Norgestimate

Source: Wikipedia, the free encyclopedia.
Not to be confused with Norgestomet.

Norgestimate
Clinical data
Trade namesCilest, Ortho-Cyclen, Prefest, others
Other namesNGM; 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
AHFS/Drugs.comProfessional Drug Facts
Professional Drug Facts
MedlinePlusa601050
Pregnancy
category
  • Use is contraindicated
Progestin; Progestogen ester[1]
ATC code
Legal status
Legal status
conjugation)[1][3][4]
Metabolites• Norelgestromin[1]
• Levonorgestrel[1]
• Levonorgestrel acetate[1]
Elimination half-life• Norgestimate: very short[1]
• Norelgestromin: 17–37 hours[3][1]
• Levonorgestrel: 24–32 hours[1]
ExcretionUrine: 47%[4]
Feces: 37%[4]
Identifiers
  • [(3E,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-yl] acetate
JSmol)
Melting point214 to 218 °C (417 to 424 °F)
  • 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
  • InChI=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 checkY
  • Key:KIQQMECNKUGGKA-NMYWJIRASA-N checkY
  (verify)

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a

menopausal hormone therapy.[1][3][4][5] The medication is available in combination with an estrogen and is not available alone.[6] It is taken by mouth.[1]

hormonal activity.[1] The medication is a prodrug of norelgestromin and to a lesser extent of levonorgestrel in the body.[1]

Norgestimate was patented in 1965 and introduced for medical use, specifically in birth control pills, in 1986.[7][8] It was introduced for use in menopausal hormone therapy in the United States in 1999.[9] Norgestimate is sometimes referred to as a "third-generation" progestin.[10] 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.[6] Norgestimate is available as a generic medication.[11] In 2021, the version with ethinylestradiol was the 76th most commonly prescribed medication in the United States, with more than 8 million prescriptions.[12][13]

Medical uses

Norgestimate is used in

birth control pills and in combination with estradiol in menopausal hormone therapy.[6][14]

Available forms

Norgestimate is available only in combination with the estrogens ethinylestradiol and estradiol.[6] These formulations are for use by mouth and are indicated specifically for hormonal contraception and menopausal hormone therapy.[6] Norgestimate is not available on its own (i.e., as a standalone medication).[6]

Contraindications

See also:
Progestin § Contraindications

Side effects

See also:
Progestin § Side effects

Norgestimate has mostly been studied in combination with an estrogen, so the side effects of norgestimate specifically or on its own have not been well-defined.[3][4]

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

discharge, and enlargement) (6.3%), mood disorders (including depression and mood alterations) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%).[4]

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%),

coughing (5%).[3]

Overdose

See also:
Progestin § Overdose

Interactions

See also:
Progestin § Interactions

Pharmacology

Pharmacodynamics

Norelgestromin, also known as 17β-deacetylnorgestimate, the main active metabolite of norgestimate.

Norgestimate is a rapidly and completely converted

hormonal activity.[1]

Relative affinities (%) of norgestimate and metabolites
Compound PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Norgestimate 15 0 0 1 0 0 0
Norelgestromin (17β-deAc-NGM) 10 0 ? ? ? 0 ?
Levonorgestrel (3-keto-17β-deAc-NGM) 150–162 45 0 1–8 17–75 50 0
Levonorgestrel 17β-acetate
(3-keto-NGM)		 135 ? 0 ? ? 0 ?
Notes: Values are percentages (%). Reference
CBGTooltip Corticosteroid-binding globulin. Sources: [18][1][19]

Progestogenic activity

Norgestimate is a

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.[1][4][20] The ovulation-inhibiting dosage of norgestimate is 200 µg/day.[1]

Androgenic activity

In addition to its progestogenic activity, norgestimate has weak

liver production of SHBG and by extension circulating levels of SHBG.[20]

The relative binding affinity of norgestimate and its metabolite norelgestromin for the rat

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%.[20] Based on these findings, the ratios of AR to PR binding are 219 for norgestimate and 48 for norelgestromin, whereas the ratios for progesterone, levonorgestrel, and gestodene are 93, 11, and 28, respectively.[20] As such, norgestimate and norelgestromin would appear to have much lower androgenic potency than other 19-nortestosterone progestins.[20] However, levonorgestrel is an important metabolite of both norgestimate and norelgestromin, and it may serve to increase their androgenic potency to some degree.[1][20]

When norgestimate is combined with ethinylestradiol, which is potently antiandrogenic, there are only antiandrogenic effects overall and the combination is suitable for treatment of hyperandrogenism.[14]

Other activities

Norgestimate and its active metabolites do not bind to other

5α-reductase and hepatic cytochrome P450 enzymes in vitro to some extent.[1]

Pharmacokinetics

Norgestimate is rapidly and almost completely

plasma proteins and is bound to both albumin and SHBG.[1][4]

Norgestimate is extensively metabolized into its active metabolites during

terminal half-life of norelgestromin is between 17 and 37 hours and of levonorgestrel is between 24 and 32 hours.[3][1] The metabolites of norgestimate are eliminated 47% in urine and 37% in feces.[3][4] Unchanged norgestimate is undetectable in urine.[4]

Chemistry

See also: List of progestogens, Progestogen ester, and 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

19-nortestosterone family of progestins.[25] It is the C3 oxime and C17β acetate ester of levonorgestrel and is also known as levonorgestrel acetate oxime.[26] A related compound is norethisterone acetate oxime (norethisterone-3-oxime 17β-acetate).[23]

History

Norgestimate was introduced as a component of combined oral contraceptives in 1986.[7] Based on its year of introduction, norgestimate is sometimes described as a "third-generation" progestin.[10] 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.[9]

Society and culture

Generic names

Norgestimate is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française.[23][6] It is also known by its developmental code name ORF-10131.[23][6]

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.[23][6] It is marketed in combination with estradiol for menopausal hormone therapy under the brand name Prefest.[6]

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.[6] Unlike the combined birth control pills of norgestimate with ethinylestradiol, the combination of norgestimate with estradiol, sold under the brand name Prefest for menopausal hormone therapy, is reportedly only marketed in the United States and Brazil.[6]

Research

A 2017 study found that norgestimate inhibits

β-lactam antibiotics.[27] In contrast, norelgestromin showed much weaker activity, indicating that the acetyl group of norgestimate is important for the activity.[27] It was suggested by the researchers that norgestimate may be a promising lead compound for the development of new antibiotics.[27]

References

  1. ^
    S2CID 24616324
    .
  2. ^
    PMID 8842581
    .
  3. ^ a b c d e f g h i j k l m n o p "Prefest- estradiol/norgestimate kit". DailyMed. 29 February 2016. Retrieved 9 November 2020.
  4. ^ a b c d e f g h i j k l m n o p q r s "Ortho Tri Cyclen- norgestimate and ethinyl estradiol kit Ortho Cyclen- norgestimate and ethinyl estradiol kit". DailyMed. 16 May 2019. Retrieved 9 November 2020.
  5. ^
    ISBN 978-0-7817-6879-5
    .
  6. ^ a b c d e f g h i j k l m "Norgestimate and Ethinyl Estradiol - FDA prescribing information, side effects and uses".
  7. ^
    ISBN 978-3-642-73790-9
    .
  8. ISBN 9783527607495
    .
  9. ^
    ISBN 978-1-934899-83-0
    .
  10. ^
    ISBN 978-3-319-14385-9
    .
  11. ^ "Generic Ortho Tri-Cyclen Availability". Drugs.com.
  12. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  13. ^ "Ethinyl Estradiol; Norgestimate - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  14. ^
    PMID 11499185
    .
  15. ISBN 978-0-323-03309-1
    .
  16. ISBN 978-92-832-1291-1
    .
  17. S2CID 27018468
    .
  18. PMID 2170822
    .
  19. PMID 10599548
    .
  20. ^
    PMID 1415445
    .
  21. ^
    PMID 2571595
    .
  22. ^
    ISBN 978-0-8247-8291-7
    .
  23. ^
    ISBN 978-1-4757-2085-3
    .
  24. ^ 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 
  25. ISBN 978-1-4160-4907-4
    .
  26. ISBN 978-1-85070-786-8
    .
  27. ^
    PMID 28758016
    .

Further reading
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