Generic Name

Exemestane

Mechanism

Exemestane is a steroidal aromatase inhibitor (AI).
• Irreversible inactivation of the aromatase enzyme by covalent binding to the heme group.
• Produces a catalytic suicide inactivation, forming a stable hormone‑binding complex; the enzyme requires new synthesis to restore activity.
• Results in a dramatic decrease of peripheral estrogen synthesis (≈70–90% reduction) in post‑menopausal women and aromatase‑expressing tumors.
• Effect is dose‑dependent and not reversible by estrogen replacement.
• Compared with non‑steroidal AIs (anastrozole, letrozole), exemestane’s irreversible mechanism may cause fewer rebound effects after discontinuation.

Pharmacokinetics

• Absorption: Oral bioavailability ≈ 20–30 % at 25 mg; increases dose‑dependently with a 100 mg dose (≈32 % bioavailability).
• Distribution: Highly bound to plasma proteins (≈92 %) and highly lipophilic; penetrates adipose tissue and bone marrow.
• Metabolism: Primarily hepatic CYP3A4/5‑mediated metabolism to inactive 3‑desmethyl‑exemestane; minor CYP2C19 involvement.
• Elimination: Excreted in feces (≈35 %) and urine (≈12 %); terminal half‑life ≈ 10 h, but the effect on aromatase persists for several weeks due to enzyme turnover.
• Drug interactions: Concomitant use of CYP3A4 inhibitors (ketoconazole, itraconazole) may increase levels; CYP3A4 inducers (rifampin, phenobarbital) reduce plasma concentration.
• Special populations: No dose adjustment needed for mild‑to‑moderate hepatic or renal impairment; cautious use in severe liver disease.

Indications

• Early‑stage, hormone‑receptor‑positive breast cancer in post‑menopausal women: adjuvant therapy ≥5 yr after tamoxifen or aromatase‑inhibitor therapy.
• Metastatic breast cancer relapse after prior AI therapy (second‑line).
• Metastatic hormone‑positive breast cancer when combined with fulvestrant.
• Investigational: ovarian cancer, uterine endometrial carcinoma, and breast cancer in pre‑menopausal women with ovarian suppression.

Contraindications

• Contraindicated in lactation and pregnancy (teratogenic potential).
• Caution in patients with hepatic impairment (monitor LFTs).
• Warnings:
• Osteoporosis: chronic estrogen depletion accelerates bone mineral density loss; contraindicated if severe osteoporosis untreated.
• Venous thromboembolism (VTE): increased risk in post‑menopausal women; monitor for symptoms.
• Cardiovascular events: mixed data; monitor BP, lipids.
• Precautions in patients with a history of endocrine disorders (e.g., thyroid dysfunction, adrenal insufficiency).

Dosing

• Timing: Take at roughly the same time each day to maintain consistent plasma levels.
• Diet: Food has negligible effect on absorption.
• Missed dose: Take as soon as remembered; do not double‑dose to catch up.

Adverse Effects

Common (≥10 %)
• Hot flashes, night sweats
• Arthralgia / myalgia
• Vaginal dryness, dyspareunia
• Fatigue
• Gastrointestinal upset (nausea, abdominal discomfort)

Less common (<10 %)
• Bone pain, fractures (especially with prolonged use)
• Decreased bone mineral density → osteopenia/osteoporosis
• Elevated LDL‑cholesterol
• Headache, insomnia
• Weight gain

Serious (≤1 %)
• Deep vein thrombosis / pulmonary embolism
• Osteonecrosis of the jaw (rare, often with bisphosphonate use)
• Severe hypersensitivity (rash, pruritus, eosinophilia)
• Hepatotoxicity (elevated transaminases)

Monitoring

• Baseline: CBC, LFTs, lipid panel, bone mineral density (DEXA) before initiation.
• Regular:
• LFTs every 3 months for first 2 yr, then at least yearly.
• Lipids every 6 months.
• DEXA every 12–18 months; consider bisphosphonate/denosumab if T‑score ≤ −2.0.
• Clinical: Monitor for VTE signs; assess symptom burden of hot flashes and musculoskeletal pain.
• Hormone levels: Not routinely required; estradiol <15 pg/mL typically achieved.

Clinical Pearls

• “Sustained Estrogen Blockade” – Exemestane’s irreversible binding means aromatase activity remains suppressed even weeks after stopping the drug, offering an advantage in patients who miss doses.
• Combination Insight – Adding fulvestrant to a previously failed AI regimen can overcome resistance; however, monitor for additive fatigue and arthralgia.
• Bone Health First – Begin bisphosphonate/denosumab prophylaxis at the time of AI initiation, especially in women with baseline osteopenia or prior fractures.
• VTE Screening – Use Khorana score to identify high‑risk patients; consider prophylaxis (e.g., LMWH) in those with additional risk factors.
• Adherence Tip – Bundle the daily tablet with a routine (e.g., breakfast) and use a pill organizer; reminders can increase persistence >75 %.
• Drug‑Drug Interaction Check – Avoid concurrent high‑dose ketoconazole; counsel patients on over‑the‑counter supplements that may affect CYP3A4.
• Patient Education – Emphasize that hot flashes are manageable with lifestyle changes (cooling pillows, clothing layers) and that therapy does not shorten lifespan but improves recurrence risk.
• Re‑exposure Strategy – If therapy is interrupted (e.g., due to surgery), restart the same dose; the long‑term effect typically persists.

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• *This drug card consolidates high‑yield, evidence‑based information for clinicians and medical students. For detailed evidence citations, refer to the latest NCCN guidelines, FDA prescribing information, and contemporary meta‑analyses on aromatase inhibitors.*