SEROSOL

Anastrozole is a non-steroidal aromatase inhibitor (AI), similar to letrozole, used to decrease circulating estrogen levels in the treatment of postmenopausal women with estrogen-responsive breast cancer.

Anastrozole is also related to exemestane, a steroidal AI, but its non-steroidal nature provides stark advantages including a lack of steroid-associated adverse effects such as weight gain and acne.

Aromatase inhibitors, including anastrozole, have become endocrine drugs of choice in the treatment of postmenopausal breast cancer due to a more favourable efficacy and adverse effect profile as compared to earlier estrogen receptor modulators such as tamoxifen. 5, 8 Anastrozole was first approved for use in the United States in 1995.

Anastrozole is indicated as adjunct therapy in the treatment of hormone receptor-positive early breast cancer in postmenopausal women, and as a first-line treatment for hormone receptor-positive (or hormone receptor-unknown) locally advanced or metastatic breast cancer in postmenopausal women.

It may also be used in the treatment of advanced breast cancer in postmenopausal women who experience disease progression despite treatment with tamoxifen. 11,

Anastrozole prevents the conversion of adrenal androgens (e.g. testosterone ) to estrogen in peripheral and tumour tissues.

As the growth of many breast cancers is stimulated and/or maintained by the presence of estrogen, anastrozole helps to treat these cancers by decreasing the levels of circulating estrogens. 12, 9 Anastrozole has a relatively long duration of action allowing for once daily dosing.

• serum estradiol is reduced by approximately 70% within 24 hours of beginning therapy with 1 mg once daily, and levels remain suppressed for up to 6 days following cessation of therapy.

The incidence of ischemic cardiovascular events was increased during anastrozole therapy and patients with pre-existing ischemic heart disease should consider the risks and benefits of anastrozole before beginning therapy.

Anastrozole has also been reported to decrease spine and hip bone mineral density (BMD), so consideration should be given to monitoring of BMD in patients receiving long-term therapy. 10, 8.

Anastrozole is rapidly absorbed and

T max is typically reached within 2 hours of dosing under fasted conditions. 5, 12 Coadministration with food reduces the rate but not the overall extent of absorption.

• mean C max decreased by 16% and the median T max was extended to 5 hours when anastrozole was administered 30 minutes after ingestion of food, 10 though this relatively minor alteration in absorption kinetics is not expected to result in clinically significant effects.

The volume of distribution of anastrozole into brain tissue in mice is 3.19 mL/g.

Distribution into the CNS is limited due to the activity of P-gp efflux pumps at the blood brain barrier, of which anastrozole is a substrate.

Anastrozole is primarily metabolized in the liver via oxidation and glucuronidation to a number of inactive metabolites, including hydroxyanastrozole (both free and glucuronidated) and anastrozole glucuronide. 1, 10, 12 Oxidation to hydroxyanastrozole is catalyzed predominantly by CYP3A4 (as well as CYP3A5 and CYP2C8, to a lesser extent) and the direct glucuronidation of anastrozole appears to be catalyzed mainly by UGT1A4.

Anastrozole may also undergo

N-dealkylation to form triazole and 3,5-Bis-(2-methylpropiononitrile)-benzoic acid.

Labels for anastrozole state the main metabolite found in plasma following administration is triazole, 10, 12 but a recent pharmacokinetic study was unable to detect any products of N-dealkylation in vitro.

Hover over products below to view reaction partners Anastrozole Anastrozole glucuronide metabolite Hydroxyanastrozole Hydroxyanastrozole glucuronide metabolite Triazole 3,5-Bis-(2-methylpropiononitrile)-benzoic acid.

Hepatic metabolism accounts for approximately 85% of anastrozole elimination.

Approximately 10% of the administered dosage is eliminated unchanged in the urine. 12, 13.

The elimination half-life of anastrozole is approximately 50 hours. 10, 12, 5.

Anastrozole's clearance is mainly via hepatic metabolism and can therefore be altered in patients with hepatic impairment.

• patients with stable hepatic cirrhosis exhibit an apparent oral clearance approximately 30% lower compared with patients with normal liver function. 10, 12 Conversely, renal impairment has a negligible effect on total drug clearance as the renal route is a relatively minor clearance pathway for anastrozole.

In volunteers with severe renal impairment, renal clearance was reduced by 50% while total clearance was only reduced by approximately 10%. 10, 12.

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The reported oral

TDLo in a human woman is 1.68 mg/kg given intermittently over the course of 12 weeks.

Knowledge of the signs and symptoms of anastrozole overdose is incomplete as there are no documented descriptions of a patient receiving more than 60 mg, 13 a dose which was administered to a healthy male volunteer and was well-tolerated. 10, 12 There is no antidote for anastrozole and treatment should be supportive and symptomatic, including close monitoring of patient vital signs.

As anastrozole exhibits relatively low protein binding, dialysis may be helpful and should be considered in select cases. 10, 12.

Anastrozole is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients.

Observed reactions include anaphylaxis, angioedema, and urticaria.

Patients with demonstrated hypersensitivity to anastrozole or any excipient.

One 1 mg tablet taken once daily 2.1 Recommended Dose The dose of anastrozole tablet is one 1 mg tablet taken once a day. For patients with advanced breast cancer, anastrozole tablets should be continued until tumor progression.

Anastrozole tablets can be taken with or without food.

For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown.

In the

ATAC trial, anastrozole was administered for five years.

No dosage adjustment is necessary for patients with renal impairment or for elderly patients. 2.2 Patients with Hepatic Impairment No changes in dose are recommended for patients with mild-to-moderate hepatic impairment.

Anastrozole has not been studied in patients with severe hepatic impairment.

Anastrozole tablets, USP 1 mg are white to off-white, round biconvex, film coated tablets, with “AHI” debossing on one side and plain on other side and are supplied as follows: Bottles of 30 tablets with a child-resistant closure (NDC 16729-035-10) Bottles of 90 tablets with a child-resistant closure (NDC 16729-035-15) Bottles of 500 tablets (NDC 16729-035-16) Bottles of 1000 tablets (NDC 16729-035-17) Storage Store at controlled room temperature, 20 to 25°C (68 to 77°F) .

Preserve in tight container.

Based on findings from animal studies and its mechanism of action, anastrozole may cause fetal harm when administered to a pregnant woman.

There are no studies of anastrozole use in pregnant women.

Anastrozole caused embryo-fetal toxicities in rats at maternal exposure that were 9 times the human clinical exposure, based on area under the curve (AUC).

In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m 2 basis.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal reproduction studies, pregnant rats and rabbits received anastrozole during organogenesis at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively, (about and 1/3 the recommended human dose on a mg/m 2 basis, respectively).

In both species, anastrozole crossed the placenta, and there was increased pregnancy loss (increased pre-and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses).

In rats, these effects were dose related, and placental weights were significantly increased at doses equal to or greater than 0.1 mg/kg/day. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at anastrozole doses of 1 mg/kg/day that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC 0-24hr 9 times higher).

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/m 2 basis).

Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty.

The efficacy of anastrozole in the treatment of pubertal gynecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated.

A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged to 18 years.

Patients were randomized to a daily regimen of either anastrozole 1 mg or placebo.

After 6 months of treatment there was no statistically significant difference in the percentage of patients who experienced a ≥50% reduction in gynecomastia (primary efficacy analysis).

Secondary efficacy analyses (absolute change in breast volume, the percentage of patients who had any reduction in the calculated volume of gynecomastia, breast pain resolution) were consistent with the primary efficacy analysis.

Serum estradiol concentrations at

Month of treatment were reduced by 15.4% in the anastrozole group and 4.5% in the placebo group.

Adverse reactions that were assessed as treatment-related by the investigators occurred in 16.3% of the anastrozole-treated patients and 8.1% of the placebo-treated patients with the most frequent being acne (7% anastrozole and 2.7% placebo) and headache (7% anastrozole and 0% placebo); all other adverse reactions showed small differences between treatment groups.

One patient treated with anastrozole discontinued the trial because of testicular enlargement.

The mean baseline-subtracted change in testicular volume after 6 months of treatment was + 6.6 ± 7.9 cm in the anastrozole-treated patients and + 5.2 ± 8.0 cm in the placebo group.

A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged to <10 years.

All patients received a 1 mg daily dose of anastrozole.

The trial duration was 12 months.

Patients were enrolled on the basis of a diagnosis of typical (27/28) or atypical (1/27) McCune-Albright Syndrome, precocious puberty, history of vaginal bleeding, and/or advanced bone age.

Patients’ baseline characteristics included the following: a mean chronological age of 5.9 ± 2.0 years, a mean bone age of 8.6 ± 2.6 years, a mean growth rate of 7.9 ± 2.9 cm/year and a mean Tanner stage for breast of 2.7 ± 0.81.

Compared to pre-treatment data there were no on-treatment statistically significant reductions in the frequency of vaginal bleeding days, or in the rate of increase of bone age (defined as a ratio between the change in bone age over the change of chronological age).

There were no clinically significant changes in Tanner staging,mean ovarian volume, mean uterine volume and mean predicted adult height.

A small but statistically significant reduction of growth rate from 7.9 ± 2.9 cm/year to 6.5 ± 2.8 cm/year was observed but the absence of a control group precludes attribution of this effect to treatment or to other confounding factors such as variations in endogenous estrogen levels commonly seen in McCune-Albright Syndrome patients.

Five patients (18%) experienced adverse reactions that were considered possibly related to anastrozole.

These were nausea, acne, pain in an extremity, increased alanine transaminase and aspartate transaminase, and allergic dermatitis.

Following 1 mg once daily multiple administration in pediatric patients, the mean time to reach the maximum anastrozole concentration was 1 hr. The mean (range) disposition parameters of anastrozole in pediatric patients were described by a CL/F of 1.54 L/h (0.77 to 4.53 L/h) and V/F of 98.4 L (50.7 to 330.0 L).

The terminal elimination half-life was 46.8 h, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer.

Based on a population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune.

In studies and 0027, about 50% of patients were 65 or older.

Patients ≥ 65 years of age had moderately better tumor response and time to tumor progression than patients < 65 years of age regardless of randomized treatment.

In studies and 0005, 50% of patients were 65 or older.

Response rates and time to progression were similar for the over and younger patients.

In the

ATAC study, 45% of patients were 65 years of age or older.

The efficacy of anastrozole compared to tamoxifen in patients who were 65 years or older (N=1413 for anastrozole and N=1410 for tamoxifen, the hazard ratio for disease-free survival was 0.93 [95% CI: 0.80, 1.08]) was less than efficacy observed in patients who were less than 65 years of age (N=1712 for anastrozole and N=1706 for tamoxifen, the hazard ratio for disease-free survival was 0.79 [95% CI: 0.67, 0.94]).

The pharmacokinetics of anastrozole are not affected by age.