Letrozole

Generic Name: Letrozole
Pharmacological Class: Aromatase Inhibitor (Non-steroidal)
Therapeutic Class: Antineoplastic agent (Hormonal)
ATC Code: L02BG04
Common Brand Name: Femara
Regulatory Category: Prescription-only (Rx)
Formulations Available: Oral tablets (most commonly 2.5 mg)

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Chemical and Pharmacological Overview

• Chemical Formula: C17H11N5

• Molecular Weight: 285.3 g/mol

• Chemical Structure: A triazole derivative that binds to the aromatase enzyme

• Pharmacologic Type: Non-steroidal aromatase inhibitor

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Mechanism of Action

Letrozole functions as a selective and potent non-steroidal aromatase inhibitor, which works by:

1. Inhibiting the aromatase enzyme (CYP19A1): This enzyme converts androgens (androstenedione and testosterone) into estrogens (estrone and estradiol) in peripheral tissues.

2. Reducing circulating estrogen levels: Especially critical in postmenopausal women, whose primary source of estrogen is peripheral conversion rather than ovarian synthesis.

3. Antitumor effect: Estrogen fuels the growth of hormone receptor-positive breast cancers. By suppressing estrogen synthesis, letrozole helps slow or stop tumor progression.

Letrozole does not exhibit androgenic, progestogenic, or estrogenic activity.

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Therapeutic Indications

Letrozole is primarily indicated for use in postmenopausal women in the treatment of hormone receptor-positive breast cancer.

Approved Indications:

1. Adjuvant treatment of early breast cancer in postmenopausal women with hormone receptor-positive tumors

2. Extended adjuvant therapy following 5 years of tamoxifen therapy

3. First-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer

4. Second-line treatment in patients with advanced disease following anti-estrogen therapy

5. Prevention of cancer recurrence in early-stage disease

Off-label/Investigational Uses:

• Ovulation induction in women with polycystic ovary syndrome (PCOS) or anovulatory infertility (as an alternative to clomiphene citrate)

• Gynecomastia in males (rare)

• Endometriosis (off-label, uncommonly)

• Breast cancer chemoprevention in high-risk populations

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Dosage and Administration

Standard Dosage:

• Early breast cancer (adjuvant/extended): 2.5 mg once daily for up to 5 years

• Metastatic breast cancer: 2.5 mg once daily until disease progression

• Post-tamoxifen therapy: Letrozole may be started immediately after completing tamoxifen

For Ovulation Induction (off-label):

• 2.5–5 mg orally once daily for 5 days, usually started on day 3 or 5 of the menstrual cycle

• Doses may be increased to 7.5 mg/day in resistant cases under close supervision

Administration Notes:

• Can be taken with or without food

• Should be taken at the same time daily

• No dosage adjustment required for mild to moderate hepatic or renal impairment

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Pharmacokinetics

• Absorption: Rapid and complete oral bioavailability

• Time to Peak Concentration: ~1 hour

• Protein Binding: ~60% (mainly albumin)

• Metabolism: Primarily hepatic (CYP3A4 and CYP2A6 mediated)

• Elimination:

  • Half-life: ~2 days

  • 90% of the dose is eliminated in the urine (mostly as metabolites)

• Steady-State: Reached in ~2–6 weeks with daily dosing

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Contraindications

• Premenopausal women with intact ovarian function (except for fertility use under specialist care)

• Known hypersensitivity to letrozole or any excipients

• Pregnancy (Category X – teratogenic)

• Breastfeeding

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Warnings and Precautions

1. Bone Health:

   • Estrogen suppression leads to reduced BMD

   • Increased risk of osteoporosis and fractures

   • Baseline and periodic bone mineral density monitoring recommended (DEXA)

2. Lipid Metabolism:

   • Possible rise in cholesterol and LDL levels

   • Monitor lipid profile periodically in long-term use

3. Cardiovascular Risk:

   • Caution in patients with pre-existing ischemic heart disease

   • May increase risk of cardiovascular events compared to tamoxifen

4. Fertility Use:

   • Letrozole is not FDA-approved for ovulation induction but widely used

   • Requires pregnancy testing before initiation

   • Should not be used in pregnant women due to fetal toxicity

5. Hepatic Impairment:

   • Use with caution in patients with severe hepatic dysfunction

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Adverse Effects

Very Common (>10%):

• Hot flashes

• Arthralgia/myalgia

• Fatigue

• Night sweats

• Nausea

• Headache

• Increased sweating

• Dizziness

Common (1–10%):

• Vaginal dryness

• Weight gain

• Hair thinning or alopecia

• Bone pain

• Peripheral edema

• Hypercholesterolemia

• Insomnia

• Depression or mood changes

Less Common/Rare (<1%):

• Osteoporotic fractures

• Ischemic cardiovascular events (MI, stroke)

• Hepatotoxicity (transaminase elevations)

• Hypersensitivity reactions (rash, urticaria)

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Drug Interactions

Letrozole does not significantly inhibit or induce major CYP enzymes, but interactions may still occur.

Pharmacodynamic interactions:

• Tamoxifen: Should not be co-administered; antagonizes the estrogen-depleting effect

• Estrogen-containing therapies (HRT, contraceptives): Oppose letrozole's effect; avoid during treatment

• Bisphosphonates: Often co-prescribed to reduce bone loss

Pharmacokinetic interactions:

• Letrozole is metabolized by CYP3A4 and CYP2A6 but does not meaningfully inhibit these enzymes

• Clinically relevant drug-drug interactions are rare

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Use in Special Populations

Pregnancy:

• Category X (contraindicated)

• Teratogenic effects observed in animal studies

• Not to be used in women who are or may become pregnant

• Effective contraception required during and after treatment

Lactation:

• Excretion in breast milk not studied

• Contraindicated due to potential harm to the nursing infant

Geriatric Use:

• No dose adjustment necessary

• Similar efficacy and safety profile compared to younger adults

Renal Impairment:

• Mild to moderate: No adjustment required

• Severe renal impairment: Use with caution

Hepatic Impairment:

• Mild to moderate: No adjustment

• Severe: Use with caution due to prolonged exposure

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Monitoring Parameters

• Bone mineral density (DEXA scan): Every 1–2 years

• Lipid profile: Baseline and periodically

• Liver function tests: Periodic if risk factors present

• Signs of fracture, joint pain, cardiovascular symptoms

• For ovulation induction: Monitor follicular development via ultrasound, serum estradiol levels

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Overdose and Toxicity

• No specific antidote

• Symptoms: Dizziness, nausea, vomiting, fatigue

• Supportive and symptomatic management

• Letrozole is not dialyzable

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Comparative Overview: Letrozole vs. Similar Agents

Drug	Class	Distinctive Features
Letrozole	Non-steroidal AI	Higher estrogen suppression; once-daily dosing
Anastrozole	Non-steroidal AI	Similar profile; slight variation in toxicity
Exemestane	Steroidal AI	Irreversible inhibitor; different metabolism
Tamoxifen	SERM	Antagonist in breast but agonist in uterus; higher VTE risk

Letrozole is considered more potent than anastrozole in suppressing estrogen and may offer superior disease-free survival in high-risk early breast cancer.

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Patient Counseling Points

• Take once daily, with or without food

• Do not use hormone replacement therapy or estrogen-containing products

• Report signs of bone pain, fractures, or joint stiffness

• Periodic monitoring of bone health and cholesterol is important

• Use effective contraception if premenopausal or using for fertility

• Inform your physician if experiencing persistent fatigue, mood changes, or vaginal bleeding

• Do not discontinue abruptly unless instructed

• Store at room temperature, away from moisture and heat