PDA

View Full Version : Must read Awesome info on Femera & Interactions of femera with other drugs.



madchemist36
11-22-2002, 02:39 PM
Guys i posted these study a while back at FB and i just came across check it out. its good info.

madchemist36
11-22-2002, 02:40 PM
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 ********* 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

madchemist36
11-22-2002, 02:40 PM
Thanks to JohnnyB for finding this study

Nolvadex (tamoxifin) and Letrozole.

Pharmacokinetic interactions

The combination of an aromatase inhibitor with tamoxifen is a possible route whereby improved efficacy of endrocrine therapy might be achieved. The consideration of such clinical combinations requires assessment of potential pharmacokinetic interactions. This was stressed by the study of Lien et al. (1990), who demonstrated that combination with AG led to decreases in tamoxifen concentrations of about 70%. We have now performed an analogous study with anastrozole, and found that this inhibitor does not lead to decreased tamoxifen concentrations (Dowsett et al. 1999b). In this issue of Endocrine-Related Cancer, Ingle et al. (1999) also report that letrozole has no impact on tamoxifen concentrations. Thus these two compounds may be added to tamoxifen
with no concern that the pharmacokinetics of the antioestrogen will be compromised. However, unexpectedly, we have noted that, conversely, in combination with tamoxifen, the plasma concentrations of letrozole are reduced by between 35 and 40% (Dowsett et al. 1997). The mechanism underlying this highly unexpected finding is at present unknown. No other drugs are known to interact with tamoxifen in this manner, but it is of concern that systematic pharmacokinetic interaction studies with tamoxifen have been relatively limited, despite the millions of women years of its usage. Decreases in AG concentration did not occur when it was combined with tamoxifen. The question of whether the anastrozole-tamoxifen combination will demonstrate this difference is currently under study. As a result of this pharmacokinetic interaction, the plasma concentrations of letrozole are equivalent to those predicted to be achieved by 1.5-2.0 mg/day when given alone. It is possible that this may be of clinical importance because, as mentioned above, there is a dose-response relationship between letrozole 0.5 mg/day and 2.5 mg/day (Dombernowsky et al. 1998, Gershanovich et al. 1998). Thus, with the combination, the complete additive efficacy of letrozole may not be achieved.

madchemist36
11-22-2002, 02:41 PM
this is not a study but this guy Dizzy posted his experience with femera

Letrozole Femera

Im currently on cycle and started the first four weeks with 40mg of dbol a day. I think within the first two days my nips became really puffy. I was taking nolvadex everyday because I knew I was prone to gyno....so they never got sore or itchy....just very puffy.

Even after I discontinued the dbol....my nipples still remained this way. Well...week 7 of my current cycle...I added 1.25mg (half a tab) of letrozole every other day. Its only been four days and my puffy nips have completely disappeared. Not only that...but my skin has become much tighter. All estrogen related fat seems to be going away. Im so freakin stoked.

If your nips get puffy from large doses of test or dbol like I do I highly recomend getting some Letrozole (Femera). It isn the cheapest of the anti-aromatases...but EXTREMELY EFFECTIVE. And if you look in the right place...you can find it pretty darn cheap

gearedup
11-22-2002, 05:54 PM
I guess I will have to try one of my free bottles! :)

madchemist36
11-22-2002, 06:36 PM
i am definitly hitting up femera from now on.

madchemist36
11-22-2002, 10:24 PM
bump for the newbeez

gearedup
11-24-2002, 03:11 AM
I think researchlist has a sale on it now!

madchemist36
11-24-2002, 04:20 AM
away does too!!!!

gearedup
11-24-2002, 04:40 AM
I doubt as cheap research GUARANTEES to beat anyones prices!

Email him and he will beat anyones pricing he guarantees it!

bigdan
11-24-2002, 09:58 AM
i see in the post from Madchemist that guy was taking 1.25mg eod. I ran the numbers and at this dose it is cheaper than .5mg of liquidex everyday. I am wondering if that dose is enough. Even if 1.25 mg was taken ed it is not much more expensive than liquidex.

gearedup
11-24-2002, 06:04 PM
It is actually cheaper to get the femara right now than the liquidex with researchlist he has it on sale!

madchemist36
11-24-2002, 07:49 PM
Originally posted by bigdan
i see in the post from Madchemist that guy was taking 1.25mg eod. I ran the numbers and at this dose it is cheaper than .5mg of liquidex everyday. I am wondering if that dose is enough. Even if 1.25 mg was taken ed it is not much more expensive than liquidex.


yes bro u are rite. i will be definitly hitting femera from now on.

madchemist36
11-24-2002, 07:52 PM
Originally posted by gearedup
I doubt as cheap research GUARANTEES to beat anyones prices!

Email him and he will beat anyones pricing he guarantees it!


thanx i'll check it out. i have already ordered one vial so for the next time i will see where i can get it the cheapest.

rooster1
11-24-2002, 10:59 PM
It souds like you guys are suggesting to use the femera in place of the liquidex.Is that true or would I use it in place of nolva(I already have nolva on hand becuase I didn't need it the first cycle.

madchemist36
11-25-2002, 12:01 AM
bro femera is a lot better so i would definilty hit femera instead.
but dont use nol with femera. cuz it decreases femeras absorbtion rate. read the article i post above. regarding this matter.

rooster1
11-25-2002, 02:19 AM
:) I went over that last article and it sounds like you shouldn't mix the 2.I researched my first cycle for 2 months b4 starting and that was about 4-5 months ago and everyone said the liquidex was the best so I wanted to make sure what I was hearing here.I was up to 900 mg of test/wk the second half of my first cycle,but that was after I was off the D-bol and was taking winny with only a 1/4 mg liquidex/ed.I don't think I'm prone to gyno.But for safety I would like to have the best thing to stop it.Cycle 2 will look like this:

1-12 900mg/wk test split betwen enanthate and prop
1-12 700mg/wk EQ
1-5 50mg/ed D-bol
1-8 50mg/ed winny inj
9-14 50mg/ed winny oral
9-14 80mg/ed fina(I am seriously thinking about doing 50mg/ed and maybe running it weeks 3-14,coming off the same time as winny and then straight to clomid.So what would a femera dose look like on this cycle??:D

madchemist36
11-25-2002, 12:26 PM
i dont have first hand experience with femera yet but from all the research i here is the best advice i can give u.

take 2.5mg/day for week 1-8 then u can switch to 2.5mg eod.
u should do 2.5mg ed cuz u have a lot of androgens during that period.

damn i cannot wait to hit femera cuz hopefully it is gonna take the puffiness off my nipples.

rooster1
11-25-2002, 07:42 PM
I can't wait to hit anything period.I've been off 4 weeks now and already miss it.I think number 2 will be a lot better though. Boooyaawwwww!

madchemist36
11-25-2002, 08:12 PM
finally received my femera today. i will already start it even though i am not on a cycle to see if it helps with the puffy nipples. i will hit 1.25mg ed.

rooster1
11-26-2002, 12:36 PM
let us know Mad>>>>

madchemist36
11-28-2002, 05:40 PM
its my third day hitting femer havent noticed any decrease in nipple puffiness may be i need to wait a little longer.