Raloxifene

Raloxifene
Clinical data
Trade names Evista, Optruma, others
Synonyms Keoxifene; Pharoxifene; LY-139481; LY-156758; CCRIS-7129
AHFS/Drugs.com Monograph
MedlinePlus a698007
License data
Pregnancy
category
  • AU: X (High risk)
  • US: X (Contraindicated)
    Routes of
    administration    		 By mouth
    Drug class Selective estrogen receptor modulator
    ATC code
    Legal status
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability 2.0%[1]
    Protein binding >95%[1]
    Metabolism Liver, intestines (glucuro-
    nidation    );[1][2] CYP450 system not involved[1]
    Elimination half-life 27.7 hours[1]
    Excretion Feces[1]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    ChEBI
    ChEMBL
    PDB ligand
    ECHA InfoCard 100.212.655 Edit this at Wikidata
    Chemical and physical data
    Formula C28H27NO4S
    Molar mass 473.584 g/mol
    3D model (JSmol)
      (verify)

    Raloxifene, developed by Eli Lilly in 1997 and sold under the brand name Evista among others, is a medication which is used in the prevention and treatment of osteoporosis in postmenopausal women and to reduce the risk of breast cancer in postmenopausal women with osteoporosis or at high risk for breast cancer.[3][4] It is taken by mouth.[3]

    Side effects of raloxifene include hot flashes, leg cramps, and an increased risk of blood clots and other cardiovascular events such as stroke.[3][4] The drug is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist–antagonist of the estrogen receptor (ER), the biological target of estrogens like estradiol.[5][6][7] It has estrogenic effects in bone and the liver and antiestrogenic effects in the breasts and uterus.[8]

    Raloxifene was first introduced, for the prevention of postmenopausal osteoporosis, in 1997.[9][10] It was subsequently approved for the treatment of postmenopausal osteoporosis in 1999 and to reduce the risk of breast cancer in certain women in 2007.[10] It is available as a generic medication.[11]

    Medical uses

    Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. It is also used for reduction of risk and treatment of invasive breast cancer, and it also reduces breast density.[12] Raloxifene has been found to be effective in the treatment of gynecomastia (male breast development) in adolescents.[13][14] For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.

    Contraindications

    Raloxifene is contraindicated in lactating women or women who are or may become pregnant, in women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis and in women known to be hypersensitive to raloxifene.[15]

    Side effects

    Common adverse events considered to be drug-related were hot flashes and leg cramps.[15] Raloxifene does not cause breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer.[4] It does not appear to affect cognition or memory.[7] Raloxifene is a teratogen; i.e., it can cause developmental abnormalities such as birth defects.

    Raloxifene may infrequently cause serious blood clots to form in the legs, lungs, or eyes. Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, and vision changes. Black box warnings were added to the label of raloxifene in 2007 warning of increased risk of death due to stroke for postmenopausal women with documented coronary heart disease or at increased risk for major coronary events, as well as increased risk for deep vein thrombosis and pulmonary embolism.[15]

    A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen and raloxifene, used to treat breast cancer, significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.[16]

    A recent human case report in July 2016 suggests that raloxifene may in fact, at some point, also stimulate breast cancer growth leading to a reduction of advanced breast cancer disease upon the withdrawal of the drug.[17]

    Pharmacology

    Pharmacodynamics

    The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). Its agonistic activity at some receptors and its antagonistic activity at others makes it a SERM. Raloxifene appears to act as an estrogen agonist in bone.[15]

    Raloxifene has been found to decrease insulin-like growth factor 1 levels in women and men.[18]

    Pharmacokinetics

    The absorption of raloxifene is approximately 60%.[1] However, due to extensive first-pass metabolism, the absolute bioavailability of raloxifene is only 2.0%.[1] Peak plasma levels of raloxifene occur 6 hours after an oral dose.[1] Raloxifene shows high plasma protein binding (>95%), including to both albumin and α1 acid glycoprotein, but not to sex hormone-binding globulin.[1] Raloxifene is metabolized in the liver and undergoes enterohepatic recycling.[1] It is metabolized exclusively by glucuronidation and is not metabolized by the cytochrome P450 system.[1] Less than 1% of radiolabeled material in plasma comprises unconjugated raloxifene.[1] The elimination half-life of raloxifene is 27.7 hours.[1] Raloxifene and its glucuronide conjugates are interconverted by reversible metabolism and enterohepatic recycling, which prolongs the elimination half-life of raloxifene with oral administration.[1] Raloxifene is excretion mainly in the feces, with less than 0.2% of a dose excreted unchanged in the urine and less than 6% of a dose excreted in the urine as glucuronide conjugates.[1]

    Chemistry

    Raloxifene hydrochloride has the empirical formula C28H27NO4S•HCl, which corresponds to a molecular weight of 510.05 g/mol. Raloxifene hydrochloride is an off-white to pale-yellow solid that is slightly soluble in water.[15]

    Raloxifene is a benzothiophene derivative and is structurally distinct from the triphenylethylene SERMs like tamoxifen, clomifene, and toremifene.[19] It is the only benzothiophene SERM to have been marketed.[19] A benzothiophene SERM that was not marketed is arzoxifene (LY-353381).[20] Bazedoxifene (Duavee, Viviant) and pipendoxifene (ERA-923) are structurally related to raloxifene but are technically not benzothiophenes and instead are indoles.[20]

    History

    Raloxifene was approved in the United States for the prevention of postmenopausal osteoporosis in 1997, the treatment of postmenopausal osteoporosis in 1999, and to prevent or reduce the risk of breast cancer in certain postmenopausal women in 2007.[21][9][22][10] It received orphan designation in 2005.[21]

    Society and culture

    A bottle of raloxifene.

    Generic names

    Raloxifene is the generic name of the drug and its INN and BAN, while raloxifène is its DCF and raloxifene hydrochloride is its USAN, BANM, and JAN.[23][24][25][26] It has also been known by the name keoxifene.[23][24][26]

    Brand names

    Raloxifene is sold mainly under the brand name Evista and to a lesser extent the brand name Optruma.[26][24] It is also sold under a variety of other brand names in various countries.[26]

    Availability

    Raloxifene is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, Australia, New Zealand, South Africa, Latin America, Southern, Eastern, and Southeastern Asia, and elsewhere in the world such as in Israel and Egypt.[26][24]

    Controversy

    An editorial in Lancet Oncology criticized the way that information about the drug was released.[27]

    Research

    Raloxifene has been studied in men for a variety of purposes, such as for the treatment of schizophrenia, prostate cancer, and osteoporosis.[28][29][30][31][32][33][34][35][36][37]

    Raloxifene has been studied as an adjunct in the treatment of schizophrenia in postmenopausal women.[38] A 2017 meta-analysis concluded that it was safe and effective for this indication, although further studies with larger sample sizes are needed for confirmation.[38] It may be effective in women with less severe symptoms.[38]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Hochner-Celnikier D (1999). "Pharmacokinetics of raloxifene and its clinical application". Eur. J. Obstet. Gynecol. Reprod. Biol. 85 (1): 23–9. doi:10.1016/s0301-2115(98)00278-4. PMID 10428318.
    2. ↑ Jeong, Eun Ju; Liu, Yong; Lin, Huimin; Hu, Ming (2005-03-15). "Species- and Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of UGT1A10". Drug Metabolism and Disposition. ASPET. 33 (6): 785–794. doi:10.1124/dmd.104.001883. PMID 15769887. Retrieved 2010-10-20.
    3. 1 2 3 "Evista" (PDF). U.S. Food and Drug Administration.
    4. 1 2 3 Seeman E (2001). "Raloxifene". J. Bone Miner. Metab. 19 (2): 65–75. doi:10.1007/s007740170043. PMID 11281162.
    5. ↑ Bryant HU (2001). "Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulation". Rev Endocr Metab Disord. 2 (1): 129–38. PMID 11704975.
    6. ↑ Thiebaud D, Secrest RJ (2001). "Selective estrogen receptor modulators: mechanism of action and clinical experience. Focus on raloxifene". Reprod. Fertil. Dev. 13 (4): 331–6. PMID 11800172.
    7. 1 2 Gizzo S, Saccardi C, Patrelli TS, Berretta R, Capobianco G, Di Gangi S, Vacilotto A, Bertocco A, Noventa M, Ancona E, D'Antona D, Nardelli GB (2013). "Update on raloxifene: mechanism of action, clinical efficacy, adverse effects, and contraindications". Obstet Gynecol Surv. 68 (6): 467–81. doi:10.1097/OGX.0b013e31828baef9. PMID 23942473.
    8. ↑ Muchmore DB (2000). "Raloxifene: A selective estrogen receptor modulator (SERM) with multiple target system effects". The Oncologist. 5 (5): 388–392. doi:10.1634/theoncologist.5-5-388. PMID 11040275.
    9. 1 2 Reducing Breast Cancer Risk with Drugs. Am Cncl on Science, Health. pp. 10–. GGKEY:CBEALLAHP8W.
    10. 1 2 3 Jie Jack Li; Douglas S. Johnson (27 March 2013). Modern Drug Synthesis. John Wiley & Sons. pp. 2–. ISBN 978-1-118-70124-9.
    11. ↑ https://www.drugs.com/availability/generic-evista.html
    12. ↑ Jeon-Hor, Chen; et al. (September 15, 2003). "Reduction of Breast Density Following Tamoxifen Treatment Evaluated by 3-D MRI: Preliminary Study". Magn Reson Imaging. 29: 91–8. doi:10.1016/j.mri.2010.07.009. PMC 3005955. PMID 20832226.
    13. ↑ Nordt CA, DiVasta AD (2008). "Gynecomastia in adolescents". Curr. Opin. Pediatr. 20 (4): 375–82. doi:10.1097/MOP.0b013e328306a07c. PMID 18622190.
    14. ↑ Leung KC, Leung AC (2017). "Gynecomastia in Infants, Children, and Adolescents". Recent Pat Endocr Metab Immune Drug Discov. 10 (2): 127–137. doi:10.2174/1872214811666170301124033. PMID 28260521.
    15. 1 2 3 4 5 Raloxifene label Last updated 09/2007]
    16. ↑ Agency for Healthcare Research and Quality, Rockville, MD. (September 2009). "Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects". Retrieved 2009-09-14.
    17. ↑ Lemmo, W (2016). "Anti-Estrogen Withdrawal Effect With Raloxifene? A Case Report". Integrative Cancer Therapies. Published Online Before Print July 13: 245–249. doi:10.1177/1534735416658954.
    18. ↑ Duarte FH, Jallad RS, Bronstein MD (November 2016). "Estrogens and selective estrogen receptor modulators in acromegaly". Endocrine. 54 (2): 306–314. doi:10.1007/s12020-016-1118-z. PMID 27704479.
    19. 1 2 Eric S. Orwoll; Michael Bliziotes (2 August 2002). Osteoporosis: Pathophysiology and Clinical Management. Springer Science & Business Media. pp. 320–. ISBN 978-1-59259-278-4.
    20. 1 2 Stuart Silverman; Bo Abrahamsen (29 December 2015). The Duration and Safety of Osteoporosis Treatment: Anabolic and Antiresorptive Therapy. Springer. pp. 24–. ISBN 978-3-319-23639-1.
    21. 1 2 Institute of Medicine; Board on Health Sciences Policy; Committee on Accelerating Rare Diseases Research and Orphan Product Development (3 April 2011). Rare Diseases and Orphan Products: Accelerating Research and Development. National Academies Press. pp. 113–. ISBN 978-0-309-15806-0.
    22. ↑ Sydney Lou Bonnick (10 November 2007). Bone Densitometry for Technologists. Springer Science & Business Media. pp. 277–. ISBN 978-1-59259-992-9.
    23. 1 2 J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1063–. ISBN 978-1-4757-2085-3.
    24. 1 2 3 4 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 909–. ISBN 978-3-88763-075-1.
    25. ↑ I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 245–. ISBN 978-0-7514-0499-9.
    26. 1 2 3 4 5 https://www.drugs.com/international/raloxifene.html
    27. ↑ Thelancetoncology, (2006). "A STARring role for raloxifene?". Lancet Oncol. 7 (6): 443. doi:10.1016/S1470-2045(06)70701-X. PMID 16750489.
    28. ↑ Blum A, Hathaway L, Mincemoyer R, Schenke WH, Csako G, Waclawiw MA, Panza JA, Cannon RO (2000). "Hormonal, lipoprotein, and vascular effects of the selective estrogen receptor modulator raloxifene in hypercholesterolemic men". Am. J. Cardiol. 85 (12): 1491–4, A7. doi:10.1016/s0002-9149(00)00802-x. PMID 10856400.
    29. ↑ Doran PM, Riggs BL, Atkinson EJ, Khosla S (2001). "Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men". J. Bone Miner. Res. 16 (11): 2118–25. doi:10.1359/jbmr.2001.16.11.2118. PMID 11697809.
    30. ↑ Dimaraki EV, Symons KV, Barkan AL (2004). "Raloxifene decreases serum IGF-I in male patients with active acromegaly". Eur. J. Endocrinol. 150 (4): 481–7. doi:10.1530/eje.0.1500481. PMID 15080777.
    31. ↑ Duschek EJ, Gooren LJ, Netelenbos C (2004). "Effects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men". Eur. J. Endocrinol. 150 (4): 539–46. doi:10.1530/eje.0.1500539. PMID 15080785.
    32. ↑ Smith MR, Fallon MA, Lee H, Finkelstein JS (2004). "Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial". J. Clin. Endocrinol. Metab. 89 (8): 3841–6. doi:10.1210/jc.2003-032058. PMID 15292315.
    33. ↑ Uebelhart B, Herrmann F, Pavo I, Draper MW, Rizzoli R (2004). "Raloxifene treatment is associated with increased serum estradiol and decreased bone remodeling in healthy middle-aged men with low sex hormone levels". J. Bone Miner. Res. 19 (9): 1518–24. doi:10.1359/JBMR.040503. PMID 15312253.
    34. ↑ Birzniece V, Sutanto S, Ho KK (2012). "Gender difference in the neuroendocrine regulation of growth hormone axis by selective estrogen receptor modulators". J. Clin. Endocrinol. Metab. 97 (4): E521–7. doi:10.1210/jc.2011-3347. PMID 22319035.
    35. ↑ Ho TH, Nunez-Nateras R, Hou YX, Bryce AH, Northfelt DW, Dueck AC, Wong B, Stanton ML, Joseph RW, Castle EP (2017). "A Study of Combination Bicalutamide and Raloxifene for Patients With Castration-Resistant Prostate Cancer". Clin Genitourin Cancer. 15 (2): 196–202.e1. doi:10.1016/j.clgc.2016.08.026. PMID 27771244.
    36. ↑ Khodaie-Ardakani MR, Khosravi M, Zarinfard R, Nejati S, Mohsenian A, Tabrizi M, Akhondzadeh S (2015). "A Placebo-Controlled Study of Raloxifene Added to Risperidone in Men with Chronic Schizophrenia". Acta Med Iran. 53 (6): 337–45. PMID 26069170.
    37. ↑ Weickert TW, Weinberg D, Lenroot R, Catts SV, Wells R, Vercammen A, O'Donnell M, Galletly C, Liu D, Balzan R, Short B, Pellen D, Curtis J, Carr VJ, Kulkarni J, Schofield PR, Weickert CS (2015). "Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia". Mol. Psychiatry. 20 (6): 685–94. doi:10.1038/mp.2015.11. PMC 4444978. PMID 25980345.
    38. 1 2 3 Wang Q, Dong X, Wang Y, Li X (2017). "Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a meta-analysis of randomized controlled trials". Arch Womens Ment Health. doi:10.1007/s00737-017-0773-2. PMID 28849318.

    Further reading

    • Barrett-Connor E (2001). "Raloxifene: risks and benefits". Ann N Y Acad Sci. 949: 295–303. doi:10.1111/j.1749-6632.2001.tb04036.x. PMID 11795366.
    • Heringa M (2003). "Review on raloxifene: profile of a selective estrogen receptor modulator". Int J Clin Pharmacol Ther. 41 (8): 331–45. PMID 12940590.
    • Sporn MB, Dowsett SA, Mershon J, Bryant HU (2004). "Role of raloxifene in breast cancer prevention in postmenopausal women: clinical evidence and potential mechanisms of action". Clin Ther. 26 (6): 830–40. doi:10.1016/s0149-2918(04)90127-0. PMID 15262454.
    • Vogel VG (2009). "The NSABP Study of Tamoxifen and Raloxifene (STAR) trial". Expert Rev Anticancer Ther. 9 (1): 51–60. doi:10.1586/14737140.9.1.51. PMC 2785111. PMID 19105706.
    • Wickerham DL, Costantino JP, Vogel VG, Cronin WM, Cecchini RS, Ford LG, Wolmark N (2009). "The use of tamoxifen and raloxifene for the prevention of breast cancer". Recent Results Cancer Res. 181: 113–9. PMC 5110043. PMID 19213563.
    • Vogel VG (2011). "Update on raloxifene: role in reducing the risk of invasive breast cancer in postmenopausal women". Breast Cancer (Dove Med Press). 3: 127–37. doi:10.2147/BCTT.S11288. PMC 3846694. PMID 24367182.
    • Yang ZD, Yu J, Zhang Q (2013). "Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women: a systematic review of randomized controlled trials". Maturitas. 75 (4): 341–8. doi:10.1016/j.maturitas.2013.05.010. PMID 23764354.
    • Gizzo S, Saccardi C, Patrelli TS, Berretta R, Capobianco G, Di Gangi S, Vacilotto A, Bertocco A, Noventa M, Ancona E, D'Antona D, Nardelli GB (2013). "Update on raloxifene: mechanism of action, clinical efficacy, adverse effects, and contraindications". Obstet Gynecol Surv. 68 (6): 467–81. doi:10.1097/OGX.0b013e31828baef9. PMID 23942473.
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