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anastrozole tablet, coated
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Adjuvant Treatment
Anastrozole is indicated for adjuvant treatment of postmenopausal women with
hormone receptor-positive early breast cancer.
1.2 First-Line Treatment
Anastrozole is indicated for the first-line treatment of
postmenopausal women with hormone receptor-positive or hormone receptor unknown
locally advanced or metastatic breast cancer.
1.3 Second-Line Treatment
Anastrozole is indicated for the treatment of advanced breast cancer in postmenopausal 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.
2 DOSAGE AND ADMINISTRATION
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 STRENGTH
The tablets are round, film-coated, white to off-white tablets.
One side is debossed with “0376”, and the other side is plain.
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
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)]
5.2 Bone Effects
Results from the ATAC trial bone substudy at 12 and 24 months
demonstrated that patients receiving Anastrozole had a mean decrease in both
lumbar spine and total hip bone mineral density (BMD) compared to baseline.
Patients receiving tamoxifen had a mean increase in both lumbar spine and total
hip BMD compared to baseline. [see Adverse Reactions,(6.1)]
6 ADVERSE REACTIONS
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.
6.1 Clinical Trials Experience
Adverse reaction data for adjuvant therapy are based on the ATAC trial. [see
Clinical Studies (14.1)] The median duration of adjuvant treatment for safety
evaluation was 59.8 months and 59.6 months for patients receiving Anastrozole 1
mg and tamoxifen 20 mg, respectively.
Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1.
Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see Table 2).
Ischemic Cardiovascular Events
In the overall population, angina pectoris was reported in 71/3092 (2.3%)
patients in the Anastrozole arm and 51/3094 (1.6%) patients in the tamoxifen
arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the
Anastrozole arm and 34/3094 (1.1%) patients in the tamoxifen arm.
In women with pre-existing ischemic heart disease 465/6186 (7.5%), the
incidence of ischemic cardiovascular events was 17% in patients on Anastrozole
and 10% in patients on tamoxifen. In this patient population, angina pectoris
was reported in 25/216 (11.6%) patients receiving Anastrozole and 13/249 (5.2%)
patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%)
patients receiving Anastrozole and 8/249 (3.2%) patients receiving
Bone Mineral Density Findings
Because Anastrozole lowers circulating estrogen levels it may cause a
reduction in bone mineral density.
A post-marketing trial assessed the combined effects of Anastrozole and the
bisphosphonate risedronate on changes from baseline in BMD and markers of bone
resorption and formation in postmenopausal women with hormone receptor-positive
early breast cancer. All patients received calcium and vitamin D
supplementation. At 12 months, small reductions in lumbar spine bone mineral
density were noted in patients not receiving bisphosphonates. Bisphosphonate
treatment preserved bone density in most patients at risk of fracture.
Postmenopausal women with early breast cancer scheduled to be treated with
Anastrozole should have their bone status managed according to treatment
guidelines already available for postmenopausal women at similar risk of
A post-marketing trial also evaluated any potential effects of Anastrozole on
In the primary analysis population for lipids (Anastrozole alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months
In secondary population for lipids (Anastrozole +risedronate), there also was
no clinically significant change in LDL-C and HDL-C from baseline to 12
In both populations for lipids, there was no clinically significant
difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months
compared with baseline.
In this trial, treatment for 12 months with Anastrozole alone had a neutral
effect on lipid profile. Combination treatment with Anastrozole and risedronate
also had a neutral effect on lipid profile.
The trial provides evidence that postmenopausal women with early breast
cancer scheduled to be treated with Anastrozole should be managed using the
current National Cholesterol Education Program guidelines for cardiovascular
risk-based management of individual patients with LDL elevations.
Other Adverse Reactions
Patients receiving Anastrozole had a higher incidence of carpal tunnel
syndrome [78 (2.5%)] compared with patients receiving tamoxifen [22 (0.7%)].
Vaginal bleeding occurred more frequently in the tamoxifen-treated patients
versus the Anastrozole-treated patients 317 (10%) versus 167 (5%),
Patients receiving Anastrozole had a lower incidence of hot flashes, vaginal
bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events
and ischemic cerebrovascular events compared with patients receiving
Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3.
*A patient may have had more than 1 adverse event.
Less frequent adverse experiences reported in patients receiving Anastrozole
l mg in either Trial 0030 or Trial 0027 were similar to those reported for
Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre-specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups.
*A patient may have had more than 1 adverse event.
Anastrozole was tolerated in two 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
an adverse reaction.
The principal adverse reaction more common with Anastrozole than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below:
*A patient may have had more than one adverse reaction.
Other less frequent (2% to 5%) adverse reactions 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
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 reactions captured in the groups, were prospectively defined. The results are shown in the table below.
6.2 Post-Marketing Experience
Hepatobiliary events including increases in alkaline phosphatase,
alanine aminotransferase, aspartate aminotransferase have been reported (greater
than or equal to 1% and less than 10%) and gamma-GT, bilirubin and hepatitis
have been reported (greater than or equal to 0.1% and less than 1%) in patients
Anastrozole may also be associated with rash including cases of mucocutaneous
disorders such as erythema multiforme and Stevens-Johnson syndrome.
Cases of allergic reactions including angioedema, urticaria and anaphylaxis
have been reported in patients receiving Anastrozole. [see Contraindications
Trigger finger has been reported (greater than 0.1% and less than 1%) in
patients receiving Anastrozole.
7 DRUG INTERACTIONS
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.
Estrogen-containing therapies should not be used with Anastrozole as they may
diminish its pharmacological action.
In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by Cmax and AUC) and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin.
8 USE IN SPECIFIC POPULATIONS
PREGNANCY CATEGORY X [see Contraindications (4.1)]
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)]
8.3 Nursing Mothers
It is not known if anastrozole is excreted in human milk. Because
many drugs are excreted in human milk and because of the tumorigenicity shown
for anastrozole in animal studies, or the potential for serious adverse
reactions in nursing infants, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
8.4 Pediatric Use
The efficacy of anastrozole tablets 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.
Labeling describing clinical trials and pharmacokinetic studies of
anastrozole in pubertal boys of adolescent age with gynecomastia and in girls
with McCune-Albright Syndrome and progressive precocious puberty is approved for
AstraZeneca Pharmaceuticals LP’s Arimidex®. However, due to AstraZeneca
Pharmaceuticals LP’s marketing exclusivity rights, a description of those trials
and studies is not approved for this anastrozole product.
8.5 Geriatric Use
In studies 0030 and 0027 about 50% of patients were 65 or older.
Patients greater than or equal to 65 years of age had moderately better tumor
response and time to tumor progression than patients less than 65 years of age
regardless of randomized treatment. In studies 0004 and 0005 50% of patients
were 65 or older. Response rates and time to progression were similar for the
over 65 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.
8.6 Renal Impairment
Since only about 10% of anastrozole is excreted unchanged in the
urine, the renal impairment does not influence the total body clearance. Dosage
adjustment in patients with renal impairment is not necessary [see Dosage and
Administration (2.1) and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
The plasma anastrozole concentrations in the subjects with
hepatic cirrhosis were within the range of concentrations seen in normal
subjects across all clinical trials. Therefore, dosage adjustment is also not
necessary in patients with stable hepatic cirrhosis. Anastrozole has not been
studied in patients with severe hepatic impairment. [see Dosage and
Administration (2.2) and Clinical Pharmacology (12.3)]
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.
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
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.
Effect on Estradiol
The effect of Anastrozole in premenopausal women with early or advanced
breast cancer has not been studied. Because aromatization of adrenal androgens
is not a significant source of estradiol in premenopausal women, Anastrozole
would not be expected to lower estradiol levels in premenopausal women.
Effect on Corticosteroids
Other Endocrine Effects
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 cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.
Effect of Gender and Age
Effect of Race
Effect of Renal Impairment
Effect of Hepatic Impairment
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
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 CSSmax 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
14 CLINICAL STUDIES
14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women
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).
N=Number of patients randomized to the treatment.
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
The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8.
A summary of the study efficacy results is provided in Table 9.
*The combination arm was discontinued due to lack of dfficacy benefit at 33 months to-follow-up.
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
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.
For the primary endpoints, trial 0030 showed that Anastrozole had a
statistically significant advantage over tamoxifen (p=0.006) for time to tumor
progression; objective tumor response rates were similar for Anastrozole and
tamoxifen. Trial 0027 showed that Anastrozole and tamoxifen had similar
objective tumor response rates and time to tumor progression (see Table 11 and
Figure 3 and 4)
Table 11 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.
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 draw conclusions on overall survival
14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy
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
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.
When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to Anastrozole 1 mg and megestrol acetate. There is, in this data, no indication that Anastrozole 10 mg is superior to Anastrozole 1 mg.
16 HOW SUPPLIED/STORAGE AND HANDLING
These tablets are supplied in bottles of 30 tablets (NDC 42291-105-30).
17 PATIENT COUNSELING INFORMATION
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.
17.2 Allergic (Hypersensitivity) Reactions
Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to immediately report this to their doctor.
17.3 Ischemic Cardiovascular Events
Patients with pre-existing ischemic heart disease should be informed that an increased incidence of cardiovascular events has been observed with Anastrozole use compared to tamoxifen use.
17.4 Bone Effects
Patients should be informed that Anastrozole lowers the level of estrogen. This may lead to a loss of the mineral content of bones, which might decrease bone strength. A possible consequence of decreased mineral content of bones is an increase in the risk of fractures.
Patients should be informed that an increased level of
cholesterol might be seen while receiving Anastrozole.
17.7 FDA-Approved Patient Labeling
What is Anastrozole?
Anastrozole does not work in women with breast cancer who have not finished
menopause (premenopausal women).
Who should not take Anastrozole?
What is the most important information I should know about
What should I tell my doctor before taking Anastrozole?
Anastrozole may not be right for you. Before taking
Anastrozole, tell your doctor about all your medical conditions, including if
Tell your doctor about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. Especially tell
your doctor if you take:
Know the medicines you take. Keep a list of them and show it to your doctor
and pharmacist each time you get a new medicine.
How should I take Anastrozole?
Talk with your doctor about any health changes you have while taking Anastrozole.
What are possible side effects of Anastrozole?
Common side effects in women taking Anastrozole include:
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
HOW SHOULD I STORE Anastrozole?
General information about Anastrozole.
This patient information leaflet summarizes the most important information
about Anastrozole. If you would like more information, talk with your doctor.
You can ask your pharmacist or doctor for information about Anastrozole that is
written for health professionals.
What are the ingredients in Anastrozole?
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
USUAL DOSAGE: See accompanying Prescribing Information.
WARNING: As with all medication, KEEP OUT OF REACH OF CHILDREN.
Store at controlled room temperature, 20o to 25oC (68o to 77oF). [See USP].
N3 42291 10530 0
Revised: 02/2011 AvKARE, Inc.
Reproduced with permission of U.S. National Library of Medicine
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