Letrozole

Letrozole is a synthetic hormone and antineoplastic agent belonging to the pharmacological class of non-steroidal type II aromatase inhibitors.

FDA has approved Letrozole for postmenopausal women treating hormone receptor-positive early breast cancer as adjuvant treatment and extended adjuvant treatment.

Once administered, Letrozole is rapidly and completely absorbed from the gastrointestinal tract and extensively distributed to various tissues throughout the body. The liver metabolizes Letrozole, and the primary route of elimination is through urine.

The most common side effects of Letrozole include hot flashes, fatigue, increased sweating, increased cholesterol (hypercholesterolemia), bone and joint pain, dizziness, oedema, and flushing.

Letrozole is available in the form of an oral tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Italy, Australia, Germany, France, Japan and Spain.

Letrozole is a synthetic hormone and antineoplastic agent belonging to the pharmacological class of non-steroidal type II aromatase inhibitors.

Letrozole inhibits CYP19A1's active site and its electron transfer chain. Because of this competitive inhibition, androgens cannot be converted to estrogen. Elevated luteinizing hormone and decreased uterine weight are the results of this activity. Aromatase is primarily responsible for the synthesis of estrogen in postmenopausal women. Tumors that are dependent on estrogen shrink when there is less estrogen available. Third-generation aromatase inhibitors do not considerably impact cortisol, aldosterone, and thyroxine levels.

Letrozole is available in the form of an oral tablet.

Tablet: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, preferably after meals as directed.

Letrozole can be used in the following health conditions:

• Treatment of Breast cancer
• Treatment of Infertility due to anovulation

• Treatment of Breast Cancer: As an essential factor in hormone receptor-positive breast tumours, Letrozole inhibits the production of oestrogen, which is beneficial in treating breast cancer. Letrozole efficiently inhibits the growth of tumours in postmenopausal women with locally advanced or metastatic breast cancer when used as a first-line treatment. It also helps patients with advanced breast cancer when the illness progresses following antiestrogen therapy.
• Treatment of Infertility due to anovulation: Infertility resulting from anovulation has been effectively treated with Letrozole, especially in those women with polycystic ovarian syndrome (PCOS). Letrozole stimulates follicular growth and ovulation by preventing the generation of estrogen. Letrozole has shown comparable or better success rates with a lower risk of multiple pregnancies when compared to standard ovulation-inducing drugs. Higher pregnancy rates, better ovulation, and a lower risk of ovarian hyperstimulation syndrome are all linked to its usage in fertility treatments.

• Letrozole tablets are indicated to treat hormone receptor-positive early breast cancer in postmenopausal women adjuvantly.
• Letrozole tablets are indicated for postmenopausal women with early breast cancer who have undergone five years of adjuvant tamoxifen therapy as extended adjuvant treatment.
• Letrozole tablets indicate first-line treatment for postmenopausal women with hormone receptor-positive or unknown, locally advanced, or metastatic breast cancer. They also show treatment for advanced breast cancer in postmenopausal women with disease progression after antiestrogen therapy.

Orally: Letrozole, administered orally, is typically prescribed as a once-daily tablet. Patients are advised to take the medication simultaneously daily, usually after meals. The tablets should be swallowed whole with a glass of water, avoiding crushing or breaking them. Individuals must adhere strictly to the prescribed dosage and administration schedule. Patients are also advised to consult their healthcare provider about the medication's benefits and potential side effects.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 2.5 mg

Letrozole is available in the form of oral tablets.

Dose Adjustment in Adult Patients:

Breast Cancer

Adjuvant therapy for early-stage breast cancer

In postmenopausal women with early-stage breast cancer that is hormone receptor-positive

Daily, 2.5 mg PO

Extended adjuvant treatment for early breast cancer

2.5 mg PO qDay

For advanced cancers of the breast, both first- and second-line therapy

2.5 mg PO qDay; continue until tumour progression is evident.

Ovarian Epithelial Cancer (Off-label)

2.5 mg PO qDay

Dosing Considerations

Based on an analysis of patients' disease-free survival after receiving medication for a median of 60 months, Letrozole is considered effective in extended adjuvant treatment of early breast cancer.

When taking Letrozole, adhere to dietary recommendations and safety guidelines for optimal well-being. It is essential to maintain a healthy diet rich in essential nutrients, incorporating leafy vegetables, fruits, fatty fish, and dairy. Limit intake of processed foods, refined carbs, and added sugars. Encourage regular exercise to support overall health and weight management. Refrain from smoking and excessive alcohol consumption.

The dietary restriction should be individualized as per patient requirements.

Letrozole may be contraindicated in the following conditions:-

• Anyone who has previously experienced hypersensitivity to any of the product's constituents.
• Pregnancy, premenopausal women.

• Exercise caution in individuals with liver impairment; administer a low dose to those with hepatic issues, and the impact of hepatic impairment on drug exposure in cancer patients with increased bilirubin levels is undetermined.

• Be vigilant for decreases in bone mineral density; consider regular monitoring as there is a higher risk of osteoporosis associated with the use of this medication.

• This drug may induce dizziness, drowsiness, and fatigue; use cautiously when operating machinery or engaging in activities requiring alertness.

• Potential elevation in total serum cholesterol levels may occur; regular cholesterol monitoring is advisable.

• Avoid concurrent use with estrogens to prevent potential interactions and adverse effects. Regular monitoring and adherence to safety guidelines contribute to the responsible use of this medication.

It is unsafe to consume Letrozole with alcohol.

It is not recommended for use during breastfeeding.

It is not recommended for use during pregnancy.

Limit intake of saturated fats for safety and consume nutrient-rich foods.

The adverse reactions related toLetrozole can be categorized as

•Common Adverse Effects: Diaphoresis, bone pain, hot flashes, back pain, dyspnea, nausea, night sweats, cough, and fatigue.

•Less Common Adverse Effects: Constipation, hypertension, chest pain, diarrhoea, weight decrease, oedema, breast pain, bone fractures, urinary tract infections (UTI), hypercalcemia, headache, weakness, vomiting, and osteoporosis.

•Rare Adverse Effects: Blurred vision and increased hepatic enzyme levels

Reports from postmarketing

Blurred Vision

Elevated hepatic enzyme levels

Anaphylactic reactions

Angioedema

Epidermal necrolysis toxin

Multiple forms of erythema

Trigger finger

The condition known as carpal tunnel syndrome

The clinically relevant drug interactions of Letrozole are briefly summarized here.

• Tamoxifen: Coadministering Letrozole with a daily dose of 20 mg tamoxifen resulted in an average reduction of letrozole plasma levels by 38%. Clinical experience from second-line breast cancer trials indicates that the therapeutic effect of letrozole therapy remains uncompromised when administered immediately after tamoxifen.
• Cimetidine: A pharmacokinetic interaction study involving cimetidine revealed no clinically significant impact on letrozole pharmacokinetics.
• Warfarin: In an interaction study with warfarin, no clinically significant effect of Letrozole on warfarin pharmacokinetics was observed.

The common side effects of Letrozole include:

• Fatigue
• Hypercholesterolemia (high cholesterol)
• Increased sweating
• Hot flashes
• Dizziness
• Joint and bone pain
• Edema (swelling)
• Hot flushes (feeling of warmth)

• Pregnancy

Pregnancy Category X (FDA): The risks outweigh the potential benefits. Safer alternatives exist.

Letrozole has not been proven to be clinically beneficial for premenopausal women with breast cancer, and it may harm a fetus if given to a pregnant woman. Femara should not be used by women who are pregnant or may become pregnant. Patients should be informed of the possible risks to a fetus if they use this medication while pregnant or if they get pregnant while taking it.

Use during pregnancy has been associated with spontaneous abortions and congenital birth problems in post-marketing reports; nevertheless, there is not enough information to conclude that the medicine carries a danger. Therapy can harm a fetus and should not be used by pregnant women, according to the mechanism of action, post-marketing reports, and results from research conducted on animals.

Contraception

Instruct women who are fertile to utilize birth control during their therapy and for three weeks following their last dosage.

Infertility

Infertility treatment may reduce fertility in both males and females who are capable of having children.

• Nursing Mothers

The excretion of Letrozole in human milk is unknown. Because Letrozole can cause significant adverse reactions in nursing infants and many medicines are excreted in human milk, a choice should be taken regarding the drug's value to the mother and whether to stop breastfeeding or stop taking it altogether.

• Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population have not been established.

Dose Adjustment in Kidney Impairment Patients:

Moderate to mild (CrCl ≥30 mL/min): No dose modification is required

Severe (CrCl ≥10 to <30 mL/min): No dose modification is required.

Dose Adjustment in Hepatic Impairment Patients:

Mild-to-moderate: No dosage modification is required

Patients with severe hepatic dysfunction and cirrhosis should take half their dose (i.e., 2.5 mg every other day).

There is no research on noncirrhotic patients with high bilirubin levels.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Letrozole.

Signs and Symptoms

The maximum dose utilized in single-dose studies was 30 mg, which was well tolerated; in multiple-dose trials, the highest dose used was 10 mg, also well taken. However, overconsumption of Letrozole may include nausea, vomiting, dizziness, and drowsiness.

Management

There is no specific antidote or treatment for excessive Letrozole intake, so treatment typically involves symptomatic and supportive measures. Measures may include gastric lavage or induced emesis to remove unabsorbed medication, followed by supportive care to maintain vital functions. Dialysis might not be beneficial due to Letrozole's large volume of distribution and extensive protein binding. Continuous observation and appropriate, timely medical interventions to address specific symptoms or complications are recommended.

Pharmacodynamics:

With daily doses ranging from 0.1 mg to 5 mg, Letrozole exhibits a dose-dependent suppression of plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline in postmenopausal patients with advanced breast cancer. The maximal suppression is achieved within two to three days. The drug is particularly effective in inhibiting aromatase activity without impairing adrenal steroidogenesis. No clinically relevant changes are observed in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH, or plasma renin activity in postmenopausal patients treated with Letrozole at doses from 0.1 mg to 5 mg daily. The ACTH stimulation test indicates no attenuation of aldosterone or cortisol production, eliminating the need for glucocorticoid or mineralocorticoid supplementation. Moreover, Letrozole does not lead to the accumulation of androgenic precursors, as evidenced by unchanged plasma concentrations of androgens (androstenedione and testosterone) and LH and FSH levels in treated patients. Thyroid function remains unaffected, as evaluated by TSH levels, T3 uptake, and T4 levels.

Pharmacokinetics:

• Absorption: Letrozole rapidly and completely absorbs from the GI tract, ensuring efficient uptake into the bloodstream.
• Distribution: The drug exhibits rapid and extensive distribution to various tissues, reflecting its widespread presence throughout the body. The volume of distribution is approximately 1.9 L/kg.
• Plasma Protein Binding: Letrozole demonstrates substantial plasma protein binding, with around 60% of the drug binding mainly to albumin. This binding influences its availability and activity within the bloodstream.
• Metabolism: Letrozole undergoes hepatic metabolism by CYP3A4 and CYP2A6 enzymes, transforming the drug into an inactive carbinol metabolite. This metabolic process occurs in the liver, influencing the drug's pharmacokinetics.
• Excretion: The primary route of elimination for Letrozole is through urine. This process includes 6% of the drug being excreted as the unchanged form, 75% as the glucuronide carbinol metabolite, and 9% as unidentified metabolites. Letrozole exhibits a relatively short terminal elimination half-life of approximately two days.

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