Note: This will be my last EF post providing detailed information (extracts) on the products often referenced on this board. The reason, they do not seem to be well received by the masses and as a result they "fall off" too fast to be of any help (why waste the drive space?). So enjoy it, and hopefully this and a few of the previous "editions" (i.e. Clomid) remain in the archives.

Later,

Mosby's GenRx�, 10th ed.
Copyright � 2000 Mosby, Inc.

Anastrozole (003272)

CATEGORIES:

Indications: Carcinoma, breast
Pregnancy Category D
FDA Approved 1995 Dec
DRUG CLASS: Antineoplastics

BRAND NAMES: Arimidex(US);

DESCRIPTION:

Anastrozole tablets for oral administration contain 1 mg of anastrozole, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacentonitrile, alpha, alpha, alpha', alpha'-tetramethyl -5-(1H-1,2,4-triazol -1-ylmethyl). Its molecular formula is C17H19N5.

Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25�C), solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrite.

Inactive Ingredients: lactose, magnesium stearate, hydroxypropylmethycellulose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.

CLINICAL PHARMACOLOGY:

Mechanism of Action
Many breast cancers have estrogen receptors and growth of these tumors can be stimulated by estrogens. In post-menopausal women, the principle source of circulating estrogen (primarily estradiol) is conversion of adrenally-generated androstenedione to estrone by aromatase in peripheral tissues, such as adipose tissue, with further conversion of estrone to estradiol. Many breast cancers also contain aromatase; the importance of tumor-generated estrogens is uncertain.

Treatment of breast cancer has included efforts to decrease estrogen levels by ovariectomy premenopausally and by use of anti-estrogens and progestational agents both pre- and post-menopausally, these interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.

Anastrozole is a potent and selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.

Pharmacokinetics
Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Studies with radiolabeled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation with 83 to 85% of the radiolabel recovered in the urine and feces. Food does affect the extent of absorption. elimination of anastrazole is primarily via hepatic metabolism (approximately 85% and to a lesser extent, renal excretion (approximately 11%), and anastrozole has a mean terminal elimination half-life of approximately 50 hours in post menopausal women. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity. The pharmacokinetic parameters are similar in patients and in healthy post-menopausal volunteers. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg and do not change with repeated dosing. Consistent with the approximately 2-day terminal elimination half-life, plasma concentrations approach steady-state levels at about 7 days of once daily dosing and steady-state levels are approximately three-to four-fold higher than levels observed after a single dose of anastrozole. Anastrozole is 40% bound to plasma proteins in the therapeutic range.

Metabolism and Excretion: Studies in post-menopausal women demonstrated that anastrozole is extensively metabolized with about 10% of the dose excreted in the urine as unchanged drug within 72 hours of dosing, and the remainder (about 60% of the dose) excreted in the urine as metabolites. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole have been identified in human plasma and urine. The known metabolites are triazole, a glucuronide conjugate of hydroxy-anastrozole, and a glucuronide of anastrozole itself. Several minor (less than 5% of the radioactive dose) metabolites have not been identified.

Because renal elimination is not a significant pathway of elimination, total body clearance of anastrozole is unchanged even in severe (creatinine clearance less then 30 mL/min/1.73m2) renal impairment; dosing adjustment in patients with renal dsyfunction is not necessary (see Special Populations and DOSAGE AND ADMINISTRATION sections). Dosage adjustment is also unnecessary in patients with stable hepatic cirrhosis (see Special Populations and DOSAGE AND ADMINISTRATIONsections).

Special Populations
Geriatric: Anastrozole pharmacokinetics have been investigated in post-menopausal female volunteers and patients with breast cancer. No age related effects were seen over the range <50 to >80 years.

Race: Anastrozole pharmacokinetic differences due to race have not been studied.

Renal insufficiency: Anastrozole pharmacokinetics have been investigated in subjects with renal insufficiency. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m2) compared to controls. Since only about 10% of anastrozole is excreted unchanged in the urine, the reduction in renal clearance did not influence the total body clearance (see DOSAGE AND ADMINISTRATION).

Hepatic insufficiency: Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials (see DOSAGE AND ADMINISTRATION), so that no dosage adjustment is needed.

Pharmacodynamics
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 anastrozole 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 the mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, 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 1 mg of anastrozole.

Effect on Corticosteroids: In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of anastrozole was assessed by examining effects on corticosteroid synthesis. For all doses, anastrozole did not effect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralicorticoid replacement therapy is necessary with anastrozole.

Other Endocrine Effects: In multiple daily dosing trials with 5 and 10 mg, thyroid stimulation hormone (TSH) was measured; there was no increase in TSH during the administration of anastrozole. Anastrozole does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens

CLINICAL STUDIES:
Anastrozole was studied in two well-controlled clinical trials (0004, a North American study; 0005, a predominantly European study) in post-menopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER positive; a small fraction were either ER unknown or ER negative (the ER negative patients were eligible only if they had had a positive response to tamoxifen). Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of anastrozole or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to anastrozole. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were calculated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated.

Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients who entered who had prior tamoxifen therapy for advanced disease (58 % in Trial 0004; 57 % in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER positive, 13% were ER unknown, and 6% were ER negative. In Trial 0005, 58% of patients were ER positive, 37% were ER unknown, and 5% were ER negative. In Trial 0004, 60% of patients had measurable disease compared to 80% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trails. On average, 40% of the patients had soft tissue metastases, 60% had bone metastases, and 40% had visceral (15% liver) metastases.

As shown in TABLE 1, similar results were observed among treatment groups and between the two trials. None of the within-trial differences were statistically significant.

Median Follow-up (days) 179 182 176
Time to Progression (days) 170 143 151
Approximately 1/3 of the patients in each treatment group in both studies had either an objective response or stabilization of their disease for greater than 24 weeks. Among the 263 patients who received anastrozole 1 mg, there were 6 complete responders and 21 partial responders. In patients who had an objective response, over 60% of the patients responded for greater than 6 months and over 15% responded for greater than 12 months.

To compare the three treatments, hazard ratios for the time to progression (ratio of the likelihood of progression for two treatments over the period of study) and odds ratios for response rates, together with their confidence intervals, were calculated for the pooled studies. These show that in general the three treatments were similar in efficacy, but that confidence intervals were fairly wide. There is, in these data, no indication that anastrozole 10 mg is superior to anastrozole 1 mg. For time to progression for the anastrozole 1 mg comparison to megestrol acetate, the hazard ratio (anastrozole/megestrol acetate) was 0.97 [0.75, 1.24] (p=0.76); for anastrozole 10 mg compared to megestrol acetate, the hazard ratio was 0.93 [0.71, 1.19] (p=0.47). The odds ratio and confidence intervals of the comparison between each dose of anastrozole and megestrol acetate for objective response rate demonstrate that both anastrozole 1 mg and anastrozole 10 mg were similar in efficacy to the comparator. For the anastrozole 1 mg comparison to megestrol acetate, the odds ratio (anastrozole/megestrol acetate) was 1.32 [0.66, 2.65] (p=0.37); for the anastrozole 10 mg comparison to megestrol acetate, the odds ratio was 1.15 [0.55, 2.36] (p=0.68). There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.

There were no differences in response seen between women over or under 65. There were too few non-white patients studied to draw conclusions about racial difference in response rates.

INDICATIONS AND USAGE:
Anastrozole is indicated for the treatment of advanced breast cancer in post-menopausal women with disease progression following tamoxifen therapy.

Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to anastrozole.

CONTRAINDICATIONS:
None known.

WARNINGS:
Anastrozole can cause fetal harm when administered to a pregnant woman. Anastrozole has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits (about 3/4 and 1.5 times the recommended human dose, respectively, on a mg/m2 basis). Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 3/4 and 1/3, respectively, the recommended human dose on a mg/m2 basis), administered during a period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or post-implatation loss, increased resorption, and decreased numbers of live fetuses); effects were dose related in rats. Placental weights were significantly increased in rats at doses of 0.1 mg/kg/day or more.

Evidence of fetotoxicity, including delayed fetal development (i.e. incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (which produced plasma anastrozole CSSMAXand AUC0-24 hr that were 19 times and 9 times higher than the respective values found in healthy post-menopausal humans at the recommended dose). There was no evidence of teratogenicity in rats administered doses up to 1.0 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m2 basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women using anastrozole. If anastrozole is used during pregnancy or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

PRECAUTIONS:
General
Before starting treatment with anastrozole, pregnancy must be excluded (see WARNINGS).

Anastrozole should be administered under the supervision of a qualified physician experienced in the use of anticancer agents.

Laboratory Tests
Three-fold elevations of mean serum gamma glutamyl transferase (GT) levels have been observed among patients with liver metastases receiving anastrozole or megestrol acetate. These changes were likely related to the progression of liver metastases in these patients, although other contributing factors could not be ruled out.

Carcinogenesis
No long term studies have been conducted to assess the carcinogenic potential of anastrozole.

Mutagenesis
Anastrozole has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vivo (chromosome aberrations in human lymphocytes) or in in vitro (micronucleus test in rats).

Impairment of Fertility
Studies to investigate the effect of anastrozole on fertility have not been conducted; however, chronic studies indicated hypertrophy of the ovaries and the presence of follicular cysts in rats administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole CSSMAXand AUC0-24 hr that were 19 and 9 times higher than the respective values found in post-menopausal humans at the recommended dose). In addition, hyperplastic uteri were observed in chronic studies of female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrazole CSSMAXand AUC0-24 hr that were 22 times and 16 times higher than the respective values found in post-menopausal humans at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in humans.

Pregnancy Category D: (see WARNINGS).

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

Pediatric Use The safety and efficacy of anastrozole in pediatric patients have not been established.

Geriatric Use Fifty percent of patients in studies 0004 and 0005 were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients.

DRUG INTERACTIONS:
Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1-mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochome P450 2A6 or 2D6 in vitro . Administration of a single 30mg/kg or multiple 10 mg/kg doses of anastrozole to subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. Based on these in vitro and in vivo results, it is unlikely that co-administration of anastrozole 1 mg with other drugs will result in clinically significant inhibition of cytochrome P450 mediated metabolism.

Anastrozole inhibited in vitro metabolic reactions catalyzed by cytochromes P450 1A2, 2C8/9, and 3A4 but only at relatively high concentrations. Anastrozole did not inhibit P450 2A6 or the polymorphic P450 2D6 in human liver microsomes. Anastrozole did not alter the pharmacokinetics of antipyrine. Although there have been no formal interaction studies other than with antipyrine, based on these in vivo and in vitro studies, it is unlikely that co-administration of a 1-mg dose of anastrozole with other drugs will result in clinically significant drug inhibition of cytochrome P450-mediated metabolism of the other drugs.

Drug/Laboratory Test Interactions
No clinically significant changes in the results of clinical laboratory tests have been observed.

ADVERSE REACTIONS:
Anastrozole was generally well tolerated in two well-controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the anastrozole-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to adverse event.

The principle adverse event more common with anastrozole than megestrol acetate was diarrhea. Adverse events reported in greater than 5% of the patients in any of the treatment groups in these two well-controlled clinical trials, regardless of causality, are presented in TABLE 2>>>snipped for clarity<<<.

Other less frequent (2% to 5%) adverse experiences reported in patients receiving anastrozole 1 mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.

Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection.
Cardiovascular: Hypertension; thrombophlebitis.
Hepatic: Gamma GT increased; SGOT increased; SGPT increased.
Hematologic: Anemia; leukopenia.
Metabolic and Nutritional: Alkaline phosphatase increased; weight loss; Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving anastrozole. Increases in LDL cholesterol have been shown to contribute to these changes.
Musculoskeletal: Myalgia; arthralgia; pathological fracture.
Nervous: Somnolence; confusion; insomnia; anxiety; nervousness.
Respiratory: Sinusitis; bronchitis; rhinitis.
Skin and Appendages: Hair thinning; pruritus.
Urogenital: Urinary tract infection; breast pain.

The incidences of the following adverse event groups, potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse events captured in the groups, were prospectively defined. The results are shown in TABLE 3>>>snipped for clarity<<<.

More patients treated with megestrol acetate reported weight gain as an adverse event compared to patients treated with anastrozole 1 mg (p<0.0001). Other differences were not statistically significant.

An examination of the magnitude of change in weight in all patients was also conducted. Thirty-four percent (87/253) of the patients treated with megestrol acetate experienced weight gain of 5% or more and 11% (27/253) of the patients treated with megestrol acetate experienced weight gain of 10% or more. Among patients treated with anastrozole 1 mg, 13% (33/262) experienced weight gain of 5% or more and 3% (6/262) experienced weight gain of 10% or more. On average, this 5 to 10% weight gain represented between 6 and 12 pounds.

No patients receiving anastrozole or megestrol acetate discontinued treatment due to drug-related weight gain.

OVERDOSAGE:
Clinical trial have been conducted with anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to post-menopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life threatening symptoms has not been established. In rats, lethality was observed after single oral doses that were greater than 100 mg/kg (about 800 times the recommended human dose on a mg/m2 basis) and was associated with severe irritation to the stomach (necrosis, gastritis, ulceration, and hemorrhage).

There is no specific antidote to overdosage and treatment must by symptomatic. In the management of an overdose, consider that multiple agents may haven been taken. Vomiting may be induced if patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

DOSAGE AND ADMINISTRATION:
The dose of anastrozole is one 1 mg tablet taken once a day.

Patients treated with anastrozole do not require glucocorticoid or mineralocorticoid replacement therapy.

Patients with Hepatic Impairment: (See CLINICAL PHARMACOLOGY) Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Although clearance of anastrozole was decreased in patients with cirrhosis due to alcohol abuse, plasma anastrozole concentraions stayed in the usual range seen in patients without liver disease. Therefore, no changes in dose are recommended for patients with mild-to-moderate hepatic impairment, although patients should be monitored for side effects. Anastrozole has not been studied in patients with severe hepatic impairment.

Patients with Renal Impairment: No changes in dose are necessary for patients with renal impairment.

PATIENT INFORMATION:
Anastrozole is used for the treatment of advanced breast cancer. Do not use if you are pregnant. Inform your doctor if you are nursing. Take once daily on an empty stomach. May cause weakness, nausea and stomach upset, headache, hot flashes, and back pain. Inform your doctor or pharmacist if these effects occur.
--------------------------------------------------------------------------------

HOW SUPPLIED:

Arimidex
White, biconvex, film coated tablets containing 1 mg of anastrozole. The tablets are impressed on one side with a logo consisting of a letter"A" (upper case) with an arrowhead attached to the foot of the extended right leg of the "A" and on the reverse with the tablet strength marking "Adx 1".