Approval date: November 27, 2006
Revision date: 11 November 2013
Modification date: 08/14/2007
Modification date: 01 December 2013
Modification date: December 24, 2007
Modification date: 01 December 2015
Modification Date: 03/01/2008
Modification Date.
Revision Date: 02/12/2011
Anastrozole Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warning: This product is desiccant in the package, please do not eat by mistake.
Drug Name]
Generic Name: Anastrozole Tablets
English name: Anastrozole Tablets
Hanyu Pinyin：Anaquzuo Pian
Ingredients
The main ingredient of this product is: Anastrozole.
Chemical name: α,α,α’,α’-Tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-l,3-benzenediacetonitrile
Chemical structure formula.
Molecular formula: C17H19N5
Molecular weight: 293.37
Excipients: lactose, povidone K30, sodium carboxymethyl starch, magnesium stearate, film-coated premix (gastric soluble type)
【Properties】.
This product is a white film-coated tablet, which appears white after removing the coating.
Indications】
It is indicated for the treatment of advanced breast cancer in postmenopausal women. It may be considered for use in estrogen receptor negative patients who show positive clinical response to tamoxifen.
Indicated for the adjuvant treatment of early stage breast cancer in postmenopausal women with positive hormone receptors.
For the adjuvant treatment of hormone receptor positive early stage breast cancer in postmenopausal women who have received adjuvant tamoxifen therapy for 2 to 3 years.
Specification】 1mg
Dosage]
Adults (including the elderly): Take 1 tablet orally once daily.
Children: This drug is not recommended for children (see section “Pharmacology”, “Pharmacokinetics”).
Renal impairment: No dose adjustment is necessary for patients with mild to moderate renal impairment.
Hepatic impairment: No dose adjustment is necessary for mild hepatic impairment.
For early stage breast cancer, the recommended course of treatment is 5 years.
[Adverse Reactions].
Unless otherwise stated, the following adverse event frequencies are based on the number of adverse events reported in a large phase III study (ATAC study) of 9,366 postmenopausal women with operable breast cancer treated for 5 years.
Frequency Organ system category adverse reactions were very common
(≥10%) Vascular system: hot flashes, usually mild to moderate General: malaise, usually mild to moderate Musculoskeletal and connective tissue: arthralgia/joint stiffness
Arthritis Nervous system: headache, usually mild to moderate Gastrointestinal: nausea, usually mild to moderate Skin and subcutaneous tissues: rash, usually mild to moderate Common
(≥1%, <10%) Skin and subcutaneous tissues: hair thinning (alopecia), usually mild to moderate
Allergic reactions gastrointestinal: diarrhea, usually mild to moderate
Vomiting, usually mild to moderate Neurological: drowsiness, usually mild to moderate
Carpal tunnel syndrome*
Sensory disturbances (including abnormal sensation, loss of taste, and abnormal taste) Hepatobiliary system: elevated alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase Reproductive system and breast: vaginal dryness, usually mild to moderate
Vaginal bleeding, usually mild to moderate* Metabolic and nutritional: anorexia, usually mild to moderate
Hypercholesterolemia, usually mild to moderate Musculoskeletal and connective tissue: bone pain, myalgia occasionally
(≥0.1%, <1%) Metabolic and nutritional: hypercalcemia (with or without elevated thyroxine) Hepatobiliary system: elevated gamma-GT and bilirubin
Hepatitis skin and subcutaneous tissue: urticaria musculoskeletal and connective tissue: trigger finger rare
(≥0.01%, <0.1%) Skin and subcutaneous tissues: erythema multiforme
Allergic-like reactions
Cutaneous vasculitis (including some reports of allergic purpura) Unknown skin and subcutaneous tissues: Stevens-Johnson syndrome**
Angioedema*** Vaginal bleeding is commonly reported, primarily in the first few weeks of treatment change from the original hormonal therapy to this product in patients with advanced breast cancer. Further evaluation should be considered if there is persistent bleeding.
**The available data do not allow assessment of
Because this product reduces circulating levels of estrogen, it is possible that it may cause a decrease in bone mineral density, putting some patients at increased risk of fracture.
Adverse events in the ATAC trial
The median duration of treatment for adjuvant therapy used for safety assessment was 59.8 months and 59.6 months for the anastrozole 1 mg group and the tamoxifen 20 mg group, respectively.
The table below lists adverse events with an incidence of at least 5% that occurred during or within 14 days after the end of treatment in each treatment group.
Adverse events with an incidence of at least 5% during or within 14 days of the end of treatment for each treatment group
Body system and adverse events, preferred COSTART vocabulary* Number of patients (%) Anastrozole 1 mg (N=3092) Tamoxifen 20 mg (N=3094) General debilitation 575 (19) 544 (18) Pain 533 (17) 485 (16) Back pain 321 (10) 309 (10) Headache 314 (10) 249 (8) Abdominal pain 271 ( 9) 276 (9) Infection 285 (9) 276 (9) Accidental injury 311 (10) 303 (10) Influenza syndrome 175 (6) 195 (6) Chest pain 200 (7) 150 (5) Tumors 162 (5) 144 (5) Cysts 138 (5) 162 (5) Cardiovascular system Vasodilation (hot flashes) 1104 (36) 1264 (41) Hypertension 402 (13) 349 (11) Digestive system Nausea 343 (11) 335 (11) Constipation 249 (8) 252 (8) Diarrhea 265 (9) 216 (7) Dyspepsia 206 (7) 169 (6) Gastrointestinal discomfort 210 (7) 158 (5) Blood and lymphatic system Lymphedema 304 (10) 341 (11) Anemia 113 (4 ) 159 (5) Metabolism and nutrition Peripheral edema 311 (10) 343 (11) Weight gain 285 (9) 274 (9) Hypercholesterolemia 278 (9) 108 (3.5) Musculoskeletal system Arthritis 512 (17) 445 (14) Arthralgia 467 (15) 344 (11) Osteoporosis 325 (11) 226 (7) Fractures 315 ( (10) 209 (7) bone pain 201 (7) 185 (6) arthrosis 207 (7) 156 (5) joint abnormalities 184 (6) 160 (5) myalgia 179 (6) 160 (5) nervous system depression 413 (13) 382 (12) insomnia 309 (10) 281 (9) dizziness 236 (8) 234 (8) anxiety 195 (6) 180 (6 ) Sensory abnormalities 215 (7) 145 (5) Respiratory system Pharyngitis 443 (14) 422 (14) Increased cough 261 (8) 287 (9) Dyspnea 234 (8) 237 (8) Sinusitis 184 (6) 159 (5) Bronchitis 167 (5) 153 (5) Skin and adnexa Rash 333 (11) 387 (13) Hyperhidrosis 145 (5) 177 (6) Special sensations Cataracts 182 (6) 213 (7) Genitourinary system Leukorrhea abnormalities 86 (3) 286 (9) Urinary tract infection 244 (8) 313 (10) Breast pain 251 (8) 169 (6) Breast tumor 164 (5) 139 (5) Vulvovaginitis 194 (6) 150 (5) Vaginal bleeding† 122 (4) 180 (6) Vaginitis 125 (4) 158 (5)
N = number of patients treated
*. A patient may have more than one adverse event, including more than one in the same body system
+ vaginal bleeding without further diagnosis
The table below shows the incidence of patient-reported pre-defined adverse events (with or without causality) during treatment or within 14 days after the end of treatment in the ATAC trial.
Number of patients with adverse events (%) Anastrozole (N=3092) Tamoxifen (N=3094) Hot flashes 1104 (35.7%) 1264 (40.9%) Arthralgia/stiffness 1100 (35.6%) 911 (29.4%) Mood abnormalities 597 (19.3%) 554 (17.9%) Fatigue/weakness 575 (18.6%) 544 ( 17.6%) Nausea and vomiting393 (12.7%) 384 (12.4%) Fractures315 (10.2%) 209 (6.8%)
Spine, hip, carpal/Colles fractures 133 (4.3%) 91 (2.9%)
Carpal/Colles fracture 67 (2.2%) 50 (1.6%) Spine fracture 43 (1.4%) 22 (0.7%) Hip fracture 28 (0.9%) 26 (0.8%) Cataract 182 (5.9%) 213 (6.9%) Vaginal bleeding 167 (5.4%) 317 (10.2%) Ischemic cardiovascular disease 127 (4.1%) 104 (3.4%) Angina 71 (2.3%) 51 (1.6%) Myocardial infarction 37 (1.2%) 34 (1.1%)
Coronary artery abnormalities 25 (0.8%) 23 (0.7%) Myocardial ischemia 22 (0.7%) 14 (0.5%) Vaginal overflow 109 (3.5%) 408 (13.2%) Any venous thromboembolic event 87 (2.8%) 140 (4.5%)
Deep vein thromboembolic events (including pulmonary embolism) 48 (1.6%) 74 (2.4%) Ischemic cerebrovascular events 62 (2.0%) 88 (2.8%) Endometrial cancer 4 (0.2%) 13 (0.6%) After a median follow-up period of 68 months, the incidence of fracture in the anastrozole and tamoxifen groups was 22/1000 patient-years and 15/1000 patient-years, respectively . The fracture rates observed in the anastrozole group were similar to the range reported in the corresponding age-menopausal population. It was not possible to determine whether the fracture and osteoporosis rates observed in patients in the anastrozole group in the ATAC trial reflected a protective effect of tamoxifen, a specific effect of anastrozole, or both.
The incidence of osteoporosis was 10.5% in the anastrozole group and 7.3% in the tamoxifen group.
Suspected adverse reaction reports
It is important to report suspected adverse reactions after the drug is approved. It allows continuous monitoring of the benefit/risk balance of the drug. Drug manufacturers, operators and medical institutions should report all suspected adverse reactions through the national adverse drug reaction monitoring system in a timely manner.
[Contraindications].
This product is contraindicated in the following conditions.
-Premenopausal women.
-Pregnant or lactating women.
-Patients with severe renal impairment (creatinine clearance less than 30 ml/min).
-Patients with moderate to severe hepatic disease.
-Patients with known hypersensitivity to anastrozole or any of its components.
Other estrogen-containing therapies may reduce the pharmacological effects of this product, so its use in combination with this product is prohibited.
Combination therapy with tamoxifen (see “Drug Interactions” section).
Precautions]
The safety and efficacy of this product have not been established in children and therefore it is not recommended for use in children (see section “Pharmacokinetics” of “Pediatric Use”).
In patients with suspected hormonal status, menopause (natural or artificial) should be determined by biochemical testing.
There is no information to support the safe use of this product in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (creatinine clearance less than 30 ml/min).
Because it decreases circulating levels of estrogen, it may lead to decreased bone mineral density and possibly an increased risk of fracture. The use of bisphosphonates may prevent further decreases in BMD caused by anastrozole in postmenopausal women and may be considered. Women with osteoporosis or potential risk of osteoporosis should have regular bone density examinations, such as DEXA scans, at the start of treatment and periodically thereafter. Treatment or prevention of osteoporosis should be initiated at the appropriate time and carefully monitored.
This product contains lactose. Patients with galactose intolerance, primary intestinal lactase deficiency, or glucose-galactose malabsorption genetic disorders should not take this product.
In the ATAC trial, more patients treated with anastrozole reported elevated serum cholesterol compared to those treated with tamoxifen (9% in the anastrozole-treated group and 3.5% in the tamoxifen-treated group).
In the ATAC trial, an increased incidence of ischemic cardiovascular events was observed in women with pre-existing cardiac disease (17% in the anastrozole group and 10% in the tamoxifen group). Therefore, patients with pre-existing ischemic heart disease need to weigh the risk benefit before using anastrozole.
Use with caution in athletes.
Effects on driving and mechanical handling ability
This product is unlikely to affect the patient’s ability to drive and operate machinery, but malaise and drowsiness have been reported, and special attention should be paid when these symptoms persist in driving and operating machinery.
Pregnant women and nursing mothers
This product is contraindicated in pregnant or lactating women.
Pediatric use]
The safety and efficacy of this product have not been established in children; therefore, this product is not recommended for use in children.
Three clinical trials have been conducted in pediatric patients (two in adolescent boys with male gynecomastia and one in girls with Mc-Old’s syndrome).
Male female-pattern breast study
Trial 0006 was a randomized, double-blind, multicenter study in 82 adolescent boys (aged 11 to 18 years, including 11 and 18 years) with male female-pattern breasts lasting 12 months or more, treated with anastrozole 1 mg/day or once-daily placebo for up to 6 months. After 6 months of treatment, there was no significant difference in the number of patients with a 50% or greater decrease in total breast volume between the anastrozole 1 mg treatment group and the placebo group of subjects.
Trial 001 was an open, multi-dose pharmacokinetic study of anastrozole 1 mg/day in 36 adolescent boys with male female-pattern breasts of less than 12 months’ duration. The secondary objective was to evaluate the proportion of patients with at least 50% reduction in male gynecomastia volume from baseline in both breasts calculated from Day 1 to 6 months after study treatment, as well as patient tolerability and safety.
A pharmacodynamic subgroup study of 25 boys selected in this study aimed to explore the potential benefit of anastrozole. A decrease in total breast volume of 50% or more at 6 months was found in 55.6% (as measured by ultrasound) and 77.8% (as measured by calipers) of boys (observational data only, no statistical analysis of the above results was performed).
Mai-O’er’s Syndrome Study
Trial 0046 was an international multicenter, open, exploratory trial of anastrozole in 28 girls (aged 2 years to ≤10 years) with Mai-O’er syndrome (MAS). The primary endpoint was to evaluate the safety and efficacy of anastrozole 1 mg/day in patients with Mc-Older’s syndrome. Efficacy of study treatment was based on the proportion of patients meeting pre-specified criteria related to vaginal bleeding, bone age and growth rate.
No statistically significant changes in the frequency of vaginal bleeding days were seen when treatment was administered. There were no clinically significant changes in Tanner stage, mean ovarian volume or mean uterine volume. No statistically significant change in the rate of bone age growth was observed at the time of treatment compared to the rate of bone age growth at baseline. The growth rate (cm/year) decreased significantly (p<0.05) from pre-treatment and from month 0 to month 12 and from pre-treatment to month 2 six months (month 7 to month 12). Among patients with vaginal bleeding at baseline, the daily frequency of bleeding decreased by more than 50% in 28% of patients at the time of treatment; 40% of patients experienced cessation of bleeding for more than 6 months; and 12% of patients experienced cessation of bleeding for more than 12 months.
The overall evaluation of adverse events in children under 18 years of age did not indicate any safety or tolerability concerns.
[Geriatric Use].
See [Dosage].
Drug Interactions]
Clinical interaction studies with antipyrine and cimetidine have shown that this product is less likely to cause cytochrome P-450-mediated drug interactions when combined with other drugs.
A review of safety data from clinical trials did not reveal any significant interactions with other drugs commonly used in clinical practice. There were no clinically significant interactions with bisphosphonate drugs.
Estrogen-containing therapies may reduce the pharmacological effects of this product and should not be used in combination with this product.
Tamoxifen may reduce the pharmacological effect of this product, so it should not be used in combination with this product.
Drug overdose
There is limited experience with accidental drug overdose. The acute toxicity of anastrozole has been shown to be very low in animal studies. Different doses have been studied in clinical studies: single doses up to 60 mg in healthy male volunteers and up to 10 mg per day in postmenopausal women with advanced breast cancer were still well tolerated. Single doses with life-threatening symptoms have not been observed. There is no specific antidote for overdose and treatment can only be symptomatic.
The possibility of simultaneous application of multiple drugs should be considered when managing an overdose.
If the patient is awake, induced vomiting can be performed. Dialysis may be effective because of the low protein binding rate of the product. General supportive supervision should be given including close observation of the patient and monitoring of vital signs.
Pharmacology and Toxicology
Pharmacological effects
Anastrozole is a selective non-steroidal aromatase inhibitor that significantly reduces serum estradiol concentrations and does not significantly affect the production of adrenocorticotropic hormones or aldosterone. The main source of estradiol in postmenopausal women is the conversion of androstenedione to estrone by the action of aromatase complexes in peripheral tissues and the subsequent conversion of estrone to estradiol. Reducing circulating levels of estradiol has proven beneficial in breast cancer treatment.
Effect on estradiol
When treated with the recommended daily dose of 1 mg anastrozole, estradiol levels are reduced by approximately 70% within 24 hours and by approximately 80% after 14 days of dosing. Inhibition of serum estradiol persisted for up to 6 days after discontinuation of daily anastrozole 1 mg.
Effects on corticosteroids
Cortisol or aldosterone secretion was not affected by daily doses of up to 10 mg, as measured before or after ACTH stimulation tests. Therefore, corticosteroid supplementation is not required when taking this product.
Effects on other endocrine hormones
This product has no progestin-like, androgen-like or estrogen-like activity.
As with all treatment decisions, women with breast cancer and their physicians should evaluate the relative benefits and risks of treatment.
When this product is used in combination with tamoxifen, the efficacy and safety profile is similar to that of tamoxifen alone, regardless of hormone receptor status. The exact mechanism is unknown, but it is not thought to be caused by a reduction in the degree of estradiol suppression by this product.
Toxicological studies.
Acute toxicity
In acute toxicity tests in rodents, the LD50 for anastrozole was >100 mg/kg/day orally and >50 mg/kg/day intraperitoneally. In dogs, the LD50 was >45 mg/kg/day orally and >50 mg/kg/day intraperitoneally.
Long-term toxicity
Multiple administration toxicity tests using rats and dogs did not establish anastrozole as a non-effective dose level, and the responses observed in the small (1 mg/kg/day) and medium (3 mg/kg/day in dogs and 5 mg/kg/day in rats) dose groups were related to the pharmacological effects of the compound itself or to the enzyme-induced properties of anastrozole, with no significant toxic effects or degenerative changes.
Mutagenicity test
Genotoxicity studies with anastrozole have demonstrated that it is not a mutagenic or divisive agent.
Reproductive toxicity
Female rats given anastrozole orally at 1 mg/kg/day had a high rate of sterility and an increased rate of preimplantation failure at 0.02 mg/kg/day. All of these effects occurred at doses corresponding to clinical applications. Effects in humans cannot be excluded. These effects are related to the pharmacological action of the compound and are completely reversed after 5 weeks of discontinuation.
No teratogenic effects were observed in pregnant rats and rabbits given anastrozole orally up to 1.0 and 0.2 mg/kg/day, respectively, and these observed phenomena (placenta enlargement in rats and abortion in rabbits) were related to the pharmacological action of the compound.
In rats given anastrozole at doses of 0.02 mg/kg/day or higher (rats from 17 days after pregnancy to 22 days after delivery) the survival rate of the offspring was reduced, and these phenomena were related to the pharmacological effects of the compound on delivery. No side effects on the behavior or reproductive function of the first generation offspring were observed in rats treated with anastrozole in the maternal generation.
Carcinogenicity tests
Results of a 2-year tumor formation study in rats showed an increase in the incidence of liver tumors and uterine stromal polyps in females and thyroid adenomas in males only at high doses of anastrozole (25 mg/kg/day). The doses that caused such alterations were 100 times higher than the human therapeutic dose and therefore were not considered to be clinically relevant to anastrozole treatment.
The results of a 2-year tumor formation study in mice showed that disturbances in the incidence of benign ovarian tumors and lymphoreticular tumors (decreased female histiocytic tumors and increased death due to lymphoma) could be induced. Such alterations are thought to be specific to the effects of aromatase inhibitors in mice and are therefore not considered to be clinically relevant to the treatment with anastrozole.
[Pharmacokinetics].
Anastrozole is rapidly absorbed orally, with maximum plasma concentrations usually occurring within 2 hours after dosing (under fasting conditions).
Anastrozole is slowly cleared, with a plasma clearance half-life of 40-50 hours. Food mildly affects the rate of absorption, but not the extent of absorption. When the tablet is taken once daily, the slight effect of food on the rate of absorption does not affect the plasma steady-state concentration. Plasma concentrations reach 90-95% of steady-state concentrations after seven days of administration, and there is no evidence that the pharmacokinetic parameters of anastrozole are time- or dose-dependent.
The age of postmenopausal women does not affect the pharmacokinetics of the drug.
Pharmacokinetic studies of the drug have not been performed in children. In boys with adolescent male gynecomastia, anastrozole is rapidly absorbed, widely distributed, and slowly eliminated with an elimination half-life of approximately 2 days. Anastrozole was widely distributed and slowly eliminated in girls with an elimination half-life of approximately 0.8 days. The plasma protein binding rate of anastrozole was only 40%. Both sex and body surface area significantly affected oral clearance (CL/F) and apparent volume of the central compartment (V/F). Comparison of the pharmacokinetics of anastrozole in boys and girls yielded mean CL/F and V/F that were approximately 30% and 40% lower in girls than in boys, respectively.
The product is extensively metabolized in postmenopausal women, with less than 10% of the dose excreted in its original form in the urine within 72 hours of administration. Metabolic processes include N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily in the urine, and the major metabolite triazole in plasma does not inhibit aromatase activity.
The apparent clearance of this drug in patients with stable cirrhosis and renal impairment is within the range of values observed in healthy volunteers.
Storage
Sealed storage
Package
Polyethylene plastic bottle, silica gel desiccant in paper bag for solid medicine. 14 tablets per bottle, 1 bottle per box; 30 tablets per bottle, 1 bottle per box.
Expiration date】 24 months
【Execution standard
Approval number】
State Drug Certificate H20050328
【Manufacturing enterprise】
Company Name: Yangtze River Pharmaceutical Group Co.
Address: No.1, Yangzijiang South Road, Taizhou City, Jiangsu Province
Postal Code: 225321
Telephone number: 400-988-1999
Fax number: (0523)86976161
Web
Address: www.yangzijiang.com