femara for fertility

The following prescribing information is based on official labeling in effectJuly 2003 femara for fertility.

DESCRIPTION
Femara ® (letrozole tablets) for oral administration contains 2.5 mg ofletrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis) femara for fertility. It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile,and its structural formula is

Letrozole is a white to yellowish crystalline powder, practically odorless,freely soluble in dichloromethane, slightly soluble in ethanol, and practicallyinsoluble in water femara for fertility. It has a molecular weight of 285.31, empirical formula C17 H 11 N 5 , and a melting range of 184°C-185°C femara for fertility.

Femara ® (letrozole tablets) is available as 2.5 mg tablets for oral administration femara for fertility.

Inactive Ingredients: Colloidal silicon dioxide, ferric oxide, hydroxypropylmethylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystallinecellulose, polyethylene glycol, sodium starch glycolate, talc, and titaniumdioxide femara for fertility.

CLINICAL PHARMACOLOGY
Mechanism of Action: The growth of some cancers of the breast is stimulatedor maintained by estrogens femara for fertility. Treatment of breast cancer thought to be hormonallyresponsive (i.e., estrogen and/or progesterone receptor positive or receptorunknown) has included a variety of efforts to decrease estrogen levels (ovariectomy,adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens andprogestational agents) femara for fertility. These interventions lead to decreased tumor mass ordelayed progression of tumor growth in some women femara for fertility.

In postmenopausal women, estrogens are mainly derived from the action of thearomatase enzyme, which converts adrenal androgens (primarily androstenedioneand testosterone) to estrone and estradiol femara for fertility. The suppression of estrogen biosynthesisin peripheral tissues and in the cancer tissue itself can therefore be achievedby specifically inhibiting the aromatase enzyme femara for fertility.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system;it inhibits the conversion of androgens to estrogens femara for fertility. In adult nontumor- andtumor-bearing female animals, letrozole is as effective as ovariectomy in reducinguterine weight, elevating serum LH, and causing the regression of estrogen-dependenttumors femara for fertility. In contrast to ovariectomy, treatment with letrozole does not lead toan increase in serum FSH femara for fertility. Letrozole selectively inhibits gonadal steroidogenesisbut has no significant effect on adrenal mineralocorticoid or glucocorticoidsynthesis femara for fertility.

Letrozole inhibits the aromatase enzyme by competitively binding to the hemeof the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogenbiosynthesis in all tissues femara for fertility. Treatment of women with letrozole significantlylowers serum estrone, estradiol and estrone sulfate and has not been shown tosignificantly affect adrenal corticosteroid synthesis, aldosterone synthesis,or synthesis of thyroid hormones femara for fertility.

Pharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinaltract and absorption is not affected by food femara for fertility. It is metabolized slowly to aninactive metabolite whose glucuronide conjugate is excreted renally, representingthe major clearance pathway femara for fertility. About 90% of radiolabeled letrozole is recoveredin urine femara for fertility. Letrozole's terminal elimination half-life is about 2 days and steady-stateplasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks femara for fertility. Plasmaconcentrations at steady-state are 1.5 to 2 times higher than predicted fromthe concentrations measured after a single dose, indicating a slight non-linearityin the pharmacokinetics of letrozole upon daily administration of 2.5 mg femara for fertility. Thesesteady-state levels are maintained over extended periods, however, and continuousaccumulation of letrozole does not occur femara for fertility. Letrozole is weakly protein boundand has a large volume of distribution (approximately 1.9 L/kg) femara for fertility.

Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinolmetabolite (4,4'-methanol-bisbenzonitrile) and renal excretion of the glucuronideconjugate of this metabolite is the major pathway of letrozole clearance femara for fertility. Ofthe radiolabel recovered in urine, at least 75% was the glucuronide of the carbinolmetabolite, about 9% was two unidentified metabolites, and 6% was unchangedletrozole femara for fertility.

In human microsomes with specific CYP isozyme activity, CYP3A4 metabolizedletrozole to the carbinol metabolite while CYP2A6 formed both this metaboliteand its ketone analog femara for fertility. In human liver microsomes, letrozole strongly inhibitedCYP2A6 and moderately inhibited CYP2C19 femara for fertility.

Special Populations: Pediatric, Geriatric and Race: In the study populations(adults ranging in age from 35 to >80 years), no change in pharmacokineticparameters was observed with increasing age femara for fertility. Differences in letrozole pharmacokineticsbetween adult and pediatric populations have not been studied femara for fertility. Differences inletrozole pharmacokinetics due to race have not been studied femara for fertility.

Renal Insufficiency: In a study of volunteers with varying renal function (24-hourcreatinine clearance: 9-116 mL/min), no effect of renal function on the pharmacokineticsof single doses of 2.5 mg of Femara ® (letrozole tablets) was found femara for fertility. Inaddition, in a study of 347 patients with advanced breast cancer, about halfof whom received 2.5 mg Femara and half 0.5 mg Femara, renal impairment (calculatedcreatinine clearance: 20-50 mL/min) did not affect steady-state plasma letrozoleconcentration femara for fertility.

Hepatic Insufficiency: In a study of subjects with mild to moderate non-metastatichepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), themean AUC values of the volunteers with moderate hepatic impairment were 37%higher than in normal subjects, but still within the range seen in subjectswithout impaired function femara for fertility. In a pharmacokinetics study, subjects with livercirrhosis and severe hepatic impairment (Child-Pugh classification C, whichincluded bilirubins about 2-11 times ULN with minimal to severe ascites) hadtwo-fold increase in exposure (AUC) and 47% reduction in systemic clearance femara for fertility. Breast cancer patients with severe hepatic impairment are thus expected to beexposed to higher levels of letrozole than patients with normal liver functionreceiving similar doses of this drug femara for fertility. (See DOSAGE AND ADMINISTRATION , HepaticImpairment .)

Drug/Drug Interactions: A pharmacokinetic interaction study with cimetidineshowed no clinically significant effect on letrozole pharmacokinetics femara for fertility. An interactionstudy with warfarin showed no clinically significant effect of letrozole onwarfarin pharmacokinetics femara for fertility. In in-vitro experiments, letrozole showed no significantinhibition in the metabolism of diazepam femara for fertility. Similarly, no significant inhibitionof letrozole metabolism by diazepam was observed femara for fertility.

Coadministration of Femara and tamoxifen 20 mg daily resulted in a reductionof letrozole plasma levels of 38% on average femara for fertility. Clinical experience in the second-linebreast cancer pivotal trials indicates that the therapeutic effect of Femaratherapy is not impaired if Femara is administered immediately after tamoxifen femara for fertility.

There is no clinical experience to date on the use of Femara in combinationwith other anticancer agents femara for fertility.

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

Letrozole is highly specific in inhibiting aromatase activity femara for fertility. There is noimpairment of adrenal steroidogenesis femara for fertility. No clinically-relevant changes were foundin the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone,ACTH or in plasma renin activity among postmenopausal patients treated witha daily dose of Femara 0.1 mg to 5 mg femara for fertility. The ACTH stimulation test performed after6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and5 mg did not indicate any attenuation of aldosterone or cortisol production femara for fertility. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary femara for fertility.

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

Clinical Studies: First-Line Breast Cancer: A randomized, double-blinded, multinationaltrial compared Femara 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patientswith locally advanced (Stage IIIB or locoregional recurrence not amenable totreatment with surgery or radiation) or metastatic breast cancer femara for fertility. Time to progression(TTP) was the primary endpoint of the trial femara for fertility. Selected baseline characteristicsfor this study are shown in Table 1 femara for fertility.

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