Norelgestromin

Last updated
Norelgestromin
Norelgestromin.svg
Norelgestromin molecule ball.png
Clinical data
Trade names Evra, Ortho Evra, Xulane, others
Other namesNorelgestromine; 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
AHFS/Drugs.com International Drug Names
MedlinePlus a602006
License data
Routes of
administration
Transdermal patch
Drug class Progestogen; Progestin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding 99% (to albumin but not to SHBG Tooltip sex hormone-binding globulin) [1] [2] [3]
Metabolism Liver (oxime to ketone reaction, hydroxylation, conjugation) [4]
Metabolites Levonorgestrel [4]
Elimination half-life 17–37 hours [1] [3]
Excretion Urine and feces [4]
Identifiers
  • (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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.170.714 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H29NO2
Molar mass 327.468 g·mol−1
3D model (JSmol)
  • ON=C4\C=C3/[C@@H]([C@H]2CC[C@]1([C@@H](CC[C@]1(C#C)O)[C@@H]2CC3)CC)CC4
  • InChI=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 Yes check.svgY
  • Key:ISHXLNHNDMZNMC-XUDSTZEESA-N Yes check.svgY
   (verify)

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. [5] [6] [7] The medication is available in combination with an estrogen and is not available alone. [5] It is used as a patch that is applied to the skin. [6] [7]

Contents

Side effects of the combination of an estrogen and norelgestromin include menstrual irregularities, headaches, nausea, abdominal pain, breast tenderness, mood changes, and others. [4] Norelgestromin is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [8] [9] It has very weak androgenic activity and no other important hormonal activity. [8] [9]

Norelgestromin was introduced for medical use in 2002. [10] It is sometimes referred to as a "third-generation" progestin. [11] [12] Norelgestromin is marketed widely throughout the world. [5] It is available as a generic medication. [13]

Medical uses

Norelgestromin is used in combination with ethinyl estradiol in contraceptive patches. [6] [4] [7] 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. [4]

Available forms

Norelgestromin is available only as a transdermal contraceptive patch in combination with ethinyl estradiol. [6] The Ortho Evra patch is a 20 cm2, 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. [4] [14]

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. [4] 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%). [4]

Overdose

Interactions

Pharmacology

Pharmacodynamics

Norelgestromin is a progestogen. [3] [4] It is one of the active metabolites of norgestimate. [8] [9] Unlike many related progestins, norelgestromin reportedly has negligible androgenic activity. [9] However, it produces levonorgestrel as an active metabolite to some extent, which does have some androgenic activity. [4] [3] Nonetheless, transdermally-administered norelgestromin does not counteract the increase in sex hormone-binding globulin levels produced by ethinyl estradiol. [4]

Relative affinities (%) of norelgestromin and metabolites
Compound PR Tooltip Progesterone receptor AR Tooltip Androgen receptor ER Tooltip Estrogen receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Norelgestromin100 ? ? ?0 ?
Levonorgestrel (3-keto-NGMN)150–1624501–817–75500
Notes: Values are percentages (%). Reference ligands (100%) were prome- gestone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, E2 for the ER Tooltip estrogen receptor, DEXA Tooltip dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, DHT Tooltip dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Sources: [15] [3] [16]

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. [4] 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. [4] 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. [4] The plasma protein binding of norelgestromin is 99%, and it is bound to albumin but not to sex hormone-binding globulin. [1] [2] [3]

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. [4] However, because norelgestromin is used parenterally, first-pass metabolism in the liver and gastrointestinal tract that normally occurs with oral administration are avoided. [4] The biological half-life of norelgestromin is 17 to 37 hours. [1] [3] The metabolites of norelgestromin, along with those of ethinyl estradiol, are eliminated in the urine and feces. [4]

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. [5] It is a racemic mixture of E and Z isomers, which have approximately the same activity. [17] 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. [18] [19] 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. [20] A related progestin is norethisterone acetate oxime (17α-ethynyl-19-nortestosterone 3-oxime 17β-acetate). [21]

History

Norelgestromin was introduced for medical use in 2002. [10]

Society and culture

Generic names

Norelgestromin is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name. [5] The combined ethinyl estradiol and norelgestromin contraceptive patch is also known by its developmental code name RWJ-10553. [22]

Brand names

Norelgestromin is marketed under the brand names Evra, Ortho Evra, Xulane, and others, all in combination with ethinylestradiol. [5] [13]

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. [5] It is not listed as being marketed in Australia, New Zealand, Japan, South Korea, China, India, or certain other countries. [5]

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. [23]

See also

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Levonorgestrel</span> Hormonal medication used for birth control

Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand names Plan B One-Step and Julie, among others, it is useful within 72 hours of unprotected sex. The more time that has passed since sex, the less effective the medication becomes, and it does not work after pregnancy (implantation) has occurred. Levonorgestrel works by preventing ovulation or fertilization from occurring. It decreases the chances of pregnancy by 57 to 93%. In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy. A levonorgestrel-releasing implant is also available in some countries.

<span class="mw-page-title-main">Contraceptive patch</span> Transdermal patch applied to prevent pregnancy

A contraceptive patch, also known as "the patch", is a transdermal patch applied to the skin that releases synthetic oestrogen and progestogen hormones to prevent pregnancy. They have been shown to be as effective as the combined oral contraceptive pill with perfect use, and the patch may be more effective in typical use.

<span class="mw-page-title-main">Ethinylestradiol</span> Estrogen medication

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Drospirenone</span> Medication drug

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Norgestrel</span> Progestin medication used for birth control

Norgestrel is a progestin which is used in birth control pills sold under the brand name Ovral in combination with the estrogen ethinylestradiol and Opill by itself. It is also used in menopausal hormone therapy. It is taken by mouth.

<span class="mw-page-title-main">Estrogen patch</span> Transdermal delivery system for estrogens

An estrogen patch, or oestrogen patch, is a transdermal delivery system for estrogens such as estradiol and ethinylestradiol which can be used in menopausal hormone therapy, feminizing hormone therapy for transgender women, hormonal birth control, and other uses. Transdermal preparations of estrogen are metabolized differently than oral preparations. Transdermal estrogens avoid the first pass through the liver and thus potentially reduce the risk of blood clotting and stroke.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Gestodene</span> Progestin medication

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norgestrienone</span> Chemical compound

Norgestrienone, sold under the brand names Ogyline, Planor, and Miniplanor, is a progestin medication which has been used in birth control pills, sometimes in combination with ethinylestradiol. It was developed by Roussel Uclaf and has been registered for use only in France. Under the brand name Planor, it has been marketed in France as 2 mg norgestrienone and 50 μg ethinylestradiol tablets. It is taken by mouth.

<span class="mw-page-title-main">Dienogest</span> Chemical compound

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone enanthate</span> Chemical compound

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

<span class="mw-page-title-main">Segesterone acetate</span> Progestin medication

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

Norelgestromin/ethinylestradiol, sold under the brand name Ortho Evra among others, is a contraceptive patch containing the progestin norelgestromin and the estrogen ethinylestradiol.

<span class="mw-page-title-main">Levonorgestrel acetate</span> Chemical compound

Levonorgestrel acetate (LNG-A), or levonorgestrel 17β-acetate, also known as 3-ketonorgestimate, is a progestin which was never marketed. It is a progestogen ester and is the C17β acetate ester and a prodrug of levonorgestrel. Norgestimate is the C3 oxime of LNG-A. The drug is a minor active metabolite of norgestimate, which is a prodrug of norelgestromin and to a lesser extent of levonorgestrel and LNG-A. LNG-A has high affinity for the progesterone receptor, about 135% of that of promegestone. Along with levonorgestrel butanoate, LNG-A was investigated as a hormonal contraceptive by the Population Council.

<span class="mw-page-title-main">Combined hormonal contraception</span> Form of hormonal contraception combining both an estrogen and a progestogen

Combined hormonal contraception (CHC), or combined birth control, is a form of hormonal contraception which combines both an estrogen and a progestogen in varying formulations.

References

  1. 1 2 3 4 "PREFEST (estradiol/norgestimate) tablets" (PDF). Teva Pharmaceuticals. U.S. Food and Drug Administration. November 2017.
  2. 1 2 "ORTHO-CYCLEN and ORTHO TRI-CYCLEN (norgestimate/ethinyl estradiol) tablets, for oral use" (PDF). Janssen Pharmaceuticals, Inc. U.S. Food and Drug Administration. August 2017.
  3. 1 2 3 4 5 6 7 Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID   16112947. S2CID   24616324.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 "ORTHO EVRA (norelgestromin / ethinyl estradiol TRANSDERMAL SYSTEM)" (PDF). Janssen Pharmaceuticals, Inc. U.S. Food and Drug Administration. August 2012.
  5. 1 2 3 4 5 6 7 8 "Norelgestromin - brand name list from". Drugs.com. Retrieved 2022-09-17.
  6. 1 2 3 4 "Norelgestromin/Ethinyl Estradiol Patch". Drugs.com.
  7. 1 2 3 Crosignani PG, Nappi C, Ronsini S, Bruni V, Marelli S, Sonnino D (June 2009). "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". BMC Women's Health. 9 (1): 18. doi: 10.1186/1472-6874-9-18 . PMC   2714834 . PMID   19566925.
  8. 1 2 3 Doherty AM (2003). Annual Reports in Medicinal Chemistry. Academic Press. pp. 362–. ISBN   978-0-12-040538-1.
  9. 1 2 3 4 Offermanns S, Rosenthal W (14 August 2008). Encyclopedia of Molecular Pharmacology. Springer Science & Business Media. pp. 391–. ISBN   978-3-540-38916-3.
  10. 1 2 Macor JE (2012). Annual Reports in Medicinal Chemistry. Academic Press. pp. 620–. ISBN   978-0-12-396492-2.
  11. Borgelt LM (2010). Women's Health Across the Lifespan: A Pharmacotherapeutic Approach. ASHP. pp. 294–. ISBN   978-1-58528-194-7.
  12. Vaamonde D, du Plessis SS, Agarwal A (7 March 2016). Exercise and Human Reproduction: Induced Fertility Disorders and Possible Therapies. Springer. pp. 288–. ISBN   978-1-4939-3402-7.
  13. 1 2 "First Generic Ortho Evra Patch Launched". Medical Professionals Reference (MPR). Haymarket Media, Inc. 17 April 2014.
  14. Galzote RM, Rafie S, Teal R, Mody SK (2017). "Transdermal delivery of combined hormonal contraception: a review of the current literature". International Journal of Women's Health. 9: 315–321. doi: 10.2147/IJWH.S102306 . PMC   5440026 . PMID   28553144.
  15. Kuhl H (September 1990). "Pharmacokinetics of oestrogens and progestogens". Maturitas. 12 (3): 171–197. doi:10.1016/0378-5122(90)90003-o. PMID   2170822.
  16. Philibert D, Bouchoux F, Degryse M, Lecaque D, Petit F, Gaillard M (October 1999). "The pharmacological profile of a novel norpregnance progestin (trimegestone)". Gynecological Endocrinology. 13 (5): 316–326. doi:10.3109/09513599909167574. PMID   10599548.
  17. US 7345183,Tombari DG, Vecchioli A,"Process for obtaining norelgestromin in different relations of isomers E and Z",issued 18 March 2008, assigned to Gador SA.
  18. Brucker MC, King TL (8 September 2015). Pharmacology for Women's Health. Jones & Bartlett Publishers. pp. 368–. ISBN   978-1-284-05748-5.
  19. Shoupe D (7 November 2007). The Handbook of Contraception: A Guide for Practical Management. Springer Science & Business Media. pp. 16–. ISBN   978-1-59745-150-5.
  20. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 150–151. ISBN   978-92-832-1291-1.
  21. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 886–. ISBN   978-1-4757-2085-3.
  22. "Ethinylestradiol/Norelgestromin transdermal - Johnson & Johnson". AdisInsight. Springer Nature Switzerland AG.
  23. "Ethinylestradiol/Norelgestromin". AdisInsight. Springer Nature Switzerland AG.

Further reading