More anti E info.

[silverfox]

DESCRIPTION

Femara (letrozole tablets) for oral administration contain 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4 -Triazol-1-ylmethylene) dibenzonitrile.

Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical formula C17H11N5 and a melting range of 184o C-185o C.

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

Inactive Ingredients.

Colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide.

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

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.

Pharmacodynamics

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.

[Lush]

Originally posted by eye_candy
DESCRIPTION





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.


Effect on Estradiol: Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of ARIMIDEX in post-menopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, ARIMIDEX 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with ARIMIDEX 1 mg.

Intersting stuff eye_Candy.

So if i'm interpreting this right, does this mean 0.5mg of femara is as effective as 1mg of arimidex?

if so femara sounds like more anti-e bang for the buck.

[silverfox]

That is how i read it too, but again kinda have to experiment on yourself and see. Ferma is pricy right now 3-6 per tab street price i beleive, so bit much for most.

[AZlifter]

Good read EC

I'm going to be running femara in my cycle (aww yeah just weeks away ) at a dosage of 1.25mg EOD. From what i hear its some really powerful stuff, but i especially like the idea of raising the IGF-1 levels. I've also been told by a good bro of mine who has used it, that it help get rid of the puffy fat around his nip and it helped to make his skin tighter.

I'll keep you all posted once i start in a few more weeks!

AZ

[Lush]

Ok now I'm confused.

I did some searching and most people do 2.5mg femaraED- equivalent to 1mg liquidex ED. With lots doing 2.5mg EOD, or 1.25EOD as a bare minimum.

In all cases liquidex is a cheaper alternative at 1mgED, 0.5mgED or .25mgED respectively.

but if 0.5mg femara works near as well as 1mg liquidex then femara becomes a way cheaper alternative.