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Exemestane

Pronunciation

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

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

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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 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

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

Determine BMD prior to and at annual intervals during therapy.12 13 15 Oral bisphosphonate recommended in patients with osteoporosis; carefully monitor patients with osteopenia.12 13 15

Lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation in alcohol consumption) and supplemental calcium and vitamin D recommended in all women receiving adjuvant exemestane therapy.12 13 14 15

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 Scr 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 considering BMD monitoring.12 13 15

  • 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.

* 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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Aromasin 25MG Tablets (PFIZER U.S.): 30/$451.00 or 90/$1,318.00

Exemestane 25MG Tablets (GREENSTONE): 30/$229.98 or 90/$669.92

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 9, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Aromasin (exemestane) tablets prescribing information. New York, NY; 2011 Apr.

2. Johannessen DC, Engan T, Di Salle E et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res. 1997; 3:1101-8. [IDIS 389585] [PubMed 9815789]

3. Evans TRJ, Di Salle E, Ornati G et al. Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res. 1992; 52:5933-9. [IDIS 304969] [PubMed 1394219]

4. Geisler J, King N, Anker G et al. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res. 1998; 4:2089-93. [IDIS 410748] [PubMed 9748124]

5. Reddy P. A review of the newer aromatase inhibitors in the management of metastatic breast cancer. J Clin Pharm Ther. 1998; 23:81-90. [IDIS 415373] [PubMed 9786093]

6. Goss PE, Gwyn KMEH. Current perspectives on aromatase inhibitors in breast cancer. J Clin Oncol. 1994; 12:2460-70. [IDIS 338078] [PubMed 7964964]

7. Anker GB, Refsum H, Ueland PM et al. Influence of aromatase inhibitors on plasma total homocysteine in postmenopausal breast cancer patients. Clin Chem. 1999; 45:252-6. [IDIS 424029] [PubMed 9931048]

8. Coombes RC, Hall E, Gibson LJ et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004; 350:1081-92. [PubMed 15014181]

9. Coombes RC, Kilburn LS, Snowdon CF et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007; 369:559-70. [PubMed 17307102]

10. Burstein HJ, Prestrud AA, Seidenfeld J et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010; 28:3784-96. [PubMed 20625130]

11. Bliss JM, Kilburn LS, Coleman RE et al. Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study. J Clin Oncol. 2012; 30:709-17. [PubMed 22042946]

12. Gaillard S, Stearns V. Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management. Breast Cancer Res. 2011; 13:205. [PubMed 21457526]

13. Hilner BE, Ingle JN, Chelbowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003; 21:4042-57. [IDIS 513063] [PubMed 12963702]

14. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003; 349: 1793-802. [IDIS 506722] [PubMed 14551341]

15. Reviewers’ comments (personal observations) on letrozole.

16. Kaufmann M, Bajetta E, Dirix LY et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol. 2000; 18:1399-411. [PubMed 10735887]

17. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2011 Nov 21.

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