Anastrozole (anastrozole)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Anastrozole, an aromatase inhibitor, is an antineoplastic agent.
Anastrozole, a benzyltriazole derivative, is a selective, nonsteroidal aromatase inhibitor. Competitive aromatase inhibitors, such as anastrozole, also have been referred to as type II inhibitors of the enzyme. Anastrozole differs structurally from aminoglutethimide but shares the pharmacologic activity of competitive aromatase inhibition; although both drugs are selective nonsteroidal inhibitors, anastrozole is more potent and selective on a molar basis.
Anastrozole is a triazole derivative; the N-4 nitrogen of the triazole ring, which coordinates with the heme iron atom of the aromatase enzyme complex, is thought to be responsible for the high affinity of the drug for the estrogen synthetase enzyme.
Anastrozole selectively inhibits the conversion of androgens to estrogens. In postmenopausal women, ovarian secretion of estrogen declines and conversion of adrenal androgens (mainly androstenedione and testosterone) to estrone and estradiol in peripheral tissues (adipose, muscle, and liver), catalyzed by the aromatase enzyme, is the principal source of estrogens. Anastrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P-450 unit of the enzyme; suppression of estrogen biosynthesis in all tissues reduces serum concentrations of circulating estrogens, including estrone, estradiol, and estrone sulfate.
Because estrogen acts as a growth factor for hormone-dependent breast cancer cells, anastrozole-induced reduction of serum and tumor concentrations of estrogen inhibits tumor growth and delays disease progression.
Anastrozole selectively inhibits synthesis of estrogens and does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone. In animals, anastrozole has not been shown to possess direct progestogenic, androgenic, or estrogenic activity, but alterations in the circulating concentrations of progesterone, androgens, and estrogens have been observed.
The effect of anastrozole on serum estradiol concentrations in premenopausal women has not been studied. Ovarian secretion is the principal source of estrogen in premenopausal women; because it acts by suppressing other sources of estrogens, anastrozole would not be expected to lower serum estradiol concentrations in women with functioning ovaries.
The pharmacokinetics of anastrozole are linear over the dose range of 1-20 mg and are not altered with repeated dosing. The pharmacokinetic disposition of anastrozole is similar in female patients with breast cancer and in healthy postmenopausal women. Anastrozole is rapidly and well absorbed into systemic circulation following oral administration; peak plasma concentrations generally are attained within 2 hours when the drug is administered in the fasted state.
Plasma concentrations approach steady state after about 7 days of once-daily dosing, and steady-state concentrations are approximately 3-4 times higher than concentrations achieved after a single dose of the drug. Food reduces the rate but does not affect the extent of oral absorption of anastrozole. When anastrozole was administered 30 minutes after food, the mean peak plasma concentration of the drug was decreased by 16% and the median time to peak plasma concentration was delayed by 3 hours.
Within the therapeutic plasma concentration range, anastrozole is 40% bound to plasma proteins. A mean terminal elimination half-life of approximately 50 hours has been reported. Anastrozole is extensively metabolized in the liver.
Hepatic metabolism accounts for about 85% of the elimination of anastrozole, with renal excretion accounting for only about 10% of total clearance. Studies with radiolabeled drug have shown that about 85% of an orally administered dose is recovered in urine and feces. Metabolism of anastrozole occurs via N-dealkylation, hydroxylation, and glucuronidation.
Three metabolites of anastrozole have been identified in human plasma and urine: triazole, a glucuronide conjugate of anastrozole, and a glucuronide conjugate of hydroxyanastrozole. Triazole, the major circulating metabolite of anastrozole, lacks pharmacologic activity, and the aromatase-inhibiting activity of anastrozole results principally from the parent drug.
Among healthy postmenopausal women and female patients with breast cancer, no age-related differences in pharmacokinetics of anastrozole have been observed in women older than 80 years of age compared with women younger than 50 years of age.
Steady-state minimum plasma concentrations averaged 25.7 and 30.4 ng/mL, respectively, in white and Japanese postmenopausal women receiving anastrozole 1 mg daily for 16 days; serum estradiol and estrone sulfate concentrations were similar between the groups.
USES: Anastrozole is used to treat breast cancer in women after menopause. Some breast cancers are made to grow faster by a natural hormone called estrogen. Anastrozole decreases the amount of estrogen the body makes and helps to slow or reverse the growth of these breast cancers.
Generic name: anastrozole
Pronunciation: (an-AS-troe-zole)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Anastrozole
Indications
The following indications are listed for Anastrozole:
- Early Breast Cancer Hormone Receptor Positive And Postmenopausal
- Hormone Receptor Positive Postmenopausal Advanced Breast Cancer
- Metastatic Breast Carcinoma
Also known as: Advanced Breast Carcinoma, Metastatic Breast Cancer, Metastatic Malignancy Of Breast, Metastatic Malignant Neoplasm Of Breast, Metastatic Malignant Tumor Of Breast.
Dosing
No dosing information is available for this tab.
Anastrozole is administered orally.
Food does not affect the absorption of anastrozole, and the drug may be administered without regard to meals.
Commercially available anastrozole tablets should be stored at a controlled room temperature of 20-25degreesC.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Anastrozole has been shown to inhibit in vitro metabolic reactions catalyzed by cytochrome P-450 (CYP) isoenzymes 1A2, 2C8/9, and 3A4, but only at relatively high concentrations. It is considered unlikely that anastrozole, when administered at the recommended dosage, will result in clinically important interactions with drugs metabolized by CYP enzymes.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
* Known hypersensitivity to anastrozole or any ingredient in the formulation.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
In the early breast cancer study (ATAC), the most common adverse effects (occurring in 10% or more of patients) included hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea, vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, and lymphedema.
In advanced breast cancer studies, the most common adverse effects (occurring in 10% or more of patients) included hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis, and peripheral edema.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Efficacy of anastrozole for the treatment of pubertal gynecomastia+ in adolescent males and for the treatment of progressive precocious puberty associated with McCune-Albright syndrome+ in girls has not been established.
Results of a randomized, double-blind, placebo-controlled trial in 80 adolescent males 11-18 years of age with pubertal gynecomastia failed to establish efficacy of anastrozole (1 mg daily for 6 months) in reducing gynecomastia or relieving breast pain. Serum estradiol concentrations were reduced by 15.4 or 4.5% in patients receiving anastrozole or placebo, respectively. Patients receiving anastrozole were more likely to experience treatment-related adverse effects (16.3 versus 8.1%), and the difference was related mainly to higher rates of acne and headache in those receiving anastrozole. One patient discontinued anastrozole therapy because of testicular enlargement.
Results of a noncomparative open-label trial of anastrozole (1 mg daily for 12 months) in 28 girls (2 to less than 10 years of age) with McCune-Albright syndrome and progressive precocious puberty showed no reduction from baseline in the frequency of vaginal bleeding days or in the rate of increase in bone age and no clinically important changes in Tanner staging, mean ovarian or uterine volume, or mean predicted adult height. A small reduction in growth rate was observed; however, because the study was uncontrolled, it is unclear whether this effect was related to anastrozole or to other confounding factors (e.g., variations in endogenous estrogen levels commonly observed in patients with McCune-Albright syndrome). Adverse effects (i.e., nausea, acne, extremity pain, increased aminotransferase concentrations, allergic dermatitis) were reported in 18% of patients.
Pharmacokinetics of anastrozole were similar in adolescent males with pubertal gynecomastia and in girls with McCune-Albright syndrome, and the elimination half-life in these pediatric populations (about 47 hours) was similar to that observed in postmenopausal women with breast cancer.
Anastrozole may cause fetal harm; the drug has been shown to be embryotoxic, fetotoxic, and abortifacient in animals. The manufacturer states that a pregnancy test should be performed prior to initiation of anastrozole therapy in females of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of therapy. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus and the potential risk for loss of the pregnancy.
Adequate, well-controlled studies of anastrozole in pregnant women have not been conducted. Anastrozole has been shown to cross the placenta in rats and rabbits receiving oral doses of 0.1 mg/kg (approximately 1 and 1.9 times the recommended human dose, respectively, on a mg/m2 basis). Increased pregnancy loss (increased preimplantation and/or postimplantation loss, increased resorption, and decreased numbers of live fetuses) was demonstrated in rats and rabbits receiving anastrozole dosages equal to or exceeding 0.1 and 0.02 mg/kg daily, respectively (about one and one-third times the recommended human dosage, respectively, on a mg/m2 basis), during the period of organogenesis; in rats, this effect was dose-related. In rats receiving dosages equal to or exceeding 0.1 mg/kg daily, placental weights were increased.
In rats, anastrozole dosages of 1 mg/kg daily (which produced steady-state peak plasma anastrozole concentrations and AUC0-24h values that were 19 and 9 times higher, respectively, than those observed in healthy postmenopausal women receiving the recommended dose) resulted in fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights). In rats, no evidence of teratogenicity was observed at dosages of up to 1 mg/kg daily. In rabbits, anastrozole dosages equal to or exceeding 1 mg/kg daily (about 16 times the recommended human dosage on a mg/m2 basis) caused pregnancy failure. No evidence of teratogenicity was observed in rabbits receiving anastrozole 0.2 mg/kg daily (about 3 times the recommended human dosage on a mg/m2 basis).
It is not known whether anastrozole or its metabolites are distributed into human milk or if the drug has any effect on nursing infants or on milk production. Because many drugs are distributed into milk and because tumorigenic effects of anastrozole have been observed in animals and anastrozole has the potential to cause serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding during anastrozole therapy and for 2 weeks after discontinuance of the drug.
Because no evidence of altered pharmacokinetics has been observed in women older than 80 years of age compared with women younger than 50 years of age, the manufacturer states that adjustment of anastrozole dosage is not necessary in geriatric patients.
Among patients receiving anastrozole as adjuvant therapy for early-stage breast cancer in the ATAC trial, 45% were 65 years of age or older. Subgroup analysis showed that anastrozole did not provide the same benefit for disease-free survival in women 65 years of age or older (hazard ratio of 0.93 with a 95% confidence interval of 0.8-1.08) that it provided in postmenopausal women younger than 65 years of age (hazard ratio of 0.79 with a 95% confidence interval of 0.67-0.94).
Among patients receiving anastrozole as first-line or second-line therapy in clinical trials, about 50% were 65 years of age or older. No difference in efficacy was observed for geriatric patients (65 years or older) compared with younger patients receiving anastrozole as second-line therapy for advanced breast cancer; moderately greater efficacy was observed for geriatric patients (65 years or older) receiving either anastrozole or tamoxifen as first-line therapy for advanced breast cancer.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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