Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Norgestimate: Difference between pages

{{Short description|Chemical compound}}

{{Distinguish|Norgestomet}}

{{Use dmy dates|date=October 2021}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Verifiedfields = verified

| Watchedfields = verified

| verifiedrevid = 462263110

| width = 250

| alt =

| image2 = Norgestimate molecule ball.png

| width2 = 250

| alt2 =

<!-- Clinical data -->

| pronounce =

| tradename = Ortho Tri-Cyclen, others

| Drugs.com = {{drugs.com|ppa|ethinyl-estradiol-and-norgestimate}}<br />{{drugs.com|ppa|estradiol-and-norgestimate}}

| DailyMedID = Norgestimate

| pregnancy_AU_comment =

| pregnancy_category = Use is contraindicated

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Progestogen (medication)|Progestogen]]; [[Progestin]]; [[Progestogen ester]]<ref name="pmid16112947" />

| ATC_prefix = G03

| ATC_suffix = AA11

| ATC_supplemental = {{ATC|G03|FA13}} (only combinations with [[estrogen (medication)|estrogen]]s)

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| 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 -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment =

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| 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>

| protein_bound = • Norelgestromin: 99% (to [[human serum albumin|albumin]])<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" />

| metabolism = [[Liver]], [[intestine]]s ([[acetylation|deacetylation]], [[redox|reduction]], [[hydroxylation]], [[conjugation (biochemistry)|conjugation]])<ref name="pmid16112947" /><ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" />

| metabolites = • [[Norelgestromin]]<ref name="pmid16112947" /><br />• [[Levonorgestrel]]<ref name="pmid16112947" /><br />• [[Levonorgestrel acetate]]<ref name="pmid16112947" />

| onset =

| 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" />

| duration_of_action =

| excretion = [[Urine]]: 47%<ref name="Ortho Cyclen FDA Label" /><br />[[Feces]]: 37%<ref name="Ortho Cyclen FDA Label" />

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|CAS}}

| IUPHAR_ligand = 7091

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1200934

| NIAID_ChemDB =

| PDB_ligand =

| 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

<!-- Chemical and physical data -->

| IUPAC_name = [(3''E'',8''R'',9''S'',10''R'',13''S'',14''S'',17''R'')-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[''a'']phenanthren-17-yl] acetate

| C=23 | H=31 | N=1 | O=3

| SMILES = O=C(O[C@@]2(C#C)CC[C@H]1[C@H]4[C@H](CC[C@@]12CC)[C@@H]3/C(=C\C(=N\O)CC3)CC4)C

| density =

| density_notes =

| melting_point = 214

| melting_high = 218

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Norgestimate''', sold under the brand name '''Ortho Tri-Cyclen''' among others, is a [[progestin]] medication which is used in [[birth control pill]]s for women and in [[menopausal hormone therapy]].<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 [[estrogen (medication)|estrogen]] and is not available alone.<ref name="Drugs.com" /> It is taken [[oral administration|by mouth]].<ref name="pmid16112947" />

<!-- Side effects and mechanism -->

[[Side effect]]s of the combination of an estrogen and norgestimate include [[menstrual irregularities]], [[headache]]s, [[nausea]], [[abdominal pain]], [[breast tenderness]], [[mood (psychology)|mood]] changes, and others.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> Norgestimate is a progestin, or a [[synthetic compound|synthetic]] [[progestogen (medication)|progestogen]], and hence is an [[agonist]] of the [[progesterone receptor]], the [[biological target]] of progestogens like [[progesterone]].<ref name="pmid16112947" /> It has very weak [[androgen]]ic activity and no other important [[hormonal agent|hormonal]] activity.<ref name="pmid16112947" /> The medication is a [[prodrug]] of [[norelgestromin]] and to a lesser extent of [[levonorgestrel]] in the body.<ref name="pmid16112947" />

<!-- History, society and culture -->

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 [[generic drug|generic medication]].<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 [[ethinylestradiol]] 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>

{{TOC limit}}

==Medical uses==

Norgestimate is used in [[hormonal contraception]] and in [[menopausal hormone therapy]] for the treatment of [[menopause|menopausal]] [[symptom]]s.<ref name="LemkeWilliams2008" /> It is used in combination with [[ethinylestradiol]] in [[birth control pill]]s and in combination with [[estradiol (medication)|estradiol]] in menopausal hormone therapy.<ref name="Drugs.com" /><ref name="pmid11499185" />

===Available forms===

Norgestimate is available only in combination with the [[estrogen (medication)|estrogen]]s [[ethinylestradiol]] and [[estradiol (medication)|estradiol]].<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" />

==Contraindications==

{{See also|Progestin#Contraindications}}

==Side effects==

{{See also|Norelgestromin#Side effects|Progestin#Side effects}}

Norgestimate has mostly been studied in combination with an estrogen, so the [[side effect]]s of norgestimate specifically or on its own have not been well-defined.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" />

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 [[menstrual cycle]]s, include [[headache]]/[[migraine]] (33%), [[abdominal pain|abdominal/gastrointestinal pain]] (7.8%), [[vaginal infection]] (8.4%), [[vaginal discharge]] (6.8%), [[breast disorder|breast issues]] (including [[breast pain]], [[breast discharge|discharge]], and [[breast enlargement|enlargement]]) (6.3%), [[mood disorder]]s (including depression and mood alterations) (5.0%), [[flatulence]] (3.2%), [[anxiety|nervousness]] (2.9%), and [[rash]] (2.6%).<ref name="Ortho Cyclen FDA Label" />

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 (medical)|fatigue]] (6%), [[pain]] (6%), [[nausea]] (6%), [[viral infection]] (6%), flatulence (5%), [[tooth disorder]] (5%), [[myalgia]] (5%), [[dizziness]] (5%), [[depression (mood)|depression]] (5%), and [[coughing]] (5%).<ref name="Prefest FDA Label" />

==Overdose==

{{See also|Progestin#Overdose}}

== Interactions ==

{{See also|Progestin#Interactions}}

==Pharmacology==

===Pharmacodynamics===

[[File:Norelgestromin.svg|thumb|right|225px|[[Norelgestromin]], also known as 17β-deacetylnorgestimate, the main [[active metabolite]] of norgestimate.]]

Norgestimate is a rapidly and completely converted [[prodrug]], mainly of [[norelgestromin]] (17β-deacetylnorgestimate or levonorgestrel 3-oxime), but also of [[levonorgestrel]] (3-keto-17β-deacetylnorgestimate) to a lesser extent (22 ± 6% of an administered dose or about 40–70&nbsp;μg)<ref name="pmid8842581" /> and of [[levonorgestrel acetate]] (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 [[active metabolite]]s, norgestimate has [[progestogen (medication)|progestogen]]ic activity, [[antigonadotropic]] effects, very weak [[androgen]]ic activity, and no other important [[hormonal]] activity.<ref name="pmid16112947" />

{| class="wikitable mw-collapsible mw-collapsed" style="text-align:left; margin-left:auto; margin-right:auto; border:none;"

|+ class="nowrap" | Relative affinities (%) of norgestimate and metabolites

|-

! 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}}

|-

| Norgestimate || 15 || 0 || 0 || 1 || 0 || 0 || 0

|-

| [[Norelgestromin]] ({{abbr|17β-deAc-NGM|17β-deacetylnorgestimate}}) || 10 || 0 || ? || ? || ? || 0 || ?

|-

| [[Levonorgestrel]] ({{abbr|3-keto-17β-deAc-NGM|3-keto-17β-deacetylnorgestimate}}) || 150–162 || 45 || 0 || 1–8 || 17–75 || 50 || 0

|-

| [[Levonorgestrel 17β-acetate]] ({{abbr|3-keto-NGM|3-ketonorgestimate}}) || 135 || ? || 0 || ? || ? || 0 || ?

|- class="sortbottom"

| colspan="8" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' Values are percentages (%). Reference [[ligand (biochemistry)|ligand]]s (100%) were [[promegestone]] for the {{abbrlink|PR|progesterone receptor}}, [[metribolone]] for the {{abbrlink|AR|androgen receptor}}, [[estradiol (medication)|{{abbr|E2|estradiol}}]] for the {{abbrlink|ER|estrogen receptor}}, {{abbrlink|DEXA|dexamethasone}} for the {{abbrlink|GR|glucocorticoid receptor}}, [[aldosterone]] for the {{abbrlink|MR|mineralocorticoid receptor}}, {{abbrlink|DHT|dihydrotestosterone}} for {{abbrlink|SHBG|sex hormone-binding globulin}}, and [[hydrocortisone|cortisol]] 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>

|}

====Progestogenic activity====

Norgestimate is a [[progestogen (medication)|progestogen]], or an [[agonist]] of the [[progesterone receptor]].<ref name="pmid16112947" /> The [[relative binding affinity|relative binding affinities]] of norgestimate and its active metabolites for the progesterone receptor compared to [[promegestone]] (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 [[biological activity]] of norgestimate.<ref name="pmid16112947" /> In addition, although levonorgestrel binds to the progesterone receptor with much higher [[affinity (pharmacology)|affinity]] than norelgestromin, levonorgestrel has high affinity for [[sex hormone-binding globulin]] (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 [[ovulation]]-inhibiting dosage of norgestimate is 200&nbsp;μg/day.<ref name="pmid16112947" />

====Androgenic activity====

In addition to its progestogenic activity, norgestimate has weak [[androgen]]ic activity.<ref name="pmid16112947" /> However, the medication shows less androgenic activity than related [[19-nortestosterone]] progestins like levonorgestrel and [[norethisterone]].<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 [[androgen receptor]] (both 0% of the affinity of [[metribolone]]), 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 [[testosterone]] 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, [[clinical trial]]s of norgestimate have observed minimal androgenic [[side effect]]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 [[ethinylestradiol]].<ref name="pmid1415445" /> This is of interest because [[estrogen (medication)|estrogen]]s increase and [[androgen]]s decrease [[liver protein production|liver production]] of SHBG and by extension circulating levels of SHBG.<ref name="pmid1415445" />

The relative binding affinity of norgestimate and its metabolite norelgestromin for the rat [[prostate gland|prostatic]] [[androgen receptor]] (AR) are 0.3% and 1.3% of those of [[dihydrotestosterone]] (DHT), respectively, whereas the respective values for [[levonorgestrel]] and [[gestodene]] 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 [[progesterone (medication)|progesterone]], 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" />

When norgestimate is combined with ethinylestradiol, which is potently [[antiandrogen]]ic, there are only antiandrogenic effects overall and the combination is suitable for treatment of [[hyperandrogenism]].<ref name="pmid11499185" />

====Other activities====

Norgestimate and its active metabolites do not bind to other [[steroid hormone receptor]]s besides the progesterone and androgen receptors and hence have no other [[off-target activity|off-target]] hormonal activity.<ref name="pmid16112947" /> This includes [[estrogen (medication)|estrogen]]ic, [[glucocorticoid]], [[antimineralocorticoid]], and [[neurosteroid]] activity.<ref name="pmid16112947" /> However, levonorgestrel has been found to [[enzyme inhibitor|inhibit]] [[5α-reductase]] and [[liver|hepatic]] [[cytochrome P450]] [[enzyme]]s ''[[in vitro]]'' to some extent.<ref name="pmid16112947" />

===Pharmacokinetics===

Norgestimate is rapidly and almost completely [[metabolism|metabolized]] into its [[active metabolite]]s, mainly [[norelgestromin]] (the primary active metabolite) and to a lesser extent [[levonorgestrel]], upon [[oral administration|oral]] ingestion.<ref name="pmid16112947" /><ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> As a result, only very low concentrations (70&nbsp;pg/mL) of norgestimate itself are detectable in the circulation, and only for about 6&nbsp;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 [[bioavailability]] 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 [[area-under-the-curve (pharmacokinetics)|area-under-the-curve]] (AUC) to do so.<ref name="Mishell1999" /> [[Cmax (pharmacology)|Peak levels]] of norelgestromin (3,500&nbsp;pg/mL) are reached at approximately 2&nbsp;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 [[area under the curve (pharmacokinetics)|area-under-the-curve]] levels of norelgestromin are not significantly altered by food.<ref name="Prefest FDA Label" /> [[Steady state (pharmacokinetics)|Steady-state]] levels of norelgestromin and levonorgestrel are reached within 21&nbsp;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 [[affinity (pharmacology)|affinity]] for SHBG, which limits its [[biological activity]].<ref name="Ortho Cyclen FDA Label" /> The [[plasma protein binding]] of norelgestromin is approximately 99% and it is bound to [[human serum albumin|albumin]] 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 [[plasma protein]]s and is bound to both albumin and SHBG.<ref name="pmid16112947" /><ref name="Ortho Cyclen FDA Label" />

Norgestimate is extensively metabolized into its active metabolites during [[first-pass metabolism]] in the [[liver]] and [[intestine]]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 [[deacetylation]] 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&nbsp;μg norgestimate,<ref name="Mishell1999" /><ref name="pmid8842581" /> and a very minor metabolite of norgestimate is [[levonorgestrel 17β-acetate]].<ref name="Prefest FDA Label" /> Both of these [[metabolite]]s are [[biological activity|active]] similarly to norgelstromin.<ref name="pmid16112947" /><ref name="Prefest FDA Label" /> With a typical oral contraceptive dosage of norgestimate of 200 to 250&nbsp;μg/day, an amount of 50 to 60&nbsp;μg/day levonorgestrel may be produced.<ref name="Mishell1999" /> This is similar to the [[ovulation]]-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 [[active metabolite]]s of norgestimate are inactivated via [[redox|reduction]], [[hydroxylation]], and [[conjugation (biochemistry)|conjugation]] into levonorgestrel metabolites.<ref name="pmid16112947" /><ref name="Ortho Cyclen FDA Label" /> The [[terminal half-life]] of norelgestromin is between 17 and 37&nbsp;hours and of levonorgestrel is between 24 and 32&nbsp;hours.<ref name="Prefest FDA Label" /><ref name="pmid16112947" /> The metabolites of norgestimate are [[elimination (pharmacology)|eliminated]] 47% in [[urine]] and 37% in [[feces]].<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> Unchanged norgestimate is undetectable in urine.<ref name="Ortho Cyclen FDA Label" />

==Chemistry==

{{See also|List of progestogens|Progestogen ester|List of progestogen esters}}

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 [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[testosterone (medication)|testosterone]].<ref name="Elks2014" /><ref name="Drugs.com" /> It is a [[racemic mixture]] of [[cis–trans isomerism|''E'' and ''Z'' isomer]]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 [[norethisterone]] (17α-ethynyl-19-nortestosterone) and is a member of the [[gonane]] (18-methylestrane) subgroup of the [[19-nortestosterone]] 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 [[oxime]] and C17β [[acetate]] [[ester]] of [[levonorgestrel]] 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&nbsp;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 acetate oxime]] (norethisterone-3-oxime 17β-acetate).<ref name="Elks2014" />

==History==

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>

==Society and culture==

===Generic names===

Norgestimate is the [[generic term|generic name]] 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" />

===Brand names===

Norgestimate is marketed in combination with [[ethinylestradiol]] 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 [[estradiol (medication)|estradiol]] for menopausal hormone therapy under the brand name Prefest.<ref name="Drugs.com" />

===Availability===

Norgestimate in combination with [[ethinylestradiol]] 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 [[estradiol (medication)|estradiol]], sold under the brand name Prefest for menopausal hormone therapy, is reportedly only marketed in the United States and Brazil.<ref name="Drugs.com" />

==Research==

A 2017 study found that norgestimate inhibits [[staphylococcus|staphylococcal]] [[biofilm]] formation and resensitizes [[methicillin]]-resistant ''[[Staphylococcus aureus]]'' to [[β-lactam antibiotic]]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, [[norelgestromin]] showed much weaker activity, indicating that the [[acetyl group]] of norgestimate is important for the activity.<ref name="pmid28758016" /> It was suggested by the researchers that norgestimate may be a promising [[lead compound]] for the development of new antibiotics.<ref name="pmid28758016" />

== References ==

{{Reflist}}

== Further reading ==

{{refbegin}}

* {{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 }}

* {{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 }}

* {{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 }}

{{refend}}

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