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Exemestane

Pronunciation

Pronunciation

(ex e MES tane)

Dosage Forms

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

Tablet, Oral:

Aromasin: 25 mg

Generic: 25 mg

Brand Names: U.S.

  • Aromasin

Pharmacologic Category

  • Antineoplastic Agent, Aromatase Inhibitor

Pharmacology

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. Significantly lowers circulating estrogens in postmenopausal breast cancers where growth is estrogen-dependent.

Absorption

Rapid and moderate (~42%) following oral administration; AUC and Cmax increased by 59% and 39%, respectively, following a high-fat breakfast (compared to fasted state)

Distribution

Extensive into tissues

Metabolism

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

Excretion

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

Time to Peak

Women with breast cancer: 1.2 hours

Half-Life Elimination

~24 hours

Protein Binding

90%, primarily to albumin and α1-acid glycoprotein

Special Populations: Renal Function Impairment

AUC is about 3 times higher in those with moderate or severe renal insufficiency.

Special Populations: Hepatic Function Impairment

AUC increased approximately 3 times in those with moderate or severe hepatic insufficiency.

Use: Labeled Indications

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

Use: Unlabeled

Risk reduction for invasive breast cancer in postmenopausal women; first-line adjuvant treatment of estrogen receptor-positive early breast cancer in postmenopausal women

Contraindications

Known hypersensitivity to exemestane or any component of the formulation; women who are or may become pregnant; premenopausal women

Dosing: Adult

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

Breast cancer, early (adjuvant treatment): Postmenopausal females: Oral: 25 mg once daily (following 2 to 3 years of tamoxifen therapy) for a total duration of 5 years of endocrine therapy (in the absence of recurrence or contralateral breast cancer). Note: The American Society of Clinical Oncology (ASCO) guidelines for Adjuvant Endocrine Therapy of Hormone Receptor-Positive Breast Cancer (Focused Update) recommend a maximum duration of 5 years of aromatase inhibitor (AI) therapy for postmenopausal women; AIs may be combined with tamoxifen for a total duration of up to 10 years of endocrine therapy. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Burstein 2014).

Breast cancer, early (first-line adjuvant treatment; off-label use): Postmenopausal females: Oral: 25 mg once daily for 5 years (Burstein 2010; van de Velde 2011). Note: ASCO guidelines for Adjuvant Endocrine Therapy of Hormone Receptor-Positive Breast Cancer (Focused Update) recommend a maximum duration of 5 years of aromatase inhibitor (AI) therapy for postmenopausal women; AIs may be combined with tamoxifen for a total duration of up to 10 years of endocrine therapy. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Burstein 2014).

Breast cancer, risk reduction (off-label use): Postmenopausal females ≥35 years: Oral: 25 mg once daily for 5 years (Goss 2011; Visvanathan 2013)

Dosage adjustment with strong CYP3A4 inducers: U.S. labeling: 50 mg once daily when used with potent inducers (eg, rifampin, phenytoin)

Dosing: Geriatric

Refer to adult dosing.

Dosing: 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: 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

Administer after a meal. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

Patients on aromatase inhibitor therapy should receive vitamin D and calcium supplements.

Storage

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

Drug Interactions

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Exemestane. Management: Exemestane U.S. product labeling recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. The Canadian product labeling does not recommend a dose adjustment with concurrent use of strong CYP3A4 inducers. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Estrogen Derivatives: May diminish the therapeutic effect of Exemestane. Avoid combination

Methadone: Aromatase Inhibitors may increase the serum concentration of Methadone. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Exemestane. Management: Exemestane US product labeling recommends using an increased dose (50 mg/day) in patients receiving St Johns Wort or strong CYP3A4 inducers. The Canadian product labeling does not recommend a dose adjustment with this combination. Consider therapy modification

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

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% (Limited to important or life-threatening): Acute generalized exanthematous pustulosis, cardiac failure, cholestatic hepatitis, endometrial hyperplasia, gastric ulcer, GGT increased, hepatitis, hypersensitivity, neuropathy, osteochondrosis, pruritus, thromboembolism, transaminases increased, trigger finger, urticaria, 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.

Warnings/Precautions

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 over time. Decreases (from baseline) in lumbar spine and femoral neck density have been observed. Assess bone mineral density at baseline in patients with, or at risk for osteoporosis; monitor exemestane therapy and initiate osteoporosis treatment if indicated.

• Lymphopenia: Grade 3 or 4 lymphopenia has been observed with exemestane, although most patients had preexisting lower grade lymphopenia; some patients improved or recovered while continuing exemestane. Lymphopenia did not result in a significant increase in viral infections, and no opportunistic infections were observed.

• Lab parameters: Elevations of AST, ALT, alkaline phosphatase, and gamma glutamyl transferase >5 times ULN have been observed (rarely) in patients with advanced breast cancer; may be attributable to underlying liver and/or bone metastases. In patients with early breast cancer, elevations of bilirubin, alkaline phosphatase, and serum creatinine were more common with exemestane treatment than with tamoxifen or placebo.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dose adjustment recommended with concomitant strong CYP3A4 inducers.

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

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Vitamin D deficiency: Due to high prevalence of vitamin D deficiency in women with breast cancer, assess 25-hydroxy vitamin D levels at baseline and supplement accordingly.

Monitoring Parameters

25-hydroxy vitamin D levels (at baseline); bone mineral density

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Exemestane is not indicated for use in premenopausal women and use during pregnancy is contraindicated. Based on the mechanism of action, exemestane is expected to cause fetal harm if administered to a pregnant woman.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hot flashes, arthralgia, alopecia, asthenia, hyperhidrosis, back pain, diarrhea, or anxiety. Have patient report immediately to prescriber angina, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, dyspnea, excessive weight gain, edema of extremities, skin discoloration, painful extremities, paresthesia, osteodynia, vision changes, depression, severe headache, considerable dizziness, syncope, significant dyspepsia, jaundice, or intolerable nausea (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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