Norelgestromin

{{Drugbox

| Verifiedfields = verified

| Watchedfields = verified

| verifiedrevid = 464196488

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

| image = Norelgestromin.svg

| width = 250px

| image2 = Norelgestromin molecule ball.png

| width2 = 250px

| tradename = Evra, Ortho Evra, Xulane, others

| Drugs.com = {{drugs.com|international|norelgestromin}}

| MedlinePlus = a602006

| pregnancy_US =

| licence_EU = yes

| legal_status = Rx

| routes_of_administration = Transdermal patch

| class = Progestogen; Progestin

| bioavailability =

| protein_bound = 99% (to albumin but not to {{abbrlink|SHBG|sex hormone-binding globulin}}){{cite web | title = ORTHO-CYCLEN and ORTHO TRI-CYCLEN (norgestimate/ethinyl estradiol) tablets, for oral use | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019653s058,019697s054lbl.pdf | work = Janssen Pharmaceuticals, Inc. | date = August 2017 | publisher = U.S. Food and Drug Administration }}

| metabolism = Liver (oxime to ketone reaction, hydroxylation, conjugation)

| metabolites = • Levonorgestrel

| elimination_half-life = 17–37 hours{{cite web | title = PREFEST (estradiol/norgestimate) tablets | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021040s013lbl.pdf | date = November 2017 | work = Teva Pharmaceuticals | publisher = U.S. Food and Drug Administration }}

| excretion = Urine and feces

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

| CAS_number = 53016-31-2

| ATC_prefix = G03

| ATC_suffix = AA13

| ATC_supplemental = (only combinations with estrogens)

| PubChem = 62930

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB06713

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 56648

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = R0TAY3X631

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D05205

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

| ChEBI = 135398

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

| ChEMBL = 1200807

| synonyms = Norelgestromine; NGMN; RWJ-10553; Levonorgestrel 3-oxime; 17β-Deacetylnorgestimate; 17α-Ethynyl-18-methyl-19-nortestosterone 3-oxime; 17α-Ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime

| C=21 | H=29 | N=1 | O=2

| SMILES = ON=C4\C=C3/[C@@H]([C@H]2CC[C@]1([C@@H](CC[C@]1(C#C)O)[C@@H]2CC3)CC)CC4

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C21H29NO2/c1-3-20-11-9-17-16-8-6-15(22-24)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,13,16-19,23-24H,3,5-12H2,1H3/t16-,17+,18+,19-,20-,21-/m0/s1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = ISHXLNHNDMZNMC-XUDSTZEESA-N

}}

Norelgestromin, or norelgestromine, sold under the brand names Evra and Ortho Evra among others, is a progestin medication which is used as a method of birth control for women.{{cite web | work = Drugs.com | url = https://www.drugs.com/cdi/norelgestromin-ethinyl-estradiol-patch.html | title = Norelgestromin/Ethinyl Estradiol Patch }}{{cite journal | vauthors = Crosignani PG, Nappi C, Ronsini S, Bruni V, Marelli S, Sonnino D | title = Satisfaction and compliance in hormonal contraception: the result of a multicentre clinical study on women's experience with the ethinylestradiol/norelgestromin contraceptive patch in Italy | journal = BMC Women's Health | volume = 9 | issue = 1 | pages = 18 | date = June 2009 | pmid = 19566925 | pmc = 2714834 | doi = 10.1186/1472-6874-9-18 | doi-access = free }} The medication is available in combination with an estrogen and is not available alone. It is used as a patch that is applied to the skin.

Side effects of the combination of an estrogen and norelgestromin include menstrual irregularities, headaches, nausea, abdominal pain, breast tenderness, mood changes, and others. Norelgestromin is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has very weak androgenic activity and no other important hormonal activity.

Norelgestromin was introduced for medical use in 2002. It is sometimes referred to as a "third-generation" progestin.{{cite book| vauthors = Borgelt LM |title=Women's Health Across the Lifespan: A Pharmacotherapeutic Approach|url=https://books.google.com/books?id=riP3pxq2jWAC&pg=PA294|year=2010|publisher=ASHP|isbn=978-1-58528-194-7|pages=294–}}{{cite book| vauthors = Vaamonde D, du Plessis SS, Agarwal A |title=Exercise and Human Reproduction: Induced Fertility Disorders and Possible Therapies|url=https://books.google.com/books?id=d86zCwAAQBAJ&pg=PA288|date=7 March 2016|publisher=Springer|isbn=978-1-4939-3402-7|pages=288–}} Norelgestromin is marketed widely throughout the world. It is available as a generic medication.{{cite web|url=https://www.empr.com/generics-news/first-generic-ortho-evra-patch-launched/article/343041/|title=First Generic Ortho Evra Patch Launched|date=17 April 2014 | work = Medical Professionals Reference (MPR) | publisher = Haymarket Media, Inc. }}

Medical uses

Norelgestromin is used in combination with ethinyl estradiol in contraceptive patches. These patches mediate their contraceptive effects by suppressing gonadotropin levels as well as by causing changes in the cervical mucus and endometrium that diminish the likelihood of pregnancy.

=Available forms=

Norelgestromin is available only as a transdermal contraceptive patch in combination with ethinyl estradiol. The Ortho Evra patch is a 20 cm{{Sup|2}}, once-weekly adhesive that contains 6.0 mg norelgestromin and 0.6 mg ethinyl estradiol and delivers 200 μg/day norelgestromin and 35 μg/day ethinyl estradiol.{{cite journal | vauthors = Galzote RM, Rafie S, Teal R, Mody SK | title = Transdermal delivery of combined hormonal contraception: a review of the current literature | journal = International Journal of Women's Health | volume = 9 | pages = 315–321 | date = 2017 | pmid = 28553144 | pmc = 5440026 | doi = 10.2147/IJWH.S102306 | doi-access = free }}

Contraindications

Side effects

Norelgestromin has mostly been studied in combination with an estrogen, so the side effects of norelgestromin specifically or on its own have not been well-defined. Side effects associated with the combination of ethinylestradiol and norelgestromin as a transdermal patch in premenopausal women, with greater than or equal to 2.5% incidence over 6 to 13 menstrual cycles, include breast symptoms (including discomfort, engorgement, and/or pain; 22.4%), headaches (21.0%), application site reactions (17.1%), nausea (16.6%), abdominal pain (8.1%), dysmenorrhea (7.8%), vaginal bleeding and menstrual disorders (6.4%), mood, affect, and anxiety disorders (6.3%), vomiting (5.1%), diarrhea (4.2%), vaginal yeast infections (3.9%), dizziness (3.3%), acne (2.9%), migraine (2.7%), weight gain (2.7%), fatigue (2.6%), and pruritus (2.5%).

Overdose

Interactions

Pharmacology

=Pharmacodynamics=

Norelgestromin is a progestogen. It is one of the active metabolites of norgestimate.{{cite book| vauthors = Doherty AM |title=Annual Reports in Medicinal Chemistry|url=https://books.google.com/books?id=ECfQ6D5JLusC&pg=PA362|year=2003|publisher=Academic Press|isbn=978-0-12-040538-1|pages=362–}}{{cite book| vauthors = Offermanns S, Rosenthal W |title=Encyclopedia of Molecular Pharmacology|url=https://books.google.com/books?id=iwwo5gx8aX8C&pg=PA391|date=14 August 2008|publisher=Springer Science & Business Media|isbn=978-3-540-38916-3|pages=391–}} Unlike many related progestins, norelgestromin reportedly has negligible androgenic activity. However, it produces levonorgestrel as an active metabolite to some extent, which does have some androgenic activity.{{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 }} Nonetheless, transdermally-administered norelgestromin does not counteract the increase in sex hormone-binding globulin levels produced by ethinyl estradiol.

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}}
class="wikitable mw-collapsible mw-collapsed" style="text-align:left; margin-left:auto; margin-right:auto; border:none;" \|+ class="nowrap" \| Relative affinities (%) of norelgestromin and metabolites
Norelgestromin	10	0	?	?	?	0	?
Levonorgestrel ({{abbr\|3-keto-NGMN\|3-ketonorelgestromin}})	150–162	45	0	1–8	17–75	50	0
class="sortbottom" \| colspan="9" style="width:1px; background:#eaecf0; text-align:center;"\| Notes: Values are percentages (%). Reference ligands (100%) were prome- gestone for the {{abbrlink\|PR\|progesterone receptor}}, metribolone for the {{abbrlink\|AR\|androgen receptor}}, estradiol (medication) 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 cortisol for {{abbrlink\|CBG\|Corticosteroid-binding globulin}}. Sources: {{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 }}{{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 }}

=Pharmacokinetics=

Upon application of a transdermal patch containing norelgestromin and ethinyl estradiol, plateau levels of both are reached by approximately 48 hours, and steady-state levels are reached within 2 weeks of application. Absorption following application to the buttock, upper outer arm, abdomen, and upper torso was assessed and, while absorption from the abdomen was slightly lower, it was considered to be therapeutically equivalent for the various areas. Mean levels of norelgestromin at steady-state ranged from 0.305 ng/mL to 1.53 ng/mL, with an average of about 0.725 ng/mL. The plasma protein binding of norelgestromin is 99%, and it is bound to albumin but not to sex hormone-binding globulin.

The metabolism of norelgestromin takes place in the liver and is via transformation into levonorgestrel (conversion of the C3 oxime into a ketone) as well as hydroxylation and conjugation.{{cite web | title = ORTHO EVRA (norelgestromin / ethinyl estradiol TRANSDERMAL SYSTEM) | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021180s043lbl.pdf | work = Janssen Pharmaceuticals, Inc. | publisher = U.S. Food and Drug Administration | date = August 2012 }} However, because norelgestromin is used parenterally, first-pass metabolism in the liver and gastrointestinal tract that normally occurs with oral administration are avoided. The biological half-life of norelgestromin is 17 to 37 hours. The metabolites of norelgestromin, along with those of ethinyl estradiol, are eliminated in the urine and feces.

Chemistry

Norelgestromin, also known as 17α-ethynyl-18-methyl-19-nortestosterone 3-oxime or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime, is a synthetic estrane steroid and a derivative of testosterone. It is a racemic mixture of E and Z isomers, which have approximately the same activity.{{cite patent |url=https://www.google.com/patents/US7345183 | country = US | number = 7345183|title = Process for obtaining norelgestromin in different relations of isomers E and Z | inventor = Tombari DG, Vecchioli A | assign1 = Gador SA | gdate = 18 March 2008 | postscript = . }} Norelgestromin 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.{{cite book| vauthors = Brucker MC, King TL |title=Pharmacology for Women's Health|url=https://books.google.com/books?id=AniUCgAAQBAJ&pg=PA368|date=8 September 2015|publisher=Jones & Bartlett Publishers|isbn=978-1-284-05748-5|pages=368–}}{{cite book| vauthors = Shoupe D |title=The Handbook of Contraception: A Guide for Practical Management|url=https://books.google.com/books?id=sczb0Tk_2IwC&pg=PA16|date=7 November 2007|publisher=Springer Science & Business Media|isbn=978-1-59745-150-5|pages=16–}} It is the C3 oxime derivative of levonorgestrel and the C17β deacetyl derivative of norgestimate and is also known as levonorgestrel 3-oxime and as 17β-deacetylnorgestimate.{{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=PA150|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=150–151}} A related progestin is norethisterone acetate oxime (17α-ethynyl-19-nortestosterone 3-oxime 17β-acetate).{{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=PA886|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=886–}}

History

Norelgestromin was introduced for medical use in 2002.{{cite book| vauthors = Macor JE |title=Annual Reports in Medicinal Chemistry|url=https://books.google.com/books?id=xpe9Mk50BGsC&pg=PA620|year=2012|publisher=Academic Press|isbn=978-0-12-396492-2|pages=620–}}

Society and culture

=Generic names=

Norelgestromin is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}.{{cite web|url=https://www.drugs.com/international/norelgestromin.html |title=Norelgestromin - brand name list from |publisher=Drugs.com |date= |access-date=2022-09-17}} The combined ethinyl estradiol and norelgestromin contraceptive patch is also known by its developmental code name RWJ-10553.{{cite web|url=http://adisinsight.springer.com/drugs/800013168|title = Ethinylestradiol/Norelgestromin transdermal - Johnson & Johnson | work = AdisInsight | publisher = Springer Nature Switzerland AG }}

=Brand names=

Norelgestromin is marketed under the brand names Evra, Ortho Evra, Xulane, and others, all in combination with ethinylestradiol.

=Availability=

Norelgestromin is marketed widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, South Africa, Latin America, Asia, and elsewhere in the world. It is not listed as being marketed in Australia, New Zealand, Japan, South Korea, China, India, or certain other countries.

Research

A transdermal gel formulation of norgelstromin and ethinyl estradiol was under development by Antares Pharma for use as a method of birth control with the code name AP-1081 but development was discontinued.{{cite web|url=http://adisinsight.springer.com/drugs/800022316|title = Ethinylestradiol/Norelgestromin | work = AdisInsight | publisher = Springer Nature Switzerland AG }}