Raloxifene
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Raloxifene
Raloxifene
Raloxifene Chemical Structure V.1.svg
Raloxifene molecule ball.png
Clinical data
Trade namesEvista, Optruma, others
Other namesKeoxifene; Pharoxifene; LY-139481; LY-156758; CCRIS-7129
AHFS/Drugs.comMonograph
MedlinePlusa698007
License data
Pregnancy
category
  • AU: X (High risk)
  • US: X (Contraindicated)
Routes of
administration
By mouth
Drug classSelective estrogen receptor modulator
ATC code
Legal status
Legal status
  • In general (Prescription only)
Pharmacokinetic data
Bioavailability2%[1][2]
Protein binding>95%[1][2]
MetabolismLiver, intestines (glucuro-
nidation
);[1][2][3]CYP450 system not involved[1][2]
Elimination Single-dose: 28 hours[1][2]
Multi-dose: 33 hours[1]
ExcretionFeces[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.212.655 Edit this at Wikidata
Chemical and physical data
FormulaC28H27NO4S
Molar mass473.584 g/mol g·mol-1
3D model (JSmol)
  (verify)

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids.[4] For osteoporosis it is less preferred than bisphosphonates.[4] It is also used to reduce the risk of breast cancer in those at high risk.[4] It is taken by mouth.[4]

Common side effects include hot flashes, leg cramps, swelling, and joint pain.[4] Severe side effects may include blood clots and stroke.[4] Use during pregnancy may harm the baby.[4] The medication may worsen menstrual symptoms.[5] Raloxifene is a selective estrogen receptor modulator (SERM) and therefore a mixed agonist-antagonist of the estrogen receptor (ER).[4] It has estrogenic effects in bone and antiestrogenic effects in the breasts and uterus.[4]

Raloxifene was approved for medical use in the United States in 1997.[4] It is available as a generic medication.[4][6] A month supply in the United Kingdom costs the NHS about 3.50 £ as of 2019.[6] In the United States the wholesale cost of this amount is about 16 USD.[7] In 2016 it was the 294th most prescribed medication in the United States with more than a million prescriptions.[8]

Medical uses

Raloxifene is used for the treatment and prevention of osteoporosis in postmenopausal women.[9] It is also used for reduction of risk and treatment of invasive breast cancer, and it also reduces breast density.[10] The medication is used at a dosage of 60 mg/day for both the prevention and treatment of osteoporosis and for prevention of breast cancer.[11] Raloxifene at a dosage of 60 mg/day is some amount less effective in the prevention of breast cancer than 20 mg/day tamoxifen.[12] For either osteoporosis treatment or prevention, supplemental calcium and vitamin D should be added to the diet if daily intake is inadequate.[13]

As with other SERMs,[14] raloxifene has been found to be effective in the treatment of gynecomastia (male breast development) in adolescents as well as adult men with prostate cancer treated with bicalutamide monotherapy.[15][16][17]

Contraindications

Raloxifene is contraindicated in lactating women or women who are or who may become pregnant[18]. It also may be of concern to women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.[19]

Side effects

Common side effects of raloxifene include hot flashes, vaginal dryness, and leg cramps.[18][1] Raloxifene does not cause breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer.[20] It does not appear to affect cognition or memory.[19] 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.[1] 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.[18] The risk of venous thromboembolism with raloxifene is increased by several-fold in postmenopausal women (RR = 3.1).[21] Raloxifene has a lower risk of thromboembolism than tamoxifen.[12]

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.[22]

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.[23]

Unlike other SERMs, such as tamoxifen, raloxifene has no risk of uterine hyperplasia or endometrial cancer (RR = 0.8).[1][21][12]

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.[18]

Raloxifene has been found to disinhibit the hypothalamic-pituitary-gonadal axis and thereby increase total testosterone levels in men.[24][25][26][27] Due to a simultaneous increase in sex hormone-binding globulin levels however, free testosterone levels often remain unchanged.[24]

Raloxifene has been found to decrease insulin-like growth factor 1 levels in women and men.[25]

Raloxifene has been found to possess estrogenic effects in adipose tissue in women, promoting a shift from an android fat distribution to a gynoid fat distribution in postmenopausal women.[28][29]

Medication Breast Bone Liver Uterus Vagina Brain
Lipids Coagulation SHBG IGF-1 Hot flashes Antigonadotropic
Estradiol + + + + + + + + + +
"Ideal SERM" - + + - ± ± - + + ±
Bazedoxifene - + + + + ? - ± - ?
Clomifene - ? ? ? + + ? ? - ±
Lasofoxifene - + + + ? ? ± ± - ?
Ospemifene - + + + + + ± ± - ±
Raloxifene - + + + + + ± - - ±
Tamoxifen - + + + + + + - - ±
Toremifene - + + + + + + - - ±
Effect: + = Estrogenic / agonistic. ± = Mixed or neutral. - = Antiestrogenic / antagonistic. Sources: See template.

Pharmacokinetics

The absorption of raloxifene is approximately 60%.[1][2] However, due to extensive first-pass metabolism, the absolute bioavailability of raloxifene is only 2.0%.[1][2] Raloxifene is rapidly absorbed from the intestines upon oral administration.[1]Peak plasma levels of raloxifene occur 0.5 to 6 hours after an oral dose.[1][2]

The volume of distribution of raloxifene with a single 30 to 150 mg mg oral dose is approximately 2348 L.[1][30] Raloxifene is widely distributed throughout the body.[1] There is extensive distribution of raloxifene into the liver, serum, lungs, and kidneys.[1] Both raloxifene and its metabolites show high plasma protein binding (>95%), including to both albumin and ?1 acid glycoprotein, but not to sex hormone-binding globulin.[1][2]

Raloxifene is metabolized in the liver and undergoes enterohepatic recycling.[2] It is metabolized exclusively by glucuronidation and is not metabolized by the cytochrome P450 system.[1][2] Less than 1% of radiolabeled material in plasma comprises unconjugated raloxifene.[2] The metabolites of raloxifene include several glucuronides.[1] The elimination 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).[1][2] The extended half-life of raloxifene is attributed to enterohepatic recirculation and its high plasma protein binding.[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.[2] The medication is deconjugated into its active form in a variety of tissues, including liver, lungs, spleen, bone, uterus, and kidneys.[1]

Raloxifene is mainly excreted in bile and is eliminated in feces.[1][2] Less than 0.2% of a dose is excreted unchanged in urine and less than 6% of a dose is excreted in urine as glucuronide conjugates.[2]

Chemistry

Raloxifene hydrochloride has the empirical formula C28H27NO4SoHCl, 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.[18]

Raloxifene is a benzothiophene derivative and is structurally distinct from the triphenylethylene SERMs like tamoxifen, clomifene, and toremifene.[31] It is the only benzothiophene SERM to have been marketed.[31] A benzothiophene SERM that was not marketed is arzoxifene (LY-353381).[32]Bazedoxifene (Duavee, Viviant) and pipendoxifene (ERA-923) are structurally related to raloxifene but are technically not benzothiophenes and instead are indoles.[32]

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.[33][34][35][36] It received orphan designation in 2005.[33]

Society and culture

A bottle of raloxifene.

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.[37][38][39][40] It has also been known by the name keoxifene.[37][38][40]

Raloxifene is sold mainly under the brand name Evista and to a lesser extent the brand name Optruma.[40][38] It is also sold under a variety of other brand names in various countries.[40]

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.[40][38]

Raloxifene is provided in the form of 60 mg oral tablets.[11]

Controversy

An editorial in Lancet Oncology criticized the way that research about the medication for breast cancer prevention was released.[41]

Research

Raloxifene has been studied in men for a variety of purposes, such as for the treatment of schizophrenia, prostate cancer, and osteoporosis.[42][43][44][45][46][27][26][47][48][49]

Raloxifene has been studied as an adjunct in the treatment of schizophrenia in postmenopausal women.[50] 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.[50] It may be effective in women with less severe symptoms.[50]

A tissue-selective estrogen-receptor complex of estradiol and raloxifene has been studied in postmenopausal women.[51]

References

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  3. ^ 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.
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Raloxifene
 



 



 
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