Search. Learn. Save

Platform for Pharmaceutical Products for Healthcare Professionals
Search By
☰ Generic Formulas

Generic Formulas X

Exemestane

Exemestane

Introduction

Exemestane is a potent aromatase inhibitor used primarily in the treatment of hormone receptor-positive breast cancer in postmenopausal women. As an irreversible steroidal inhibitor of aromatase, Exemestane belongs to the class of drugs known as "suicidal inhibitors" due to its mechanism of permanently disabling the enzyme. It has become a vital component in hormonal therapy, especially in the management of early and advanced breast cancer.

Chemical and Pharmacological Profile

  • Chemical Name: 6-methyleneandrosta-1,4-diene-3,17-dione

  • Molecular Formula: C20H24O2

  • Molecular Weight: 296.40 g/mol

  • Drug Class: Aromatase inhibitor (steroidal, irreversible)

Exemestane works by inhibiting aromatase, the enzyme responsible for converting androgens to estrogens in peripheral tissues. By decreasing estrogen levels, it deprives estrogen receptor-positive (ER+) cancer cells of their growth stimulus.

Mechanism of Action

Exemestane binds irreversibly to the aromatase enzyme, thereby permanently disabling it. This inhibition results in a profound reduction in circulating estrogen levels, which helps slow or halt the growth of hormone-dependent breast tumors. Unlike non-steroidal aromatase inhibitors like anastrozole and letrozole, Exemestane’s binding is irreversible, mimicking the structure of natural androgens.

Clinical Applications

  1. Early Breast Cancer

    • Used as adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer after 2–3 years of tamoxifen, completing a total of 5 years of hormonal therapy.

  2. Advanced or Metastatic Breast Cancer

    • Used as first-line or subsequent-line hormonal therapy in advanced breast cancer after progression on tamoxifen.

  3. Breast Cancer Prevention (Off-label)

    • Investigated in high-risk postmenopausal women to reduce the incidence of breast cancer.

Dosage and Administration

  • Standard Dose: 25 mg orally once daily after a meal.

  • Duration: Varies depending on treatment goals; typically 2–3 years following tamoxifen in adjuvant settings.

  • Dose Adjustments: Generally not required for renal or hepatic impairment, although caution is advised in severe cases.

Pharmacokinetics

  • Absorption: Rapid and enhanced by food; peak plasma levels in 1–2 hours.

  • Bioavailability: Approximately 42% (increased with high-fat meals).

  • Distribution: Widely distributed; 90% bound to plasma proteins.

  • Metabolism: Hepatically metabolized by CYP3A4 and aldoketoreductases.

  • Elimination: Primarily via urine and feces; half-life ~24 hours.

Adverse Effects

Common Side Effects:

  • Hot flashes

  • Fatigue

  • Arthralgia and myalgia

  • Nausea

  • Insomnia

  • Increased sweating

Serious Adverse Effects:

  • Osteoporosis and fractures (due to estrogen depletion)

  • Cardiovascular events (rare)

  • Hepatotoxicity (uncommon)

  • Depression and mood disorders

Bone Health Considerations

Estrogen plays a key role in maintaining bone density. Prolonged use of Exemestane may result in bone mineral loss. Patients on long-term therapy should undergo periodic bone mineral density (BMD) assessments and may require bisphosphonates or denosumab.

Monitoring Parameters

  • Bone mineral density

  • Liver function tests

  • Lipid profiles

  • Signs of depression or mood changes

Drug Interactions

  • CYP3A4 Interactions: Exemestane is metabolized by CYP3A4. Strong inducers like rifampin may reduce its plasma levels, while inhibitors like ketoconazole may increase levels.

  • Hormone Therapy: Should not be used with estrogen-containing therapies, as they may counteract the effects.

Contraindications and Warnings

  • Premenopausal Women: Ineffective and contraindicated in premenopausal women unless ovarian suppression is used.

  • Pregnancy and Lactation: Category X—teratogenic and contraindicated.

  • Hypersensitivity: Avoid in patients with known allergy to Exemestane.

Exemestane vs. Other Aromatase Inhibitors

Compared to non-steroidal AIs (anastrozole, letrozole), Exemestane:

  • Has a steroidal structure

  • Causes irreversible inhibition of aromatase

  • May have slightly different side effect profiles, particularly regarding bone and lipid metabolism

Emerging Research and Future Directions

  1. Combination Therapy: Studies are evaluating the combination of Exemestane with CDK4/6 inhibitors (like palbociclib) and mTOR inhibitors (like everolimus) to enhance efficacy in advanced breast cancer.

  2. Neoadjuvant Settings: Ongoing trials are assessing the efficacy of Exemestane before surgery to reduce tumor size.

  3. Chemoprevention: Investigated in high-risk women to prevent breast cancer development. Results from the MAP.3 trial showed a significant risk reduction.

Real-World Effectiveness

Data from observational studies suggest that Exemestane is well tolerated in real-world settings and improves disease-free survival in early-stage breast cancer. Adherence and persistence are critical to its success.

Patient Education and Counseling

  • Importance of daily dosing and compliance

  • Managing side effects like hot flashes and joint pain

  • Need for calcium and vitamin D supplementation

  • Regular follow-up and BMD monitoring

Cost and Accessibility

Exemestane is available as a generic medication, improving its affordability. Branded versions like Aromasin are still used in some settings but are generally more expensive. Insurance typically covers Exemestane when used for approved indications.

Global Regulatory Status

  • FDA Approval: For adjuvant treatment and advanced breast cancer

  • EMA Approval: Similar indications; widely used across Europe and other regions

  • WHO Essential Medicines List: Included due to its importance in cancer therapy

Conclusion

Exemestane has revolutionized hormone therapy for postmenopausal women with breast cancer. Its unique pharmacology as an irreversible aromatase inhibitor offers advantages in certain clinical contexts, particularly in patients who have completed tamoxifen therapy or require alternative strategies due to intolerance to other AIs. With emerging research suggesting additional roles in prevention and combination therapy, Exemestane continues to be a critical weapon in the fight against hormone-dependent breast cancer. However, careful monitoring of bone health, mood changes, and metabolic parameters is essential to maximize benefits and minimize risks.