Class: Antineoplastic Agents
VA Class: AN900
Molecular Formula: C₂₀H₂₄O₂
CAS Number: 107868-30-4
Brands: Aromasin

Introduction

Antineoplastic agent; irreversible, selective steroidal aromatase inhibitor (type I), structurally related to the natural substrate androstenedione.^{1 2 3 4 5 6}

Uses for Exemestane

Breast Cancer

Sequential adjuvant therapy in postmenopausal women with early-stage estrogen receptor-positive breast cancer who have received 2–3 years of adjuvant tamoxifen and are switched to exemestane to complete a total of 5 consecutive years of adjuvant hormonal therapy.^{1 8 9 11}

May be considered a reasonable choice (accepted, with possible conditions) for initial adjuvant therapy† in postmenopausal women with early-stage hormone receptor-positive breast cancer.^{10001 10002 10008}

May be considered a reasonable choice (accepted, with possible conditions) for extended adjuvant therapy† in postmenopausal women with early-stage hormone receptor-positive breast cancer who have received 5 years of adjuvant tamoxifen therapy.^{10005 10009}

Aromatase inhibitors are a treatment of choice for adjuvant hormonal therapy to lower risk of breast cancer recurrence in postmenopausal women with early-stage hormone receptor-positive breast cancer.^{10 17} An aromatase inhibitor-containing regimen is modestly more effective than tamoxifen alone.^{10 17}

ASCO states that most postmenopausal women with early-stage hormone receptor-positive breast cancer should consider receiving an aromatase inhibitor during the course of adjuvant therapy, either as primary (initial) therapy or following 2–3 years of tamoxifen (sequential therapy), for a total of 5 years of adjuvant endocrine therapy.¹⁰ Data also support switching to an aromatase inhibitor following 5 years of adjuvant tamoxifen (extended adjuvant therapy).¹⁰

Consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen.^{10 10008 10009} Adverse cardiovascular (e.g., hypertension, cardiac ischemia) and musculoskeletal effects (e.g., arthralgia/arthritis, osteoporosis, fracture, carpal tunnel syndrome) reported more frequently in patients receiving adjuvant exemestane, whereas venous thromboembolism and adverse gynecologic effects (e.g., vaginal bleeding, endometrial hyperplasia, uterine dilatation and curettage, uterine polyp/fibroid) reported more frequently in those receiving tamoxifen.^{1 9 11}

Treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.^{1 16}

Exemestane Dosage and Administration

Administration

Oral Administration

Administer orally after a meal.¹

Dosage

Adults

If used with a potent CYP3A4 inducer, dosage adjustment recommended.¹ (See Interactions.)

Breast Cancer

Sequential Adjuvant Treatment of Early-stage Breast Cancer

Oral

25 mg once daily.¹ Initiate following completion of 2–3 years of adjuvant tamoxifen therapy to complete a total of 5 consecutive years of adjuvant hormonal therapy.¹

Initial Adjuvant Treatment† of Early-stage Breast Cancer

Oral

Dosage of 25 mg once daily for 5 years has been used.^{10001 10002}

Extended Adjuvant Treatment† of Early-stage Breast Cancer

Oral

Dosage of 25 mg once daily for 5 years following 5 years of adjuvant tamoxifen therapy has been recommended.^{10 10005}

Second-line Treatment of Advanced Breast Cancer

Oral

25 mg once daily; continued in clinical trial until tumor progression or unacceptable toxicity occurred.^{1 16}

Prescribing Limits

Adults

Dosages >25 mg daily not shown to provide substantially greater suppression of plasma estrogens but may increase adverse effects.^{1 2 3}

Special Populations

Hepatic Impairment

Dosage adjustment does not appear to be necessary.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustment does not appear to be necessary.¹ (See Special Populations under Pharmacokinetics.)

Cautions for Exemestane

Contraindications

• Known hypersensitivity to exemestane or any ingredient in the formulation.¹

• Premenopausal women.¹ (See Premenopausal Women under Cautions.)

• Pregnancy.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic, fetotoxic, and abortifacient in animals.¹ Contraindicated in women who are or may become pregnant (i.e., premenopausal women).¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard and potential risk for pregnancy loss.¹

Estrogenic Agents

Do not administer estrogenic agents concomitantly with exemestane.¹ (See Specific Drugs under Interactions.)

Effects on Bone

Postmenopausal women receiving an aromatase inhibitor as adjuvant therapy are at high risk for osteoporosis.^{12 13}

Greater reductions in bone mineral density (BMD) at lumbar spine and hip observed over 2 years in patients receiving exemestane (3.1 and 4.2%, respectively) versus tamoxifen (0.2 and 0.3%, respectively).¹ Another study showed greater reductions in lumbar spine and hip BMD over 2 years in patients receiving exemestane (3.5 and 4.6%, respectively) versus placebo (2.4 and 2.6%, respectively).¹

Incidence of fractures higher in patients switched to exemestane after receiving 2–3 years of adjuvant tamoxifen than in those continuing tamoxifen to complete 5 years of adjuvant therapy.^{1 11}

Evaluate all postmenopausal women initiating adjuvant aromatase inhibitor therapy for risk of osteoporotic fractures;^{70 71 73} determine BMD and assess other risk factors for fracture (e.g., age, low body mass index, family history of hip fracture, prior fragility fracture, history of cigarette smoking, excess alcohol consumption, current or prior corticosteroid use).^{70 71 73} Closely monitor patients for changes in risk status during therapy, and assess BMD at regular intervals (e.g., every 1–2 years in those with osteopenia or osteoporosis).^{1 70 71 73} Consider other potential causes of osteoporosis (e.g., vitamin D deficiency, hyperthyroidism, hyperparathyroidism, hypercalciuria).^{70 71 73} Manufacturer recommends routine measurement of 25-hydroxyvitamin D concentration before initiating exemestane; supplement vitamin D in women with vitamin D deficiency.¹

Initiate appropriate therapy to prevent further bone loss as clinically indicated.^{1 71} Base decision to initiate antiresorptive therapy (e.g., bisphosphonate, denosumab) on overall risk of fracture and rate of bone loss.^{70 71 72 73}

All women receiving adjuvant therapy with an aromatase inhibitor should be advised to adopt lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation in alcohol consumption) and dietary supplementation with calcium and vitamin D to reduce the risk of osteoporosis.^{12 13 14 15 70 71 72 73}

Hematologic Effects

Grade 3 or 4 lymphocytopenia reported in 20% of exemestane-treated patients with advanced breast cancer.¹ Most patients (89%) had preexisting lower-grade lymphocytopenia; 40% recovered or improved during exemestane therapy.¹ No substantial increase in viral infections and no opportunistic infections observed in clinical studies.¹

In early-stage breast cancer, hematologic abnormalities reported less frequently with exemestane than with tamoxifen treatment; grade 3 or 4 abnormalities reported rarely.¹

Hepatic Effects

In advanced breast cancer, serum AST, ALT, alkaline phosphatase, and γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations >5 times the ULN (i.e., grade 3 or worse) reported rarely in patients receiving exemestane; generally attributable to bone or liver metastasis.¹ In patients without evidence of liver metastasis, grade 3–4 GGT elevations reported at similar rates in exemestane- or megestrol-treated patients.¹

In early-stage breast cancer, elevated bilirubin and alkaline phosphatase concentrations reported more frequently with exemestane than with tamoxifen or placebo treatment.¹ Grade 3–4 bilirubin elevations reported rarely.¹

Renal Effects

Elevated S_cr reported.¹

Specific Populations

Pregnancy

Category X.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Not indicated; safety and efficacy not established.¹

Geriatric Use

No special precautions.¹

Premenopausal Women

Clinical benefit not established in premenopausal women with breast cancer.¹ Possible incomplete estrogen suppression and reflex increases in gonadotropin levels (ovarian hyperstimulation syndrome).⁶ Contraindicated in premenopausal women.¹

Hepatic Impairment

Safety of chronic administration not established in patients with moderate or severe hepatic impairment.¹

Renal Impairment

Safety of chronic administration not established in patients with moderate or severe renal impairment.¹

Common Adverse Effects

Early-stage breast cancer: Hot flushes (flashes), fatigue, arthralgia, increased sweating, alopecia, hypertension.¹

Advanced-stage breast cancer: Fatigue, nausea.¹

Interactions for Exemestane

Metabolized by CYP3A4.¹ Does not inhibit CYP1A2, 2C9, 2D6, 2E1, or 3A4.¹

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Clinically important pharmacokinetic interactions are unlikely.¹

CYP3A4 inducers: Possible decreased exposure to exemestane.¹ If a potent CYP3A4 inducer is used concomitantly, increase exemestane dosage to 50 mg once daily.¹

Specific Drugs

Drug	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased exposure to exemestane1	Increase exemestane dosage to 50 mg once daily1
Estrogenic agents	May diminish pharmacologic action of exemestane1	Do not use concomitantly1
Ketoconazole	No substantial effect on pharmacokinetics of exemestane1
Rifampin	Decreased AUC and peak plasma concentrations of exemestane 1	Increase exemestane dosage to 50 mg once daily1
St. John's wort (Hypericum perforatum)	Possible decreased exposure to exemestane1	Increase exemestane dosage to 50 mg once daily1

Exemestane Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak concentrations in women with breast cancer or healthy women attained within about 1.2 or 2.9 hours, respectively.¹

Steady-state plasma concentrations achieved in approximately 7 days.¹

Food

High-fat meal increases plasma exemestane concentrations by approximately 40%.¹

Distribution

Extent

Extensively distributed into tissues.¹

Crosses placenta.

Distributed into milk in animals; not studied in pregnant or nursing women.¹

Plasma Protein Binding

90% (mainly α₁-acid glycoprotein and albumin).¹

Elimination

Metabolism

Extensively metabolized via CYP3A4 and aldoketoreductases; metabolites are inactive or inhibit aromatase with decreased potency compared with parent drug.¹ One metabolite, 17-hydroexemestane, may have androgenic activity.¹

Elimination Route

Excreted similarly (42%) in both urine and feces; <1% excreted as unchanged drug in urine.¹

Half-life

Approximately 24 hours.¹

Special Populations

In patients with moderate or severe hepatic or renal impairment, AUC is approximately 3 times higher than in healthy individuals.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

• Acts as a false substrate and is converted by aromatase to reactive alkylating intermediates that bind covalently to the substrate binding site of the enzyme; this irreversible binding to the active site of aromatase results in its inactivation (i.e., “suicide” inhibition).^{1 2 4 5 6}

• Selectively inhibits conversion of androgens to estrogens;^{1 2 4 5 6} resulting reduction in serum and tumor concentrations of estrogen inhibits tumor growth and delays disease progression.^{1 6}

• Selectively inhibits synthesis of estrogens; does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.^{1 2 3 6}

• Dose-dependent decrease in sex hormone binding globulin (SHBG) observed with dosages ≥ 2.5 mg daily.^{1 2}

• Slight, dose-independent increases in serum LH and FSH concentrations observed even at low dosages as result of negative feedback on the pituitary gland.^{1 2 3}

• At dosages ≤25 mg daily, no clinically important effect on circulating concentrations of androstenedione, dehydroepiandrostenedione sulfate, or 17-hydroxyprogesterone and only small decreases in circulating concentrations of testosterone observed.^{1 3}

• At dosages ≥200 mg daily, testosterone and androstenedione concentrations are increased.^{1 3} 17-Hydroexemestane, a metabolite, exhibits substantial intrinsic androgenic activity, which may become clinically important at high (e.g., 200 mg daily) dosages.^{1 2 3}

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.¹ Importance of not taking estrogenic agents concomitantly.¹

• Warn of potential hazard to the fetus in cases of inadvertent exposure of pregnant women to exemestane.¹ Advise patients that exemestane is indicated for use only in postmenopausal women.¹

• Risk of osteoporosis.^{1 12} Life-style changes (e.g., weight-bearing exercise, abstinence from smoking, moderation of alcohol consumption) and dietary supplementation with calcium and vitamin D advised.^{12 13 14 15} Importance of BMD monitoring.^{1 12 13 15 71 73}

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Exemestane

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	25 mg*	Aromasin	Pfizer
			Exemestane Tablets