Exemestane, sold under the brand name Aromasin among others, is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

used to treat

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

. It is a member of the class of

antiestrogen Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhi ...

s known as

aromatase inhibitor Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exog ...

s. Some breast cancers require

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

to grow. Those cancers have estrogen

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

(ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive.

Aromatase Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many ...

is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.

Medical uses

Exemestane is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the

adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesic ...

treatment of

postmenopausal Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

women with estrogen-receptor positive early breast cancer who have received two to three years of

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

and are switched to it for completion of a total of five consecutive years of adjuvant hormonal therapy. US FDA approval was in October 1999. Exemestane is also indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. For premenopausal women with hormone-receptor–positive breast cancer, adjuvant treatment with ovarian suppression plus the aromatase inhibitor exemestane, as compared with ovarian suppression plus tamoxifen, provides a new treatment option that reduces the risk of recurrence. The TEXT and SOFT trials demonstrated improved disease free survival in patients treated with exemestane and ovarian suppression compared to the tamoxifen and ovarian suppression group. Premenopausal women who receive ovarian suppression may now benefit from an aromatase inhibitor, a class of drugs that until now has been recommended only for postmenopausal women.

Contraindications

The drug is contraindicated in

premenopausal Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

women, which of course includes pregnant and lactating women.

Side effects

The most common side effects (more than 10% of patients) are

hot flash Hot flashes (also known as 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 ...

es and sweating, which are typical of estrogen deficiency as caused by exemestane, and also

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

, headache, and

joint pain Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

. Nausea and

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

are mainly observed in patients with advanced breast cancer.Drugs.com: on exemestane. An occasional decrease in lymphocytes has been observed in approximately 20% of patients receiving Aromasin, particularly in patients with pre-existing lymphopenia. Exemestane has

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...

ic properties similarly to

formestane Formestane, formerly sold under the brand name Lentaron among others, is a steroidal, selective aromatase inhibitor which is used in the treatment of estrogen receptor-positive breast cancer in postmenopausal women. The drug is not active orally ...

and can produce androgenic side effects such as

acne Acne, also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, black ...

and

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs wh ...

, although these are generally associated with supratherapeutic dosages of the drug.

Overdose

Single doses of up to at least 32-fold (800 mg), as well as continuous therapy with 24-fold (600 mg) the usual daily dose are well tolerated. No life-threatening overdosing is known in humans, but only in animal studies with 2000- to 4000-fold doses (adjusted to

body surface area In physiology and medicine, the body surface area (BSA) is the measured or calculated surface area of a human body. For many clinical purposes, BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal ad ...

Interactions

Exemestane is metabolized by the liver enzyme

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

. While the CYP3A4 inhibitor

ketoconazole Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...

had no significant effect on exemestane levels in a clinical trial, the strong CYP3A4 inductor

rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), mycobacterium avium complex, ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. ...

significantly cut exemenstane levels about in half ( AUC −54%, C_max −41% for a single dose), potentially compromising its effectiveness. Other 3A4 inductors such as

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...

and

St John's Wort ''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''. Possibly a hybrid between '' H. maculatum'' and '' H. attenuatum'', the species can be found a ...

are expected to have similar effects. The clinical relevance of this effect has not been investigated. Estrogens probably reduce exemestane effectiveness: It would usually be counter-productive to reduce the body's estrogen synthesis with exemestane and then substitute estrogen with pharmaceuticals.

Pharmacology

Pharmacodynamics

Exemestane is an oral steroidal aromatase inhibitor that is used in ER-positive breast cancer in addition to surgery and/or radiation in post-menopausal women. The main source of

is the ovaries in premenopausal women, while in post-menopausal women most of the body's estrogen is produced via the conversion of

s into estrogen by the aromatase enzyme in the peripheral tissues (i.e. adipose tissue like that of the breast) and a number of sites in the brain. Estrogen is produced locally via the actions of the aromatase enzyme in these peripheral tissues where it acts locally. Any circulating estrogen in post-menopausal women as well as men is the result of estrogen escaping local metabolism and entering the circulatory system. Exemestane is an irreversible, steroidal aromatase inactivator of type I, structurally related to the natural substrate

4-androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroep ...

. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "

suicide inhibition In biochemistry, suicide inhibition, also known as suicide inactivation or mechanism-based inhibition, is an irreversible form of enzyme inhibition that occurs when an enzyme binds a substrate analog and forms an irreversible complex with it thr ...

." By being structurally similar to enzyme targets, exemestane permanently binds to the enzymes, preventing them from converting androgen into estrogen. Type II aromatase inhibitors such as

anastrozole Anastrozole, sold under the brand name Arimidex among others, is a medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast ca ...

and

letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer. It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most common ...

, by contrast, are not steroids and work by interfering with the aromatase's

heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consisti ...

. A study conducted on young adult males found that the estrogen suppression rate for exemestane varied from 35% for

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...

(E2) to 70% for

estrone Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...

(E1).

Pharmacokinetics

Exemestane is quickly absorbed from the gut, but undergoes a strong first-pass effect in the liver. Highest blood plasma concentrations are reached after 1.2 hours in breast cancer patients and after 2.9 hours in healthy subjects. Maximal aromatase inhibition occurs after two to three days. 90% of the absorbed substance are bound to

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s. The liver enzyme CYP3A4 oxidizes the

methylidene Methylene (systematically named methylidene and dihydridocarbon; also called carbene) is an organic compound with the chemical formula (also written ). It is a colourless gas that fluoresces in the mid-infrared range, and only persists in dilut ...

group in position 6, and the 17- keto group (on the five-membered ring) is reduced by

aldo-keto reductase The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xyl ...

s to an

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

. Of the resulting metabolites, 40% are excreted via the urine and 40% via the feces within a week. The original substance accounts for only 1% of excretion in the urine. The terminal half-life is 24 hours.

Chemistry

Exemestane is known chemically as 6-methylideneandrosta-1,4-diene-3,17-dione. Like the aromatase inhibitors

and atamestane, exemestane is a

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

that is structurally similar to 4-androstenedione, the natural substrate of aromatase. It is distinguished from the natural substance only by the methylidene group in position 6 and an additional double bond in position 1. Pure exemestane is a white to off-white powder that is soluble in

DMSO Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds an ...

to at least 20 mg/mL.

Optical rotation Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

�sub>''D'' is +250 to 300° (per g/100 cm³ and decimetre at 589 nm wavelength).

Society and culture

Performance enhancement

Exemestane has been used in doping to raise

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 (GnRH) ...

(LH) and

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, pubertal maturation, an ...

(FSH) levels, which in turn increases the ratio of male over female sexual hormones and so improves performance. The drug also counteracts

gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (1 ...

as well as fat and water retention following excessive aromatase production due to

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

doping. Along with other aromatase inhibitors, exemestane is on the

World Anti-Doping Agency The World Anti-Doping Agency (WADA; french: Agence mondiale antidopage, AMA) is a foundation initiated by the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against drugs in sports. The agency's key ...

's list of prohibited substances.

Research

Oral exemestane 25 mg/day for 2–3 years of adjuvant therapy was generally more effective than 5 years of continuous adjuvant

in the treatment of postmenopausal women with early-stage estrogen receptor-positive/unknown receptor status breast in a large well-designed trial. Preliminary data from the open-label TEAM trial comparing exemestane with tamoxifen indicated in 2009 that exemestane 25 mg/day is also effective in the primary adjuvant treatment of early-stage breast cancer in postmenopausal women. Interim phase III trial results in 2011 showed that adding

everolimus Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours. It is the 40 ...

to exemestane therapy against advanced breast cancer can significantly improve

progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...

compared with exemestane therapy alone. A Phase III trial was reported in 2011, concluding that the use of exemestane in postmenopausal women at an increased risk for breast cancer reduced the incidence of invasive breast cancer. In 4,560 women, after 35 months, the administration of exemestane at a dose of 25 mg/day resulted in a 65% reduction in the risk of breast cancer compared with placebo; annual incidence rates were 0.19% and 0.55%, respectively (hazard ratio: 0.35; 95% CI .18-0.70 p = 0.002).

References

External links

Aromasin official website

Aromasin prescribing information
{{Androgen receptor modulators Androgens and anabolic steroids Androstanes Aromatase inhibitors Diketones Enantiopure drugs Hormonal antineoplastic drugs Pfizer brands World Anti-Doping Agency prohibited substances