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

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

postmenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...

women and those on

glucocorticoids Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

. For osteoporosis it is less preferred than

bisphosphonates Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed to treat osteoporosis. Evidence shows that they reduce the risk of fracture in p ...

. It is also used to reduce the risk of

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

in those at high risk. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Common

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s include

hot flash Hot flushes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from t ...

es, leg cramps, swelling, and

joint pain Arthralgia () literally means 'joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication Medication (also called medicament, medicine, pharmaceutic ...

. Severe side effects may include

blood clots A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulati ...

and

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

. Use during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

may harm the baby. The medication may worsen menstrual symptoms. Raloxifene is a

selective estrogen receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists (e.g., full agonists and silent ...

(SERM) and therefore a mixed

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

–

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

(ER). It has

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

ic effects in

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

and antiestrogenic effects in the

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

s and

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

. Raloxifene was approved for medical use in the United States in 1997. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. In 2020, it was the 292nd most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Raloxifene is used for the treatment and prevention of

women. It is used at a dosage of 60 mg/day for both the prevention and treatment of osteoporosis. In the case of either osteoporosis prevention or treatment, supplemental

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

and

vitamin D Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...

should be added to the diet if daily intake is inadequate. Raloxifene is used to reduce the risk of

in postmenopausal women. It is used at a dosage of 60 mg/day for this indication. In the Multiple Outcomes of Raloxifene (MORE)

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

, raloxifene decreased the risk of all types of breast cancer by 62%, of invasive breast cancer by 72%, and of invasive

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

-positive breast cancer by 84%. Conversely, it does not reduce the risk of estrogen receptor-negative breast cancer. 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. In the Study of Tamoxifen and Raloxifene (STAR) trial, 60 mg/day raloxifene was 78% as effective as 20 mg/day

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...

in preventing non-invasive breast cancer. 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.

Contraindications

Raloxifene is

contraindicated In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

lactating Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...

women or women who are or who may become

pregnant Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

. It also may be of concern to women with active or past history of venous thromboembolic events, including

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...

pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...

, and

retinal vein thrombosis Central retinal vein occlusion, also CRVO, is when the central retinal vein becomes occluded, usually through thrombosis. The central retinal vein is the venous equivalent of the central retinal artery and both may become occluded. Since the cent ...

Side effects

Common side effects of raloxifene include

es (25–28% vs. 18–21% for

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

vaginal dryness Vaginal lubrication is a naturally produced fluid that lubricates the vagina. Vaginal lubrication production increases significantly during sexual arousal in anticipation of sexual intercourse. Vaginal dryness is the condition in which this l ...

, and leg cramps (generally mild; 5.5% vs. 1.9% for placebo).Raloxifene label
Last updated 09/2007] Raloxifene does ''not'' cause

breast tenderness Breast pain is the symptom of discomfort in either one or both breasts. Pain in both breasts is often described as ''breast tenderness'', is usually associated with the menstrual period and is not serious. Pain that involves only one part of a ...

endometrial hyperplasia Endometrial hyperplasia is a condition of excessive proliferation of the cells of the endometrium, or inner lining of the uterus. Most cases of endometrial hyperplasia result from high levels of estrogens, combined with insufficient levels of th ...

, menstrual bleeding, or

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...

. It does not appear to affect

cognition Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...

. Raloxifene is a teratogen; i.e., it can cause developmental abnormalities such as

birth defect A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...

s. Raloxifene may infrequently cause serious

blood clot A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...

s to form in the legs,

lungs The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...

, or

eyes An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...

. 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

and

. The risk of

venous thromboembolism Venous thrombosis is the blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lun ...

with raloxifene is increased by several-fold in postmenopausal women ( = 3.1). Raloxifene has a lower risk of thromboembolism than tamoxifen. 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 Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

, although there was no decrease in cardiovascular events for the group as a whole. 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. 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. Unlike other SERMs, such as

, raloxifene has no risk of uterine hyperplasia or

( = 0.8). Raloxifene does not increase the incidence of breast pain or tenderness in postmenopausal women.

Overdose

Raloxifene has been studied in

s across a dosage range of 30 to 600 mg/day, and was well-tolerated at all dosages.

Pharmacology

Pharmacodynamics

Mechanism of action

Raloxifene is a

(SERM) and hence is a mixed

and

(ER) in different tissues. It has

ic activity in some tissues, such as

and the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

, and antiestrogenic activity in other tissues, such as the

s and

. Its

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

(K_d) for the

ERα Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the se ...

is approximately 50 pM, which is similar to that of

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

. Relative to estradiol, raloxifene has been reported to possess about 8 to 34% of the

for the ERα and 0.5 to 76% of the affinity for the

ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by t ...

. Raloxifene acts as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the ERα and as a pure antagonist of the ERβ. In contrast to the classical ERs, raloxifene is an agonist of the G protein-coupled estrogen receptor (GPER) ( = 10–100 nM), a

membrane estrogen receptor Membrane estrogen receptors (mERs) are a group of receptor (biochemistry), receptors which bind estrogen. Unlike nuclear estrogen receptors, which mediate their effects via slower Genome, genomic mechanisms, mERs are cell surface receptors that rapi ...

Clinical effects

Raloxifene has antiestrogenic effects in the

mammary gland A mammary gland is an exocrine gland that produces milk in humans and other mammals. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in primates (for example, human ...

s in preclinical studies. In accordance, raloxifene reduces breast density in

women, a known risk factor for

. It does not stimulate the

in postmenopausal women, and results in no increase in risk of

endometrial The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...

thickening, vaginal bleeding,

, or

. At the same time, raloxifene has minimal antiestrogenic effect in the uterus in premenopausal women. This may possibly be due to inadequate tissue exposure of the uterus to raloxifene in these estrogen-rich individuals. In premenopausal women, raloxifene increases levels of

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, puberty, pubertal maturat ...

(FSH) and

. Conversely, in postmenopausal women, raloxifene has been found to reduce levels of the gonadotropins,

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...

(LH) and FSH, while not affecting levels of estradiol. Raloxifene also decreases

prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...

levels in postmenopausal women. In men, raloxifene has been found to disinhibit the

hypothalamic–pituitary–gonadal axis The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single en ...

(HPG axis) and thereby increase total

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

levels. Due to the simultaneous increase in

sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...

(SHBG) levels however, free testosterone levels often remain unchanged in men during therapy with raloxifene. Raloxifene has

ic effects on liver protein synthesis. It increases SHBG levels in both pre- and

women as well as in men. The medication decreases levels of total and

low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...

(LDL)

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

C-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin ...

apolipoprotein B Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene. Its measurement is commonly used to detect the risk of Atherosclerosis, atherosclerotic Coronary artery disease, cardiovascular disease. Isoforms The protein occur ...

, and homocysteine. Conversely, it has little effect on levels of

triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...

s and

high-density lipoprotein High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...

(HDL). Raloxifene has been shown to inhibit the

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

of LDL cholesterol ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

''. The medication has been found to decrease

insulin-like growth factor 1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in tertiary structure, molecular structure to insulin which plays an important role in childhood growth, and has Anabolism, anabolic effects in adults. In the ...

(IGF-1) levels in pre- and postmenopausal women as well as in men. It has also been found to increase insulin-like growth factor binding protein 3 (IGFBP-3) levels in pre- and postmenopausal women. Due to activation of

s in the liver, raloxifene has procoagulatory effects, such as decreasing levels of

fibrinogen Fibrinogen (coagulation factor I) is a glycoprotein protein complex, complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted Enzyme, enzymatically by thrombin to fibrin ...

and influencing levels of other coagulation factors. For these reasons, raloxifene increases the risk of

thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...

. Raloxifene increases

bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to opti ...

in postmenopausal women but decreases it in premenopausal women. In the MORE trial, the risk of

vertebral fracture A spinal fracture, also called a vertebral fracture or a broken back, is a fracture affecting the vertebrae of the spinal column. Most types of spinal fracture confer a significant risk of spinal cord injury. After the immediate trauma, there is ...

s was decreased by 30%, and bone mineral density was increased in the

spine Spine or spinal may refer to: Science Biology * Spinal column, also known as the backbone * Dendritic spine, a small membranous protrusion from a neuron's dendrite * Thorns, spines, and prickles, needle-like structures in plants * Spine (zoology), ...

(by 2.1% at 60 mg, 2.4% at 120 mg) and femoral neck (2.6% at 60 mg, 2.7% at 120 mg). It has been found to possess estrogenic effects in

adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

in postmenopausal women, promoting a shift from an android fat distribution to a

gynoid fat distribution Gynoid fat is the body fat that forms around the lower body, specifically the hips, thighs and buttocks. "As women reach puberty, fat accumulates in the gynoid fat regions, notably, on the buttocks, thighs, and hips , 10" Gynoid fat in female ...

. The medication has been found to increase levels of

leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...

, an adipokine.

Pharmacokinetics

Absorption

The absorption of raloxifene is approximately 60%. However, due to extensive

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

, the

absolute bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of raloxifene is only 2.0%. Raloxifene is rapidly absorbed from the

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

s upon

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Peak plasma levels of raloxifene occur 0.5 to 6 hours after an oral dose. 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).

Distribution

Raloxifene is widely

distributed Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...

throughout the body. There is extensive distribution of raloxifene into the

, serum,

lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...

s, and

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

s. The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

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. Both raloxifene and its glucuronide

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s show high

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

(>95%), including to both

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

and α₁ acid glycoprotein, but not to

. More specifically, raloxifene is 98.2 ± 0.4% bound to plasma proteins.

Metabolism

Raloxifene is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

in the

and undergoes enterohepatic recycling. It is metabolized exclusively by

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

and is not metabolized by the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

system. Less than 1% of radiolabeled material in plasma comprises unconjugated raloxifene. The metabolites of raloxifene include several

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

s. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

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). The extended half-life of raloxifene is attributed to enterohepatic recirculation and its high plasma protein binding. Raloxifene and its

conjugates are interconverted by reversible metabolism and enterohepatic recycling, which prolongs the elimination half-life of raloxifene with oral administration. The medication is deconjugated into its active form in a variety of tissues, including liver, lungs,

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

, and kidneys.

Elimination

Raloxifene is mainly excreted in

bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...

and is eliminated in

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

. Less than 0.2% of a dose is excreted unchanged in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

and less than 6% of a dose is excreted in urine as glucuronide conjugates.

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. Raloxifene is a benzothiophene

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

and is structurally distinct from the

triphenylethylene Triphenylethylene (TPE) is the organic compound with the formula . It is a colorless solid. Synthesis and reactions The compound is prepared in two steps from benzophenone via the intermediacy of 1,2,2-triphenylethanol. Triphenylethylene reacts ...

SERMs like

clomifene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. It is taken by mouth. Common side effects include pelvic pain and hot flashes. Oth ...

, and toremifene. It is the only benzothiophene SERM to have been marketed. A benzothiophene SERM that was not marketed is arzoxifene (LY-353381). Bazedoxifene (Duavee, Viviant) and pipendoxifene (ERA-923) are structurally related to raloxifene but are technically not benzothiophenes and instead are

indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...

History

Raloxifene was approved in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

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. It received orphan designation in 2005.

Society and culture

Names

''Raloxifene'' is the generic name of the drug and its and , while ''raloxifène'' is its and ''raloxifene hydrochloride'' is its , , and . It has also been known by the name ''keoxifene''. Raloxifene is sold mainly under the brand name Evista and to a lesser extent the brand name Optruma. It is also sold under a variety of other brand names in various countries.

Availability

Raloxifene is available widely throughout the world, including in the

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

, the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...

Ireland Ireland (, ; ; Ulster Scots dialect, Ulster-Scots: ) is an island in the North Atlantic Ocean, in Northwestern Europe. Geopolitically, the island is divided between the Republic of Ireland (officially Names of the Irish state, named Irelan ...

, elsewhere throughout

Europe Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west, the Mediterranean Sea to the south, and Asia to the east ...

Australia Australia, officially the Commonwealth of Australia, is a country comprising mainland Australia, the mainland of the Australia (continent), Australian continent, the island of Tasmania and list of islands of Australia, numerous smaller isl ...

New Zealand New Zealand () is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and List of islands of New Zealand, over 600 smaller islands. It is the List of isla ...

South Africa South Africa, officially the Republic of South Africa (RSA), is the Southern Africa, southernmost country in Africa. Its Provinces of South Africa, nine provinces are bounded to the south by of coastline that stretches along the Atlantic O ...

Latin America Latin America is the cultural region of the Americas where Romance languages are predominantly spoken, primarily Spanish language, Spanish and Portuguese language, Portuguese. Latin America is defined according to cultural identity, not geogr ...

, Southern, Eastern, and Southeastern Asia, and elsewhere in the world such as in

Israel Israel, officially the State of Israel, is a country in West Asia. It Borders of Israel, shares borders with Lebanon to the north, Syria to the north-east, Jordan to the east, Egypt to the south-west, and the Mediterranean Sea to the west. Isr ...

and

Egypt Egypt ( , ), officially the Arab Republic of Egypt, is a country spanning the Northeast Africa, northeast corner of Africa and Western Asia, southwest corner of Asia via the Sinai Peninsula. It is bordered by the Mediterranean Sea to northe ...

. Raloxifene is provided in the form of 60 mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

tablets.

Controversy

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

Research

Clinical studies of raloxifene for

metastatic breast cancer Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary l ...

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. In contrast to tamoxifen, raloxifene is not approved for the treatment of breast cancer. Raloxifene has been studied in men for a variety of uses, such as for treatment of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

, and

. It has been studied in combination with

castration Castration is any action, surgery, surgical, chemical substance, chemical, or otherwise, by which a male loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical cas ...

and

bicalutamide Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...

, a

nonsteroidal antiandrogen A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens lik ...

, for the treatment of prostate cancer. Raloxifene has been studied as an adjunct in the treatment of

in postmenopausal women. A 2017

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

concluded that it was safe and effective for this indication, although further studies with larger

sample size Sample size determination or estimation is the act of choosing the number of observations or replicates to include in a statistical sample. The sample size is an important feature of any empirical study in which the goal is to make inferences abo ...

s are needed for confirmation. It may be effective in women with less severe symptoms. A tissue-selective estrogen-receptor complex (TSEC) of

and raloxifene has been studied in postmenopausal women. Raloxifene (60 mg/day) was reported to be effective in the treatment of pubertal gynecomastia in adolescent boys in a small retrospective chart review. Other SERMs are also known to be effective in the treatment of gynecomastia. Raloxifene has been reported to augment the

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

effects of

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

s (SSRIs).

Medical uses

Contraindications

Side effects

Overdose

Pharmacology

Pharmacodynamics

Mechanism of action

Clinical effects

Pharmacokinetics

Absorption

Distribution

Metabolism

Elimination

Chemistry

History

Society and culture

Names

Availability

Controversy

Research

References

Further reading