Nonsteroidal Aromatase Inhibitor
Action And Clinical Pharmacology: Many breast cancers have estrogen receptors and growth of these tumors can be stimulated by estrogens. In postmenopausal women, the principal source of circulating estrogen (primarily estrone) is conversion of adrenally-generated androstenedione to estrone by aromatase in peripheral tissues, such as adipose tissue, with further conversion of estrone to estradiol. Many breast cancers also contain aromatase; the importance of tumor-generated estrogens is uncertain.
Treatment of breast cancer has included efforts to decrease estrogen levels by ovariectomy premenopausally and by use of anti-estrogens and progestational agents both pre- and postmenopausally, and these interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.
Anastrozole is a potent and selective nonsteroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteriods or aldosterone.
The relationship between dose and response, measured as suppression of serum estradiol, was studied in postmenopausal women. Daily doses of anastrozole at 1 mg for 14 days produced estradiol suppression of greater than 80%. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with 1 mg anastrozole.
The selectivity of anastrozole to the aromatase enzyme, rather than other cytochrome P450 enzymes controlling glucocorticoid and mineralocorticoid synthesis in the adrenal gland, has been established. Furthermore, provocative stimulation of the adrenal glands by ACTH in subjects under treatment with anastrozole up to 10 mg, produced a normal response in terms of cortisol and aldosterone secretion. Therefore, patients treated with anastrozole do not require glucocorticoid or mineralocorticoid replacement therapy.
Anastrozole does not possess direct progestogenic, androgenic or estrogenic activity and does not interfere with secretion of thyroid stimulating hormone (TSH).
Pharmacokinetics: Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabeled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of anastrozole absorption.
Anastrozole is eliminated slowly with a plasma elimination half-life of approximately 50 hours in postmenopausal women. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg and do not change with repeated dosing. Consistent with the 50 hour plasma elimination half-life, plasma concentrations of anastrozole approach steady-state concentrations after 7 days of once daily dosing and are approximately 3- to 4-fold higher than the concentrations observed after a single dose of anastrozole. The protein binding of anastrozole to plasma proteins is about 40% and independent of concentration over a range which includes therapeutic concentrations.
Studies in postmenopausal women with radiolabeled anastrozole demonstrated that elimination occurs primarily via metabolism (approximately 85%) and to a lesser extent renal excretion of unchanged anastrozole (approximately 11%). Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole (triazole, a glucuronide conjugate of hydroxy-anastrozole, and a glucuronide conjugate of anastrozole itself) have been identified in human plasma or urine. Several minor (less than 5% of the radioactive dose) metabolites excreted in the urine have not been identified. The major metabolite of anastrozole in the circulation, triazole, lacks pharmacologic activity.
Special Populations: Geriatrics: Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. The pharmacokinetics were similar in volunteers and in patients and no age related effects were seen.
Race: Anastrozole pharmacokinetic differences due to race have not been studied.
Renal Insufficiency: Anastrozole pharmacokinetics have been investigated in subjects with renal insufficiency. Anastrozole renal clearance decreased proportionately with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m compared to controls. Because renal clearance is not a significant pathway of elimination, the apparent oral clearance of anastrozole is unchanged even in severe renal impairment. Dosage adjustment in patients with renal dysfunction is not necessary (see Dosage).
Hepatic Insufficiency: Anastrozole pharmacokinetics have been investigated in subjects with stable hepatic cirrhosis related to alcohol abuse. The apparent oral clearance of anastrozole was approximately 30% lower in subjects with hepatic cirrhosis than in control subjects with normal liver function. However, plasma anastrozole concentrations in the subjects with hepatic cirrhosis are within the range of concentrations seen in normal subjects across all clinical trials. Dosage adjustment in patients with hepatic dysfunction is not necessary (see Dosage).
Drug Interactions: Anastrozole inhibits reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which are approximately 30 times higher than the mean plasma steady-state Cmax values observed following a 1 mg daily dose. Anastrozole has no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg or multiple 10 mg doses of anastrozole to subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. Based on these in vitro and in vivo results, it is unlikely that the administration of anastrozole 1 mg will result in clinically significant inhibition of cytochrome P450-mediated metabolism of coadministered drugs.
Clinical Experience: Anastrozole was studied in 2 well-controlled clinical trials (0004, a North American study; 0005, a predominantly European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy. Most patients were estrogen receptor-positive; a smaller fraction was estrogen receptor-unknown or estrogen receptor-negative. Eligible patients were randomized to receive either a single daily dose of 1 or 10 mg of anastrozole, or megestrol acetate 40 mg 4 times a day. The studies were double-blinded with respect to anastrozole. Approximately 1/3 of the patients in each treatment group in both studies had either an objective response or stabilization of their disease for greater than 24 weeks. Hazard ratios for time to progression and odds ratios for response rates were calculated for the pooled studies were shown to be similar. After analysis of mature data involving 473 patients among 764 randomized participants, the hazard ratios for survival demonstrated a significant prolongation of survival in the 1 mg anastrozole group compared to hormonal treatment with megestrol acetate.
Patients with estrogen receptor-negative disease rarely responded to anastrozole, but there were too few patients in this group for a meaningful analysis.
Indications And Clinical Uses: For hormonal treatment of metastatic breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Because of its pharmacological action, patients with estrogen receptor-positive disease and patients who responded to previous anti-estrogen therapy are more likely to respond to anastrozole.
Contra-Indications: Patients with hypersensitivity to the drug or any of its components.
Pregnancy and Lactation: Anastrozole is contraindicated in pregnant or lactating women.
Manufacturers’ Warnings In Clinical States: Premenopausal Women: Anastrozole is not recommended for use in premenopausal women as safety and efficacy have not been established in this group of patients.
Pregnancy: There are no adequate and well-controlled studies in pregnant women using anastrozole. If the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy (see Contraindications).
Reproductive Toxicology: Anastrozole has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits. Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 3/4 and 1/3, respectively, the recommended human dose on a mg/mbasis), administered during the period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or postimplantation loss, increased resorption and decreased numbers of live fetuses). Effects were dose related in rats. Placental weights were significantly increased in rats at doses of 0.1 mg/kg/day or more.
Evidence of fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (about 7 times the recommended human dose on a mg/mbasis). There was no evidence of teratogenicity in rats administered doses up to 1 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1 mg/kg/day (about 16 times the recommended human dose on a mg/mbasis). There was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/mbasis).
Children: The safety and efficacy of anastrozole in pediatric patients have not been established.
Severe Hepatic/Renal Impairment: Anastrozole has not been investigated in patients with severe hepatic or severe renal impairment. The potential risk/benefit to such patients should be carefully considered before administration of anastrozole (see Pharmacology, Special Populations – Renal Insufficiency and Hepatic Insufficiency and Dosage).
Other: Anastrozole has not been investigated in patients with any degree of brain or leptomeningeal involvement or with pulmonary lymphangitic disseminated disease.
Precautions: General: Anastrozole should be administered under the supervision of a qualified physician experienced in the use of anti-cancer agents.
Drug Interactions: Antipyrine and cimetidine clinical interaction studies indicate that the co-administration of anastrozole with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450 (see Pharmacology, Drug Interactions).
Drug/Laboratory Test Interactions: Anastrozole has not been observed to interfere with routine clinical laboratory tests results.
Occupational Hazards: Effect on Ability to Drive and Use Machinery: Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.
Adverse Reactions: Anastrozole was generally well tolerated in two controlled clinical trials, with less than 3.3% of the anastrozole-treated patients and 4% of the megestrol acetate-treated patients withdrawing due to an adverse event.
The pharmacological action of anastrozole may give rise to certain expected effects. These include hot flushes, vaginal dryness and hair thinning. Anastrozole may also be associated with gastrointestinal disturbances (anorexia, nausea, vomiting and diarrhea), asthenia, somnolence, headache or rash.
Hepatic changes (elevated gamma-GT or less commonly alkaline phosphatase) have been reported in patients with advanced breast cancer, many of whom had liver and/or bone metastases. A causal relationship for these changes has not been established. Slight increases in total cholesterol have also been observed in clinical trials with anastrozole.
Other less frequent (2 to 5%) adverse experiences reported in patients receiving anastrozole 1 mg in the 2 pivotal clinical trials 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.
Cardiovascular: hypertension, thrombophlebitis.
Hepatic: gamma GT increased, ALT increased, AST increased.
Hematologic: anemia, leukopenia.
Metabolic and Nutritional: alkaline phosphatase increased, weight loss.
Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving anastrozole. Increases in LDL cholesterol have been shown to contribute to these changes.
Musculoskeletal: myalgia, arthralgia, pathological fracture.
Nervous: somnolence, confusion, insomnia, anxiety, nervousness.
Respiratory: sinusitis, bronchitis, rhinitis.
Skin and Appendages: hair thinning, pruritus.
Urogenital: urinary tract infection, breast pain.
The incidence 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 6 groups, and the adverse events captured in the groups, were prospectively defined.
An examination of the magnitude of change in weight in all patients was also conducted. Thirty-four percent (87/253) of the patients treated with megestrol acetate experienced weight gain of 5% or more and 11% (27/253) of the patients treated with megestrol acetate experienced weight gain of 10% or more. Among patients treated with anastrozole 1 mg, 13% (33/262) experienced weight gain of 5% or more and 3% (6/262) experienced weight gain of 10% or more. On average, this 5 to 10% weight gain represented between 6 and 12 pounds.
No patients receiving anastrozole or megestrol acetate discontinued treatment due to drug-related weight gain.
Postmarketing Experience: Vaginal bleeding has been reported infrequently, mainly in patients during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no clinical experience of accidental overdosage. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of 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 well 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, consideration should be given to the possibility 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.
Dosage And Administration: Anastrozole should be administered 1 mg orally, once a day. Concomitant administration of steroid therapy is not necessary.
Patients with Hepatic Impairment: Although the apparent oral clearance of anastrozole was decreased in subjects with cirrhosis due to alcohol abuse, plasma anastrozole concentrations remained within the range seen across all clinical trials in subjects without liver disease. Therefore, no changes in dose are recommended for patients with mild-to-moderate hepatic impairment, although patients should be monitored for side effects. Anastrozole has not been studied in patients with severe hepatic impairment (see Pharmacology, Special Populations – Hepatic Insufficiency).
Patients with Renal Impairment: No changes in dose are necessary for patients with renal impairment (see Pharmacology, Special Populations – Renal Insufficiency).
Information for the Patient: See Blue Section – Information for the Patient “Arimidex”.
Availability And Storage: Each white, biconvex, film-coated tablet, intagliated with “Adx 1” on one side and a logo on the other side (“A” for Arimidex), contains: anastrozole 1 mg. Nonmedicinal ingredients: lactose, macrogol 300, magnesium stearate, methylhydroxypropylcellulose, polyvidone, sodium starch glycolate and titanium dioxide. Calendar packs of 30. Store at room temperature (15 to 30°C).
ARIMIDEX® Zeneca Anastrozole Nonsteroidal Aromatase Inhibitor