anastrozole 1 MG Oral Tablet
Generic Name: ANASTROZOLE
Brand Name: Anastrozole
- Substance Name(s):
- ANASTROZOLE
DRUG INTERACTIONS
7 Tamoxifen: Do not use in combination with anastrozole.
No additional benefit seen over tamoxifen monotherapy ( 7.1, 14.1).
Estrogen-containing products: Combination use may diminish activity of anastrozole ( 7.2).
7.1 Tamoxifen Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%.
However, the co-administration 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.
7.2 Estrogen Estrogen-containing therapies should not be used with anastrozole as they may diminish its pharmacological action.
7.3 Warfarin In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by C max and AUC), and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin.
7.4 Cytochrome P450 Based on in vitro and in vivo results, it is unlikely that co-administration of anastrozole 1 mg will affect other drugs as a result of inhibition of cytochrome P450 [see Clinical Pharmacology ( 12.3)].
OVERDOSAGE
10 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.
DESCRIPTION
11 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 C 17H 19N 5 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: lactose monohydrate, magnesium stearate, hypromellose, macrogol, povidone, sodium starch glycolate, and titanium dioxide.
Chemical Structure for anastrozole
CLINICAL STUDIES
14 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 (ie, 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 Characteristic Anastrozole 1 mg (N N=Number of patients randomized to the treatment=3125) Tamoxifen 20 mg (N =3116) Anastrozole 1 mg plus Tamoxifen 20 mg The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up (N =3125) Mean age (yrs.) 64.1 64.1 64.3 Age Range (yrs.) 38.1 to 92.8 32.8 to 94.9 37 to 92.2 Age Distribution (%) <45 yrs.
0.7 0.4 0.5 45 to 60 yrs.
34.6 35.0 34.5 >60 <70 yrs.
38.0 37.1 37.7 >70 yrs.
26.7 27.4 27.3 Mean Weight (kg) 70.8 71.1 71.3 Receptor Status (%) Positive Includes patients who were estrogen receptor (ER) positive or progesterone receptor (PgR) positive, or both positive 83.5 83.1 84.0 Negative Includes patients with both ER negative and PgR negative receptor status 7.4 8.0 7.0 Other Includes all other combinations of ER and PgR receptor status unknown 8.8 8.6 9.0 Other Treatment (%) prior to Randomization Mastectomy 47.8 47.3 48.1 Breast conservation Among the patients who had breast conservation, radiotherapy was administered to 95.0% of patients in the anastrozole arm, 94.1% in the tamoxifen arm and 94.5% in the anastrozole plus tamoxifen arm.
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 (≤2 cm) 63.9 62.9 64.1 T2 (>2 cm and ≤5 cm) 32.6 34.2 32.9 T3 (>5 cm) 2.7 2.2 2.3 Nodal Status (%) Node positive 34.9 33.6 33.5 1 to 3 (# of nodes) 24.4 24.4 24.3 4 to 9 7.5 6.4 6.8 >9 2.9 2.7 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.
Figure 1- Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC trial (Intent-to-Treat) Figure 2- Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial 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 The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.
Intent-To-Treat Population Patients may fall into more than one category.
Hormone Receptor-Positive Subpopulation Anastrozole 1 mg (N N=Number of patients randomized=3125) Tamoxifen 20 mg (N =3116) Anastrozole 1 mg (N =2618) Tamoxifen 20 mg (N =2598 Number (%) of Patients Number (%) of Patients 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 in situ 8 (0.3) 6 (0.2) 5 (0.2) 5 (0.2) Unknown 0 1 (<0.1) 0 1 (<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) 193 (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 The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.
Intent-To-Treat Population Hormone Receptor-Positive Subpopulation Anastrozole 1 mg (N=3125) Tamoxifen 20 mg (N=3116) Anastrozole 1 mg (N=2618) Tamoxifen 20 mg (N=2598) Number of Events Number of Events Disease-free Survival 575 651 424 497 Hazard ratio 0.87 0.78 to 0.97 0.0127 0.83 0.73 to 0.94 0.0049 2-sided 95% CI p-value Distant Disease-free Survival 500 530 370 394 Hazard ratio 0.94 0.83 to 1.06 0.93 0.80 to 1.07 2-sided 95% CI Overall Survival 411 420 296 301 Hazard ratio 0.97 0.85 to 1.12 0.97 0.83 to 1.14 2-sided 95% CI 10-year median follow-up Efficacy Results from the ATAC Trial In a subsequent analysis of the ATAC trial, patients in the two monotherapy arms were followed for a median of 120 months (10 years).
Patients received study treatment for a median of 60 months (5 years) (see Table 10).
Table 10 – Efficacy Summary Intent-To-Treat Population Hormone Receptor-Positive Subpopulation Anastrozole 1 mg (N=3125) Tamoxifen 20 mg (N=3116) Anastrozole 1 mg (N=2618) Tamoxifen 20 mg (N=2598) Number of Events Number of Events Disease-free Survival 953 1022 735 924 Hazard ratio 0.91 0.86 2-sided 95% CI 0.83 to 0.99 0.78 to 0.95 p-value 0.0365 0.0027 Overall Survival 734 747 563 586 Hazard ratio 0.97 0.88 to 1.08 0.95 0.84 to 1.06 2-sided 95% CI Figure 3 – Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat) (a) a The proportion of patients with 120 months’ follow-up was 29.4%.
Figure 4 – Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial (b) bThe proportion of patients with 120 months’ follow-up was 29.8%.
Figure 1 Figure 2 figure 3 figure 4 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 endpoints 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 11 – Demographic and Other Baseline Characteristics Number (%) of subjects Trial 0030 Trial 0027 Receptor status Anastrozole 1 mg (n=171) Tamoxifen 20 mg (n=182) Anastrozole 1 mg (n=340) Tamoxifen 20 mg (n=328) ER ER=Estrogen receptor and/or PgR PgR=Progesterone receptor 151 (88.3) 162 (89.0) 154 (45.3) 144 (43.9) ER unknown, PgR unknown 19 (11.1) 20 (11.0) 185 (54.4) 183 (55.8) 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 12 and Figures 5 and 6) Table 12 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.
Table 12– Efficacy Results of First-line Treatment End point Trial 0030 Trial 0027 Anastrozole 1 mg (n=171) Tamoxifen 20 mg (n=182) Anastrozole 1 mg (n=340) Tamoxifen 20 mg (n=328) Time to progression (TTP) Median TTP (months) 11.1 5.6 8.2 8.3 Number (%) of subjects who progressed 114 (67%) 138 (76%) 249 (73%) 247 (75%) Hazard ratio (LCL LCL=Lower Confidence Limit ) Tamoxifen:Anastrozole 1.42 (1.15) 1.01 (0.87) 2-sided 95% CI CI=Confidence Interval (1.11, 1.82) (0.85, 1.20) p-value Two-sided Log Rank 0.006 0.920 Best objective response rate Number (%) of subjects With CR CR=Complete Response + PR PR=Partial Response 36 (21.1%) 31 (17.0%) 112 (32.9%) 107 (32.6%) Odds Ratio (LCL ) Anastrozole:Tamoxifen 1.30 (0.83) 1.01 (0.77) Figure 5 — Kaplan-Meier probability of time to disease progression for all randomized patients (intent to- treat) in Trial 0030 Figure 6 — Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027 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 differences.
Figure 5 Figure 6 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 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 cal culated 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 13.
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 13– Efficacy Results of Second-line Treatment Anastrozole 1 mg Anastrozole 10 mg Megestrol Acetate 160 mg Trial 0004 ( N.
America) (N=128) (N=130) (N=128) Median Follow-up (months) Surviving Patients 31.3 30.9 32.9 Median Time to Death (months) 29.6 25.7 26.7 2 Year Survival Probability (%) 62.0 58.0 53.1 Median Time to Progression (months) 5.7 5.3 5.1 Objective Response (all patients ) (%) 12.5 10.0 10.2 Stable Disease for >24 weeks (%) 35.2 29.2 32.8 Progression (%) 86.7 85.4 90.6 Trial 0005 ( Europe, Australia, S.
Africa) (N=135) (N=118) (N=125) Median Follow-up (months) 31.0 30.9 31.5 Median Time to Death (months) 24.3 24.8 19.8 2 Year Survival Probability (%) 50.5 50.9 39.1 Median Time to Progression (months) 4.4 5.3 3.9 Objective Response (all patients) (%) 12.6 15.3 14.4 Stable Disease for >24 weeks (%) 24.4 25.4 23.2 Progression (%) 91.9 89.8 92.0 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.
Table 14 – Pooled Efficacy Results of Second-line Treatment Trials 0004 & 0005 (Pooled Data) Anastrozole 1 mg N=263 Anastrozole 10 mg N=248 Megestrol Acetate 160 mg N=253 Median Time to Death (months) 26.7 25.5 22.5 2 Year Survival Probability (%) 56.1 54.6 46.3 Median Time to Progression 4.8 5.3 4.6 Objective Response (all patients) (%) 12.5 12.5 12.3
HOW SUPPLIED
16 /STORAGE AND HANDLING Anastrozole tablets, 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 (NDC 16729-035-10) Bottles of 90 tablets (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) [see USP].
GERIATRIC USE
8.5 Geriatric Use In studies 0030 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 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 is not affected by age.
DOSAGE FORMS AND STRENGTHS
3 The tablets are white to off-white, round biconvex, film coated tablets, with “AHI” debossing on one side and plain on other side.
1 mg tablets ( 3)
MECHANISM OF ACTION
12.1 Mechanism of Action The growth of many cancers of the breast is stimulated or maintained by estrogens.
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 selective non-steroidal aromatase inhibitor.
It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
INDICATIONS AND USAGE
1 Anastrozole is an aromatase inhibitor indicated for: Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer ( 1.1) First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer ( 1.2) 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 ( 1.3) 1.1 Adjuvant Treatment Anastrozole tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
1.2 First-Line Treatment Anastrozole tablets are 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 tablets are 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 tablets.
PEDIATRIC USE
8.4 Pediatric Use 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.
Gynecomastia Study A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 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 6 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 3 in the anastrozole-treated patients and + 5.2 ± 8.0 cm 3 in the placebo group.
McCune-Albright Syndrome Study A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged 2 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.
Pharmacokinetics in Pediatric Patients 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- Albright Syndrome.
PREGNANCY
8.1 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/m 2 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 (AUC 0-24hr 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/m 2 basis [see Animal Toxicology and/or Pharmacology ( 13.2)].
NUSRING MOTHERS
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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events occurred with anastrozole use compared to tamoxifen use.
Consider risks and benefits.
( 5.1, 6.1) Decreases in bone mineral density may occur.
Consider bone mineral density monitoring.
( 5.2, 6.1) Increases in total cholesterol may occur.
Consider cholesterol monitoring.
( 5.3, 6.1) 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.
Consider bone mineral density monitoring in patients treated with anastrozole [see Adverse Reactions ( 6.1)] .
5.3 Cholesterol During the ATAC trial, more patients receiving anastrozole were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively) [see Adverse Reactions ( 6.1)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION “See FDA approved patient labeling (Patient Information).” 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 tablets 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 seek medical attention immediately.
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.
If patients have new or worsening chest pain or shortness of breath they should seek medical attention immediately.
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.
17.5 Cholesterol Patients should be informed that an increased level of cholesterol might be seen while receiving anastrozole.
17.6 Tickling, Tingling or Numbness Patients should be informed that if they experience tickling, tingling, or numbness they should notify their health care provider.
17.7 Tamoxifen Patients should be advised not to take anastrozole with tamoxifen.
17.8 Missed Doses Inform patients that if they miss a dose, take it as soon as they remember.
If it is almost time for their next dose, skip the missed dose and take the next regularly scheduled dose.
Patients should not take two doses at the same time.
DOSAGE AND ADMINISTRATION
2 One 1 mg tablet taken once daily ( 2.1) 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 [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)].
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 [see Use in Specific Populations ( 8.7)].