Raloxifene

Source: Wikipedia, the free encyclopedia.
Raloxifene
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)
Routes of
administration		By mouth
Drug classSelective estrogen receptor modulator
ATC code
Legal status
Legal status
  • US: WARNING[1]Rx-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
CYP450 system not involved[2][3]
Elimination half-lifeSingle-dose: 28 hours[2][3]
Multi-dose: 33 hours[2]
ExcretionFeces[3]
Identifiers
  • [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophen-3-yl]-[4-[2-(1-piperidyl)ethoxy]phenyl]-methanone
JSmol)
  • O=C(c1c3ccc(O)cc3sc1c2ccc(O)cc2)c5ccc(OCCN4CCCCC4)cc5
  • InChI=1S/C28H27NO4S/c30-21-8-4-20(5-9-21)28-26(24-13-10-22(31)18-25(24)34-28)27(32)19-6-11-23(12-7-19)33-17-16-29-14-2-1-3-15-29/h4-13,18,30-31H,1-3,14-17H2 checkY
  • Key:GZUITABIAKMVPG-UHFFFAOYSA-N checkY
  (verify)

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat

bisphosphonates.[5] It is also used to reduce the risk of breast cancer in those at high risk.[5] It is taken by mouth.[5]

Common

menstrual symptoms.[6] Raloxifene is a selective estrogen receptor modulator (SERM) and therefore a mixed agonist–antagonist of the estrogen receptor (ER).[5] It has estrogenic effects in bone and antiestrogenic effects in the breasts and uterus.[5]

Raloxifene was approved for medical use in the United States in 1997.[5] It is available as a generic medication.[5][7] In 2020, it was the 292nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[8][9]

Medical uses

Raloxifene is used for the treatment and prevention of osteoporosis in postmenopausal 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, supplemental calcium and vitamin D should be added to the diet if daily intake is inadequate.[12]

Raloxifene is used to reduce the risk of breast 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 invasive estrogen 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 the Study of Tamoxifen and Raloxifene (STAR) trial, 60 mg/day raloxifene was 78% as effective as 20 mg/day tamoxifen 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]

Contraindications

Raloxifene is

retinal vein thrombosis.[16]

Side effects

Common side effects of raloxifene include

menstrual bleeding, or endometrial cancer.[18] It does not appear to affect cognition or memory.[16][13] Raloxifene is a teratogen; i.e., it can cause developmental abnormalities such as birth defects
.

Raloxifene may infrequently cause serious

venous 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 for coronary 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 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.[21]

Unlike other SERMs, such as tamoxifen, raloxifene has no risk of uterine hyperplasia or endometrial cancer (RRTooltip relative risk = 0.8).[2][19][14]

Raloxifene does not increase the incidence of

tenderness in postmenopausal women.[17][22]

Overdose

Raloxifene has been studied in clinical trials across a dosage range of 30 to 600 mg/day, and was well-tolerated at all dosages.[17]

Pharmacology

Pharmacodynamics

Mechanism of action

Raloxifene is a

EC50Tooltip half-maximal effective concentration = 10–100 nM), a membrane estrogen receptor.[27][28]

Clinical effects

Raloxifene has antiestrogenic effects in the

premenopausal women.[30] This may possibly be due to inadequate tissue exposure of the uterus to raloxifene in these estrogen-rich individuals.[30]

In premenopausal women, raloxifene increases levels of follicle-stimulating hormone (FSH) and estradiol.[13] Conversely, in postmenopausal women, raloxifene has been found to reduce levels of the gonadotropins, luteinizing hormone (LH) and FSH, while not affecting levels of estradiol.[13][30] Raloxifene also decreases prolactin levels in postmenopausal women.[30] In men, raloxifene has been found to disinhibit the hypothalamic–pituitary–gonadal axis (HPG axis) and thereby increase total testosterone levels.[31][32][33][34] Due to the simultaneous increase in sex hormone-binding globulin (SHBG) levels however, free testosterone levels often remain unchanged in men during therapy with raloxifene.[31]

Raloxifene has

coagulation factors.[13][30][17] For these reasons, raloxifene increases the risk of thrombosis.[13][30]

Raloxifene increases

vertebral fractures was decreased by 30%, and bone mineral density was increased in the spine (by 2.1% at 60 mg, 2.4% at 120 mg) and femoral neck (2.6% at 60 mg, 2.7% at 120 mg).[19] It has been found to possess estrogenic effects in adipose tissue in postmenopausal women, promoting a shift from an android fat distribution to a gynoid fat distribution.[35][36] The medication has been found to increase levels of leptin, an adipokine.[13]

Tissue-specific estrogenic and antiestrogenic activity of SERMs
Medication Breast Bone Liver Uterus Vagina Brain
Lipids
 Coagulation SHBGTooltip Sex hormone-binding globulin IGF-1Tooltip Insulin-like growth factor 1 Hot flashes Gonadotropins
Estradiol + + + + + + + + + +
"Ideal SERM" – + + ± ± ± – + + ±
Bazedoxifene – + + + + ? – ± – ?
Clomifene – + + ? + + – ? – ±
Lasofoxifene – + + + ? ? ± ± – ?
Ospemifene – + + + + + ± ± – ±
Raloxifene – + + + + + ± – – ±
Tamoxifen – + + + + + + – – ±
Toremifene – + + + + + + – – ±
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.

Pharmacokinetics

Absorption

The

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]

Distribution

Raloxifene is widely

serum, lungs, and kidneys.[2] The volume of distribution of raloxifene with a single 30 to 150 mg oral dose is approximately 2348 L/kg, which corresponds to ~170,000 L for a 72 kg person.[2][37] Both raloxifene and its glucuronide metabolites show high plasma protein binding (>95%), including to both albumin and α1 acid glycoprotein, but not to sex hormone-binding globulin.[2][3] More specifically, raloxifene is 98.2 ± 0.4% bound to plasma proteins.[38]

Metabolism

Raloxifene is

deconjugated into its active form in a variety of tissues, including liver, lungs, spleen, bone, uterus, and kidneys.[2]

Elimination

Raloxifene is mainly excreted in bile and is eliminated in feces.[2][3] 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.[3]

Chemistry

See also: List of selective estrogen receptor modulators and Benzothiophene

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

derivative and is structurally distinct from the triphenylethylene SERMs like tamoxifen, clomifene, and toremifene.[39] It is the only benzothiophene SERM to have been marketed.[39] A benzothiophene SERM that was not marketed is arzoxifene (LY-353381).[40] Bazedoxifene (Duavee, Viviant) and pipendoxifene (ERA-923) are structurally related to raloxifene but are technically not benzothiophenes and instead are indoles.[40]

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.[41][42][43][44] It received orphan designation in 2005.[41]

Society and culture

A bottle of raloxifene.

Names

Raloxifene is the

INNTooltip International Nonproprietary Name and BANTooltip British Approved Name, while raloxifène is its DCFTooltip Dénomination Commune Française and raloxifene hydrochloride is its USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[45][46][47][48] It has also been known by the name keoxifene.[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]

Availability

Raloxifene is available widely throughout the world, including in the

Southeastern Asia, and elsewhere in the world such as in Israel and Egypt.[48][46]

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.[49]

Research

Clinical studies of raloxifene for metastatic 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 in men for a variety of uses, such as for treatment of schizophrenia, prostate cancer, and osteoporosis.[52][53][54][55][56][34][33][57][58][59][60] It has been studied in combination with castration and bicalutamide, a nonsteroidal antiandrogen, for the treatment of prostate cancer.[60][57]

Raloxifene has been studied as an

sample sizes are needed for confirmation.[61] It may be effective in women with less severe symptoms.[61]

A tissue-selective estrogen-receptor complex (TSEC) of estradiol and raloxifene has been studied in postmenopausal women.[62]

Raloxifene (60 mg/day) was reported to be effective in the treatment of

retrospective chart review.[63][64][65] Other SERMs are also known to be effective in the treatment of gynecomastia.[66]

Raloxifene has been reported to augment the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs).[67]

June 18th 2020, Exscalate4CoV, the private-public consortium supported by the EU’s Horizon 2020 programme for research and innovation, led by

Dompé farmaceutici
and currently representing 18 partners (including Fraunhofer Institute, CINECA, Chelonia Applied Science, Swiss Institute of Bioinformatics and others) has requested access to clinical trials for the use of Raloxifene in COVID-19 patients. Raloxifene, already proven effective against Mers and Sars in preclinical tests, has been indicated as effective against SARS-CoV-2 by the “in-silico” research conducted by the consortium which has shown efficacy in countering the replication of the virus in cells. The IP for its use against SARS-CoV-2 has already been protected on May 6 2020 in the name Dompé farmaceutici, Fraunhofer Institute and KU Leuven, to facilitate the largest possible access. Raloxifene would be used in mildly symptomatic COVID-19 patients to halt the spread of infection. This result emerged from the first virtual (in silico) screening conducted on the Consortium’s supercomputers of more than 400.000 molecules (safe-in-man drugs and natural products) made available by Dompé farmaceutici and the partner Fraunhofer (IME) to the Consortium. The molecules were prioritized if in clinical stage or already on the market. 7.000 molecules with certain promising characteristics were tested.

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Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Raloxifene&oldid=1190949869"