Premarin

Premarin
Combination of
Sodium estrone sulfate Estrogen
Sodium equilin sulfate Estrogen
Sodium 17α-dihydroequilin sulfate Estrogen
Clinical data
Trade names Premarin
AHFS/Drugs.com Consumer Drug Information
Pregnancy
category
  • X
Routes of
administration		 Oral, topical, IV
ATC code G03CA57 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Protein binding >90%
Biological half-life ~12 hours[1]
Excretion Renal
Identifiers
Synonyms Conjugated equine estrogens
CAS Number 12126-59-9 YesY
PubChem (CID) 656613
ChemSpider 570974 YesY
UNII IU5QR144QX YesY
  (verify)

Premarin is the brand name for an estrogen medication that consists of conjugated estrogens isolated from the urine of pregnant mares (pregnant mares' urine).[2] It is manufactured by Wyeth (now a part of Pfizer), and was first marketed in 1941 and 1942 in Canada and the United States, respectively, for the treatment of menopausal symptoms.[2]

Premarin is available in oral (0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg, or 2.5 mg pills),[3] intravenous, and vaginal (cream) forms.[4]

Medical uses

Premarin is a form of hormone replacement therapy (HRT).[5] It is used most commonly in postmenopausal women who have had a hysterectomy to treat hot flashes, and burning, itching, and dryness of the vagina and surrounding areas.[6] It can also be used in conjunction with a progestogen in women who have not had a hysterectomy. For women already taking the medication, it can be used to treat osteoporosis, although it is not recommended solely for this use.[7] Some lesser known uses are the treatment of breast cancer in both men and women and the treatment of prostate cancer in men.[8][9]

Side effects

The most common side effects associated with Premarin use are vaginal yeast infections, vaginal spotting or bleeding, painful menses, and cramping of the legs. While there are some contradictory data, estrogen alone does not appear to increase the risk of coronary heart disease or breast cancer, unlike the case of estrogen in combination with certain progestins such as levonorgestrel or medroxyprogesterone acetate.[10]

Pharmacology

Premarin consists of conjugated equine estrogens (CEEs), or, more exactly, the sodium salts of the sulfate esters of equine estrogens.[2] The exact composition of Premarin is as follows: sodium estrone sulfate (49.3%), sodium equilin sulfate (22.4%), sodium 17α-dihydroequilin sulfate (13.8%), sodium 17α-estradiol sulfate (4.5%), sodium 8,9-dehydroestrone sulfate (3.5%), sodium equilenin sulfate (2.2%), sodium 17β-dihydroequilin sulfate (1.7%), sodium 17α-dihydroequilenin sulfate (1.2%), sodium 17β-estradiol sulfate (0.9%), sodium 17β-dihydroequilenin sulfate (0.5%), and sodium 8,9-dehydroestradiol sulfate (small amounts).[2][11] There are many different steroids in Premarin, even androgens and progestogens, but only the above-mentioned estrogens are present in sufficient amounts to produce clinically-relevant effects.[2]

The major estrogen in Premarin, sodium estrone sulfate, itself is inactive, and rather serves as a prodrug to estrone and, to a lesser extent, estradiol.[12][13] The transformation of estrone sulfate to estrone is catalyzed by estrone sulfatase.[1] Premarin and estrone have been found to be equivalent in potency in an animal model of estrogenic activity.[2]

Oral Premarin, at a daily dosage of 0.625 mg, achieves estrone and estradiol levels of 150 pg/mL and 30–50 pg/mL, respectively, while a daily oral dosage of 1.25 mg achieves levels of 120–200 pg/mL and 40–60 pg/mL of estrone and estradiol, respectively.[14] The oral ingestion of 10 mg Premarin, which contains about 4.5 mg sodium estrone sulfate and 2.5 mg sodium equilin sulfate, produces maximal plasma concentrations of estrone and equilin of 1400 pg/mL and 560 pg/mL within 3 and 5 hours, respectively.[14] By 24 hours post-dose of 10 mg, the levels of estrone and equilin fall to 280 pg/mL and 125 pg/mL, respectively.[14] Oral Premarin 1.25 mg/daily and oral micronized estradiol 1 mg/daily result in similar plasma concentrations of estrone and estradiol (150–300 pg/mL and 30–50 pg/mL for micronized estradiol, respectively) (oral estradiol is extensively metabolized into estrone during hepatic first-pass metabolism),[14] although this does not account for equilin and other equine estrogens involved in the effects of Premarin, which may be significantly more potent in comparison to estrone.[15][16]

17β-Dihydroequilenin has unexpectedly shown a selective estrogen receptor modulator-like profile of estrogenic activity in studies with monkeys, in which beneficial effects on bone and the cardiovascular system were noted but proliferative responses in breast or endometrium were not observed.[17]

Similarly to ethinyl estradiol, Premarin has disproportionate effects on the hepatic protein production relative to bioidentical estradiol, although to a lesser extent.[11]

Relative oral potency (by weight) of CEEs (Premarin) and various other estrogens[11]
Estrogen Hot flashes FSH HDL cholesterol SHBG CBG Angiotensinogen
Estradiol 100 100 100 100 100 100
Estriol 30 30 20 ? ? ?
Estrone sulfate ? 90 50 90 70 150
CEEs (Premarin) 120 110 150 300 150 500
Equilin sulfate ? ? 600 750 600 750
Ethinyl estradiol 12,000 12,000 40,000 50,000 60,000 35,000
Diethylstilbestrol ? 340 ? 2,560 2,450 1,950
Hot flashes = clinical relief of hot flashes; FSH = suppression of FSH levels; HDL cholesterol, SHBG, CBG,
and angiotensinogen = increase in the serum levels of these hepatic proteins.

Society and culture

History

Estrone sulfate was first isolated from pregnant mares' urine in the late 1930s by researchers in the Department of Biochemistry at University of Toronto.[18] Premarin was first introduced in 1941 by Wyeth Ayerst as a treatment for hot flashes and other symptoms of menopause; at that time, Wyeth Ayerst only had to prove its safety, and not its efficacy.[19] In response to the 1962 Kefauver Harris Amendment the FDA had its efficacy reviewed, and in 1972 found it effective for menopausal symptoms and probably effective for osteoporosis.[20] The review also determined that two estrogens—estrone sulfate and equilin sulfate—were primarily responsible for Premarin’s activity, and it laid the groundwork for Abbreviated New Drug Application (ANDA) submissions of generic versions.[19] In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosis[21] and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.[22] This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.[19]

Health effects

Research starting in 1975 showed substantially increased risk of endometrial cancer.[23][24] Since 1976 the drug has carried a label warning about the risk.[25] As part of the Women's Health Initiative sponsored by the National Institutes of Health, a large-scale clinical trial of menopausal HRT showed that long-term use of estrogen and a progestin may increase the risk of strokes, heart attacks, blood clots, and breast cancer.[26] Following these results, Wyeth experienced a significant decline in its sales of Premarin, Prempro (conjugated equine estrogens) and related hormones, from over $2 billion in 2002 to just over $1 billion in 2006.[27]

Litigation

This drug has been the subject of litigation; more than 13,000 people have sued Wyeth between 2002 and 2009. Wyeth and Pharmacia & Upjohn prevailed in the vast majority of hormone therapy cases previously set for trial through a combination of rulings by judges, verdicts by juries, and dismissals by plaintiffs themselves.[28] Of the company’s losses, two of the jury verdicts were reversed post-trial and others are being challenged on appeal. Wyeth also won five summary judgments on Prempro cases and had 15 cases voluntarily dismissed by plaintiffs. The company won dismissals in another 3,000 cases.[29] In 2006, Mary Daniel, in a trial in Philadelphia, was awarded $1.5 million in compensatory damages as well as undisclosed punitive damages. As of 2010, Wyeth had won the last four of five cases, most recently in Virginia, finding that they were not responsible for the breast cancer of plaintiff Georgia Torkie-Tork.[30] Wyeth has been quoted as saying "many risk factors associated with breast cancer have been identified, but science cannot establish what role any particular risk factor or combination play in any individual woman's breast cancer." [31] Wyeth's counsel in the case also noted that in the WHI trial, 99.62 percent of women took the drug and "did not get breast cancer."[29]

Controversy

Animal welfare groups claim that animal husbandry and urine collection methods used in Premarin's production cause undue stress and suffering to the mares involved. Allegations of abuse range from concern over stall size, access to water, exercise, cruel treatment, collection system, continuous breeding cycles, and premature death.[32]

See also

References

  1. 1 2 Joseph S. Sanfilippo (January 1998). Primary Care in Obstetrics and Gynecology: A Handbook for Clinicians. Springer Science & Business Media. pp. 220,227. ISBN 978-0-387-94739-6.
  2. 1 2 3 4 5 6 Marc A. Fritz; Leon Speroff (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 751–. ISBN 978-1-4511-4847-3.
  3. ↑ John E. Morley; Lucretia van den Berg (5 November 1999). Endocrinology of Aging. Springer Science & Business Media. pp. 172–. ISBN 978-1-59259-715-4.
  4. ↑ Premarin (conjugated estrogens) Vaginal cream - detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER) November 2008
  5. ↑ Greer, Iain A.; Ginsberg, Jeff; Forbes, Charles (29 December 2006). Women's vascular health. CRC Press. ISBN 9780340809976.
  6. ↑ Nezhat, Camran; Nezhat, Farr; Nezhat, Ceana (7 July 2008). Nezhat's Operative gynecologic laparoscopy and hysteroscopy. Cambridge University Press. ISBN 9781139472005. Retrieved 7 May 2015.
  7. ↑ Maeda, Sergio Setsuo; Lazaretti-Castro, Marise; Maeda, Sergio Setsuo; Lazaretti-Castro, Marise (2014). "An overview on the treatment of postmenopausal osteoporosis". Arquivos Brasileiros de Endocrinologia & Metabologia. 58 (2): 162–171. doi:10.1590/0004-2730000003039. ISSN 0004-2730. Retrieved 2015-05-07.
  8. ↑ "Breast cancer: major risk factors and recent developments in treatment". Asian Pac J Cancer Prev. 15 (8): 3353–8. 2014. doi:10.7314/apjcp.2014.15.8.3353. PMID 24870721.
  9. ↑ Learning, Jones & Bartlett (2015-01-14). 2015 Nurse's Drug Handbook. Jones & Bartlett Publishers. ISBN 9781284091373. Retrieved 2015-05-07.
  10. ↑ http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121062.htm
  11. 1 2 3 Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  12. ↑ H.J. Buchsbaum (6 December 2012). The Menopause. Springer Science & Business Media. pp. 64–. ISBN 978-1-4612-5525-3.
  13. ↑ Tommaso Falcone; William W. Hurd (22 May 2013). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer Science & Business Media. pp. 5–6. ISBN 978-1-4614-6837-0.
  14. 1 2 3 4 Rogerio A. Lobo (5 June 2007). Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Academic Press. pp. 771–. ISBN 978-0-08-055309-2.
  15. ↑ M. Notelovitz; P.A. van Keep (6 December 2012). The Climacteric in Perspective: Proceedings of the Fourth International Congress on the Menopause, held at Lake Buena Vista, Florida, October 28–November 2, 1984. Springer Science & Business Media. pp. 395–. ISBN 978-94-009-4145-8.
  16. ↑ G. E. Seidel (1974). Gonadotrophins: Current Research. Ardent Media. pp. 157–. ISBN 978-0-8422-7205-6.
  17. ↑ Cline JM (2007). "Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors". Birth Defects Res. B Dev. Reprod. Toxicol. 80 (2): 126–46. doi:10.1002/bdrb.20112. PMID 17443713.
  18. ↑ Schachter, B.; Marrian, G. F. (1938). "The isolation of estrone sulfate from the urine of pregnant mares". Journal of Biological Chemistry. 126: 663–669.
  19. 1 2 3 Jim Kling October 2000 The Strange Case of Premarin Modern Drug Discovery (3):8 46–52
  20. ↑ Federal Register 37, July 25, 1972 pp 14826-28
  21. ↑ National Institutes of Health Consensus Development Conference Statement. April 2–4, 1984 Osteoporosis
  22. ↑ Food and Drug Administration. May 5, 1997 Conjugated Estrogens - Letter from Dr. Janet Woodcock: Approvability of a Synthetic Generic Version of Premarin
  23. ↑ Ziel HK, Finkle WD (4 December 1975). "Increased risk of endometrial carcinoma among users of conjugated estrogens". New England Journal of Medicine. 293: 1167–1170. doi:10.1056/NEJM197512042932303. PMID 171569.
  24. ↑ McDonald TW, et al. (15 March 1977). "Exogenous estrogen and endometrial carcinoma: case-control and incidence study". American J Obstet Gynecol. 127: 572–580. PMID 190887.
  25. ↑ Natasha Singer and Duff Wilson (12 December 2009). "Menopause, as Brought to You by Big Pharma". New York Times.
  26. ↑ Brunner RL et al; Womens Health Initiative Investigators (26 September 2005). "Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative randomized clinical trial". Archives of Internal Medicine. 165 (17): 1976–1986. doi:10.1001/archinte.165.17.1976. PMID 16186467.
  27. ↑ "Earnings Results for the 2006 Fourth Quarter and Full Year" (PDF) (Press release). Wyeth.
  28. ↑ "Pfizer Statement on Prempro". Indy News Channel. Archived from the original on February 23, 2012.
  29. 1 2 Jef Feeley (February 24, 2010). "Pfizer wins trial over claim Prempro caused cancer". Bloomberg.
  30. ↑ "Pfizer properly warned about Prempro risks, jury finds". 3 December 2010.
  31. ↑ "Legal Intelligencer: Philadelphia jury returns defense verdict in HRT case, Amaris Elliott Engel".
  32. ↑ The HRT horses (NBC)
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