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Pronunciation

(ex e MES tane)

Generic Available (U.S.)

Yes

Brand Names: U.S.

• Aromasin®

Brand Names: Canada

• Aromasin®

Pharmacologic Category

• Antineoplastic Agent, Aromatase Inactivator

Use: Labeled Indications

Treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy; adjuvant treatment of postmenopausal estrogen receptor-positive early breast cancer following 2-3 years of tamoxifen (for a total of 5 years of adjuvant therapy)

Use: Unlabeled

Risk reduction for invasive breast cancer in postmenopausal women; treatment of endometrial cancer; treatment of uterine sarcoma

Pregnancy Risk Factor

X

Pregnancy Considerations

According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother. Not indicated for use in premenopausal women.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to exemestane or any component of the formulation; use in women who are or may become pregnant; use in premenopausal women

Warnings/Precautions

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Decreased bone mineral density: Due to decreased circulating estrogen levels, exemestane is associated with a reduction in bone mineral density. Decreases (from baseline) in lumbar spine and femoral neck density have been observed.

• Lymphopenia: Grade 3 or 4 lymphopenia has been observed with exemestane use, although most patients had preexisting lower grade lymphopenia.

• Lab parameters: Increases in bilirubin, alkaline phosphatase and serum creatinine have been observed.

Concurrent drug therapy issues:

• CYP3A4 inducers: Dose adjustment recommended with concomitant CYP3A4 inducers.

• Estrogen-containing drugs: Should not be administered concurrently with estrogen-containing drugs.

Adverse Reactions

>10%:

Cardiovascular: Hypertension (5% to 15%)

Central nervous system: Fatigue (8% to 22%), insomnia (11% to 14%), pain (13%), headache (7% to 13%), depression (6% to 13%)

Dermatological: Hyperhidrosis (4% to 18%), alopecia (15%)

Endocrine & metabolic: Hot flashes (13% to 33%)

Gastrointestinal: Nausea (9% to 18%), abdominal pain (6% to 11%)

Hepatic: Alkaline phosphatase increased (14% to 15%)

Neuromuscular & skeletal: Arthralgia (15% to 29%)

1% to 10%:

Cardiovascular: Edema (6% to 7%); cardiac ischemic events (2%: MI, angina, myocardial ischemia); chest pain

Central nervous system: Dizziness (8% to 10%), anxiety (4% to 10%), fever (5%), confusion, hypoesthesia

Dermatologic: Dermatitis (8%), itching, rash

Endocrine & metabolic: Weight gain (8%)

Gastrointestinal: Diarrhea (4% to 10%), vomiting (7%), anorexia (6%), constipation (5%), appetite increased (3%), dyspepsia

Genitourinary: Urinary tract infection (2% to 5%)

Hepatic: Bilirubin increased (5% to 7%)

Neuromuscular & skeletal: Back pain (9%), limb pain (9%), myalgia (6%), osteoarthritis (6%), weakness (6%), osteoporosis (5%), pathological fracture (4%), paresthesia (3%), carpal tunnel syndrome (2%), cramps (2%)

Ocular: Visual disturbances (5%)

Renal: Creatinine increased (6%)

Respiratory: Dyspnea (10%), cough (6%), bronchitis, pharyngitis, rhinitis, sinusitis, upper respiratory infection

Miscellaneous: Flu-like syndrome (6%), lymphedema, infection

<1%, postmarketing, and/or case reports: Cardiac failure, cholestatic hepatitis, endometrial hyperplasia, gastric ulcer, GGT increased, hepatitis, neuropathy, osteochondrosis, thromboembolism, transaminases increased, trigger finger, uterine polyps

A dose-dependent decrease in sex hormone-binding globulin has been observed with daily doses of ≥2.5 mg. Serum luteinizing hormone and follicle-stimulating hormone levels have increased with this medicine.

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (weak/moderate)

Drug Interactions

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Risk D: Consider therapy modification

Axitinib: CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum concentration of Axitinib. Risk X: Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Exemestane. Management: Exemestane prescribing information recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity and/or inadequate clinical response. Risk D: Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

Rifampin: May decrease the serum concentration of Exemestane. Management: Exemestane prescribing information recommends using an increased dose (50 mg/day) in patients receiving concurrent rifampin. Monitor patients closely for evidence of toxicity and/or inadequate clinical response. Risk D: Consider therapy modification

Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Food: Plasma levels increased by 40% when exemestane was taken with a fatty meal.

Herb/Nutraceutical: St John's wort may decrease exemestane levels. Avoid black cohosh, dong quai in estrogen-dependent tumors.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Mechanism of Action

Exemestane is an irreversible, steroidal aromatase inactivator. It is structurally related to androstenedione, and is converted to an intermediate that irreversibly blocks the active site of the aromatase enzyme, leading to inactivation (“suicide inhibition”) and thus preventing conversion of androgens to estrogens in peripheral tissues. In postmenopausal breast cancers where growth is estrogen-dependent, this medicine will lower circulating estrogens.

Pharmacodynamics/Kinetics

Absorption: Rapid and moderate (~42%) following oral administration; absorption increases ~40% following high-fat meal

Distribution: Extensive into tissues

Protein binding: 90%, primarily to albumin and α₁-acid glycoprotein

Metabolism: Extensively hepatic; oxidation (CYP3A4) of methylene group, reduction of 17-keto group with formation of many secondary metabolites; metabolites are inactive

Half-life elimination: 24 hours

Time to peak: Women with breast cancer: 1.2 hours

Excretion: Urine (<1% as unchanged drug, 39% to 45% as metabolites); feces (36% to 48%)

Dosage

Oral: Adults: Females: Postmenopausal:

Breast cancer, advanced: 25 mg once daily; continue until tumor progression

Breast cancer, early (adjuvant treatment): 25 mg once daily (following 2-3 years of tamoxifen therapy) for a total duration of 5 years of endocrine therapy (in the absence of recurrence or contralateral breast cancer)

Breast cancer, risk reduction (unlabeled use): 25 mg once daily for up to 5 years (Goss, 2011)

Dosage adjustment with CYP3A4 inducers: 50 mg once daily when used with potent inducers (eg, rifampin, phenytoin)

Dosing adjustment in renal impairment: No adjustment necessary (although the safety of chronic doses in patients with moderate-to-severe renal impairment has not been studied, dosage adjustment does not appear necessary).

Dosing adjustment in hepatic impairment: No adjustment necessary (although the safety of chronic doses in patients with moderate-to-severe hepatic impairment has not been studied, dosage adjustment does not appear necessary).

Administration: Oral

Administer after a meal.

Dietary Considerations

Take after a meal; patients on aromatase inhibitor therapy should receive vitamin D and calcium supplements.

Patient Education

Take after meals at approximately the same time each day; may cause indigestion. You may be more susceptible to infection. May cause headache, dizziness, confusion, fatigue, anxiety, insomnia, nausea, vomiting, loss of appetite, or hot flashes. Report chest pain; palpitations; acute headache, visual disturbances; unresolved GI problems; itching or burning on urination, vaginal discharge; acute joint, back, bone, or muscle pain; respiratory difficulty; unusual cough; or respiratory infection.

Geriatric Considerations

In pharmacokinetic trials, no significant changes were seen in women <68 years of age.

Additional Information

Oncology Comment: The American Society of Clinical Oncology (ASCO) guidelines for adjuvant endocrine therapy in postmenopausal women with HR-positive breast cancer (Burstein, 2010) recommend considering aromatase inhibitor (AI) therapy at some point in the treatment course (primary, sequentially, or extended). Optimal duration at this time is not known; however, treatment with an AI should not exceed 5 years in primary and extended therapies, and 2-3 years if followed by tamoxifen in sequential therapy (total of 5 years). If initial therapy with AI has been discontinued before the 5 years, consideration should be taken to receive tamoxifen for a total of 5 years. The optimal time to switch to an AI is also not known, but data supports switching after 2-3 years of tamoxifen (sequential) or after 5 years of tamoxifen (extended). If patient becomes intolerant or has poor adherence, consideration should be made to switch to another AI or initiate tamoxifen.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Drowsiness, depression, insomnia, and anxiety are common; may cause confusion

Mental Health: Effects on Psychiatric Treatment

None reported

Nursing: Physical Assessment/Monitoring

Use with caution in liver and kidney disease. Monitor for new or unusual bone pain and swelling of face, lips, or throat. Use with caution in uncontrolled hypertension.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral: 25 mg

Aromasin®: 25 mg

Pricing: U.S. (www.drugstore.com)

Tablets (Aromasin)

25 mg (30): $451.00

Tablets (Exemestane)

25 mg (30): $229.98

References

Bertelli G, Hall E, Ireland E, et al, “Long-Term Endometrial Effects in Postmenopausal Women With Early Breast Cancer Participating in the Intergroup Exemestane Study (IES) -- A Randomised Controlled Trial of Exemestane versus Continued Tamoxifen After 2-3 Years Tamoxifen," Ann Oncol, 2010, 21(3):498-505.

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(23):3784-96.

Buzdar AU, Robertson JF, Eiermann W, et al, “An Overview of the Pharmacology and Pharmacokinetics of the Newer Generation Aromatase Inhibitors Anastrozole, Letrozole, and Exemestane,” Cancer, 2002, 95(9):2006-16.

Chia S, Gradishar W, Mauriac L, et al, “Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor-Positive, Advanced Breast Cancer: Results From EFECT,” J Clin Oncol, 2008, 26(10):1664-70.

Goss PE, Ingle JN, Ales-Martinez JE, et al, “Exemestane for Breast-Cancer Prevention in Postmenopausal Women,” N Engl J Med, 2011, 364(25):2381-91.

Kieback DG, Harbeck N, Bauer W, et al, “Endometrial Effects of Exemestane Compared to Tamoxifen Within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) Trial: Results of a Prospective Gynecological Ultrasound Substudy,” Gynecol Oncol, 2010, 119(3):500-5.

Lonning PE, “Pharmacological Profiles of Exemestane and Fromestane, Steroidal Aromatase Inhibitors Used for Treatment of Postmenopausal Breast Cancer,” Breast Cancer Res Treat, 1998, 49(Suppl 1):45-52.

Morandi P, Rouzier R, Altundag K, et al, “The Role of Aromatase Inhibitors in the Adjuvant Treatment of Breast Carcinoma: The M. D. Anderson Cancer Center Evidence-Based Approach,” Cancer, 2004, 101(7):1482-9.

National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Uterine Neoplasms,” Version 2.2012. Available at http://www.nccn.org/professionals/physician_gls/PDF/uterine.pdf

Paridaens RJ, Dirix LY, Beex LV, et al, “Phase III Study Comparing Exemestane With Tamoxifen as First-Line Hormonal Treatment of Metastatic Breast Cancer in Postmenopausal Women: The European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group,” J Clin Oncol, 2008, 26(30):4883-90.

Njar VC and Brodie AM, “Comprehensive Pharmacology and Clinical Efficacy of Aromatase Inhibitors,” Drugs, 1999, 58(2):233-55.

Winer EP, Hudis C, Burstein HJ, et al, "American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors as Adjuvant Therapy for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Status Report 2004," J Clin Oncol, 2005, 23(3):619-29.

International Brand Names

• Aromasil (ES)
• Aromasin (AE, AR, AU, BE, BG, BH, BR, CH, CL, CN, CO, CR, CY, CZ, DE, DK, EC, EE, EG, FI, GB, GT, HK, HN, ID, IE, IL, IQ, IR, IT, JO, KP, KW, LB, LY, MY, NI, NL, NO, OM, PA, PE, PH, PL, PT, QA, SA, SE, SG, SV, SY, TH, UY, VE, YE, ZA)
• Aromasine (FR)

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Last full review/revision March 2012

Content last modified March 2012