Norelgestromin

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]

Norelgestromin
Clinical data
Trade namesEvra, 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.comInternational Drug Names
MedlinePlusa602006
License data
Routes of
administration		Transdermal patch
Drug classProgestogen; Progestin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding99% (to albumin but not to SHBG)[1][2][3]
MetabolismLiver (oxime to ketone reaction, hydroxylation, conjugation)[4]
Metabolites• Levonorgestrel[4]
Elimination half-life17–37 hours[1][3]
ExcretionUrine and feces[4]
Identifiers
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.170.714
Chemical and physical data
FormulaC21H29NO2
Molar mass327.468 g·mol−1
3D model (JSmol)
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
InChI
  • 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 Y
  • Key:ISHXLNHNDMZNMC-XUDSTZEESA-N Y
  (verify)

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 0.75 mg ethinyl estradiol and delivers 150 µg/day norelgestromin and 35 µg/day ethinyl estradiol.[4][14]

Contraindications
See also: Progestin § Contraindications

Side effects
See also: Progestin § 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
See also: Progestin § Overdose

Interactions
See also: Progestin § 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
CompoundPRARERGRMRSHBGCBG
Norelgestromin100 ? ? ?0 ?
Levonorgestrel (3-keto-NGMN)150–1624501–817–75500
Notes: Values are percentages (%). Reference ligands (100%) were prome- gestone for the PR, metribolone for the AR, E2 for the ER, DEXA for the GR, aldosterone for the MR, DHT for SHBG, and cortisol for CBG. 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
See also: List of progestogens

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, USAN, and BAN.[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

References
  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021040s013lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019653s058,019697s054lbl.pdf
  3. Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.
  4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021180s043lbl.pdf
  5. "Norelgestromin - brand name list from". Drugs.com. Retrieved 2022-09-17.
  6. Drugs.com: Norelgestromin/Ethinyl Estradiol Patch
  7. Crosignani, Pier Giorgio; Nappi, Carmine; Ronsini, Salvatore; Bruni, Vincenzina; Marelli, Silvia; Sonnino, Davide (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. ISSN 1472-6874. PMC 2714834. PMID 19566925.
  8. Annette M. Doherty (2003). Annual Reports in Medicinal Chemistry. Academic Press. pp. 362–. ISBN 978-0-12-040538-1.
  9. Stefan Offermanns; Walter Rosenthal (14 August 2008). Encyclopedia of Molecular Pharmacology. Springer Science & Business Media. pp. 391–. ISBN 978-3-540-38916-3.
  10. John E. Macor (2012). Annual Reports in Medicinal Chemistry. Academic Press. pp. 620–. ISBN 978-0-12-396492-2.
  11. Laura Marie Borgelt (2010). Women's Health Across the Lifespan: A Pharmacotherapeutic Approach. ASHP. pp. 294–. ISBN 978-1-58528-194-7.
  12. Diana Vaamonde; Stefan S du Plessis; Ashok Agarwal (7 March 2016). Exercise and Human Reproduction: Induced Fertility Disorders and Possible Therapies. Springer. pp. 288–. ISBN 978-1-4939-3402-7.
  13. "First Generic Ortho Evra Patch Launched". 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". Int J Women's Health. 9: 315–321. doi:10.2147/IJWH.S102306. PMC 5440026. PMID 28553144.
  15. Kuhl H (1990). "Pharmacokinetics of oestrogens and progestogens". Maturitas. 12 (3): 171–97. 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)". Gynecol. Endocrinol. 13 (5): 316–26. doi:10.3109/09513599909167574. PMID 10599548.
  17. "Process for obtaining norelgestromin in different relations of isomers e and Z". 25 June 2004.
  18. Mary C. Brucker; Tekoa L. King (8 September 2015). Pharmacology for Women's Health. Jones & Bartlett Publishers. pp. 368–. ISBN 978-1-284-05748-5.
  19. Donna Shoupe (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. J. Elks (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".
  23. "Ethinylestradiol/Norelgestromin - AdisInsight".

Further reading
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