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{{Short description|Chemical compound}} |
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{{Unreferenced|date=February 2007}}{{drugbox |
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{{Distinguish|Norgestomet}} |
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{{Use dmy dates|date=October 2021}} |
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| verifiedrevid = 402509711 |
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{{cs1 config |name-list-style=vanc |display-authors=6}} |
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| IUPAC_name = (13-ethyl-17-ethynyl-3-hydroxyimino- 1,2,6,7,8,9,10,11,12,14,15,16- dodecahydrocyclopenta phenanthren-17-yl) acetate |
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{{Infobox drug |
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| Verifiedfields = verified |
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| Watchedfields = verified |
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| verifiedrevid = 462263110 |
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| image = Norgestimate.svg |
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| image = Norgestimate.svg |
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| width = 250 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| alt = |
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| image2 = Norgestimate molecule ball.png |
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| width2 = 250 |
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| alt2 = |
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<!-- Clinical data --> |
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| pronounce = |
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| tradename = Ortho Tri-Cyclen, others |
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| Drugs.com = {{drugs.com|ppa|ethinyl-estradiol-and-norgestimate}}<br />{{drugs.com|ppa|estradiol-and-norgestimate}} |
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| MedlinePlus = a601050 |
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| DailyMedID = Norgestimate |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_AU_comment = |
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| pregnancy_category = Use is contraindicated |
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| routes_of_administration = ] |
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| class = ]; ]; ]<ref name="pmid16112947" /> |
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| ATC_prefix = G03 |
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| ATC_suffix = AA11 |
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| ATC_supplemental = {{ATC|G03|FA13}} (only combinations with ]s) |
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<!-- Legal status --> |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled --> |
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| legal_AU_comment = |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| legal_BR_comment = |
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| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA_comment = |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> |
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| legal_UK_comment = |
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| legal_US = Rx-only |
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| legal_US_comment = |
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| legal_EU = |
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| legal_EU_comment = |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = <!-- For countries not listed above --> |
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<!-- Pharmacokinetic data --> |
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| bioavailability = Unknown<ref name="pmid8842581">{{cite journal | vauthors = Fotherby K | title = Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy | journal = Contraception | volume = 54 | issue = 2 | pages = 59–69 | date = August 1996 | pmid = 8842581 | doi = 10.1016/0010-7824(96)00136-9 }}</ref> |
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| protein_bound = • Norelgestromin: 99% (to ])<ref name="pmid16112947" /><br />• Levonorgestrel: 98% (to albumin and {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="pmid16112947" /><br />• Levonorgestrel acetate: ? (to albumin)<ref name="pmid16112947" /> |
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| metabolism = ], ]s (], ], ], ])<ref name="pmid16112947" /><ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> |
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| metabolites = • ]<ref name="pmid16112947" /><br />• ]<ref name="pmid16112947" /><br />• ]<ref name="pmid16112947" /> |
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| onset = |
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| elimination_half-life = • Norgestimate: very short<ref name="pmid16112947" /><br />• Norelgestromin: 17–37 hours<ref name="Prefest FDA Label" /><ref name="pmid16112947" /><br />• Levonorgestrel: 24–32 hours<ref name="pmid16112947" /> |
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| duration_of_action = |
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| excretion = ]: 47%<ref name="Ortho Cyclen FDA Label" /><br />]: 37%<ref name="Ortho Cyclen FDA Label" /> |
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<!-- Identifiers --> |
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| CAS_number_Ref = {{cascite|correct|CAS}} |
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| CAS_number = 35189-28-7 |
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| PubChem = 6540478 |
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| IUPHAR_ligand = 7091 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB00957 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 5022837 |
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| ChemSpiderID = 5022837 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = C291HFX4DY |
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| UNII = C291HFX4DY |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| InChI = 1/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1 |
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| KEGG = D05209 |
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| InChIKey = KIQQMECNKUGGKA-NMYWJIRABS |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 50815 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 1200934 |
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| NIAID_ChemDB = |
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| PDB_ligand = |
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| synonyms = 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 |
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<!-- Chemical and physical data --> |
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| IUPAC_name = phenanthren-17-yl] acetate |
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| C=23 | H=31 | N=1 | O=3 |
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| SMILES = O=C(O2(C#C)CC14(CC12CC)3/C(=C\C(=N\O)CC3)CC4)C |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1 |
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| StdInChI = 1S/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = KIQQMECNKUGGKA-NMYWJIRASA-N |
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| StdInChIKey = KIQQMECNKUGGKA-NMYWJIRASA-N |
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| density = |
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| CAS_number = 35189-28-7 |
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| ATC_prefix = G03 |
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| density_notes = |
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| ATC_suffix = AA11 |
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| melting_point = 214 |
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| ATC_supplemental = |
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| melting_high = 218 |
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| melting_notes = |
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| PubChem = 6540478 |
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| boiling_point = |
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| DrugBank = APRD00569 |
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| boiling_notes = |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG = D05209 |
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| solubility = |
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| sol_units = |
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| C = 23 | H = 31 | N = 1 | O = 3 |
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| specific_rotation = |
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| molecular_weight = 369.497 g/mol |
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| smiles = O=C(O2(C#C)CC14(CC12CC)3/C(=C\C(=N\O)CC3)CC4)C |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = 12-30 hours |
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| excretion = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = |
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| legal_AU = <!-- Unscheduled / S2 / S4 / S8 --> |
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| legal_UK = <!-- GSL / P / POM / CD --> |
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| legal_US = <!-- OTC / Rx-only --> |
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| legal_status = |
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| routes_of_administration = |
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}} |
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}} |
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'''Norgestimate''' is a molecule used in ] ]. |
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<!-- Definition and medical uses --> |
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Norgestimate is a form of progesterone, which is a female hormone important for the regulation of ovulation and menstruation. Norgestimate is used with estradiol (a female sex hormone that is involved in the development and maintenance of the female reproductive system), to treat the symptoms of menopause. |
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'''Norgestimate''', sold under the brand name '''Ortho Tri-Cyclen''' among others, is a ] medication which is used in ]s for women and in ].<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref><ref name="Prefest FDA Label">{{cite web | title=Prefest- estradiol/norgestimate kit | website=DailyMed | date=29 February 2016 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=70d00600-b8d3-4820-8db6-40d4536a6f9e | access-date=9 November 2020}}</ref><ref name="Ortho Cyclen FDA Label">{{cite web | title=Ortho Tri Cyclen- norgestimate and ethinyl estradiol kit Ortho Cyclen- norgestimate and ethinyl estradiol kit | website=DailyMed | date=16 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384e7a40-dcbd-4908-bf5e-65abc9932973 | access-date=9 November 2020}}</ref><ref name="LemkeWilliams2008">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA1316|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=1316–}}</ref> The medication is available in combination with an ] and is not available alone.<ref name="Drugs.com" /> It is taken ].<ref name="pmid16112947" /> |
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<!-- Side effects and mechanism --> |
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==See also== |
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]s of the combination of an estrogen and norgestimate include ], ]s, ], ], ], ] changes, and others.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> Norgestimate is a progestin, or a ] ], and hence is an ] of the ], the ] of progestogens like ].<ref name="pmid16112947" /> It has very weak ]ic activity and no other important ] activity.<ref name="pmid16112947" /> The medication is a ] of ] and to a lesser extent of ] in the body.<ref name="pmid16112947" /> |
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* ] |
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* ] |
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<!-- History, society and culture --> |
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{{Sex hormones}} |
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Norgestimate was patented in 1965 and introduced for medical use, specifically in birth control pills, in 1986.<ref name="RunnebaumRabe2012" /><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=479 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA479 |language=en}}</ref> It was introduced for use in menopausal hormone therapy in the United States in 1999.<ref name="FDA2013" /> Norgestimate is sometimes referred to as a "third-generation" progestin.<ref name="Carp2015">{{cite book| vauthors = Carp HJ |title=Progestogens in Obstetrics and Gynecology|url=https://books.google.com/books?id=Ik8SCAAAQBAJ&pg=PA112|date=9 April 2015|publisher=Springer|isbn=978-3-319-14385-9|pages=112}}</ref> 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.<ref name="Drugs.com" /> Norgestimate is available as a ].<ref name="Drugs.com-Generic">{{Cite web |url= https://www.drugs.com/availability/generic-ortho-tri-cyclen.html |title = Generic Ortho Tri-Cyclen Availability | work = Drugs.com }}</ref> In 2022, the combination with ] was the 99th most commonly prescribed medication in the United States, with more than 6{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Ethinyl Estradiol; Norgestimate Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/EthinylEstradiolNorgestimate | access-date = 30 August 2024 }}</ref> |
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{{TOC limit}} |
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==Medical uses== |
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] |
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Norgestimate is used in ] and in ] for the treatment of ] ]s.<ref name="LemkeWilliams2008" /> It is used in combination with ] in ]s and in combination with ] in menopausal hormone therapy.<ref name="Drugs.com" /><ref name="pmid11499185" /> |
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===Available forms=== |
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Norgestimate is available only in combination with the ]s ] and ].<ref name="Drugs.com" /> These formulations are for use by mouth and are indicated specifically for hormonal contraception and menopausal hormone therapy.<ref name="Drugs.com" /> Norgestimate is not available on its own (i.e., as a standalone medication).<ref name="Drugs.com" /> |
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==Contraindications== |
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{{genito-urinary-drug-stub}} |
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{{See also|Progestin#Contraindications}} |
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==Side effects== |
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{{See also|Norelgestromin#Side effects|Progestin#Side effects}} |
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Norgestimate has mostly been studied in combination with an estrogen, so the ]s of norgestimate specifically or on its own have not been well-defined.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> |
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Side effects associated with the combination of ethinylestradiol and norgestimate in premenopausal women, with greater than or equal to 2% incidence over up to 24 ]s, include ]/] (33%), ] (7.8%), ] (8.4%), ] (6.8%), ] (including ], ], and ]) (6.3%), ]s (including depression and mood alterations) (5.0%), ] (3.2%), ] (2.9%), and ] (2.6%).<ref name="Ortho Cyclen FDA Label" /> |
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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%), ] (21%), breast pain (16%), ] (12%), ] (12%), ] (11%), ] (9%), ] (9%), ] (8%), ] (8%), ] (7%), ] (7%), ] (6%), ] (6%), ] (6%), ] (6%), flatulence (5%), ] (5%), ] (5%), ] (5%), ] (5%), and ] (5%).<ref name="Prefest FDA Label" /> |
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==Overdose== |
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{{See also|Progestin#Overdose}} |
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== Interactions == |
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{{See also|Progestin#Interactions}} |
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==Pharmacology== |
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===Pharmacodynamics=== |
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], also known as 17β-deacetylnorgestimate, the main ] of norgestimate.]] |
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Norgestimate is a rapidly and completely converted ], mainly of ] (17β-deacetylnorgestimate or levonorgestrel 3-oxime), but also of ] (3-keto-17β-deacetylnorgestimate) to a lesser extent (22 ± 6% of an administered dose or about 40–70 μg)<ref name="pmid8842581" /> and of ] (levonorgestrel 17β-acetate) in very small amounts.<ref name="pmid16112947" /><ref name="LemkeWilliams2008"/><ref name="FalconeHurd2007">{{cite book| vauthors = Falcone T, Hurd WW |title=Clinical Reproductive Medicine and Surgery|url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA389|year=2007|publisher=Elsevier Health Sciences|isbn=978-0-323-03309-1|pages=389–}}</ref><ref name="HumansOrganization2007">{{cite book| author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA151|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=150–151}}</ref><ref name="pmid12215716">{{cite journal | vauthors = Stanczyk FZ | title = Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception | journal = Reviews in Endocrine & Metabolic Disorders | volume = 3 | issue = 3 | pages = 211–224 | date = September 2002 | pmid = 12215716 | doi = 10.1023/A:1020072325818 | s2cid = 27018468 }}</ref> Via its ]s, norgestimate has ]ic activity, ] effects, very weak ]ic activity, and no other important ] activity.<ref name="pmid16112947" /> |
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{| class="wikitable mw-collapsible mw-collapsed" style="text-align:left; margin-left:auto; margin-right:auto; border:none;" |
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|+ class="nowrap" | Relative affinities (%) of norgestimate and metabolites |
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! Compound || {{abbrlink|PR|Progesterone receptor}} || {{abbrlink|AR|Androgen receptor}} || {{abbrlink|ER|Estrogen receptor}} || {{abbrlink|GR|Glucocorticoid receptor}} || {{abbrlink|MR|Mineralocorticoid receptor}} || {{abbrlink|SHBG|Sex hormone-binding globulin}} || {{abbrlink|CBG|Corticosteroid binding globulin}} |
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| Norgestimate || 15 || 0 || 0 || 1 || 0 || 0 || 0 |
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| ] ({{abbr|17β-deAc-NGM|17β-deacetylnorgestimate}}) || 10 || 0 || ? || ? || ? || 0 || ? |
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| ] ({{abbr|3-keto-17β-deAc-NGM|3-keto-17β-deacetylnorgestimate}}) || 150–162 || 45 || 0 || 1–8 || 17–75 || 50 || 0 |
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|- |
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| ] ({{abbr|3-keto-NGM|3-ketonorgestimate}}) || 135 || ? || 0 || ? || ? || 0 || ? |
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|- class="sortbottom" |
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| colspan="8" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' Values are percentages (%). Reference ]s (100%) were ] for the {{abbrlink|PR|progesterone receptor}}, ] for the {{abbrlink|AR|androgen receptor}}, ] for the {{abbrlink|ER|estrogen receptor}}, {{abbrlink|DEXA|dexamethasone}} for the {{abbrlink|GR|glucocorticoid receptor}}, ] for the {{abbrlink|MR|mineralocorticoid receptor}}, {{abbrlink|DHT|dihydrotestosterone}} for {{abbrlink|SHBG|sex hormone-binding globulin}}, and ] for {{abbrlink|CBG|Corticosteroid-binding globulin}}. '''Sources:''' <ref name="pmid2170822">{{cite journal | vauthors = Kuhl H | title = Pharmacokinetics of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 171–197 | date = September 1990 | pmid = 2170822 | doi = 10.1016/0378-5122(90)90003-o }}</ref><ref name="pmid16112947" /><ref name="pmid10599548">{{cite journal | vauthors = Philibert D, Bouchoux F, Degryse M, Lecaque D, Petit F, Gaillard M | title = The pharmacological profile of a novel norpregnance progestin (trimegestone) | journal = Gynecological Endocrinology | volume = 13 | issue = 5 | pages = 316–326 | date = October 1999 | pmid = 10599548 | doi = 10.3109/09513599909167574 }}</ref> |
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====Progestogenic activity==== |
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Norgestimate is a ], or an ] of the ].<ref name="pmid16112947" /> The ] of norgestimate and its active metabolites for the progesterone receptor compared to ] (100%) are 15% for norgestimate, 10% for norelgestromin, 150% for levonorgestrel, and 135% for levonorgestrel acetate.<ref name="pmid16112947" /> Because of their low concentrations, norgestimate and levonorgestrel acetate are not thought to contribute significantly to the ] of norgestimate.<ref name="pmid16112947" /> In addition, although levonorgestrel binds to the progesterone receptor with much higher ] than norelgestromin, levonorgestrel has high affinity for ] (SHBG) (87% of that of testosterone), which may limit its activity, whereas norelgestromin does not bind to SHBG.<ref name="pmid16112947" /><ref name="Ortho Cyclen FDA Label" /><ref name="pmid1415445" /> The ]-inhibiting dosage of norgestimate is 200 μg/day.<ref name="pmid16112947" /> |
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====Androgenic activity==== |
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In addition to its progestogenic activity, norgestimate has weak ]ic activity.<ref name="pmid16112947" /> However, the medication shows less androgenic activity than related ] progestins like levonorgestrel and ].<ref name="LemkeWilliams2008" /><ref name="pmid2571595">{{cite journal | vauthors = Chapdelaine A, Desmarais JL, Derman RJ | title = Clinical evidence of the minimal androgenic activity of norgestimate | journal = International Journal of Fertility | volume = 34 | issue = 5 | pages = 347–352 | year = 1989 | pmid = 2571595 }}</ref> Norgestimate and norelgestromin have negligible affinity for the ] (both 0% of the affinity of ]), while levonorgestrel has considerable affinity for the androgen receptor (45% of that of metribolone).<ref name="pmid16112947" /> In addition to their lack of affinity for the androgen receptor, norgestimate and norelgestromin have virtually no affinity for SHBG, and therefore do not displace ] 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).<ref name="LemkeWilliams2008" /><ref name="pmid16112947" /> In accordance, ]s of norgestimate have observed minimal androgenic ]s in women treated with the medication.<ref name="pmid2571595" /> As an example, clinical studies have found that norgestimate does not appreciably inhibit the increase in SHBG levels produced by ].<ref name="pmid1415445" /> This is of interest because ]s increase and ]s decrease ] of SHBG and by extension circulating levels of SHBG.<ref name="pmid1415445" /> |
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The relative binding affinity of norgestimate and its metabolite norelgestromin for the rat ] ] (AR) are 0.3% and 1.3% of those of ] (DHT), respectively, whereas the respective values for ] and ] are 22% and 15%.<ref name="pmid1415445">{{cite journal | vauthors = Phillips A, Hahn DW, McGuire JL | title = Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity | journal = American Journal of Obstetrics and Gynecology | volume = 167 | issue = 4 Pt 2 | pages = 1191–1196 | date = October 1992 | pmid = 1415445 | doi = 10.1016/s0002-9378(12)90410-x }}</ref> Based on these findings, the ratios of AR to PR binding are 219 for norgestimate and 48 for norelgestromin, whereas the ratios for ], levonorgestrel, and gestodene are 93, 11, and 28, respectively.<ref name="pmid1415445" /> As such, norgestimate and norelgestromin would appear to have much lower androgenic potency than other 19-nortestosterone progestins.<ref name="pmid1415445" /> However, levonorgestrel is an important metabolite of both norgestimate and norelgestromin, and it may serve to increase their androgenic potency to some degree.<ref name="pmid16112947" /><ref name="pmid1415445" /> |
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When norgestimate is combined with ethinylestradiol, which is potently ]ic, there are only antiandrogenic effects overall and the combination is suitable for treatment of ].<ref name="pmid11499185" /> |
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====Other activities==== |
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Norgestimate and its active metabolites do not bind to other ]s besides the progesterone and androgen receptors and hence have no other ] hormonal activity.<ref name="pmid16112947" /> This includes ]ic, ], ], and ] activity.<ref name="pmid16112947" /> However, levonorgestrel has been found to ] ] and ] ] ]s '']'' to some extent.<ref name="pmid16112947" /> |
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===Pharmacokinetics=== |
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Norgestimate is rapidly and almost completely ] into its ]s, mainly ] (the primary active metabolite) and to a lesser extent ], upon ] ingestion.<ref name="pmid16112947" /><ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> 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.<ref name="pmid16112947" /><ref name="Mishell1999">{{cite book| vauthors = Mishell DR |title=Progestins and Antiprogestins in Clinical Practice|url=https://books.google.com/books?id=vGJJHsJASekC|date=10 November 1999|publisher=Taylor & Francis|isbn=978-0-8247-8291-7|pages=133–151}}</ref> The oral ] of norgestimate is unknown.<ref name="Mishell1999" /><ref name="pmid8842581" /> This is due to the rapid and extensive metabolism of norgestimate, which makes determination of overall bioavailability difficult and necessitates methods other than ] (AUC) to do so.<ref name="Mishell1999" /> ] of norelgestromin (3,500 pg/mL) are reached at approximately 2 hours following administration of norgestimate.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /><ref name="pmid11499185">{{cite journal | vauthors = Henzl MR | title = Norgestimate. From the laboratory to three clinical indications | journal = The Journal of Reproductive Medicine | volume = 46 | issue = 7 | pages = 647–661 | date = July 2001 | pmid = 11499185 }}</ref> Co-administration of norgestimate with a high-fat meal has been found to significantly decrease peak levels of norelgestromin, although the ] levels of norelgestromin are not significantly altered by food.<ref name="Prefest FDA Label" /> ] levels of norelgestromin and levonorgestrel are reached within 21 days of treatment with norgestimate.<ref name="Ortho Cyclen FDA Label" /> 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.<ref name="Ortho Cyclen FDA Label" /> The accumulation of levonorgestrel is thought to be a result of its high ] for SHBG, which limits its ].<ref name="Ortho Cyclen FDA Label" /> The ] of norelgestromin is approximately 99% and it is bound to ] but not to SHBG.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /><ref name="pmid16112947" /> Conversely, levonorgestrel is approximately 98% bound to ]s and is bound to both albumin and SHBG.<ref name="pmid16112947" /><ref name="Ortho Cyclen FDA Label" /> |
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Norgestimate is extensively metabolized into its active metabolites during ] in the ] and ]s.<ref name="pmid16112947" /><ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> The major metabolite of norgestimate is norelgestromin and is formed from norgestimate via ] in the liver and intestines.<ref name="Prefest FDA Label" /> 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,<ref name="Mishell1999" /><ref name="pmid8842581" /> and a very minor metabolite of norgestimate is ].<ref name="Prefest FDA Label" /> Both of these ]s are ] similarly to norgelstromin.<ref name="pmid16112947" /><ref name="Prefest FDA Label" /> 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.<ref name="Mishell1999" /> This is similar to the ]-inhibiting dosage of levonorgestrel, and suggests that norgestimate may act in considerable part as a prodrug specifically of levonorgestrel.<ref name="Mishell1999" /><ref name="pmid16112947" /> Following their formation, the ]s of norgestimate are inactivated via ], ], and ] into levonorgestrel metabolites.<ref name="pmid16112947" /><ref name="Ortho Cyclen FDA Label" /> The ] of norelgestromin is between 17 and 37 hours and of levonorgestrel is between 24 and 32 hours.<ref name="Prefest FDA Label" /><ref name="pmid16112947" /> The metabolites of norgestimate are ] 47% in ] and 37% in ].<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> Unchanged norgestimate is undetectable in urine.<ref name="Ortho Cyclen FDA Label" /> |
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==Chemistry== |
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{{See also|List of progestogens|Progestogen ester|List of progestogen esters}} |
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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 a ] ] ] and a ] of ].<ref name="Elks2014" /><ref name="Drugs.com" /> It is a ] of ]s.<ref name="US7345183">{{Cite patent | country = US | number = 7345183 |url=https://www.google.com/patents/US7345183|title = Process for obtaining norelgestromin in different relations of isomers e and Z | assign1 = Gador SA | inventor = Tombari DG, Vecchioli A | gdate = 18 March 2008 }}</ref> Norgestimate is more specifically a derivative of ] (17α-ethynyl-19-nortestosterone) and is a member of the ] (18-methylestrane) subgroup of the ] family of progestins.<ref name="StraussBarbieri2009">{{cite book| vauthors = Schreiber CA, Barnhart K | chapter = Chapter 36 - Contraception | veditors = Strauss JF, Barbieri RL |title=Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management| chapter-url = https://books.google.com/books?id=NudwnhxY8kYC&pg=PA878|year=2009|publisher=Elsevier Health Sciences|isbn=978-1-4160-4907-4|pages=878–}}</ref> It is the C3 ] and C17β ] ] of ] and is also known as levonorgestrel acetate oxime.<ref name="Skouby1997">{{cite book| vauthors = Skouby SO |title=Clinical Perspectives on a New Gestodene Oral Contraceptive Containing 20 μg of Ethinylestradiol|url=https://books.google.com/books?id=IYj54F5zvM4C&pg=PA11|date=15 July 1997|publisher=CRC Press|isbn=978-1-85070-786-8|pages=11–}}</ref> A related compound is ] (norethisterone-3-oxime 17β-acetate).<ref name="Elks2014" /> |
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==History== |
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Norgestimate was introduced as a component of combined oral contraceptives in 1986.<ref name="RunnebaumRabe2012">{{cite book | vauthors = van Keep PA, Rekers H | chapter = Trends in Contraception and Contraceptive Research | veditors = Runnebaum BC, Rabe T, Kiesel L |title=Female Contraception: Update and Trends |chapter-url=https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA13 |date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73790-9|pages=13–}}</ref> Based on its year of introduction, norgestimate is sometimes described as a "third-generation" progestin.<ref name="Carp2015" /> 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.<ref name="FDA2013">{{cite book|author=Food and Drug Administration|title=Approved Drug Products with Therapeutic Equivalence Evaluations - FDA Orange Book 33rd Edition (2013): FDA Orange Book 33rd Edition (2013)|date=15 August 2023 |url=https://books.google.com/books?id=5uSMDAAAQBAJ&pg=PR190|publisher=Logos Press|isbn=978-1-934899-83-0|pages=190–}}</ref> |
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==Society and culture== |
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===Generic names=== |
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Norgestimate is the ] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|DCF|Dénomination Commune Française}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA887|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=887–}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/norgestimate.html|title = Norgestimate and Ethinyl Estradiol - FDA prescribing information, side effects and uses}}</ref> It is also known by its developmental code name ORF-10131.<ref name="Elks2014" /><ref name="Drugs.com" /> |
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===Brand names=== |
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Norgestimate is marketed in combination with ] 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.<ref name="Elks2014" /><ref name="Drugs.com" /> It is marketed in combination with ] for menopausal hormone therapy under the brand name Prefest.<ref name="Drugs.com" /> |
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===Availability=== |
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Norgestimate in combination with ] 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.<ref name="Drugs.com" /> Unlike the combined birth control pills of norgestimate with ethinylestradiol, the combination of norgestimate with ], sold under the brand name Prefest for menopausal hormone therapy, is reportedly only marketed in the United States and Brazil.<ref name="Drugs.com" /> |
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==Research== |
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A 2017 study found that norgestimate inhibits ] ] formation and resensitizes ]-resistant '']'' to ]s.<ref name="pmid28758016">{{cite journal | vauthors = Yoshii Y, Okuda KI, Yamada S, Nagakura M, Sugimoto S, Nagano T, Okabe T, Kojima H, Iwamoto T, Kuwano K, Mizunoe Y | display-authors = 6 | title = Norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant ''Staphylococcus aureus'' to β-lactam antibiotics | journal = npj Biofilms and Microbiomes | volume = 3 | pages = 18 | date = 2017 | pmid = 28758016 | pmc = 5522392 | doi = 10.1038/s41522-017-0026-1 }}</ref> In contrast, ] showed much weaker activity, indicating that the ] of norgestimate is important for the activity.<ref name="pmid28758016" /> It was suggested by the researchers that norgestimate may be a promising ] for the development of new antibiotics.<ref name="pmid28758016" /> |
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== References == |
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{{Reflist}} |
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== Further reading == |
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{{refbegin}} |
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* {{cite journal | vauthors = Henzl MR | title = Norgestimate. From the laboratory to three clinical indications | journal = The Journal of Reproductive Medicine | volume = 46 | issue = 7 | pages = 647–661 | date = July 2001 | pmid = 11499185 }} |
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* {{cite journal | vauthors = Curran MP, Wagstaff AJ | title = Estradiol and norgestimate: a review of their combined use as hormone replacement therapy in postmenopausal women | journal = Drugs & Aging | volume = 18 | issue = 11 | pages = 863–885 | date = 2001 | pmid = 11772126 | doi = 10.2165/00002512-200118110-00007 | s2cid = 22720686 }} |
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* {{cite journal | vauthors = Curran MP, Wagstaff AJ | title = Spotlight on estradiol and norgestimate as hormone replacement therapy in postmenopausal women | journal = Treatments in Endocrinology | volume = 1 | issue = 2 | pages = 127–129 | date = 2002 | pmid = 15765628 | doi = 10.2165/00024677-200201020-00006 | s2cid = 1936039 }} |
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{{refend}} |
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{{Progestogens and antiprogestogens}} |
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{{Androgens and antiandrogens}} |
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{{Progesterone receptor modulators}} |
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{{Androgen receptor modulators}} |
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{{Portal bar | Medicine}} |
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{{Authority control}} |
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