Raloxifene was approved for medical use in the United States in 1997.[5] It is available as ageneric medication.[5][7] In 2020, it was the 292nd most commonly prescribed medication in the United States, with more than 1million prescriptions.[8][9]
Raloxifene is used for the treatment and prevention ofosteoporosis inpostmenopausal women.[10] It is used at a dosage of 60 mg/day for both the prevention and treatment of osteoporosis.[11] In the case of either osteoporosis prevention or treatment, supplementalcalcium andvitamin D should be added to the diet if daily intake is inadequate.[12]
Raloxifene is used to reduce the risk ofbreast cancer in postmenopausal women. It is used at a dosage of 60 mg/day for this indication.[11] In the Multiple Outcomes of Raloxifene (MORE)clinical trial, raloxifene decreased the risk of all types of breast cancer by 62%, of invasive breast cancer by 72%, and of invasiveestrogen receptor-positive breast cancer by 84%.[13] Conversely, it does not reduce the risk of estrogen receptor-negative breast cancer.[13] There were no obvious differences in effectiveness of raloxifene in the MORE trial for prevention of breast cancer at a dosage of 60 mg/m2/day relative to 120 mg/m2/day.[13] In theStudy of Tamoxifen and Raloxifene (STAR) trial, 60 mg/day raloxifene was 78% as effective as 20 mg/daytamoxifen in preventing non-invasive breast cancer.[14] Women with undetectable levels of estradiol (<2.7 pg/mL) have a naturally low risk of breast cancer and, in contrast to women with detectable levels of estradiol, do not experience significant benefit from raloxifene in terms of reduction of breast cancer risk.[13]
Raloxifene may infrequently cause seriousblood clots to form in thelegs,lungs, oreyes.[2] 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 fordeep vein thrombosis andpulmonary embolism.[15] The risk ofvenous thromboembolism with raloxifene is increased by several-fold in postmenopausal women (RRTooltip relative risk = 3.1).[19][13] Raloxifene has a lower risk of thromboembolism than tamoxifen.[14] In the MORE trial, raloxifene caused a 40% decrease in risk of cardiovascular events in women who were at increased risk forcoronary artery disease, although there was no decrease in cardiovascular events for the group as a whole.[13]
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.[20]
A 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.[21]
Effect:+ =Estrogenic /agonistic.± = Mixed or neutral.– =Antiestrogenic /antagonistic.Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic).Sources: See template.
Theabsorption of raloxifene is approximately 60%.[2][3] However, due to extensivefirst-pass metabolism, theabsolute bioavailability of raloxifene is only 2.0%.[2][3] Raloxifene is rapidlyabsorbed from theintestines uponoral administration.[2]Peak plasma levels of raloxifene occur 0.5 to 6 hours after an oral dose.[2][3] In healthy postmenopausal women treated with 60 mg/day raloxifene, peak circulating raloxifene levels normalized by dose and body weight were (i.e., divided by (mg/kg)), 0.50 ng/mL (500 pg/mL) after a single dose and 1.36 ng/mL (1,360 pg/mL after multiple doses).[15]
Raloxifene ismetabolized in theliver and undergoesenterohepatic recycling.[3] It is metabolized exclusively byglucuronidation and is not metabolized by thecytochrome P450 system.[2][3] Less than 1% of radiolabeled material in plasma comprises unconjugated raloxifene.[3] The metabolites of raloxifene include severalglucuronides.[2] Theelimination half-life of raloxifene after a single dose is 27.7 hours (1.2 days), whereas its half-life at steady state at a dosage of 60 mg/day is 15.8 to 86.6 hours (0.7–3.6 days), with an average of 32.5 hours (1.4 days).[2][3][15] The extended half-life of raloxifene is attributed to enterohepatic recirculation and its high plasma protein binding.[2] Raloxifene and itsglucuronideconjugates are interconverted by reversible metabolism and enterohepatic recycling, which prolongs the elimination half-life of raloxifene with oral administration.[3] The medication isdeconjugated into its active form in a variety of tissues, including liver, lungs,spleen,bone,uterus, and kidneys.[2]
Raloxifene is mainlyexcreted inbile and iseliminated infeces.[2][3] Less than 0.2% of a dose is excreted unchanged inurine and less than 6% of a dose is excreted in urine as glucuronide conjugates.[3]
Raloxifenehydrochloride 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 was approved in theUnited 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.[41][42][43][44] It receivedorphan designation in 2005.[41]
Raloxifene is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name, whileraloxifène is itsDCFTooltip Dénomination Commune Française andraloxifene hydrochloride is itsUSANTooltip United States Adopted Name,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[45][46][47][48] It has also been known by the namekeoxifene.[45][46][48]
Raloxifene is sold mainly under the brand name Evista and to a lesser extent the brand name Optruma.[48][46] It is also sold under a variety of other brand names in various countries.[48]
Clinical studies of raloxifene formetastatic breast cancer in women have been conducted but found little effectiveness at 60 mg/day in those previously treated with tamoxifen, though modest effectiveness has been observed at higher doses.[13][50] In contrast to tamoxifen, raloxifene is not approved for the treatment of breast cancer.[51]
Raloxifene has been studied as anadjunct in the treatment ofschizophrenia inpostmenopausal women.[61] A 2017meta-analysis concluded that it was safe and effective for this indication, although further studies with largersample sizes are needed for confirmation.[61] It may be effective in women with less severe symptoms.[61]
A tissue-selective estrogen-receptor complex (TSEC) ofestradiol and raloxifene has been studied in postmenopausal women.[62]
^Jeong EJ, Liu Y, Lin H, Hu M (June 2005). "Species- and disposition model-dependent metabolism of raloxifene in gut and liver: role of UGT1A10".Drug Metabolism and Disposition.33 (6).ASPET:785–794.doi:10.1124/dmd.104.001883.PMID15769887.S2CID24273998.
^Yang ZD, Yu J, Zhang Q (August 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):341–348.doi:10.1016/j.maturitas.2013.05.010.PMID23764354.
^British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 736–737.ISBN978-0-85711-338-2.
^Ohta H, Hamaya E, Taketsuna M, Sowa H (January 2015). "Quality of life in Japanese women with postmenopausal osteoporosis treated with raloxifene and vitamin D: post hoc analysis of a postmarketing study".Current Medical Research and Opinion.31 (1):85–94.doi:10.1185/03007995.2014.975339.PMID25299349.S2CID24671531.
^abcPark WC, Jordan VC (February 2002). "Selective estrogen receptor modulators (SERMS) and their roles in breast cancer prevention".Trends in Molecular Medicine.8 (2):82–88.doi:10.1016/S1471-4914(02)02282-7.PMID11815274.
^Escande A, Pillon A, Servant N, Cravedi JP, Larrea F, Muhn P, et al. (May 2006). "Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta".Biochemical Pharmacology.71 (10):1459–1469.doi:10.1016/j.bcp.2006.02.002.PMID16554039.{{cite journal}}: CS1 maint: overridden setting (link)
^Greene GL, Shiau AK, Nettles KW (2004). "A Structural Explanation for ERα/ERβ SERM Discrimination".New Molecular Mechanisms of Estrogen Action and Their Impact on Future Perspectives in Estrogen Therapy. pp. 33–45.doi:10.1007/978-3-662-05386-7_3.ISBN978-3-662-05388-1.PMID15248503.{{cite book}}:|journal= ignored (help)
^Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S (July 1998). "Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists".Molecular Pharmacology.54 (1):105–112.doi:10.1124/mol.54.1.105.PMID9658195.
^abUebelhart B, Herrmann F, Pavo I, Draper MW, Rizzoli R (September 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.PMID15312253.S2CID36104038.
^Xu B, Lovre D, Mauvais-Jarvis F (May 2016). "Effect of selective estrogen receptor modulators on metabolic homeostasis".Biochimie.124:92–97.doi:10.1016/j.biochi.2015.06.018.PMID26133657.In healthy postmemopausal women, raloxifene treatment for one year prevented body weight gain and abdominal adiposity by promoting a shift from an android to gynoid fat distribution [46].
^Francucci CM, Daniele P, Iori N, Camilletti A, Massi F, Boscaro M (2014). "Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women".Journal of Endocrinological Investigation.28 (7):623–631.doi:10.1007/BF03347261.PMID16218045.S2CID28467435.These results [...] suggest, for the first time, that RLX promotes the shift from android to gynoid fat distribution, and prevents the uptrend of abdominal adiposity and body weight compared with untreated women.
^Miller JW, Skerjanec A, Knadler MP, Ghosh A, Allerheiligen SR (July 2001). "Divergent effects of raloxifene HCI on the pharmacokinetics and pharmacodynamics of warfarin".Pharm Res.18 (7):1024–8.doi:10.1023/a:1010904815275.PMID11496940.S2CID1713984.
^Provinciali N, Suen C, Dunn BK, DeCensi A (October 2016). "Raloxifene hydrochloride for breast cancer risk reduction in postmenopausal women".Expert Rev Clin Pharmacol.9 (10):1263–1272.doi:10.1080/17512433.2016.1231575.PMID27583816.S2CID26047863.
^Blum A, Hathaway L, Mincemoyer R, Schenke WH, Csako G, Waclawiw MA, et al. (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.PMID10856400.
^abHo TH, Nunez-Nateras R, Hou YX, Bryce AH, Northfelt DW, Dueck AC, et al. (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.PMID27771244.S2CID19043552.
^Khodaie-Ardakani MR, Khosravi M, Zarinfard R, Nejati S, Mohsenian A, Tabrizi M, et al. (2015). "A Placebo-Controlled Study of Raloxifene Added to Risperidone in Men with Chronic Schizophrenia".Acta Med Iran.53 (6):337–45.PMID26069170.
^abcWang 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.21 (1):31–41.doi:10.1007/s00737-017-0773-2.PMID28849318.S2CID4524617.
^Carneiro AL, de Cassia de Maio Dardes R, Haidar MA (July 2012). "Estrogens plus raloxifene on endometrial safety and menopausal symptoms--semisystematic review".Menopause.19 (7):830–4.doi:10.1097/gme.0b013e31824a74ce.PMID22549172.S2CID196380398.
^Leung AK, Leung AA (2017). "Gynecomastia in Infants, Children, and Adolescents".Recent Patents on Endocrine, Metabolic & Immune Drug Discovery.10 (2):127–137.doi:10.2174/1872214811666170301124033.PMID28260521.
^Lawrence SE, Faught KA, Vethamuthu J, Lawson ML (July 2004). "Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia".The Journal of Pediatrics.145 (1):71–76.doi:10.1016/j.jpeds.2004.03.057.PMID15238910.
^Sugiyama N, Barros RP, Warner M, Gustafsson JA (September 2010). "ERbeta: recent understanding of estrogen signaling".Trends in Endocrinology and Metabolism.21 (9):545–552.doi:10.1016/j.tem.2010.05.001.PMID20646931.S2CID43001363.
Heringa M (2003). "Review on raloxifene: profile of a selective estrogen receptor modulator".Int J Clin Pharmacol Ther.41 (8):331–45.doi:10.5414/cpp41331.PMID12940590.
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.PMID15262454.
Wickerham DL, Costantino JP, Vogel VG, Cronin WM, Cecchini RS, Ford LG, et al. (2009). "The Use of Tamoxifen and Raloxifene for the Prevention of Breast Cancer".Cancer Prevention II. Recent Results in Cancer Research. Vol. 181. pp. 113–9.doi:10.1007/978-3-540-69297-3_12.ISBN978-3-540-69296-6.PMC5110043.PMID19213563.{{cite book}}:|work= ignored (help)
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.PMID23764354.
