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Cytostatic Aromatase Inhibitors
Selective non-steroidal aromatase inhibitorUsed for the treatment of breast cancer in postmenopausal womenImproved disease-free survival compared with tamoxifen as adjuvant therapy for early breast cancer; overall survival was similar
Anastrozole/Arimidex Oral Tab: 1mg
1 mg PO once daily. The optimal duration of the therapy is not known, although in the ATAC trial anastrozole was administered for 5 years. After a median of 10 years follow-up, adjuvant treatment with 5 years of anastrozole (n = 3,125) significantly improved disease-free survival in the intent-to-treat population (HR 0.91) as well as the hormone receptor-positive population (HR 0.86) compared with tamoxifen (n = 3,116) in a multicenter, double-blind clinical trial (ATAC) in postmenopausal women. Overall survival was not significantly different.
1 mg PO once daily to complete a total of 5 years of adjuvant hormonal therapy. Compared with 5 consecutive years of tamoxifen, patients switched to anastrozole after 2 to 3 years of tamoxifen experienced significantly improved disease-free survival (DFS; HR 0.35) and event-free survival (EFS; HR 0.15) after a median of 36 months of follow-up. When measured after a median follow-up of 64 months, EFS was still improved by anastrozole. Adverse gastrointestinal symptoms and lipid metabolism disorders were reported more commonly in patients taking anastrozole, while gynecological complaints including endometrial carcinoma were reported more commonly in patients taking tamoxifen; bone fracture rates were similar in the 2 groups. In another phase 3 clinical trial (n = 979), treatment with anastrozole after 2 years of tamoxifen therapy to complete 5 years total significantly improved DFS (HR 0.66) and overall survival (HR 0.53) compared with tamoxifen alone. Furthermore, in a combined analysis of this trial and another phase 3 trial (n = 2,262), EFS was significantly improved by switching to anastrozole after 2 to 3 years of tamoxifen compared to continuing tamoxifen for 5 years. There were significantly more fractures and fewer thromboses in patients who received anastrozole compared with tamoxifen. In a meta-analysis of these 3 studies (data from the above studies), patients randomized to anastrozole after 2 to 3 years of tamoxifen (n = 2,009) had improved DFS (HR 0.59), EFS (HR 0.55), and overall survival (HR 0.71) compared with patients taking 5 years of tamoxifen (n = 1,997) after a median follow-up of 30 months.
1 mg PO once daily until tumor progression is noted. In a double-blind clinical trial, first-line treatment of hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women with anastrozole (n = 171) significantly improved median time to progression (TTP) compared with tamoxifen (n = 182) (11.1 months vs. 5.6 months); best objective response rate (ORR) was 21.1% versus 17%, respectively. In another double-blind clinical study with similar trial design, median TTP (8.2 months vs. 8.3 months) and ORR (32.9% vs. 32.6%) were similar between the anastrozole (n = 340) and tamoxifen (n = 328) arms.
1 mg PO once daily until disease progression. In 2 controlled clinical trials, treatment with anastrozole after progression following tamoxifen therapy resulted in similar median time to progression (4.4 to 5.7 months vs. 3.9 to 5.1 months), median time to death (24.3 to 29.6 months vs. 19.8 to 26.7 months), and objective response rate (12.5% to 12.6% vs. 10.2% to 14.4%) compared with megestrol 160 mg once daily in postmenopausal women with advanced breast cancer.
1 mg PO once daily in combination with trastuzumab (4 mg/kg IV over 90 minutes on week 1 followed by 2 mg/kg IV over 30 minutes once weekly starting week 2). Treatment should be continued until disease progression or unacceptable toxicity. In a phase III trial, 207 patients were randomized to receive anastrozole with or without trastuzumab. The primary endpoint, progression-free survival, was significantly improved with the addition of trastuzumab (4.8 months vs. 2.4 months, p = 0.0016). Overall survival was not significantly different between the treatment groups (28.5 months vs. 23.9 months, p = 0.325). Of note, 70% of patients in the anastrozole alone arm received a trastuzumab-containing regimen after developing progressive disease on anastrozole. Cardiac events occurred more frequently in the trastuzumab arm (14 events vs. 2 events); however, the incidence of grade 3 or 4 events was similar between the groups (2 events each).
1 mg PO once daily in combination with fulvestrant 500 mg IM as two 5 mL injections (one in each buttock) on day 1, followed by 250 mg IM every 2 weeks for 2 doses then 250 mg IM every 4 weeks thereafter was evaluated in 2 randomized, open label, phase III trials. Treatment was continued until disease progression.
Preliminary data indicate that 1 mg PO once daily may be effective in reducing uterine leiomyomata size and improving patient symptoms. In a study of 41 premenopausal women, anastrozole 1 mg/day PO for three 28-day cycles decreased leiomyomata volumes by 55.7%. Women with larger leiomyomata at baseline (i.e., > 50 mm) tended to experience the greatest reduction in leiomyomata volume; additionally, only women > 40 years of age experienced a reduction in leiomyomata volume. Symptoms such as vaginal bleeding and pelvic pain/pressure were less, and hematocrit concentrations increased indicating an improvement in menstrual irregularities.
1 mg/day PO for up to 6 months, with or without other hormonal therapies, has been studied. According to treatment guidelines, aromatase inhibitors (e.g., anastrozole) in combination with oral contraceptive pills, progestogens, or GnRH analogues are recommended for women with pain associated with rectovaginal endometriosis, refractory to other medical or surgical treatment.
†Indicates off-label use
1 mg per day PO.
Safety and efficacy have not been established.
Mild to moderate hepatic impairment: No dosage adjustments are recommended.Severe hepatic impairment: Anastrozole has not been studied in this patient population.
No dosage adjustment needed.
Hazardous Drugs ClassificationNIOSH 2016 List: Group 1 NIOSH (Draft) 2020 List: Table 2Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets will increase exposure.
Administer at the same time every day with or without food.
Arimidex:- Store at controlled room temperature (between 68 and 77 degrees F)
Use anastrozole with caution in patients with pre-existing hypercholesterolemia. During the ATAC trial, postmenopausal women receiving anastrozole had increased serum cholesterol compared to patients receiving tamoxifen (9% vs. 3.5%). Postmenopausal women with early breast cancer who develop hypercholesterolemia during anastrozole treatment should be managed according to current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations.
Consider bone mineral density (BMD) monitoring in patients treated with anastrozole. Use anastrozole with caution in patients with pre-existing osteoporosis. In the ATAC trial bone substudy, patients receiving anastrozole had a mean decrease in both lumbar spine and total hip BMD at 12 and 24 months compared to baseline. After a median follow-up of 68 months, significantly more bone fractures occurred in patients taking anastrozole compared with tamoxifen (11% vs. 7.7%). Significantly more bone fractures also occurred in patients treated with anastrozole compared with tamoxifen in a combined analysis of 2 other clinical trials (ABCSG 8 and ARNO 95) (2% vs. 1%).
Use anastrozole with caution in patients with pre-existing ischemic cardiac disease. In the ATAC trial, postmenopausal women with pre-existing ischemic heart disease had an increased incidence of ischemic cardiovascular events compared with tamoxifen (17% vs. 10%).
The efficacy of anastrozole in children for the treatment of pubertal gynecomastia in adolescent boys and precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated. In a multicenter, randomized clinical trial of boys with pubertal gynecomastia (n = 80), there was not a significant difference in the percentage of patients experiencing a 50% or greater reduction in gynecomastia after 6 months of treatment with anastrozole compared with placebo; secondary efficacy analyses (absolute change in breast volume, reduced calculated volume of gynecomastia, breast pain resolution) were consistent with the primary efficacy analysis. Serum estradiol concentrations at 6 months were reduced by 15.4% in the anastrozole group compared with 4.5% in the placebo arm. In another multicenter, single-arm clinical trial in girls with McCune-Albright Syndrome and progressive precocious puberty, there were no on-treatment significant reductions in the frequency of vaginal bleeding days or the rate of increased bone age. There were also no clinically significant changes in Tanner staging, mean ovarian volume, mean uterine volume, or mean predicted adult height.
Pregnancy should be avoided by females of reproductive potential during anastrozole treatment and for at least 3 weeks after the last dose. Although there are no adequately controlled studies in pregnant animals or women, anastrozole can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving anastrozole should be apprised of the potential hazard to the fetus. In animal reproduction studies, anastrozole crossed the placenta and caused increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased live fetuses) when administered to pregnant rats and rabbits during organogenesis at doses approximately 1/3 and 1 times the recommended human dose on a mg/m2 basis. These effects were dose-related in rats, and placental weights were significantly increased at doses greater than or equal to the dose comparable to the recommended human dose on a mg/m2 basis. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights) occurred in rats at doses that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose. In rabbits, pregnancy failure occurred at doses about 16 times the recommended human dose on a mg/m2 basis.
Counsel patients about the reproductive risk and contraception requirements during anastrozole treatment. Anastrozole can be fetotoxic and teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 weeks after treatment with anastrozole. Females of reproductive potential should undergo pregnancy testing prior to initiation of anastrozole. Women who become pregnant while receiving anastrozole should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of anastrozole on human fertility, female infertility has been observed in animal studies.
Due to the potential for serious adverse reactions in nursing infants from anastrozole, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether anastrozole is present in human milk, although many drugs are excreted in human milk.
bone fractures / Delayed / 2.0-15.0new primary malignancy / Delayed / 5.0-13.7thrombosis / Delayed / 2.0-4.0thromboembolism / Delayed / 2.0-4.0myocardial infarction / Delayed / 0.9-1.2endometrial cancer / Delayed / 0.2-0.2pulmonary embolism / Delayed / Incidence not knownretinal thrombosis / Delayed / Incidence not knownstroke / Early / Incidence not knownerythema multiforme / Delayed / Incidence not knownStevens-Johnson syndrome / Delayed / Incidence not knownangioedema / Rapid / Incidence not knownanaphylactoid reactions / Rapid / Incidence not known
hot flashes / Early / 12.0-36.0peripheral vasodilation / Rapid / 25.0-36.0depression / Delayed / 5.0-13.0hypertension / Early / 2.0-13.0angina / Early / 2.3-11.6osteoporosis / Delayed / 11.0-11.0peripheral edema / Delayed / 5.0-10.0dyspnea / Early / 8.0-10.0constipation / Delayed / 7.0-9.0hypercholesterolemia / Delayed / 0-9.0chest pain (unspecified) / Early / 5.0-7.0bone pain / Delayed / 6.0-7.0edema / Delayed / 0-7.0vaginitis / Delayed / 4.0-6.0cataracts / Delayed / 0-6.0vaginal bleeding / Delayed / 2.0-5.0confusion / Early / 0-5.0phlebitis / Rapid / 0-5.0leukopenia / Delayed / 0-5.0anemia / Delayed / 2.0-5.0elevated hepatic enzymes / Delayed / 0-5.0hypertonia / Delayed / 0-3.0skin ulcer / Delayed / 0-1.0hypercalcemia / Delayed / Incidence not knownjaundice / Delayed / Incidence not knownhyperbilirubinemia / Delayed / Incidence not knownhepatitis / Delayed / Incidence not knowntumor flare / Delayed / Incidence not known
nausea / Early / 11.0-19.0fatigue / Early / 16.0-19.0asthenia / Delayed / 16.0-19.0arthralgia / Delayed / 2.0-15.0infection / Delayed / 2.0-14.0headache / Early / 9.0-13.0back pain / Delayed / 10.0-11.0rash / Early / 6.0-11.0cough / Delayed / 8.0-11.0insomnia / Early / 2.0-10.0diarrhea / Early / 8.0-9.0abdominal pain / Early / 7.0-9.0vomiting / Early / 0-9.0weight gain / Delayed / 2.0-9.0dizziness / Early / 6.0-8.0dyspepsia / Early / 0-7.0anorexia / Delayed / 0-7.0influenza / Delayed / 2.0-7.0xerostomia / Early / 0-6.0anxiety / Delayed / 2.0-6.0myalgia / Early / 2.0-6.0sinusitis / Delayed / 2.0-6.0pharyngitis / Delayed / 0-6.0weight loss / Delayed / 0-5.0pelvic pain / Delayed / 0-5.0hyperhidrosis / Delayed / 2.0-5.0alopecia / Delayed / 2.0-5.0pruritus / Rapid / 2.0-5.0rhinitis / Early / 0-5.0fever / Early / 0-5.0malaise / Early / 0-5.0paresthesias / Delayed / 0-5.0vaginal discharge / Delayed / 0-4.0leukorrhea / Delayed / 2.0-3.0carpal tunnel syndrome / Delayed / 0-2.5lethargy / Early / 0-1.0urticaria / Rapid / Incidence not known
Estrogens: (Contraindicated) Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Estrogens, including those found in hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors such as Anastrozole. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Aromatase inhibitors exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme. Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA. Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA. Tamoxifen: (Major) Avoid coadministration of tamoxifen with anastrozole, as there is no benefit when compared to tamoxifen alone. Additionally, in the ATAC trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced the anastrozole plasma concentration by 27% compared to that achieved with anastrozole alone; the tamoxifen concentration was not altered.
Anastrozole is a selective non-steroidal aromatase inhibitor. 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. Suppression of estrogen biosynthesis in peripheral tissues and in cancer cells can be achieved by specifically inhibiting the aromatase enzyme. Anastrozole significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone. Anastrozole doses of 1mg or more suppressed mean serum concentrations of estradiol in postmenopausal women with advanced breast cancer to the lower limit of detection (3.7 pmol/L) in multiple daily dosing trials (range, 0.5 mg to 10 mg). The recommended dose of 1 mg reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing of anastrozole 1 mg. The effect of anastrozole in premenopausal women with early or advanced breast cancer has not been studied. However, 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. Anastrozole did not affect cortisol or aldosterone secretion at baseline or in response to ACTH in multiple daily dosing trials (range, 3 mg to 10 mg). Similarly, there was no increase in TSH during administration of anastrozole 5 mg or 10 mg daily.
Anastrozole is administered orally. It is 40% bound to plasma proteins in the therapeutic range. Steady-state plasma concentrations are approximately 3- to 4-fold higher than levels observed after a single dose of anastrozole. The mean elimination half-life of anastrozole is 50 hours; steady-state concentrations are reached after approximately 7 days of daily dosing. The pharmacokinetics of anastrozole are linear over the dose range of 1 mg to 20 mg, and do not change with repeated dosing. Hepatic metabolism by N-dealkylation, hydroxylation, and glucuronidation accounts for approximately 85% of elimination. Three metabolites have been identified in human plasma and urine (triazole, a glucuronide conjugate of anastrozole, and a glucuronide conjugate of hydroxy-anastrozole). The major circulating metabolite, triazole, lacks pharmacologic activity. Eighty-five percent of radiolabeled anastrozole was recovered in feces and urine. Renal elimination accounts for approximately 10% of total clearance. Affected cytochrome P450 isoenzymes: NoneAnastrozole inhibits CYP1A2, CYP2C8/9, and CYP3A4 in vitro with Ki values approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose.
Absorption of anastrozole is rapid, with maximum plasma concentrations occurring within 2 hours of dosing (Tmax) under fasting conditions. Studies with radiolabeled drug show that it is well absorbed into the systemic circulation, with 85% bioavailability. Food reduces the rate but not the overall extent of anastrozole absorption. The mean Cmax of anastrozole decreased by 16% and the median Tmax was delayed from 2 to 5 hours when anastrozole was administered 30 minutes after food.