Anastrozole
Anastrozole Tablets 1mg These highlights do not include all the information needed to use Anastrozole Tablets safely and effectively. See full prescribing information for Anastrozole Tablets. Anastrozole tablet for oral use Initial U.S. Approval: 1995
188c6fd5-6695-4d8b-af43-61d9c26abfe9
HUMAN PRESCRIPTION DRUG LABEL
Aug 29, 2011
Boscogen, Inc.
DUNS: 932611189
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Anastrozole
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INGREDIENTS (5)
Drug Labeling Information
NONCLINICAL TOXICOLOGY SECTION
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.
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 vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats).
Oral administration of anastrozole to female rats (from 2 weeks before mating
to pregnancy day 7) produced significant incidence of infertility and reduced
numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended
human dose on a mg/m2 basis and 9 times higher than the AUCO-24 hr found in
postmenopausal volunteers at the recommended dose). Pre-implantation loss of
ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day
(about one-fifth the recommended human dose on a mg/m2 basis). Recovery of
fertility
was observed following a 5-week non-dosing period which followed 3 weeks of
dosing. It is not known whether these effects observed in female rats are
indicative of impaired fertility in humans.
Multiple-dose studies in rats administered anastrozole for 6 months at doses
equal to or greater than 1 mg/kg/day (which produced plasma anastrozole CSSmax
and AUCO-24 hr that were 19 and 9 times higher than the respective values
found in postmenopausal volunteers at the recommended dose) resulted in
hypertrophy of the ovaries and the presence of follicular cysts. In addition,
hyperplastic uteri were observed in 6-month studies in female dogs
administered doses equal to or greater than 1 mg/kg/day (which produced plasma
anastrozole CSS max and
AUC0-24 hr that were 22 times and 16 times higher than the respective values
found in postmenopausal women at the recommended dose). It is not known
whether these effects on the reproductive organs of animals are associated
with impaired fertility in premenopausal women.
13.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology
Anastrozole has been found to cross the placenta following oral administration
of 0.1 mg/kg in rats and rabbit (about 1 and 1.9 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 1 and 1/3, respectively, the
recommended human dose on a mg/m2 basis), administered during the period of
organogenesis showed that anastrozole increased pregnancy loss (increased pre-
and/or post-implantation 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 CSSmax
and AUC0-24 hr that were 19 times and 9 times higher than the respective
values found in postmenopausal volunteers 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).
CLINICAL STUDIES SECTION
14 CLINICAL STUDIES
14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Wo****men
A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with Anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease.
The primary endpoint of the trial was disease-free survival (i.e., time to
occurrence of a distant or local recurrence, or contralateral breast cancer or
death from any cause). Secondary endpoints of the trial included distant
disease-free survival, the incidence of contralateral breast cancer and
overall survival. At a median follow-up of 33 months, the combination of
Anastrozole and
tamoxifen did not demonstrate any efficacy benefit when compared with
tamoxifen in all patients as well as in the hormone receptor positive
subpopulation. This treatment arm was discontinued from the trial. Based on
clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not
be administered with anastrozole. [see Drug Interactions (7.1)]
Demographic and other baseline characteristics were similar among the three treatment groups (see Table 7).
Table 7 - Demographic and Baseline Characteristics for ATAC Trial|
Demographic Characteristics****Anastrozole 1 mg Tamoxifen 20 mg Anastrozole
1 mg plus Tamoxifen 20 mg |
The survival data with 68 months follow-up is presented in Table 9.
In the group of patients who had previous adjuvant chemotherapy (N=698 for Anastrozole and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the Anastrozole arm compared to the tamoxifen arm.
The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8.
Table 8 - All Recurrence and Death Events|
Intent-To-Treat Population Hormone Receptor-Positive Subpopulation ****Median Duration of Therapy (mo) 60 60 60 60 |
|
** Intent-To-Treat Population Hormone Receptor-Positive Subpopulation** ****Disease-free Survival 575 651 424 497 2-sided 95% CI 0.78 to 0.97 0.73 to 0.94 |
14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer
Two double-blind, controlled clinical studies of similar design (0030, a North
American study and 0027, a predominately European study) were conducted to
assess the efficacy of Anastrozole compared with tamoxifen as first-line
therapy for hormone receptor positive or hormone receptor unknown locally
advanced or metastatic breast cancer in postmenopausal women. A total of
1021 patients between the ages of 30 and 92 years old were randomized to
receive trial treatment. Patients were randomized to receive 1 mg of
Anastrozole once daily or 20 mg of tamoxifen once daily. The primary end
points for both trials were time to tumor progression, objective tumor
response rate, and safety.
Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027.
Table 10 - Demographic and Other Baseline Characteristics|
Number (%) of subjects |
Table 11 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.
Table 11 - Efficacy Results of First-Line Treatment|
Number (%) of subjects |
Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to ddraw conclusions on overall survival differences.
Anastrozole was studied in two controlled clinical trials (0004, a North
American study; 0005, a predominately European study) in postmenopausal 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 smaller fraction were 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 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, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases.
Efficacy results from the two studies were similar as presented in Table 12. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters listed in the table below.
Table 12 - Efficacy Results of Second-Line Treatment|
Anastrozole 1 mg Anastrozole 10 mg Megestrol Acetate 160 mg Trial 0005 |
|
Trials 0004 and 0005 Anastrozole 1 mg Anastrozole 10 mg Megestrol Acetate 160
mg |