Raloxifene

Structural formula
General
Non-proprietary name	Raloxifene
other names	[6-Hydroxy-2- (4-hydroxyphenyl) benzo [ b ] thiophen-3-yl] - [4- (2-piperidin-1-yl-ethoxy) phenyl] methanone ( IUPAC ) ; Raloxifenum ( Latin ) ;
Molecular formula	C 28 H 27 NO 4 S; C 28 H 27 NO 4 S HCl (hydrochloride) ;
External identifiers / databases
EC number	686-786-1
ECHA InfoCard	100.212.655
PubChem	5035
ChemSpider	4859
DrugBank	DB00481
Wikidata	Q425223
Drug information
ATC code	G03 XC01
Drug class	Selective estrogen receptor modulator
properties
Molar mass	473.58 g · mol -1 ; 510.04 g · mol -1 (hydrochloride) ;
Melting point	143-147 ° C ; 258 ° C (hydrochloride) ;
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances	no GHS pictograms
	no GHS pictograms
H and P phrases	H: no H-phrases
	P: no P-phrases
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Raloxifene (trade name Evista ; manufacturer Eli Lilly and Company ) is a drug from the group of synthetic, non-steroidal , selective estrogen receptor modulators that is used in the treatment and prevention of osteoporosis in postmenopausal women.

Clinical information

Application areas (indications)

Raloxifene, a benzothiophene derivative , is mainly used in the prophylaxis and therapy of postmenopausal osteoporosis. A significant reduction in the incidence of vertebral fractures (in combination with basic therapy with Ca / VitD), but not of hip fractures (femoral neck fractures) was demonstrated. In contrast to the lead substance tamoxifen , raloxifene does not induce endometrial hyperplasia . There is evidence that raloxifene also lowers the risk of breast cancer and has a beneficial effect on the cardiovascular risk of postmenopausal women.

In 2018, a systematic review and meta-analysis showed that raloxifene in schizophrenia - as an addition to normal drug treatment - can noticeably reduce symptoms and can also be used over longer periods of time, both in women and in men.

Dosis, kind and Time of the Use

The daily dose is 60 mg raloxifene hydrochloride corresponding to 56 mg raloxifene base. No dose adjustment is necessary in elderly patients. Due to the nature of the disease process, raloxifene is suitable for long-term treatment.

Contraindications (contraindications)

The use of raloxifene is contraindicated in case of hypersensitivity to the active substance; in women of childbearing age; after pulmonary embolism and retinal vein thrombosis; severe liver dysfunction including cholestasis ( biliary obstruction ); venous thromboembolic processes, in the anamnesis ; in patients with deep vein thrombosis; Uterine bleeding of unknown origin; with severe kidney dysfunction ; Endometrial cancer and breast cancer ; There is no experience with systemic therapy with estrogens .

Drug interactions

A slight reduction in prothrombin time was observed with the simultaneous use of warfarin or other coumarin derivatives ; close monitoring is required. Raloxifene should not be used together with cholestyramine (or other anion exchange resins), as these significantly reduce the absorption and enterohepatic circulation of raloxifene.

Use during pregnancy and breastfeeding

Clinical studies in humans and animal studies have shown harm to the fetus . The drug is contraindicated for women who are pregnant or who may become pregnant. It is only intended for use in postmenopausal women. Raloxifene therapy should not be used in childbearing age. It can cause harm to the fetus if given during pregnancy. If this medicinal product is accidentally taken during pregnancy or if the patient becomes pregnant during treatment, she should be informed of the risk to the fetus.

It is not known whether raloxifene is excreted in breast milk. Clinical use during breastfeeding can therefore not be recommended. It can impair the child's development.

Adverse effects (side effects)

The following undesirable effects can occur:

Very common: hot flashes , sinus infections , joint pain and flu-like symptoms.
Common: calf cramps , water retention ( edema ), changes in the blood count (reduced platelets), sore throat, cough , pneumonia , laryngitis, muscle pain, arthritis , depression , insomnia , weight gain, flatulence, gastrointestinal inflammation.
Uncommon: Phlebitis with vein occlusion ( thrombophlebitis ), vascular occlusion (thrombosis), venous thrombosis, pulmonary embolism and venous thrombosis in the retina of the eye, increased liver values ( AST , ALT ).
Very rare: nausea and vomiting, abdominal pain, indigestion, increased blood pressure, headache, migraines , rashes, chest discomfort, chest pain, breast enlargement, increased sensitivity to pain.
Unspecified: tiredness, rash, herpes simplex , increased appetite, sweating, and bladder weakness (incontinence).

Studies

Raloxifene was examined for a possible cardioprotective effect in the RUTH study ( R aloxifen U se for T he H eart ). However, no effect on the rate of heart attacks, coronary deaths or hospital admissions for acute coronary syndrome could be demonstrated. However, an increased number of fatal strokes has been observed. In the RUTH study, the absolute risk of venous thromboembolism increased by 1.2 per 1000 user-years, while the rate of breast cancer fell.

Results of the Study of Tamoxifen and Raloxifene (STAR) Released: Osteoporosis Drug Raloxifene Shown to be as Effective as Tamoxifen in Preventing Invasive Breast Cancer ( Memento December 20, 2010 in the Internet Archive ) National Cancer Institute
Summaries of clinical study results

Pharmacological properties

Mechanism of action (pharmacodynamics)

Selective estrogen receptor modulators ( SERMs ) such as raloxifene are drugs that develop tissue and cell-specific agonistic and antagonistic estrogen effects. In the case of raloxifene, the steroid structure of the estrogen is not present, but it does bind to the classic estrogen receptors. Raloxifene currently belongs to the 3rd generation of this class of active ingredients. Raloxifene has an agonistic effect on the estrogen receptors in the bone tissue and develops an antiresorptive effect, whereas the effect in the breast or endometrial tissue is antagonistic. The binding affinity for ERα is four times greater than that for ERβ .

Absorption and distribution in the body (pharmacokinetics)

After oral administration , raloxifene is rapidly absorbed (approximately 60% of an oral dose). There is a characteristic presystemic glucuronidation . The absolute bioavailability of raloxifene is only 2%. The time taken to reach the maximum plasma level and bioavailability on average depends on the systemic conversion and enterohepatic cycle of raloxifen and its glucuronide metabolites. Raloxifene is extensively distributed throughout the body. The volume of distribution is not dose-dependent and the plasma protein binding is 98–99%.

Metabolism and Elimination

Raloxifene is subject to a pronounced first-pass metabolism into the corresponding glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide and raloxifene-6,4'-diglucuronide. No other metabolites were detected. The proportion of raloxifene in the total concentration of raloxifene and its glucuronide metabolites is less than 1%. The raloxifene blood levels are maintained by the enterohepatic circulation, resulting in a plasma half-life of 27.7 hours. The pharmacokinetics after multiple dosing can be derived from the results after single doses of raloxifene. Higher doses of raloxifene lead to an increase in the area under the plasma concentration-time curve ( AUC ), which is slightly smaller than a proportional increase. After a single orally administered dose, most of the raloxifene or its glucuronide metabolites are eliminated within 5 days and are mainly found in the faeces ; less than 6% is excreted renally .

toxicology

In an 8-week study with 63 postmenopausal women, a daily dose of 600 mg raloxifene · HCl was safely tolerated. There were no raloxifene overdoses in the clinical trials . Since launch, there have been spontaneous reports of very rare overdoses (less than 1 in 10,000 (<0.01%) treated patients). The highest overdose was approximately 1.5 grams of raloxifene hydrochloride and no life-threatening incidents were observed. After a single oral dose of 5 g / kg in rats and mice (810 times the human dose for rats and 405 times the human dose for mice), no lethal outcomes occurred. There is no specific antidote for raloxifene.

Chemical and pharmaceutical information

Is used medicinally raloxifene hydrochloride with molecular formula C ₂₈H ₂₈Cl N O ₄S , a molar mass of 510.04 g · mol ^-1 , CAS Number = 82640-04-8 and a melting point of 258 ° C . The substance is very sparingly soluble in water.

History

Raloxifene was invented by the American Jones Charles D. and published on November 29, 1983 by Eli Lilly and Company (USA) under patent number US 4418068.

literature

W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology . 9th edition. Urban & Fischer, Munich 2005, ISBN 3-437-42521-8 .
V. Diehl, M. Classen et al. (Ed.): Internal medicine with StudentConsult access . Urban & Fischer in Elsevier, Munich 2006, ISBN 3-437-44405-0 .

Individual evidence

↑ ^a ^b entry on raloxifene. In: Römpp Online . Georg Thieme Verlag, accessed on May 30, 2014.

↑ Data sheet Raloxifene hydrochloride from Sigma-Aldrich , accessed on April 22, 2011 ( PDF ).

↑ J. de Boer, M. Prikken, WU Lei, M. Begemann, I. Sommer: The effect of raloxifene augmentation in men and women with a schizophrenia spectrum disorder: a systematic review and meta-analysis. In: NPJ schizophrenia. Volume 4, number 1, January 2018, p. 1, doi : 10.1038 / s41537-017-0043-3 , PMID 29321530 , PMC 5762671 (free full text) (review).

↑ ^a ^b ^c Relistor: Product information, as of January 2014 on the website of the European Medicines Agency .

↑ Toshinari Takamura, Akiko Shimizu, Takuya Komura, Hitoshi Ando, Yoh Zen, Hiroshi Minato, Eiki Matsushita, Shuichi Kaneko: Selective Estrogen Receptor Modulator Raloxifene-Associated Aggravation of Nonalcoholic Steatohepatitis. In: Internal Medicine. 46 (9), 2007, pp. 579-581; PMID 17473493 ; doi : 10.2169 / internalmedicine.46.6374 PDF (free full text access , English)