posted July 29, 2000 10:10 PM            

2.5 mg Tablets

Prescribing Information

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, and its structural formula is

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 184�C-185�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 is 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 tumor-bearing 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 2.5 mg 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 non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. 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'-methanolbisbenzonitrile) 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 2.5 mg of Femara (letrozole tablets) was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg Femara and half 0.5 mg 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 & 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 postmenopausal 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 0.5 mg daily, Femara 2.5 mg daily, or a comparator (megestrol acetate 160 mg daily in one study; and aminoglutethimide 250 mg 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 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 1: Selected Study Population Demographics
Parameter megestrol acetate study aminoglutethimide study

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No. of Participants 552 557
Receptor Status
ER/PR Positive
ER/PR Unknown 57%
43% 56%
44%

Previous Therapy
Adjuvant Only
Therapeutic +/- Adj. 33%
66% 38%
62%

Sites of Disease
Visceral Metastases
Soft Tissue Metastases
Bony Metastases 40%
56%
50% 44%
50%
55%

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
Femara 0.5 mg
N = 188 Femara 2.5 mg
N = 174 Megestrol Acetate
N = 190

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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 Femara 2.5 : Femara 0.5 = 2.33
(95% Cl: 1.32, 4.17); p=0.004* Femara 2.5: Megestrol = 1.58
(95% Cl: 0.94, 2.66); p = 0.08*
Relative Risk of Progression Femara 2.5: Femara 0.5 = 0.81
(95% Cl: 0.63, 1.03); p = 0.09* Femara 2.5: Megestrol = 0.77
(95% Cl: 0.60, 0.98), p = 0.03*

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*two-sided p-value

The Kaplan-Meier Curve for progression for the megestrol acetate study is shown below.

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: Aminoglutethimide Study Results
Femara 0.5
N = 193 Femara 2.5
N = 185 Aminoglutethimide
N = 179

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Objective Response (CR + PR) 34 (17.6%) 34 (18.4%) 22 (12.3%)
Median Duration of Response 619 days 706 days 450 days
Median Time to Progression 103 days 123 days 112 days
Median Survival 636 days 792 days 592 days
Odds Ratio for Response Femara 2.5 : Femara 0.5 = 1.05
(95% Cl: 0.62, 1.79); p=0.85* Femara 2.5: Aminoglutethimide = 1.61
(95% Cl: 0.90, 2.87); p = 0.11*
Relative Risk of Progression Femara 2.5: Femara 0.5 = 0.86
(95% Cl: 0.68, 1.11); p = 0.25* Femara 2.5: Aminoglutethimide = 0.74
(95% Cl: 0.57, 0.94), p = 0.02*

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*two-sided p-value

The Kaplan-Meier Curve for progression for the aminoglutethimide study is shown below.

INDICATIONS AND USAGE
Femara (letrozole tablets) is indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

CONTRAINDICATIONS
Femara is contraindicated in patients with known hypersensitivity to Femara or any of its excipients.

WARNINGS
Pregnancy
Letrozole may cause fetal harm when administered to pregnant women. Studies in rats at doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by 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. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion.

Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hindlegs.

There are no studies in pregnant women. Femara is indicated for post-menopausal women. If there is exposure to letrozole during pregnancy, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy.

PRECAUTIONS
Laboratory Tests
No dose-related effect of Femara on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving Femara (letrozole tablets) 2.5 mg. This depression was transient in about half of those affected. Two patients on Femara developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent.

Increases in SGOT, SGPT, and gamma GT 5 times the upper limit of normal (ULN) and of bilirubin 1.5 times the ULN were most often associated with metastatic disease in the liver. About 3% of study participants receiving Femara had abnormalities in liver chemistries not associated with documented metastases; these abnormalities may have been related to study drug therapy. In the megestrol acetate comparative study about 8% of patients treated with megestrol acetate had abnormalities in liver chemistries that were not associated with documented liver metastases; in the aminoglutethimide study about 10% of aminoglutethimide-treated patients had abnormalities in liver chemistries not associated with hepatic metastases.

Drug Interactions
Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of Femara with these drugs does not result in clinically-significant drug interactions. (See CLINICAL PHARMACOLOGY)

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

Drug/Laboratory Test-Interactions
None observed.

Carcinogenesis, Mutagenesis, Impairment of Fertility
A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about one to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose.

Letrozole was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).

Studies to investigate the effect of letrozole on fertility have not been conducted; however, repeated dosing caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (about one, 0.4 and 0.4 the daily maximum recommended human dose on a mg/m2 basis, respectively).

Pregnancy
Pregnancy Category D (See WARNINGS).

Nursing Mothers
It is not known if letrozole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when letrozole is administered to a nursing woman (See WARNINGS AND PRECAUTIONS).

Pediatric Use
The safety and effectiveness in pediatric patients have not been established.

Geriatric Use
The mean age of patients in the two randomized trials, that compared Femara (0.5 mg and 2.5 mg) to megestrol acetate and to aminoglutethimide, was 64 years. Thirty percent of patients were 70 years old. The proportion of patients responding to each dose of Femara was similar for women 70 years old and <70 years old.

ADVERSE REACTIONS
Femara (letrozole tablets) was generally well tolerated in two controlled clinical trials.

Study discontinuations in the megestrol acetate comparison study for adverse events other than progression of tumor occurred in 5/188 (2.7%) of patients on Femara 0.5 mg, in 4/174 (2.3%) of the patients on Femara 2.5 mg, and in 15/190 (7.9%) of patients on megestrol acetate. There were fewer thromboembolic events at both Femara doses than on the megestrol acetate arm (2 of 362 patients or 0.6% vs. 9 of 190 patients or 4.7%). There was also less vaginal bleeding (1 of 362 patients or 0.3% vs. 6 of 190 patients or 3.2%) on letrozole than on megestrol acetate. In the aminoglutethimide comparison study, discontinuations for reasons other than progression occurred in 6/193 (3.1%) of patients on 0.5 mg Femara, 7/185 (3.8%) of patients on 2.5 mg Femara, and 7/178 (3.9%) of patients on aminoglutethimide.

Comparisons of the incidence of adverse events revealed no significant differences between the high and low dose Femara groups in either study. Most of the adverse events observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient's metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness.

Adverse events, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Femara 0.5 mg, Femara 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials are shown in the following table:

1Includes peripheral edema, leg edema, dependent edema, edema
2Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain
3Includes rash, erythematous rash, maculopapular rash, psoriaform rash, vesicular rash

Other less frequent (<5%) adverse experiences considered consequential and reported in at least 3 patients treated with Femara, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo.

OVERDOSAGE
No experience with Femara (letrozole tablets) overdose has been reported. In single dose studies the highest dose used was 30 mg, which was well tolerated; in multiple dose trials, the largest dose of 5 mg was well tolerated.

Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2000 mg/kg (about 4000 to 8000 times the daily maximum recommended human dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias.

There is no experience in humans with an overdose of Femara, so firm recommendations for treatment are not possible. Emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs is appropriate.

DOSAGE & ADMINISTRATION
Adult and Elderly Patients
The recommended dose of Femara (letrozole tablets) is one 2.5 mg tablet administered once a day, without regard to meals. Treatment with Femara should continue until tumor progression is evident. No dose adjustment is required for elderly patients. Patients treated with Femara do not require glucocorticoid or mineralocorticoid replacement therapy.

Renal Impairment
(See CLINICAL PHARMACOLOGY.) No dosage adjustment is required for patients with renal impairment if creatinine clearance is 10 mL/min.

Hepatic Impairment
(See CLINICAL PHARMACOLOGY.) Although letrozole blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis, no dosage adjustment is recommended for patients with mild-to-moderate hepatic impairment. Patients with severe impairment of liver function have not been studied. Because letrozole is eliminated almost exclusively by hepatic metabolism, patients with severe impairment of liver function should be dosed with caution.

HOW SUPPLIED
2.5 mg tablets - dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the letters FV on one side and CG on the other side).

Packaged in HDPE bottles with a safety screw cap.
Bottles of 30 tablets NDC 0078-0249-15

Store at 25�C (77�F); excursions permitted to 15�C-30�C(59�F-86�F) [see USP Controlled Room Temperature].

665080 C97-8 (Rev. 7/97)

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The Cuban

posted July 30, 2000 12:00 PM            

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"It's a good day to be alive, sir, It's a good day to be alive he said..."