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Letrozole (Systemic)

Primary: AN500

Commonly used brand name(s): Femara.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).





Carcinoma, breast (treatment)—Letrozole is indicated for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer1. {02}{03}Letrozole is also indicated for treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. {01}{02}{04}

1 Not included in Canadian product labeling.


Physicochemical characteristics:
Molecular weight—
    285.31 {01}

    Freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. {01}

Mechanism of action/Effect:

Letrozole is a nonsteroidal competitive inhibitor of aromatase and thus, in postmenopausal women, inhibits conversion of adrenal androgens (primarily androstenedione and testosterone) to estrogens (estrone and estradiol) in peripheral tissues and cancer tissue. As a result, letrozole interferes with estrogen-induced stimulation or maintenance of growth of hormonally responsive (estrogen and/or progesterone receptor positive or receptor unknown) breast cancers. {01}

Other actions/effects:

In human liver microsomes, letrozole strongly inhibits the cytochrome P450 (CYP) isoenzyme 2A6 (CYP 2A6) and moderately inhibits the CYP isoenzyme 2C19 (CYP 2C19). {01}

Letrozole has not been shown to affect synthesis of adrenal corticosteroids, aldosterone, or thyroid hormones. {01}


Rapidly and completely absorbed. Absorption is not affected by food. {01}


The volume of distribution (Vol D) is approximately 1.9 liters per kg of body weight. {01}


Hepatic, by the CYP isoenzymes 3A4 and 2A6 (CYP 3A4 and CYP 2A6), to an inactive carbinol metabolite and its ketone analog. {01}



Approximately 2 days. {01}

Time to steady-state concentration

Plasma—2 to 6 weeks. {01}

Note: Steady-state plasma concentrations are 1.5 to 2 times higher than would be predicted on the basis of single-dose measurements, indicating some nonlinearity in letrozole's pharmacokinetics with daily administration. However, steady-state concentrations are maintained for extended periods, without further accumulation of letrozole. {01}

    Renal, approximately 90% of a dose (approximately 75% as the glucuronide conjugate of the inactive metabolite, 9% as two unidentified metabolites, and 6% unchanged). {01}

Precautions to Consider


A study in mice given doses of 0.6 to 60 mg per kg of body weight (mg/kg) per day by oral gavage (approximately 1 and 100 times, respectively, the maximum recommended daily human dose [MRHD] on a mg per square meter of body surface area [mg/m 2] basis) for up to 2 years found a dose-related increase in the incidence of benign ovarian stromal tumors. When the high-dose group was excluded because of low survival rates, a significant trend in the incidences of hepatocellular adenoma and carcinoma was shown in females. A study in rats given oral doses of 0.1 to 10 mg/kg per day (approximately 0.4 and 40 times the MRHD on a mg/m 2 basis, respectively) for up to 2 years found an increase in the incidence of benign ovarian stromal tumors with 10 mg/kg per day. Ovarian hyperplasia was also seen in female rats given 0.1 mg/kg or more per day. {01}


Letrozole demonstrated no mutagenic effects in in vitro tests (Ames and E. coli bacterial tests), but was found to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). It was not clastogenic in vivo (micronucleus test in rats). {01}

Fertility studies in animals have not been done. However, in male and female mice, rats, and dogs receiving repeated dosing with 0.6, 0.1, and 0.03 mg/kg, respectively (approximately 1, 0.4, and 0.4 times the MRHD on a mg/m 2 basis, respectively), letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females. {01}

Studies in humans have not been done. Letrozole is indicated for use in postmenopausal women only. However, if a pregnant woman is exposed to the medication, she should be apprised of the possibility of fetal harm and/or loss of the pregnancy. {01}

Studies in rats given doses of 0.003 mg/kg (approximately 1/100 of the MHRD on a mg/m 2 basis) or more during the period of organogenesis found embryotoxicity and fetotoxicity, including intrauterine mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses, and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema, and incomplete ossification of frontal skull and metatarsals. Also, letrozole was teratogenic in rats, causing fetal domed head and cervical/centrum vertebral fusion at a dose of 0.03 mg/kg (approximately 1/10 of the MRHD on a mg/m 2 basis). Studies in rabbits found fetotoxicity at doses of 0.02 mg/kg (approximately 1/10,000 of the MRHD on a mg/m 2 basis) and embryotoxicity at doses of 0.002 mg/kg or greater (about 1/100,000 of the MRHD on a mg/m 2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hindlegs. {01}

FDA Pregnancy Category D. {01}


It is not known whether letrozole is distributed into human breast milk. {01}


No information is available on the relationship of age to the effects of letrozole in pediatric patients. Safety and efficacy have not been established. {01}


Clinical trials with letrozole included geriatric patients; the median age in the first-line randomized trial was 65 years, and 1/3 of the patients were 70 years of age or older. Time to tumor progression and tumor response rate were better in patients 70 years of age or older. {02}The mean age in two second-line randomized trials was 64 years, and 30% of the patients were 70 years of age or older. There were no differences in response between patients 70 years of age or older and younger patients. Also, no age-related effects on the pharmacokinetics of letrozole were found in studies that included patients ranging in age from 35 years to more than 80 years. {01}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Calcium, serum    (concentrations may be increased in some patients {01})

Cholesterol, serum    (concentrations may be increased in some patients {01})

Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin and
Gamma glutamyl transferase    (increases in serum values have been seen, but are most often associated with hepatic metastases {01}{02})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Risk-benefit should be considered when the following medical problems exist
Hepatic function impairment    (although modest increases in letrozole blood concentrations have been observed in individuals with hepatic function impairment due to cirrhosis, no dosage adjustment is recommended in mild to moderate hepatic function impairment; studies in patients with severe hepatic function impairment have not been done but, since letrozole is eliminated by hepatic metabolism, caution is recommended {01})

Renal function impairment    (no dosage adjustment is necessary when creatinine clearance is 10 mL per minute or more {02})

Hypersensitivity to letrozole {01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) {02}and
Aspartate aminotransferase (AST [SGOT]) {02}and
Gamma glutamyl transferase    (increases in serum values could be evidence of hepatic metastases {02})

Side/Adverse Effects

Note: Most side effects are mild to moderate. {01} Letrozole was generally well tolerated across all studies as first-line and second-line treatment for breast cancer. {02}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (³ 10%)
Dyspnea{02} (shortness of breath)

Incidence less frequent (< 10%)
Bone fracture {02}—less than 5% of patients
breast pain{02}
chest pain {01}
edema, peripheral {01} ( swelling of feet or lower legs)
hypertension {01} —usually asymptomatic
mental depression {01} —less than 5% of patients
pleural effusion {02}(chest pain; shortness of breath )—less than 5% of patients
viral infection {02}(chills; cough or hoarseness ; fever; cold; flu-like symptoms)

Incidence rare (£ 2%)
Myocardial infarction {02}(heart attack)
myocardial ischemia {02}(chest pain; fainting; fast heartbeat; increased sweating; nausea, continuing or severe nervousness; shortness of breath ; weakness)
pulmonary embolism {02}(chest pain; cough; fainting; fast heartbeat; sudden shortness of breath or troubled breathing; dizziness or lightheadedness)
thromboembolism {01} ( pain in chest, groin, or legs, especially the calves; severe, sudden headache; slurred speech ; sudden, unexplained shortness of breath ; sudden loss of coordination; sudden, severe weakness or numbness in arm or leg; vision changes)—specific symptoms dependent on site of thromboembolism, can result in stroke{02}
vaginal bleeding {01}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (> 10%)
Arthralgia{01} (joint pain)
back pain {02}
bone pain {02}
hot flashes (sudden sweating and feeling of warmth)
myalgia{01}{02} (muscle pain)
nausea {01}

Incidence less frequent (< 10%)
Anorexia {01} (loss of appetite; weight loss )
anxiety {01}
asthenia {01} (weakness)
constipation {01}
cough {01}
diarrhea {01}
dizziness {01}
headache {01}
hypercalcemia {02}(abdominal pain; confusion; constipation ; depression; dry mouth; headache; incoherent speech; increased urination ; loss of appetite; metallic taste; muscle weakness; nausea; thirst ; unusual tiredness; vomiting; weight loss)
hypercholesterolemia (high cholesterol) {02}
increased sweating {01}
insomnia{02} (trouble sleeping)
skin rash or itching {01}
sleepiness {01}
stomach pain or upset {01}
unusual tiredness {01}
vertigo{02} (spinning or whirling sensation, altering sense of balance)
vomiting {01}
weight gain {01}

Those not indicating need for medical attention
Incidence less frequent (< 5%)
Alopecia {01} (loss of hair)

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
Isolated cases of letrozole overdose have been reported, in which the single highest dose taken was 62.5 mg or 25 tablets. No serious adverse events were reported. Due to the limited data available, no definitive treatment recommendations can be made.{02}

Treatment of overdose
No specific treatment is recommended, although emesis could be induced if the patient is alert. {01} Supportive care with frequent monitoring of vital signs is recommended. {01}

Patients in whom overdose is confirmed or suspected should be referred for psychiatric evaluation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Letrozole (Systemic)

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to letrozole

Pregnancy—Intended for postmenopausal women only; accidental exposure during pregnancy may result in fetotoxicity and/or loss of the pregnancy

Proper use of this medication
» Compliance with prescribed regimen

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Importance of close monitoring by physician

Side/adverse effects
Stopping treatment and getting emergency help immediately if symptoms of myocardial infarction or thromboembolism occur, especially chest pain, dyspnea, hypertension, myocardial ischemia, peripheral edema, pleural effusion, and pulmonary embolism

Signs of other potential side effects, especially bone fracture, breast pain, mental depression, vaginal bleeding, and viral infection

Possibility of hair loss

General Dosing Information
Letrozole has no effect on cortisol or aldosterone secretion; therefore, glucocorticoid or mineralocorticoid replacement therapy is not required. {01}

No dosage adjustment is needed for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min.{02}{04}

No dosage adjustment is recommended for patients with mild-to-moderate hepatic impairment.{04} Although patients with severe liver function impairment have not been studied, these patients should be dosed with caution.{02}

Patients should continue to take letrozole until tumor progression is evident.{02}

Oral Dosage Forms


Usual adult dose
Carcinoma, breast
Oral, 2.5 mg once a day. {01}{04}

Usual geriatric dose
Carcinoma, breast
See Usual adult dose. {01}{04}

Strength(s) usually available

2.5 mg (Rx) [Femara (lactose monohydrate)]


2.5 mg (Rx) [Femara (lactose)]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), preferably at 25 °C (77 °F). {02}

Developed: 09/30/1997
Revised: 02/13/2001

  1. Femara package insert (Novartis—US), Rev 7/97, Rec 9/97.
  1. Product Information: Femara®, letrozole tablets. Novartis Pharmaceuticals, East Hanover, NJ, (PI issued 01/2001) reviewed 01/2001.
  1. FDA Talk Paper: FDA Approves Femara as First-Line Therapy for Advanced Breast Cancer. United States Food and Drug Administration, U.S. Department of Health and Human Services, Rockville, MD, 01/2001.
  1. Product Information: Femara®, letrozole tablets. Novartis Pharmaceuticals Canada, Dorval, Quebec, Canada, (PI issued 09/2000) reviewed 2/2001.