Complete SPL Sections
RECENT MAJOR CHANGES SECTION
RECENT MAJOR CHANGES SECTION
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1 INDICATIONS AND USAGE
INDICATIONS & USAGE SECTION
1.1 Adjuvant Treatment Anastrozole is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
2 DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION SECTION
2.1 Recommended Dose The dose of Anastrozole is one 1 mg tablet taken once a day. For patients with advanced breast cancer, Anastrozole should be continued until tumor progression. Anastrozole 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. [see Clinical Studies (14.1)] No dosage adjustment is necessary for patients with renal impairment or for elderly patients. [see Use in Specific Populations (8.6)]
3 DOSAGE FORMS AND STRENGTHS
DOSAGE FORMS & STRENGTHS SECTION
The tablets are round, film-coated, white to off-white tablets. One side is debossed with "0376", and the other side is plain.
4 CONTRAINDICATIONS
CONTRAINDICATIONS SECTION
4.1 Pregnancy and Premenopausal Women Anastrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. 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 taking this drug, the patient should be apprised of the potential hazard to a fetus or potential risk for loss of the pregnancy. [see Use in Specific Populations (8.1)]
5 WARNINGS AND PRECAUTIONS
WARNINGS AND PRECAUTIONS SECTION
5.1 Ischemic Cardiovascular Events In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with Anastrozole in the ATAC trial (17% of patients on Anastrozole and 10% of patients on tamoxifen). Consider risk and benefits of Anastrozole therapy in patients with pre-existing ischemic heart disease. [see Adverse Reactions (6.1)]
6 ADVERSE REACTIONS
ADVERSE REACTIONS SECTION
Serious adverse reactions with Anastrozole occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling. [see Adverse Reactions,(6.2)] Common adverse reactions (occurring with an incidence of >10%) in women taking Anastrozole included: hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, pain, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema. In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as a result of hot flashes in the Anastrozole group. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
7 DRUG INTERACTIONS
DRUG INTERACTIONS SECTION
7.1 Tamoxifen Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the coadministration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. 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. [see Clinical Studies (14.1)] Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.
8 USE IN SPECIFIC POPULATIONS
USE IN SPECIFIC POPULATIONS SECTION
8.1 Pregnancy PREGNANCY CATEGORY X [see Contraindications (4.1)] Anastrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. In animal studies, anastrozole caused pregnancy failure, increased pregnancy loss, and signs of delayed fetal development. There are no studies of Anastrozole use in pregnant women. 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 and potential risk for pregnancy loss. In animal reproduction studies, pregnant rats and rabbits received anastrozole during organogenesis at doses equal to or greater than 1 (rats) and 1/3 (rabbits) the recommended human dose on a mg/m2 basis. 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. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at anastrozole doses that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUCO-24hr 9 times higher). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m2 basis. [see Animal Toxicology and/or Pharmacology (13.2)]
10 OVERDOSAGE
OVERDOSAGE SECTION
Clinical trials 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 postmenopausal women with advanced breast cancer; these dosages were tolerated. A single dose of Anastrozole that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider that multiple agents may have been taken. Vomiting may be induced if the 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.
11 DESCRIPTION
DESCRIPTION SECTION
Anastrozole tablets for oral administration contain 1 mg of anastrozole, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C17H19N5 and its structural formula is: 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 acetonitrile. Each tablet contains as inactive ingredients: povidone, croscarmellose sodium, lactose monohydrate, and magnesium stearate.
12 CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY SECTION
12.1 Mechanism of Action The growth of many 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. 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.
13 NONCLINICAL TOXICOLOGY
NONCLINICAL TOXICOLOGY SECTION
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.
14 CLINICAL STUDIES
CLINICAL STUDIES SECTION
14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal W o 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 (N=3125) (N=3116) (N=3125) Mean age (yrs.) 64.1 64.1 64.3 Age Range (yrs.) 38.1-92.8 32.8-94.9 37.0-92.2 Age Distribution (%) less than 45 yrs. 0.7 0.4 0.5 45-60 yrs. 34.6 35.0 34.5 greater than 60 less than 70 yrs. 38.0 37.1 37.7 greater than 70 yrs. 26.7 27.4 27.3 Mean Weight (kg) 70.8 71.1 71.3 Receptor Status (%) Positive 83.5 83.1 84.0 Negative 7.4 8.0 7.0 Other 8.8 8.6 9.0 Other Treatment (%) prior to Randomization Mastectomy 47.8 47.3 48.1 Breast conservation 52.3 52.8 51.9 Axillary surgery 95.5 95.7 95.2 Radiotherapy 63.3 62.5 61.9 Chemotherapy 22.3 20.8 20.8 Neoadjuvant Tamoxifen 1.6 1.6 1.7 Primary Tumor Size (%) T1 (less than or equal to 2 cm) 63.9 64.1 64.1 T2 (greater than 2 cm and less than or equal to 5 cm) 32.6 32.9 32.9 t3 (greater than 5 cm) 2.7 2.3 2.3 Nodal Status (%) Node positive 34.9 33.5 33.5 1-3 (number of nodes) 24.4 24.3 24.3 4-9 7.5 6.8 6.8 greater than 9 2.9 2.3 2.3 Tumor Grade (%) Well-differentiated 20.8 20.5 21.2 Moderately differentiated 46.8 47.8 46.5 Poorly/undifferentiated 23.7 23.3 23.7 Not assessed/recorded 8.7 8.4 8.5 Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127 in the Anastrozole arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR =0.83, 95% CI: 0.73, 0.94, p=0.0049) in the Anastrozole arm compared to the tamoxifen arm. 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 Anastrozole 1 mg (N=3125) Tamoxifen 20mg (N=3116) Anastrozole 1mg (N=2618) Tamoxifen 20 mg (N=2598) Median Duration of Therapy (mo) 60 60 60 60 Median Efficacy Follow-up (mo) 68 68 68 68 Loco-regional recurrence 119 (3.8) 149 (4.8) 76 (2.9) 101 (3.9) Contralateral breast cancer 35 (1.1) 59 (1.9) 26 (1.0) 54 (2.1) Invasive 27 (0.9) 52 (1.7) 21 (0.8) 48 (1.8) Ductal carcinoma 8 (0.3) 6 (0.2) 5 (0.2) 5 (0.2) in situ Unknown 0 1(less than 0.1) 0 1 (less than 0.1) Distant recurrence 324 (10.4) 375 (12.0) 226 (8.6) 265 (10.2) Death from Any Cause 411 (13.2) 420 (13.5) 296 (11.3) 301 (11.6) Death breast cancer 218 (7.0) 248 (8.0) 138 (5.3) 160 (6.2) Death other reason (including unknown) 196 (6.2) 172 (5.5) 158 (6.0) 141 (5.4) A summary of the study efficacy results is provided in Table 9. Table 9 - ATAC Efficacy Summary Intent-To-Treat Population Hormone Receptor-Positive Subpopulation Anastrozole 1 mg (N=3125) Tamoxifen 20mg (N=3116) Anastrozole 1mg (N=2618) Tamoxifen 20 mg (N=2598) Disease-free Survival 575 651 424 497 Hazard ratio 0.87 0.83 2-sided 95% CI 0.78 to 0.97 0.73 to 0.94 p-value 0.0127 0.0049 Distant Disease-free Survival 500 530 370 394 Hazard ratio 0.94 0.93 2-sided 95% CI 0.83 to 1.06 0.80 to 1.07 Overall Survival 411 420 296 301 Hazard ratio 0.97 0.97 2-sided 95% CI 0.85 to 1.12 0.83 to 1.14
16 HOW SUPPLIED/STORAGE AND HANDLING
HOW SUPPLIED SECTION
These tablets are supplied in bottles of 30 tablets (NDC 62033-0376-6).
17 PATIENT COUNSELING INFORMATION
INFORMATION FOR PATIENTS SECTION
17.1 Pregnancy Patients should be advised that Anastrozole may cause fetal harm. They should also be advised that Anastrozole is not for use in premenopausal women; therefore, if they become pregnant they should stop taking Anastrozole and immediately contact their doctor.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL