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| Trade names | Ortho Tri-Cyclen, others |
| Other names | NGM; ORF-10131; Levonorgestrel acetate oxime; Levonorgestrel 17β-acetate 3-oxime; 17α-Ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate; 17α-Ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime 17β-acetate |
| AHFS/Drugs.com | Professional Drug Facts Professional Drug Facts |
| MedlinePlus | a601050 |
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| Routes of administration | By mouth |
| Drug class | Progestogen;Progestin;Progestogen ester[1] |
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| Pharmacokinetic data | |
| Bioavailability | Unknown[2] |
| Protein binding | • Norelgestromin: 99% (toalbumin)[1] • Levonorgestrel: 98% (to albumin andSHBGTooltip sex hormone-binding globulin)[1] • Levonorgestrel acetate: ? (to albumin)[1] |
| Metabolism | Liver,intestines (deacetylation,reduction,hydroxylation,conjugation)[1][3][4] |
| Metabolites | •Norelgestromin[1] •Levonorgestrel[1] •Levonorgestrel acetate[1] |
| Eliminationhalf-life | • Norgestimate: very short[1] • Norelgestromin: 17–37 hours[3][1] • Levonorgestrel: 24–32 hours[1] |
| Excretion | Urine: 47%[4] Feces: 37%[4] |
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| ECHA InfoCard | 100.167.085 |
| Chemical and physical data | |
| Formula | C23H31NO3 |
| Molar mass | 369.505 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 214 to 218 °C (417 to 424 °F) |
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Norgestimate, sold under the brand nameOrtho Tri-Cyclen among others, is aprogestin medication which is used inbirth control pills for women and inmenopausal hormone therapy.[1][3][4][5] The medication is available in combination with anestrogen and is not available alone.[6] It is takenby mouth.[1]
Side effects of the combination of an estrogen and norgestimate includemenstrual irregularities,headaches,nausea,abdominal pain,breast tenderness,mood changes, and others.[3][4] Norgestimate is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[1] It has very weakandrogenic activity and no other importanthormonal activity.[1] The medication is aprodrug ofnorelgestromin and to a lesser extent oflevonorgestrel in the body.[1]
Norgestimate was patented in 1965 and introduced for medical use, specifically in birth control pills, in 1986.[7][8] It was introduced for use in menopausal hormone therapy in the United States in 1999.[9] Norgestimate is sometimes referred to as a "third-generation" progestin.[10] It is marketed in birth control pills widely throughout the world, whereas it is available for use in menopausal hormone therapy only in the United States and Brazil.[6] Norgestimate is available as ageneric medication.[11] In 2022, the combination withethinylestradiol was the 99th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[12][13]
Norgestimate is used inhormonal contraception and inmenopausal hormone therapy for the treatment ofmenopausalsymptoms.[5] It is used in combination withethinylestradiol inbirth control pills and in combination withestradiol in menopausal hormone therapy.[6][14]
Norgestimate is available only in combination with theestrogensethinylestradiol andestradiol.[6] These formulations are for use by mouth and are indicated specifically for hormonal contraception and menopausal hormone therapy.[6] Norgestimate is not available on its own (i.e., as a standalone medication).[6]
Norgestimate has mostly been studied in combination with an estrogen, so theside effects of norgestimate specifically or on its own have not been well-defined.[3][4]
Side effects associated with the combination of ethinylestradiol and norgestimate in premenopausal women, with greater than or equal to 2% incidence over up to 24menstrual cycles, includeheadache/migraine (33%),abdominal/gastrointestinal pain (7.8%),vaginal infection (8.4%),vaginal discharge (6.8%),breast issues (includingbreast pain,discharge, andenlargement) (6.3%),mood disorders (including depression and mood alterations) (5.0%),flatulence (3.2%),nervousness (2.9%), andrash (2.6%).[4]
Side effects associated with the combination of estradiol and norgestimate in postmenopausal women, with greater than or equal to 5% incidence over one year, include headache (23%),upper respiratory tract infection (21%), breast pain (16%),back pain (12%),abdominal pain (12%),flu-like symptoms (11%),arthralgia (9%),vaginal bleeding (9%),dysmenorrhea (8%),sinusitis (8%),vaginitis (7%),pharyngitis (7%),fatigue (6%),pain (6%),nausea (6%),viral infection (6%), flatulence (5%),tooth disorder (5%),myalgia (5%),dizziness (5%),depression (5%), andcoughing (5%).[3]
Norgestimate is a rapidly and completely convertedprodrug, mainly ofnorelgestromin (17β-deacetylnorgestimate or levonorgestrel 3-oxime), but also oflevonorgestrel (3-keto-17β-deacetylnorgestimate) to a lesser extent (22 ± 6% of an administered dose or about 40–70 μg)[2] and oflevonorgestrel acetate (levonorgestrel 17β-acetate) in very small amounts.[1][5][15][16][17] Via itsactive metabolites, norgestimate hasprogestogenic activity,antigonadotropic effects, very weakandrogenic activity, and no other importanthormonal activity.[1]
| Compound | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin |
|---|---|---|---|---|---|---|---|
| Norgestimate | 15 | 0 | 0 | 1 | 0 | 0 | 0 |
| Norelgestromin (17β-deAc-NGM) | 10 | 0 | ? | ? | ? | 0 | ? |
| Levonorgestrel (3-keto-17β-deAc-NGM) | 150–162 | 45 | 0 | 1–8 | 17–75 | 50 | 0 |
| Levonorgestrel 17β-acetate (3-keto-NGM) | 135 | ? | 0 | ? | ? | 0 | ? |
| Notes: Values are percentages (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,E2 for theERTooltip estrogen receptor,DEXATooltip dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,DHTTooltip dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources:[18][1][19] | |||||||
Norgestimate is aprogestogen, or anagonist of theprogesterone receptor.[1] Therelative binding affinities of norgestimate and its active metabolites for the progesterone receptor compared topromegestone (100%) are 15% for norgestimate, 10% for norelgestromin, 150% for levonorgestrel, and 135% for levonorgestrel acetate.[1] Because of their low concentrations, norgestimate and levonorgestrel acetate are not thought to contribute significantly to thebiological activity of norgestimate.[1] In addition, although levonorgestrel binds to the progesterone receptor with much higheraffinity than norelgestromin, levonorgestrel has high affinity forsex hormone-binding globulin (SHBG) (87% of that of testosterone), which may limit its activity, whereas norelgestromin does not bind to SHBG.[1][4][20] Theovulation-inhibiting dosage of norgestimate is 200 μg/day.[1]
In addition to its progestogenic activity, norgestimate has weakandrogenic activity.[1] However, the medication shows less androgenic activity than related19-nortestosterone progestins like levonorgestrel andnorethisterone.[5][21] Norgestimate and norelgestromin have negligible affinity for theandrogen receptor (both 0% of the affinity ofmetribolone), while levonorgestrel has considerable affinity for the androgen receptor (45% of that of metribolone).[1] In addition to their lack of affinity for the androgen receptor, norgestimate and norelgestromin have virtually no affinity for SHBG, and therefore do not displacetestosterone from this carrier protein (although levonorgestrel does still bind with high affinity to SHBG and hence could increase free testosterone levels via occupation of SHBG).[5][1] In accordance,clinical trials of norgestimate have observed minimal androgenicside effects in women treated with the medication.[21] As an example, clinical studies have found that norgestimate does not appreciably inhibit the increase in SHBG levels produced byethinylestradiol.[20] This is of interest becauseestrogens increase andandrogens decreaseliver production of SHBG and by extension circulating levels of SHBG.[20]
The relative binding affinity of norgestimate and its metabolite norelgestromin for the ratprostaticandrogen receptor (AR) are 0.3% and 1.3% of those ofdihydrotestosterone (DHT), respectively, whereas the respective values forlevonorgestrel andgestodene are 22% and 15%.[20] Based on these findings, the ratios of AR to PR binding are 219 for norgestimate and 48 for norelgestromin, whereas the ratios forprogesterone, levonorgestrel, and gestodene are 93, 11, and 28, respectively.[20] As such, norgestimate and norelgestromin would appear to have much lower androgenic potency than other 19-nortestosterone progestins.[20] However, levonorgestrel is an important metabolite of both norgestimate and norelgestromin, and it may serve to increase their androgenic potency to some degree.[1][20]
When norgestimate is combined with ethinylestradiol, which is potentlyantiandrogenic, there are only antiandrogenic effects overall and the combination is suitable for treatment ofhyperandrogenism.[14]
Norgestimate and its active metabolites do not bind to othersteroid hormone receptors besides the progesterone and androgen receptors and hence have no otheroff-target hormonal activity.[1] This includesestrogenic,glucocorticoid,antimineralocorticoid, andneurosteroid activity.[1] However, levonorgestrel has been found toinhibit5α-reductase andhepaticcytochrome P450enzymesin vitro to some extent.[1]
Norgestimate is rapidly and almost completelymetabolized into itsactive metabolites, mainlynorelgestromin (the primary active metabolite) and to a lesser extentlevonorgestrel, uponoral ingestion.[1][3][4] As a result, only very low concentrations (70 pg/mL) of norgestimate itself are detectable in the circulation, and only for about 6 hours after an oral dose.[1][22] The oralbioavailability of norgestimate is unknown.[22][2] This is due to the rapid and extensive metabolism of norgestimate, which makes determination of overall bioavailability difficult and necessitates methods other thanarea-under-the-curve (AUC) to do so.[22]Peak levels of norelgestromin (3,500 pg/mL) are reached at approximately 2 hours following administration of norgestimate.[3][4][14] Co-administration of norgestimate with a high-fat meal has been found to significantly decrease peak levels of norelgestromin, although thearea-under-the-curve levels of norelgestromin are not significantly altered by food.[3]Steady-state levels of norelgestromin and levonorgestrel are reached within 21 days of treatment with norgestimate.[4] There is an approximate 2-fold accumulation in levels of norelgestromin and a non-linear approximate 8-fold accumulation in levels of levonorgestrel with continuous administration of norgestimate.[4] The accumulation of levonorgestrel is thought to be a result of its highaffinity for SHBG, which limits itsbiological activity.[4] Theplasma protein binding of norelgestromin is approximately 99% and it is bound toalbumin but not to SHBG.[3][4][1] Conversely, levonorgestrel is approximately 98% bound toplasma proteins and is bound to both albumin and SHBG.[1][4]
Norgestimate is extensively metabolized into its active metabolites duringfirst-pass metabolism in theliver andintestines.[1][3][4] The major metabolite of norgestimate is norelgestromin and is formed from norgestimate viadeacetylation in the liver and intestines.[3] A more minor metabolite of norgestimate is levonorgestrel, which accounts for 20 to 25% (22 ± 6%) of an administered dose or about 40 to 70 μg norgestimate,[22][2] and a very minor metabolite of norgestimate islevonorgestrel 17β-acetate.[3] Both of thesemetabolites areactive similarly to norgelstromin.[1][3] With a typical oral contraceptive dosage of norgestimate of 200 to 250 μg/day, an amount of 50 to 60 μg/day levonorgestrel may be produced.[22] This is similar to theovulation-inhibiting dosage of levonorgestrel, and suggests that norgestimate may act in considerable part as a prodrug specifically of levonorgestrel.[22][1] Following their formation, theactive metabolites of norgestimate are inactivated viareduction,hydroxylation, andconjugation into levonorgestrel metabolites.[1][4] Theterminal half-life of norelgestromin is between 17 and 37 hours and of levonorgestrel is between 24 and 32 hours.[3][1] The metabolites of norgestimate areeliminated 47% inurine and 37% infeces.[3][4] Unchanged norgestimate is undetectable in urine.[4]
Norgestimate, also known as 17α-ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime 17β-acetate, is asyntheticestranesteroid and aderivative oftestosterone.[23][6] It is aracemic mixture ofE andZ isomers.[24] Norgestimate is more specifically a derivative ofnorethisterone (17α-ethynyl-19-nortestosterone) and is a member of thegonane (18-methylestrane) subgroup of the19-nortestosterone family of progestins.[25] It is the C3oxime and C17βacetateester oflevonorgestrel and is also known as levonorgestrel acetate oxime.[26] A related compound isnorethisterone acetate oxime (norethisterone-3-oxime 17β-acetate).[23]
Norgestimate was introduced as a component of combined oral contraceptives in 1986.[7] Based on its year of introduction, norgestimate is sometimes described as a "third-generation" progestin.[10] Norgestimate was approved in combination with estradiol for use in menopausal hormone therapy in 1999 in the United States, and a generic version of this preparation became available in this country in 2005.[9]
Norgestimate is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,USPTooltip United States Pharmacopeia,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française.[23][6] It is also known by its developmental code name ORF-10131.[23][6]
Norgestimate is marketed in combination withethinylestradiol as a birth control pill under the brand names Amicette, Cilest, Cyclen, Edelsin, Effiprev, Estarylla, MonoNessa, Orlon, Ortho Tri-Cyclen, Ortho Tri-Cyclen Lo, Ortho-Cyclen, Pramino, Previfem, Sprintec, Triafemi, TriCilest, Tri-Cyclen, Tri-Cyclen LO, Tridette, Tri-Estarylla, Tri-Linyah, TriNessa, Tri-Previfem, and Tri-Sprintec.[23][6] It is marketed in combination withestradiol for menopausal hormone therapy under the brand name Prefest.[6]
Norgestimate in combination withethinylestradiol is marketed widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, South Africa, Latin America, and Asia.[6] Unlike the combined birth control pills of norgestimate with ethinylestradiol, the combination of norgestimate withestradiol, sold under the brand name Prefest for menopausal hormone therapy, is reportedly only marketed in the United States and Brazil.[6]
A 2017 study found that norgestimate inhibitsstaphylococcalbiofilm formation and resensitizesmethicillin-resistantStaphylococcus aureus toβ-lactam antibiotics.[27] In contrast,norelgestromin showed much weaker activity, indicating that theacetyl group of norgestimate is important for the activity.[27] It was suggested by the researchers that norgestimate may be a promisinglead compound for the development of new antibiotics.[27]
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