Anastrozole Information
Anastrozole () Dosage And Administration
The dose of Anastrozole () Tablets 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 () Tablets were administered for five years.
No dosage adjustment is necessary for patients with renal impairment or for elderly patients.
Anastrozole () Dosage Forms And Strengths
The tablets are white, round, biconvex, film-coated tablets with "ANA 1" debossed on one side.
Anastrozole () Contraindications
Anastrozole () Tablets may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole () Tablets are contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies in pregnant women using Anastrozole () Tablets. If Anastrozole () Tablets are 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.
Anastrozole () Warnings And Precautions
In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with Anastrozole () Tablets in the ATAC trial (17% of patients on Anastrozole () Tablets and 10% of patients on tamoxifen). Consider risk and benefits of Anastrozole () Tablets therapy in patients with pre-existing ischemic heart disease.
Anastrozole () Adverse Reactions
Serious adverse reactions with Anastrozole () Tablets 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 [].
Common adverse reactions (occurring with an incidence of >10%) in women taking Anastrozole () Tablets 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 () Tablets 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.
Anastrozole () Use In Specific Populations
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 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 () Tablets labeling.
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
In the ATAC study 45% of patients were 65 years of age or older. The efficacy of Anastrozole () Tablets compared to tamoxifen in patients who were 65 years or older (N=1413 for Anastrozole () Tablets 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 () Tablets 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.
Anastrozole () Overdosage
Clinical trials have been conducted with Anastrozole () Tablets, 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 () Tablets 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 () Tablets are not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Anastrozole () Description
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 CHN 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 Anastrozole () as the active ingredient and as inactive ingredients: lactose monohydrate, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.
Anastrozole () Clinical Pharmacology
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.
Anastrozole () Nonclinical Toxicology
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/m 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 AUC 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/m 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 () Tablets have not been shown to be mutagenic in tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either (chromosome aberrations in human lymphocytes) or (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/m basis and 9 times higher than the AUC 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/mbasis). 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 () C and AUC 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 () C and AUC 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.
Anastrozole () Clinical Studies
A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with Anastrozole () Tablets 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 () Tablets 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 () .
Demographic and other baseline characteristics were similar among the three treatment groups (see ).
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 () Tablets 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 () Tablets arm compared to the tamoxifen arm.
Figure 1 — Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole () Tablets 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 () Tablets 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 () Tablets 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 () Tablets 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.
A summary of the study efficacy results is provided in Table 9.
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 () Tablets 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 () Tablets 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.
For the primary endpoints, trial 0030 showed that Anastrozole () Tablets had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression; objective tumor response rates were similar for Anastrozole () Tablets and tamoxifen. Trial 0027 showed that Anastrozole () Tablets and tamoxifen had similar objective tumor response rates and time to tumor progression (see and and )
Table 11 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.
Figure 3 - Kaplan-Meier probability of time to disease progression for all randomized patients (intent-to-treat) in Trial 0030
Figure 4 - 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.
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 () Tablets or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to Anastrozole () Tablets. 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.
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 () Tablets 1 mg and megestrol acetate. There is, in this data, no indication that Anastrozole () Tablets 10 mg is superior to Anastrozole () Tablets 1 mg.
Anastrozole () How Supplied/storage And Handling
The Anastrozole () Tablets are white, round, biconvex, film-coated tablets with "ANA 1" debossed on one side. These tablets are supplied as follows:
Anastrozole ()
Anastrozole ()
Anastrozole ()
