Letrozole

Usage

Letrozole is primarily prescribed for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. It is also used for extended adjuvant treatment after initial tamoxifen therapy, and as first-line treatment for postmenopausal women with advanced breast cancer. Letrozole’s pharmacological classification is aromatase inhibitor, specifically a non-steroidal aromatase inhibitor. It acts by competitively binding to the heme of the aromatase cytochrome P450 enzyme, thereby reducing estrogen biosynthesis in various tissues. This estrogen suppression is the primary mechanism by which letrozole exerts its anti-cancer effects in hormone-sensitive breast cancers.

Alternate Names

Letrozole is also known by its international nonproprietary name (INN). Brand names for letrozole include Femara.

How It Works

Pharmacodynamics: Letrozole inhibits estrogen biosynthesis by competitively binding to the heme group of the aromatase cytochrome P450 enzyme. This leads to a significant reduction in estrogen production in all tissues, including breast tumor tissue. The resulting estrogen deprivation inhibits the growth of hormone-receptor-positive breast cancer cells. Letrozole does not affect adrenal steroidogenesis.

Pharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Food does not significantly impact its absorption. Peak plasma concentrations are achieved within 1-2 hours. It reaches steady-state plasma levels in 2–6 weeks with daily dosing. Letrozole is extensively distributed into tissues and moderately protein-bound (approximately 60%). It is metabolized primarily in the liver by CYP3A4 and 2A6, forming inactive metabolites. Elimination is primarily through renal excretion (approximately 90%), with a small amount excreted in feces. The elimination half-life is around 2 days.

Dosage

Standard Dosage

Adults: The standard dose is 2.5 mg orally once daily. In adjuvant and extended adjuvant settings, treatment continues for 5 years or until tumor relapse. In metastatic disease, treatment continues until tumor progression.

Children: Letrozole is not recommended for use in children. Safety and efficacy have not been established in this population.

Special Cases:

• Elderly Patients: No dose adjustment is required.
• Patients with Renal Impairment: No dose adjustment is necessary for mild to moderate renal impairment (creatinine clearance ≥10 mL/min). Limited data are available for severe renal impairment.
• Patients with Hepatic Dysfunction: No dose adjustment is needed for mild to moderate hepatic impairment (Child-Pugh A or B). For patients with severe hepatic impairment (Child-Pugh C), close monitoring is recommended, and a dose reduction of 50% (i.e., 2.5 mg every other day) may be considered.
• Patients with Comorbid Conditions: Consider individual patient factors and comorbidities, like diabetes and cardiovascular disease, which may influence treatment decisions.

Clinical Use Cases

Letrozole is not indicated for the clinical use cases you listed (Intubation, Surgical Procedures, Mechanical Ventilation, ICU use, and Emergency Situations). These procedures typically involve other classes of drugs (e.g., anesthetics, analgesics, vasopressors).

Dosage Adjustments

Dose adjustments may be needed in specific populations such as patients with hepatic impairment, as noted above.

Side Effects

Common Side Effects: Hot flashes, arthralgia, fatigue, increased sweating, nausea, headache, dizziness, edema, hypercholesterolemia, and bone pain.

Rare but Serious Side Effects: Osteoporosis, increased risk of bone fractures, thromboembolic events (rare), hypersensitivity reactions (rare).

Long-Term Effects: Potential for bone loss with long-term use, necessitating bone mineral density monitoring.

Adverse Drug Reactions (ADR): Serious hypersensitivity reactions (rare), hepatotoxicity (rare), thromboembolic events (rare).

Contraindications

• Premenopausal status (including pregnancy)
• Hypersensitivity to letrozole or its excipients.
• Breastfeeding

Drug Interactions

Letrozole is primarily metabolized by CYP3A4 and 2A6. Agents that induce or inhibit these enzymes can affect letrozole concentrations. Concomitant use with estrogen-containing medications should be avoided, as this can counteract letrozole’s therapeutic effect.

Pregnancy and Breastfeeding

Letrozole is contraindicated during pregnancy and breastfeeding. It is classified as Pregnancy Category X - positive evidence of human fetal risk.

Drug Profile Summary

• Mechanism of Action: Non-steroidal aromatase inhibitor, reduces estrogen biosynthesis.
• Side Effects: Hot flashes, arthralgia, fatigue, increased sweating, nausea, headache, bone pain. Rare but serious: osteoporosis, bone fractures.
• Contraindications: Pregnancy, breastfeeding, premenopausal status, hypersensitivity.
• Drug Interactions: CYP3A4 and 2A6 inducers/inhibitors; concomitant estrogen therapy.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: 2.5 mg orally once daily.
• Monitoring Parameters: Bone mineral density, cholesterol levels, liver function tests (especially in patients with pre-existing liver disease).

Popular Combinations

Letrozole is sometimes used in combination with other hormonal therapies like tamoxifen, or with CDK4/6 inhibitors like palbociclib or ribociclib in advanced breast cancer.

Precautions

• General Precautions: Assess menopausal status before starting therapy (measure LH, FSH, and/or estradiol). Monitor for bone mineral density changes and hypercholesterolemia.
• Specific Populations: Contraindicated in pregnancy and breastfeeding. Use with caution in patients with severe hepatic or renal impairment.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Letrozole?

A: The standard recommended dosage is 2.5 mg orally once a day.

Q2: How does Letrozole work in breast cancer?

A: Letrozole inhibits the aromatase enzyme, which reduces estrogen production. This is beneficial in hormone receptor-positive breast cancer, as estrogen promotes cancer cell growth.

Q3: What are the most common side effects of Letrozole?

A: Common side effects include hot flashes, joint pain (arthralgia), fatigue, and increased sweating.

Q4: Can Letrozole be used during pregnancy?

A: No, Letrozole is contraindicated during pregnancy and breastfeeding due to potential harm to the fetus.

Q5: Are there any drug interactions I should be aware of with Letrozole?

A: Yes, Letrozole interacts with drugs that affect CYP3A4 and 2A6 enzymes. Avoid concomitant use with estrogen-containing medications.

Q6: How long is Letrozole typically prescribed for in the adjuvant setting?

A: Adjuvant treatment typically continues for 5 years or until disease recurrence.

Q7: What monitoring is recommended for patients on Letrozole?

A: Monitoring bone mineral density and cholesterol levels is important due to the potential side effects of osteoporosis and hypercholesterolemia. Liver function should also be monitored, particularly in those with pre-existing liver disease.

Q8: What should I do if a patient misses a dose of Letrozole?

A: If a dose is missed, instruct the patient to take it as soon as they remember, unless it is close to the time of their next dose. They should not double the dose.

Q9: What should I do if a patient experiences severe side effects while on Letrozole?

A: Evaluate the severity and nature of the side effects. Some side effects might require dosage adjustments or temporary interruption of the medication. For serious adverse events, consider discontinuing the medication and consulting with an oncologist.