EXEMESTANE AURO

Indications

• First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer
• Adjuvant treatment of oestrogen-receptor-positive invasive early breast cancer in postmenopausal women following 2-3 years of tamoxifen therapy
• Advanced breast cancer in postmenopausal women in whom other anti-oestrogen therapy has failed
• Extended adjuvant treatment of hormone-dependent invasive breast cancer in postmenopausal women

Dosage

Adults: 25 mg daily by mouth.

Mechanism of action

Exemestane acts as an irreversible aromatase inactivator by binding to the active site of the aromatase enzyme. This binding permanently inhibits the enzyme's activity, leading to decreased conversion of androgens to estrogens in postmenopausal women. As a result, serum estrogen levels drop significantly, which helps to slow down or halt the proliferation of estrogen-dependent breast cancer cells.

Pharmacodynamics

By inhibiting aromatase, exemestane selectively lowers estrogen levels without affecting the synthesis of other steroid hormones, such as corticosteroids and aldosterone. This selectivity allows for effective treatment of estrogen-dependent breast cancer while minimizing potential side effects related to other hormonal pathways.

Pharmacokinetics

Exemestane is well-absorbed after oral administration, with peak plasma concentrations achieved within 2 hours. It undergoes extensive hepatic metabolism, primarily via CYP3A4, and has a half-life of approximately 24 hours. Excretion is primarily via urine, with metabolites being eliminated. Caution is advised in patients with severe hepatic impairment due to increased exposure.

Contra-indications

• Not indicated for premenopausal women

Adverse effects

• Alopecia
• Altered appetite
• Arthralgia
• Asthenia
• Bone fracture
• Bone pain
• Constipation
• Depression
• Diarrhoea
• Dizziness
• Gastrointestinal discomfort
• Headache
• Hot flush
• Hypercholesterolaemia
• Hyperhidrosis
• Hypertension
• Malaise
• Myalgia
• Nausea
• Oedema
• Osteoporosis
• Skin reactions
• Vaginal haemorrhage
• Vomiting
• Weight changes
• Anxiety
• Breast pain
• Cancer pain
• Carpal tunnel syndrome
• Cataract
• Cerebrovascular insufficiency
• Cough
• Dry mouth
• Dysesthesia
• Dyspnoea
• Embolism and thrombosis
• Eye irritation
• Insomnia
• Irritability
• Ischaemic heart disease
• Leucopenia
• Memory loss
• Mucosal dryness
• Myocardial infarction
• Palpitations
• Stomatitis
• Tachycardia
• Taste altered
• Thirst
• Urinary frequency
• Increased urinary tract infection
• Vision blurred
• Vulvovaginal disorders

Interactions

• Mitotane may decrease exposure to exemestane
• St John's Wort may decrease exposure to exemestane
• Rifampicin may decrease exposure to exemestane

Precautions

• Caution in patients with susceptibility to osteoporosis
• Effective contraception required until postmenopausal status is fully established
• Use with caution in hepatic impairment
• Use with caution in renal impairment

Pregnancy

Avoid due to isolated cases of birth defects reported.

Breast-feeding

Manufacturer advises to avoid.

Storage

Store in a cool, dry place away from

Mechanism of action

Breast cancer cell growth may be estrogen-dependent. Aromatase (exemestane) is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It irreversibly binds to the active site causing permanent inhibition necessitating de novo synthesis to restore enzymatic function. Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on the adrenal biosynthesis of corticosteroids or aldosterone. This reduction in serum and tumor concentrations of estrogen delays tumor growth and disease progression. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme. ... exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors... Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. 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." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme. ... Treatment with exemestane suppressed whole body aromatization from a mean pretreatment value of 2.059% to 0.042% (mean suppression of 97.9%). Plasma levels of estrone, estradiol, and estrone sulfate were found to be suppressed by 94.5%, 92.2%, and 93.2%, respectively. This is the first study revealing near total aromatase inhibition in vivo with the use of a steroidal aromatase inhibitor. The observation that exemestane is a highly potent aromatase inhibitor, together with the fact that the drug is administered p.o. and causes limited side effects, suggests that exemestane is a promising new drug for the treatment of hormone sensitive breast cancer. ... Exemestane induces aromatase degradation in a dose-responsive manner (25-200 nmol/L), and the effect can be seen in as early as 2 hours. Metabolic labeling with S(35)-methionine was used to determine the half-life (t(1/2)) of aromatase protein. In the presence of 200 nmol/L exemestane, the t(1/2) of aromatase was reduced to 12.5 hours from 28.2 hours in the untreated cells. ...

Pharmacodynamics

Aromatase is an enzyme that converts hormones to estrogen in the body's adrenal glands. The aromatase inhibitors (AIs) are drugs that reduce estrogen levels by blocking the action of aromatase in the adrenal glands. The selective AIs (SAIs) selectively reduce levels of estrogen without interfering with levels of other steroid hormones that are produced by the adrenal gland. Drugs in this class include anastrozole (Arimidex ™), letrozole (Femara ™) and exemestane (Aromasin ™).