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Mechanism of Action

The growth of some cancers of the breast are stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumorbearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.

Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.


Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole’s terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5mg dosing is reached in 2-6 weeks. Plasma concentrations at steady-state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight nonlinearity in the pharmacokinetics of letrozole upon daily administration of 2.5mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).

Metabolism and Excretion

Metabolism to a pharmacologically-inactive carbinol metabolite (4, 4'-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole.

In human microsomes with specific CYP isozyme activity, CYP 3A4 metabolized letrozole to the carbinol metabolite while CYP 2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP 2A6 and moderately inhibited CYP 2C19.

Special Populations

Pediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to >80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.

Renal Insufficiency: In a study of volunteers with varying renal function (24-hour creatinine clearance: 9-116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5mg of Femara (letrozole tablets) was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5mg Femara and half 0.5mg Femara, renal impairment (calculated creatinine clearance: 20-50 mL/min) did not affect steady-state plasma letrozole concentration.

Hepatic Insufficiency: In a study of subjects with varying degrees of non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. Patients with severe hepatic impairment (Child-Pugh classification C) have not been studied (see DOSAGE AND ADMINISTRATION, Hepatic Impairment).

Drug/Drug Interactions

A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on letrozole pharmacokinetics. An interaction study with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics.

There is no clinical experience to date on the use of Femara in combination with other anti-cancer agents.


In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg Femara suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75%-95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.

Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among post-menopausal patients treated with a daily dose of Femara 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Femara or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0. 1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.

Clinical Studies

Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six non-comparative phase I/II trials in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with Femara 2.5 mg daily in phase I/II trials achieved an objective tumor response (complete or partial response).

Two large randomized controlled multinational (predominantly European) trials were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to Femara 0.5mg daily, Femara 2.5mg daily, or a comparator (megestrol acetate 160 mg daily in one study; and aminoglutethimide 250mg bid with corticosteroid supplementation in the other study). In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in the following table:

Table I: Selected Study Population Demographics

Parameter megestrol acetate study
aminoglutethimide study

No. of Participants 552

Receptor Status
ER/PR Positive 57%

ER/PR Unknown 43%

Previous Therapy
Adjuvant Only 33%

Therapeutic+/- Adj. 66%

Sites of Disease
Visceral Metastases 40%

Soft Tissue Metastases 50%

Bony Metastases 56%

Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by a second evaluation 4-12 weeks after the documentation of the initial response. The following table shows the results for the first trial, with a minimum follow-up of 15 months, that compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg daily. (All analyses are unadjusted.)

Table 2: Megestrol Acetate Study Results

N = 188
Femara2. 5 mg
N = 174
Megestrol Acetate
N = 190

Objective Response (CR + PR) 22 (11.7%) 41 (23.6%) 31 (16.3%)
Median Duration of Response 552 days (Not reached) 561 days
Median Time to Progression 154 days 170 days 168 days
Median Survival 633 days 730 days 659 days
Odds Ratio for Response Femara2.5: Femara0. 5= 2.33
(95% Cl: 1.32, 4.17); p= 0.004*

Femara2. 5: Megestrol = 1. 58
(95% Cl: 0.94, 2.66); p= 0.08*

Relative Risk of Progression Femara2.5: Femara0.5= 81
(95% Cl: 0.63, 1.03); p= 0.09*
Femara2. 5: Megestrol= 0.77
(95% CI: 0.60, 0.98), p= 0.03*

*two-sided p-value

The results for the study comparing Femara to aminoglutethimide, with a minimum follow-up of nine months, are shown in the following table. (Unadjusted analysis are used).

Table 3: Aminoglutethimfde Study Results

N = 193
Femara2. 5 mg
N = 185
N = 179

Objective Response (CR + PR) 34 (17. 6%) 34 (18. 4%) 22 (12. 3%)
Median Time to Progression 619 days 706 days 450 days
Median Duration of Response 103 days 123 days 112 days
Median Survival 636 days 792 days 592 days
Odds Ratio for Response Femara2.5: Femara 0.5= 1.05 (95% Cl: 0.62, 1. 79); p= 0.85*

Aminoglutethimide= 1.61

(95% Cl: 0.90, 2.87); p= 0.11*

Relative Risk of Progression Femara2.5: Femara 0.5= 0.86
(95% Cl: 0.68, 1.11); p= 0.25*
Aminoglutethimide= 0.74

(95% CI: 0.57,0.94), p= 0.02*

*two-sided p-value