is used as a palliative, second- or third-line hormonal therapy for disseminated (metastatic) breast cancer in postmenopausal women.[23] Its mechanism of action in this context is thought to be multifactorial, potentially involving the suppression of pituitary gonadotropin production or a direct effect on hormone receptors within the tumor tissue.[23]

Off-Label Use: Menstrual Postponement

One of the most common and well-established off-label uses of Norethisterone is for the short-term delay of menstruation.[31] This is often requested for reasons of convenience, such as for vacations, athletic competitions, weddings, or religious pilgrimages.[32] The mechanism is straightforward: by taking Norethisterone for a defined period, the natural drop in progesterone levels that triggers menstruation is prevented. The uterine lining is maintained in a stable, secretory state until the medication is discontinued, after which a withdrawal bleed typically occurs within 2-3 days.[31] It is important to note that when used for this purpose, Norethisterone is not a contraceptive.[31]

Dosage, Administration, and Formulations

The clinical versatility of Norethisterone is reflected in its wide range of available formulations and indication-specific dosing regimens. Proper administration is crucial for achieving therapeutic goals while minimizing adverse effects.

Available Dosage Forms and Strengths

Norethisterone is predominantly formulated for oral administration as tablets.[17] It is available as a single-agent product and in numerous fixed-dose combination products.

  • Monotherapy: Common strengths for Norethisterone (or its acetate ester, Norethindrone Acetate) include 0.35 mg tablets, used exclusively for contraception, and 5 mg tablets, used for a variety of gynecological disorders.[15]
  • Combination Products: Norethisterone is a component in a vast array of combination therapies, including:
  • Combined Oral Contraceptives (COCs): Paired with estrogens like ethinylestradiol or mestranol.[5]
  • Hormone Replacement Therapy (HRT): Paired with estradiol, available as oral tablets or transdermal patches (e.g., CombiPatch).[1]
  • Modern Multi-Component Therapies: Included in newer formulations such as Ryeqo/Myfembree (with the GnRH antagonist relugolix and estradiol) and Lupaneta Pack (co-packaged with the GnRH agonist leuprolide).[38]
  • Orally Disintegrating Tablet (ODT): A recent innovation is the approval of Femlyv, a combination of norethindrone acetate and ethinyl estradiol in an ODT formulation.[40]

Indication-Specific Dosing Regimens

The dosage of Norethisterone varies significantly depending on the therapeutic indication, reflecting its dose-dependent effects.

Table 4: Approved Indications and Standard Dosage Regimens

IndicationDosage and AdministrationDuration of TherapySource(s)
Contraception (Progestin-Only)0.35 mg orally once daily, continuously at the same time each day.Continuous, no break between packs.17
Abnormal Uterine Bleeding / Secondary Amenorrhea2.5 to 10 mg (as acetate) orally once daily.5 to 10 days. Withdrawal bleed expected 3-7 days after stopping.17
EndometriosisInitial: 5 mg (as acetate) orally once daily. Titrate by 2.5 mg every 2 weeks up to 15 mg daily.6 to 9 months, or until breakthrough bleeding requires temporary cessation.15
Period Delay (Off-Label)5 mg orally three times daily (15 mg/day). Start 3 days before expected menses.For the desired duration of delay (max ~17-20 days).23
Premenstrual Tension5 mg orally once daily.Days 16 to 25 of the menstrual cycle.23
Disseminated Breast Cancer40 mg orally daily, may be increased to 60 mg daily.As directed by an oncologist.23

Global Brand Names and Combination Products

Norethisterone's long history and widespread use are reflected in the multitude of brand names under which it is marketed globally.

  • Monotherapy Brand Names: Aygestin (norethindrone acetate), Micronor, Nor-QD, Camila, Errin, Jencycla (North America); Primolut N, Utovlan (Europe, UK); Norcolut (Asia, Eastern Europe); Mensil-N, Norate (India).[28]
  • Representative Combination Products:
  • With Ethinylestradiol (COC): Loestrin, Junel Fe, Blisovi Fe, Microgestin Fe, Ortho-Novum, Brevinor.[38]
  • With Estradiol (HRT): Activella, CombiPatch, Mimvey, Kliogest, Evorel Conti.[38]
  • With GnRH Modulators: Ryeqo/Myfembree (with relugolix and estradiol); Lupaneta Pack (with leuprolide).[38]

Safety and Tolerability Profile

The safety profile of Norethisterone is well-established through extensive clinical experience. Its tolerability is highly dependent on the dose administered, whether it is used alone or in combination with an estrogen, and the underlying health status and risk factors of the patient. A comprehensive risk assessment requires a multi-variable analysis of these factors rather than a single, monolithic view of the drug.

Adverse Drug Reactions

Adverse reactions to Norethisterone range from common, manageable side effects to rare but serious events.

Table 5: Summary of Common and Serious Adverse Events

CategorySystem Organ ClassAdverse EventSource(s)
CommonReproductive SystemIrregular menstrual bleeding, spotting, amenorrhea5
Breast tenderness, pain, or swelling17
Nervous SystemHeadache, dizziness25
GastrointestinalNausea, vomiting, abdominal pain25
PsychiatricMood swings, nervousness17
General/MetabolicWeight changes, fluid retention (bloating)17
SkinAcne, increased hair growth (hirsutism), chloasma5
SeriousVascularVenous Thromboembolism (DVT, PE)15
Arterial Thromboembolism (Stroke, Myocardial Infarction)28
HepatobiliaryCholestatic jaundice, liver injury, hepatic adenomas (rare)15
CardiovascularIncreased blood pressure28
Nervous SystemNew onset or worsening of migraine28
PsychiatricDepression28
Immune SystemSevere allergic reaction (anaphylaxis - very rare)15

Contraindications and High-Risk Populations

The use of Norethisterone is contraindicated in several conditions where the risks are deemed to outweigh the potential benefits.

  • Absolute Contraindications:
  • Known or suspected pregnancy (Pregnancy Category X).[15]
  • Known, suspected, or history of breast cancer or other progestin-sensitive cancers.[15]
  • Undiagnosed abnormal vaginal bleeding.[15]
  • Active deep vein thrombosis (DVT), pulmonary embolism (PE), or a history of these conditions.[15]
  • Active or recent (within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).[29]
  • Active liver disease, impaired liver function, or benign/malignant liver tumors.[15]
  • Use with Caution: Close monitoring and careful risk-benefit assessment are required in patients with conditions that may be exacerbated by hormonal therapy or fluid retention, including:
  • History of clinical depression.[17]
  • Diabetes mellitus, as progestins can impair glucose tolerance.[17]
  • Hypertension, hyperlipidemia, or other cardiovascular risk factors.[17]
  • Conditions worsened by fluid retention, such as epilepsy, migraine, asthma, or renal dysfunction.[17]
  • Strong family history of VTE or known thrombophilic predisposition.[23]

Warnings, Precautions, and Black Box Warning Analysis

While Norethisterone as a single agent does not have a U.S. FDA Black Box Warning, its combination products with ethinylestradiol carry a critical warning regarding cardiovascular risks.

  • Black Box Warning (for COC formulations): "Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.".[47]
  • Venous Thromboembolism (VTE) Risk: The risk of VTE with Norethisterone appears to be dose-dependent. At the low doses used for progestin-only contraception, the risk is considered negligible.[16] However, at higher therapeutic doses, the risk is moderately increased.[16] This increased risk is likely attributable to the metabolic conversion of Norethisterone to ethinylestradiol, which carries a known VTE risk.
  • Visual Abnormalities: Prescribing information universally warns that the medication should be discontinued pending examination if there is a sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine.[23] If examination reveals papilledema or retinal vascular lesions, the medication should be permanently stopped.

Carcinogenicity and Long-Term Safety Considerations

The long-term cancer risk associated with Norethisterone requires a nuanced interpretation that balances data from animal studies with decades of human clinical experience. The U.S. National Toxicology Program (NTP) has classified Norethisterone as "reasonably anticipated to be a human carcinogen".[14] This classification is based on sufficient evidence of carcinogenicity from studies in experimental animals, where oral exposure was linked to benign and malignant tumors in the liver, pituitary, and mammary glands of rodents.[14]

However, there is a critical disconnect between this classification and the clinical risk assessment in humans. The NTP report itself notes that no epidemiological studies have specifically evaluated the relationship between human cancer and exposure to Norethisterone alone.[14] Extensive data from the use of combined oral contraceptives (which often contain Norethisterone) suggest a slightly increased risk of breast and cervical cancer, but this is often confounded by the presence of estrogen, and the absolute risk increase is small.[16] Therefore, while the potential for carcinogenicity exists based on animal models, decades of widespread human use have not produced a strong signal of high cancer risk at typical clinical doses. The risk-benefit assessment for approved indications overwhelmingly favors its use.

Clinically Significant Interactions

The efficacy and safety of Norethisterone can be significantly altered by co-administered drugs, herbal supplements, and certain foods. These interactions are primarily pharmacokinetic, involving the modulation of its metabolism, but can also be pharmacodynamic.

Pharmacokinetic Drug-Drug Interactions (CYP450 System)

Norethisterone is a substrate of the cytochrome P450 enzyme system, particularly CYP3A4. Therefore, its plasma concentrations are susceptible to modulation by CYP3A4 inducers and inhibitors.

  • CYP3A4 Inducers: Co-administration of Norethisterone with potent inducers of CYP3A4 can accelerate its metabolism, leading to lower systemic exposure and a potential loss of therapeutic effect. This is of particular concern in the context of contraception, where it can lead to contraceptive failure or breakthrough bleeding. Clinically significant inducers include:
  • Anticonvulsants: Phenytoin, carbamazepine, oxcarbazepine, barbiturates.[30]
  • Antimicrobials: Rifampicin, rifabutin, griseofulvin.[30]
  • Antivirals: Efavirenz, and some protease inhibitors (e.g., nelfinavir, ritonavir).[51]
  • Herbal Supplements: St. John's wort (Hypericum perforatum).[45]
  • CYP3A4 Inhibitors: Conversely, co-administration with strong CYP3A4 inhibitors can decrease the metabolism of Norethisterone, leading to elevated plasma concentrations and an increased risk of dose-related adverse effects. Significant inhibitors include:
  • Azole Antifungals: Ketoconazole, itraconazole, voriconazole.[51]
  • Macrolide Antibiotics: (Though not explicitly listed in the provided sources, they are a known class of inhibitors).
  • Antivirals: Certain HIV protease inhibitors (e.g., indinavir, atazanavir).[1]

Pharmacodynamic Drug-Drug Interactions

  • Anticoagulants: Progestins, including Norethisterone, may influence the activity of oral anticoagulants like warfarin. This interaction can be unpredictable, and closer monitoring of coagulation parameters may be warranted.[51]
  • Antidiabetic Agents: Norethisterone may impair glucose tolerance, which can antagonize the effects of hypoglycemic agents (e.g., acarbose, metformin, sulfonylureas, insulin). Patients with diabetes may require adjustments to their antidiabetic therapy.[1]
  • Ulipristal Acetate: Ulipristal acetate is a progesterone receptor modulator used for emergency contraception. Its efficacy can be reduced by subsequent use of a progestin like Norethisterone. It is recommended to use a non-hormonal backup contraceptive method for a period after using ulipristal acetate.[17]

Food and Herbal Supplement Interactions

  • Grapefruit Juice: Grapefruit juice is a known inhibitor of intestinal CYP3A4. Its consumption can increase the bioavailability and plasma concentrations of orally administered Norethisterone, potentially increasing the risk of side effects. Patients may be advised to limit or avoid grapefruit products during therapy.[45]
  • St. John's Wort: As mentioned, this herbal supplement is a potent inducer of CYP3A4 and can significantly reduce the effectiveness of Norethisterone. Its use is strongly discouraged in patients relying on Norethisterone for contraception.[45]

Table 6: Clinically Significant Drug and Food Interactions

Interacting Agent(s)Mechanism of InteractionClinical ConsequenceManagement RecommendationSource(s)
Carbamazepine, Phenytoin, Rifampicin, St. John's WortCYP3A4 InductionDecreased Norethisterone plasma levels; risk of reduced efficacy (e.g., contraceptive failure, breakthrough bleeding).Use an alternative or additional non-hormonal contraceptive method. Avoid co-administration if possible.30
Ketoconazole, Itraconazole, RitonavirCYP3A4 InhibitionIncreased Norethisterone plasma levels; potential for increased adverse effects.Monitor for signs of progestin-related side effects.1
Antidiabetic MedicationsImpaired Glucose ToleranceDecreased efficacy of antidiabetic agents; potential for hyperglycemia.Monitor blood glucose levels closely; may require dose adjustment of the antidiabetic drug.1
Grapefruit JuiceIntestinal CYP3A4 InhibitionIncreased Norethisterone bioavailability and plasma levels.Limit or avoid consumption of grapefruit and grapefruit juice. Monitor for increased side effects.45
Ulipristal AcetatePharmacodynamic Antagonism at PRReduced efficacy of both Norethisterone and ulipristal.Use a reliable barrier method of contraception until the next menstrual period.17

Regulatory Status and Global Approvals

The regulatory history of Norethisterone reflects its long-standing and evolving role in medicine. It has secured approvals from major regulatory agencies worldwide and continues to be incorporated into new therapeutic products.

FDA Approval History and Key Milestones

Norethisterone has been available for medical use in the United States for over 60 years.

  • Initial Introduction: Following its discovery, Norethisterone was first introduced for medical use as a standalone product in 1957.[5]
  • Contraceptive Approval: Its use in combination with an estrogen as an oral contraceptive was first approved by the U.S. Food and Drug Administration (FDA) in the 1960s (sources cite 1963 and 1968).[5]
  • Generic Approvals: Numerous generic versions have been approved over the decades. For example, an Abbreviated New Drug Application (ANDA) for Norethindrone Acetate tablets from Barr Laboratories was approved in May 2001.[55]
  • Combination Product Approvals: Many combination products have received FDA approval, such as Loestrin 24 Fe (norethindrone acetate/ethinyl estradiol) in February 2006.[43]
  • Recent Innovations: Norethisterone's journey demonstrates a remarkable lifecycle, evolving from a foundational drug to a crucial component in innovative, multi-target combination therapies. The most recent approvals place it in sophisticated products that target multiple pathways simultaneously, such as Myfembree (relugolix/estradiol/norethindrone acetate) for uterine fibroids and endometriosis, and Lupaneta Pack (leuprolide/norethindrone acetate) for endometriosis.[38] This evolution showcases that Norethisterone is not a historical relic; its well-understood pharmacology and safety profile make it an ideal, reliable progestin for developers of new women's health therapies. This adaptability is further highlighted by the FDA's approval in July 2024 of Femlyv, the first orally disintegrating tablet (ODT) combining norethindrone acetate and ethinyl estradiol. This new formulation is designed to improve adherence and expand access for individuals who have difficulty swallowing pills, demonstrating the molecule's ongoing adaptation to meet modern patient needs.[40]

EMA Approval and European Market Context

Norethisterone has a similarly long and robust regulatory history in Europe.

  • National Authorizations: It has been authorized at the national level for many years. For instance, a 5 mg tablet formulation from Wockhardt UK Ltd received its first authorization in the UK in August 1999.[23]
  • Centralized and Mutual Recognition Procedures: Norethisterone-containing products have been approved through pan-European procedures. Activelle (estradiol/norethisterone acetate), an HRT product, was approved by the European Commission in September 2008 following a mutual recognition procedure and an Article 29 referral to resolve disagreements between member states.[44]
  • Recent Combination Approvals: The European Medicines Agency (EMA) has recently approved Ryeqo (the brand name for Myfembree in Europe), which contains relugolix, estradiol, and norethisterone acetate. It received marketing authorization for the treatment of uterine fibroids in July 2021 and for the symptomatic treatment of endometriosis in November 2023.[39] These approvals highlight its integral role in the latest generation of advanced therapies for complex gynecological conditions.

Chemical Synthesis and Manufacturing Overview

The synthesis of Norethisterone was a pivotal achievement that relied on the availability of a suitable steroid precursor. Historically, this precursor was diosgenin, a steroid sapogenin extracted in large quantities from the Mexican yam (Dioscorea villosa).[4] Modern industrial synthesis has evolved to improve efficiency and yield.

The core chemical transformation in the synthesis of Norethisterone is the introduction of the 17α-ethynyl group onto a 17-keto steroid precursor. A common synthetic strategy starts with 19-norandrostenedione.[60] This starting material is reacted with a metal acetylide. This is often generated in situ by bubbling acetylene gas through a solution containing a strong base, such as potassium tert-butoxide, in an appropriate solvent like tert-butanol or tetrahydrofuran.[60] The acetylide anion then acts as a nucleophile, attacking the electrophilic carbonyl carbon at the C17 position of the steroid, resulting in the formation of the 17α-ethynyl-17β-hydroxy group characteristic of Norethisterone.

Alternative patented processes have also been described. One such method involves reacting a 19-hydroxy-3-keto-Δ⁴-steroid with a secondary amine (e.g., pyrrolidine) to form a 19-nor-3,5-diene-3-amine intermediate, with the concurrent elimination of formaldehyde. This enamine intermediate protects the 3-keto group while other transformations occur, and it can be subsequently hydrolyzed with acid to regenerate the 3-keto-Δ⁴-ene system of the final product.[62] Modern chemical process development focuses on creating more streamlined, economical, and environmentally friendly "one-pot" syntheses that minimize the number of steps and complex purification procedures.[60]

Expert Synthesis and Concluding Remarks

Norethisterone stands as a testament to the transformative power of medicinal chemistry. For over 70 years, it has remained an indispensable tool in the therapeutic armamentarium for women's health, a status owed to its remarkable versatility, well-characterized profile, and continued adaptation. Its journey from a revolutionary discovery that enabled the era of oral contraception to a reliable component in today's most advanced multi-component therapies is a paradigm of a successful pharmaceutical lifecycle.

The pharmacological profile of Norethisterone is defined by its potent progestogenic activity, but its clinical character is nuanced by its secondary hormonal effects. The most critical concept for the clinician to grasp is the dose-dependent nature of its pharmacology. At low contraceptive doses, it functions as a selective progestin. At higher therapeutic doses, its metabolic conversion to ethinylestradiol transforms it into a de facto combination hormone therapy, fundamentally altering its safety considerations, particularly regarding the risk of venous thromboembolism. This "emergent" estrogenicity requires a dynamic approach to risk assessment, where the prescribed dose dictates the scope of potential adverse effects.

The overall risk-benefit profile of Norethisterone is overwhelmingly positive when it is used appropriately for its approved indications, with careful consideration of patient-specific contraindications and risk factors. While the formal carcinogenicity classification based on animal data warrants acknowledgment, it must be balanced against the vast body of evidence from decades of widespread human use, which has not demonstrated a high risk of cancer.

Ultimately, the enduring legacy of Norethisterone is its reliability and adaptability. It is a molecule with a deeply understood mechanism of action, a predictable (if variable) pharmacokinetic profile, and a well-defined safety framework. These characteristics make it not only a valuable standalone therapy but also an ideal progestogenic component for new combination products designed to address complex pathologies like endometriosis and uterine fibroids. The recent introduction of an orally disintegrating formulation further illustrates its capacity for evolution to meet contemporary patient needs. Norethisterone is not merely a historical artifact; it is a foundational molecule that continues to be a vital and relevant agent in the practice of modern medicine.

Works cited

  1. Norethisterone: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 18, 2025, https://go.drugbank.com/drugs/DB00717
  2. The Chemistry of the Pill - PMC - PubMed Central, accessed August 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4827491/
  3. Norethindrone | C20H26O2 | CID 6230 - PubChem, accessed August 18, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Norethindrone
  4. Progestin: Synthetic Progesterone | Embryo Project Encyclopedia - Arizona State University, accessed August 18, 2025, https://embryo.asu.edu/pages/progestin-synthetic-progesterone
  5. Norethisterone - Wikipedia, accessed August 18, 2025, https://en.wikipedia.org/wiki/Norethisterone
  6. Norethindrone Acetate: Pharmacokinetics, Potency and Alternative Clinical Applications - MedCrave eBooks, accessed August 18, 2025, https://medcraveebooks.com/view/Norethindrone-Acetate-Pharmacokinetics,-Potency-and-Alternative-Clinical-Applications.pdf
  7. Norethindrone | CAS 68-22-4 | SCBT - Santa Cruz Biotechnology, accessed August 18, 2025, https://www.scbt.com/p/norethindrone-68-22-4
  8. Norethindrone (Norethisterone, NSC 9564, SC 4640, CAS Number: 68-22-4), accessed August 18, 2025, https://www.caymanchem.com/product/20941/norethindrone
  9. CAS 68-22-4 - Sigma-Aldrich, accessed August 18, 2025, https://www.sigmaaldrich.com/US/en/search/68-22-4?focus=products&page=1&perpage=30&sort=relevance&term=68-22-4&type=cas_number
  10. SAFETY DATA SHEET - Fisher Scientific, accessed August 18, 2025, https://www.fishersci.com/store/msds?partNumber=AC262890010&productDescription=NORETHISTERONE+1GR&vendorId=VN00032119&countryCode=US&language=en
  11. Table 1, Properties of Norethisterone - 15th Report on Carcinogens - NCBI Bookshelf, accessed August 18, 2025, https://www.ncbi.nlm.nih.gov/books/NBK590896/table/norethisterone_t01/
  12. Norethisterone 68-22-4 | Tokyo Chemical Industry (India) Pvt. Ltd., accessed August 18, 2025, https://www.tcichemicals.com/IN/en/p/N0449
  13. Norethindrone Datasheet - Selleck Chemicals, accessed August 18, 2025, https://www.selleckchem.com/datasheet/norethindrone-norethisterone-S404001-DataSheet.html
  14. RoC Profile: Norethisterone - National Toxicology Program, accessed August 18, 2025, https://ntp.niehs.nih.gov/sites/default/files/ntp/roc/content/profiles/norethisterone.pdf
  15. Norethindrone - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Lactation, Hepatic Dose, Pregnanacy | Drug Index | Pediatric Oncall, accessed August 18, 2025, https://www.pediatriconcall.com/drugs/norethindrone/1237
  16. Norethisterone and its acetate – what's so special about them?, accessed August 18, 2025, https://srh.bmj.com/content/47/2/102
  17. Norethindrone (oral route) - Side effects & dosage - Mayo Clinic, accessed August 18, 2025, https://www.mayoclinic.org/drugs-supplements/norethindrone-oral-route/description/drg-20137986
  18. Notes on the Design of Bioequivalence Study: Norethisterone, accessed August 18, 2025, https://extranet.who.int/prequal/sites/default/files/document_files/BE_Norethisterone_November2022_0.pdf
  19. Pharmacokinetics of norethisterone in humans - POPLINE, accessed August 18, 2025, https://popline.org/node/350785
  20. Pharmacokinetics of norethisterone in humans - PubMed, accessed August 18, 2025, https://pubmed.ncbi.nlm.nih.gov/3621943/
  21. Norethisterone Completed Phase 3 Trials for Contraception Prevention | DrugBank Online, accessed August 18, 2025, https://go.drugbank.com/drugs/DB00717/clinical_trials?conditions=DBCOND0020891&phase=3&purpose=prevention&status=completed
  22. Hypermenorrhea Unknown Status Phase 4 Trials for Norethisterone (DB00717) - DrugBank, accessed August 18, 2025, https://go.drugbank.com/indications/DBCOND0052994/clinical_trials/DB00717?phase=4&status=unknown_status
  23. Norethisterone 5mg Tablets - Summary of Product Characteristics (SmPC) - (emc) | 1494, accessed August 18, 2025, https://www.medicines.org.uk/emc/product/1494/smpc
  24. Norethisterone Completed Phase 3 Trials for Menstrual Distress (Dysmenorrhea) Treatment, accessed August 18, 2025, https://go.drugbank.com/drugs/DB00717/clinical_trials?conditions=DBCOND0041665&phase=3&purpose=treatment&status=completed
  25. Norethisterone: Uses, Side Effects, Dosage, Precautions and More - CARE Hospitals, accessed August 18, 2025, https://www.carehospitals.com/medicine-detail/norethisterone
  26. Norethindrone: MedlinePlus Drug Information, accessed August 18, 2025, https://medlineplus.gov/druginfo/meds/a604034.html
  27. go.drugbank.com, accessed August 18, 2025, https://go.drugbank.com/drugs/DB00717#:~:text=Norethisterone%2C%20taken%20in%20combination%20with,treatment%20of%20endometriosis%2Drelated%20pain.&text=Norethisterone%20is%20a%20synthetic%20oral,as%20menopausal%20symptoms%20and%20endometriosis.
  28. Norethindrone Acetate: Uses & Side Effects - Cleveland Clinic, accessed August 18, 2025, https://my.clevelandclinic.org/health/drugs/20808-norethindrone-acetate-tablets-hormone-replacement-therapy
  29. AYGESTIN (norethindrone acetate tablets, USP) - accessdata.fda.gov, accessed August 18, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf
  30. Norethisterone 5mg_Leaflet_104373-9, accessed August 18, 2025, https://www.medicines.org.uk/emc/files/pil.1494.pdf
  31. Norethisterone 5mg Tablets | Period Delay | Buy Online at TravelPharm, accessed August 18, 2025, https://www.travelpharm.com/medications/norethisterone-5mg-tablets
  32. Suppress Your Menstrual Cycle - TeleTest, accessed August 18, 2025, https://docs.teletest.ca/suppress-your-menstrual-cycle
  33. What Happens If You Take Norethisterone on the First Day of Your Period?, accessed August 18, 2025, https://www.prescriptiondoctor.com/period-delay/norethisterone/what-happens-if-you-take-norethisterone-on-the-first-day-of-your-period
  34. Delaying menstruation – GPnotebook, accessed August 18, 2025, https://gpnotebook.com/pages/gynaecology/delaying-menstruation
  35. Norethisterone | Boots Online Doctor UK, accessed August 18, 2025, https://onlinedoctor.boots.com/treatments/norethisterone
  36. Norethindrone Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 18, 2025, https://www.drugs.com/dosage/norethindrone.html
  37. Camila, Errin (norethindrone) dosing, indications, interactions, adverse effects, and more, accessed August 18, 2025, https://reference.medscape.com/drug/camila-errin-norethindrone-342791
  38. Norethindrone - brand name list from Drugs.com, accessed August 18, 2025, https://www.drugs.com/ingredient/norethindrone.html
  39. Ryeqo | European Medicines Agency (EMA), accessed August 18, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/ryeqo
  40. Femlyv (ethinyl estradiol and norethindrone acetate) FDA Approval History - Drugs.com, accessed August 18, 2025, https://www.drugs.com/history/femlyv.html
  41. Norethisterone - Drugs.com, accessed August 18, 2025, https://www.drugs.com/international/norethisterone.html
  42. Top 10 Norethisterone Tablets Brands in India - Nexwin Pharma Pvt. Ltd., accessed August 18, 2025, https://www.nexwinpharma.in/top-10-norethisterone-tablets-brands-manufacturers-in-india
  43. Loestrin 24 Fe (norethindrone acetate/ethinyl estradiol and ferrous fumarate) FDA Approval History - Drugs.com, accessed August 18, 2025, https://www.drugs.com/history/loestrin-24-fe.html
  44. Activelle - referral | European Medicines Agency (EMA), accessed August 18, 2025, https://www.ema.europa.eu/en/medicines/human/referrals/activelle
  45. Norethisterone: Uses, Side Effects and Medicines - Apollo Pharmacy, accessed August 18, 2025, https://www.apollopharmacy.in/salt/Norethisterone
  46. Norethisterone – Uses, Side Effects, Medicines & FAQs - PharmEasy, accessed August 18, 2025, https://pharmeasy.in/molecules/norethisterone-657
  47. Jacoby & Meyers | Dangerous Drugs | Norethindrone Acetate/Ethinyl Estradiol(Oral Contraceptive), accessed August 18, 2025, https://dangerousdrugs.com/drug-black-box-warnings/norethindrone-acetateethinyl-estradioloral-contraceptive/
  48. Norethindrone - Memorial Sloan Kettering Cancer Center, accessed August 18, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/adult/norethindrone
  49. www.goodrx.com, accessed August 18, 2025, https://www.goodrx.com/drugs/safety/fda-black-box-warning#:~:text=Combination%20birth%20control%20pills&text=Examples%20include%20Loestrin%20FE%201,over%20age%2035%20and%20smoke.
  50. CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning. - accessdata.fda.gov, accessed August 18, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218718s000lbl.pdf
  51. Norethindrone: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed August 18, 2025, https://www.rxlist.com/norethindrone/generic-drug.htm
  52. Aygestin (norethindrone acetate) dosing, indications, interactions, adverse effects, and more, accessed August 18, 2025, https://reference.medscape.com/drug/aygestin-norethindrone-acetate-342789
  53. Norethindrone and Alcohol/Food Interactions - Drugs.com, accessed August 18, 2025, https://www.drugs.com/food-interactions/norethindrone.html
  54. Ethinyl estradiol/norethindrone and Alcohol/Food Interactions - Drugs.com, accessed August 18, 2025, https://www.drugs.com/food-interactions/ethinyl-estradiol-norethindrone.html
  55. Drug Approval Package: Norethindrone NDA #075951 - accessdata.fda.gov, accessed August 18, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/anda/2001/075951_norethindrone_acetate_toc.cfm
  56. Relugolix/estradiol/norethisterone acetate - Wikipedia, accessed August 18, 2025, https://en.wikipedia.org/wiki/Relugolix/estradiol/norethisterone_acetate
  57. FDA Roundup: July 23, 2024, accessed August 18, 2025, https://www.fda.gov/news-events/press-announcements/fda-roundup-july-23-2024
  58. European Commission approves the commercialisation of RYEQO® - Gedeon Richter, accessed August 18, 2025, https://www.gedeonrichter.com/en/news/210521
  59. European Commission Approves the Commercialisation of RYEQO® for the Symptomatic Treatment of Endometriosis - Nov 2, 2023 - Sumitomo Pharma America Newsroom - News Releases, accessed August 18, 2025, https://news.us.sumitomo-pharma.com/2023-11-02-European-Commission-Approves-the-Commercialisation-of-RYEQO-R-for-the-Symptomatic-Treatment-of-Endometriosis
  60. WO2018185783A1 - Novel process for preparation of 19-norsteroids - Google Patents, accessed August 18, 2025, https://patents.google.com/patent/WO2018185783A1/en
  61. patents.google.com, accessed August 18, 2025, https://patents.google.com/patent/US3655649A/en#:~:text=To%20synthesize%20the%20important%2017a,such%20as%20a%20nitrogen%20atmosphere.
  62. US3655649A - Process for the preparation of 19-norsteroids - Google Patents, accessed August 18, 2025, https://patents.google.com/patent/US3655649A/en

Published at: August 18, 2025

This report is continuously updated as new research emerges.

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