letrozole

Action and Spectrum

Actions and Spectrum

Letrozole is an aromatase inhibitor that belongs to the non-steroidal type II; it inhibits CYP19A1 by binding to the active site and electron transfer chain. This inhibits the conversion of androgens to estrogen therefore resulting in a decreased uterine weight and an enhanced luteinizing hormone level. Aromatase activity is the most important source of estrogen synthesis in postmenopausal women. They work by depriving the estrogen hormone thus causing regression of the estrogen-dependent tumors. Third generation nonsteroidal aromatase inhibitors such as Letrozole have no direct impact on cortisol, aldosterone & thyroxine.

Drug Interaction

Adverse Reaction

Adverse Reaction

Frequency defined:

>10%

Edema (25%)

Hypertension (9%)

Hot flash (15%)

Constipation (23%)

Dyspepsia (6%)

Urinary tract infection (12%)

Bruise

Increased serum alanine aminotransferase

Fatigue

Insomnia

Arthralgia

Joint swelling

1%-10%

Cardiac arrhythmia

Cardiac failure

Nocturia

Headache

Bone fracture

Fever

<1%

Adrenocortical insufficiency

Black Box Warning

Black Box Warning

There is no black box warning associated with letrozole

Contraindication / Caution

Contraindication /Caution

Contraindications

Hypersensitivity

Pregnancy

Caution

Liver impairment

Increase in the risk of Osteoporosis

May lead to dizziness, somnolence and fatigue, therefore users should exercise caution especially when operating machinery.

Pregnancy / Lactation

Pregnancy/Lactation

Pregnancy consideration: Based on the animal studies it may cause harm to patients who can become pregnant.

Lactation: Excretion of letrozole in breast milk is not known.

Pregnancy category:

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester.
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women.
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits.
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women.
• Category N: There is no data available for the drug under this category.

Pharmacology

Pharmacology

Letrozole is a non-steroidal aromatase inhibitor that is applied in the treatment of hormone receptor-positive breast cancer in postmenopausal women. It inhibits aromatase, decreasing levels of estrogen and preventing estrogen-dependent tumor growth.

Pharmacodynamics

Letrozole reduces the levels of serum estrogen by more than 95% thus minimizing the ability of estrogen to stimulate cancerous cells. The decrease of estrogen levels may contribute to the increase of gonadotropin levels including luteinizing hormone (LH) and follicle stimulating hormone (FSH).

Pharmacokinetics

Absorption

Bioavailability: Letrozole is 99.9% orally bioavailable.

C_max: After a 2.5 mg oral dose, the maximum concentration (C_max) is 104 nmol/L.

T_max: The time to reach C_max (T_max) is 8.10 hours.

AUC: The area under the curve (AUC) is 7387 nmol*h/L.

Distribution

The volume of distribution is 1.87 L/kg.

Letrozole is 60% bound to plasma proteins, with 55% bound to albumin.

Metabolism

It is primarily metabolized by CYP2A6 to a ketone analog metabolite. The ketone analog is further metabolized by CYP3A4 and CYP2A6 to 4,4′-(hydroxymethylene)dibenzonitrile.

Elimination/Excretion

Letrozole is 90% eliminated in the urine. 75% of the dose is recovered as a glucuronide metabolite. The terminal elimination half-life is approximately 42 hours in healthy volunteers, and it is longer in breast cancer patients. The average clearance after a single dose is 1.52 L/h.

Adminstartion

Administration

It is administered orally along with the meals

Patient Information Leaflet

Patient information leaflet

Generic Name: Letrozole

Pronounced: le-tro-zol

Why do we use letrozole?

Letrozole is mainly administered for hormone receptor positive breast cancer in postmenopausal females.

Adjuvant Treatment of Early Breast Cancer: Letrozole is prescribed after surgery (and potentially other measures such as radiation) to minimize the risk of cancer returning in women diagnosed with hormone receptor positive breast cancer.

Extended Adjuvant Treatment: Letrozole is then administered as an extended therapy after 5 years of tamoxifen use to minimize the risks of cancer reoccurrences.

First-line Treatment of Advanced or Metastatic Breast Cancer: It is employed as a first line of treatment in postmenopausal women with hormone receptor positive or unknown locally advanced or metastatic breast cancer.

Second-line Treatment: Letrozole is prescribed to the patients with the progressive disease after anti-estrogen treatment.