1. Name Of The Medicinal Product
Arimidex® 1 mg film-coated tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 1 mg anastrozole.
Excipients
Each film-coated tablet contains 93 mg of lactose monohydrate (see section 4.4). For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
White, round, biconvex tablet with logo on one side and strength on the other.
4. Clinical Particulars
4.1 Therapeutic Indications
Arimidex is indicated for the:
• Treatment of hormone receptor-positive advanced breast cancer in postmenopausal women.
• Adjuvant treatment of hormone receptor-positive early invasive breast cancer in postmenopausal women.
• Adjuvant treatment of hormone receptor-positive early invasive breast cancer in postmenopausal women who have received 2 to 3 years of adjuvant tamoxifen.
4.2 Posology And Method Of Administration
Posology
The recommended dose of Arimidex for adults including the elderly is one 1 mg tablet once a day.
For postmenopausal women with hormone receptor-positive early invasive breast cancer, the recommended duration of adjuvant endocrine treatment is 5 years.
Special populations
Paediatric population
Arimidex is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see sections 4.4 and 5.1).
Renal impairment
No dose change is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, administration of Arimidex should be performed with caution (see section 4.4 and 5.2).
Hepatic impairment
No dose change is recommended in patients with mild hepatic disease. Caution is advised in patients with moderate to severe hepatic impairment (see section 4.4).
Method of administration
Arimidex should be taken orally.
4.3 Contraindications
Arimidex is contraindicated in:
• Pregnant or breast-feeding women.
• Patients with known hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.
4.4 Special Warnings And Precautions For Use
General
Arimidex should not be used in premenopausal women. The menopause should be defined biochemically (luteinizing-hormone [LH], follicle stimulating hormone [FSH], and/or estradiol levels) in any patient where there is doubt about menopausal status. There are no data to support the use of Arimidex with LHRH analogues.
Co-administration of tamoxifen or estrogen-containing therapies with Arimidex should be avoided as this may diminish its pharmacological action (see section 4.5 and 5.1).
Effect on bone mineral density
As Arimidex lowers circulating estrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture (see section 4.8).
Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. The use of specific treatments, e.g., bisphosphonates, may stop further bone mineral loss caused by Arimidex in postmenopausal women and could be considered (see section 4.8).
Hepatic impairment
Arimidex has not been investigated in breast cancer patients with moderate or severe hepatic impairment. Exposure to anastrozole can be increased in subjects with hepatic impairment (see section 5.2); administration of Arimidex in patients with moderate and severe hepatic impairment should be performed with caution (see section 4.2). Treatment should be based on a benefit-risk evaluation for the individual patient.
Renal impairment
Arimidex has not been investigated in breast cancer patients with severe renal impairment. Exposure to anastrozole is not increased in subjects with severe renal impairment (GRF<30ml/min, see section 5.2); in patients with severe renal impairment, administration of Arimidex should be performed with caution (see section 4.2).
Paediatric population
Arimidex is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1).
Arimidex should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In the pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces estradiol levels, Arimidex must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available.
Hypersensitivity to lactose
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Anastrozole inhibits CYPs 1A2, 2C8/9 and 3A4 in vitro. Clinical studies with antipyrine and warfarin showed that anastrozole at a 1 mg dose did not significantly inhibit the metabolism of antipyrine and R– and S-warfarin indicating the co-administration of Arimidex with other medicinal products is unlikely to result in clinically significant medicinal product interactions mediated by CYP enzymes.
The enzymes mediating metabolism of anastrozole have not been identified. Cimetidine, a weak, unspecific inhibitor of CYP enzymes, did not affect the plasma concentrations of anastrozole. The effect of potent CYP inhibitors is unknown.
A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with Arimidex who also received other commonly prescribed medicinal products. There were no clinically significant interactions with bisphosphonates (see section 5.1).
Co-administration of tamoxifen or estrogen-containing therapies with Arimidex should be avoided as this may diminish its pharmacological action (see section 4.4 and 5.1).
4.6 Pregnancy And Lactation
Pregnancy
There are no data from the use of Arimidex in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Arimidex is contraindicated during pregnancy (see section 4.3).
Breast-feeding
There are no data on the use of Arimidex during lactation. Arimidex is contraindicated during breast-feeding (see section 4.3).
Fertility
The effects of Arimidex on fertility in humans have not been studied. Studies in animals have shown reproductive toxicity (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
Arimidex has no or negligible influence on the ability to drive and use machines. However, asthenia and somnolence have been reported with the use of Arimidex and caution should be observed when driving or operating machinery while such symptoms persist.
4.8 Undesirable Effects
The following table presents adverse reactions from clinical trials, post-marketing studies or spontaneous reports. Unless specified, the frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer given adjuvant treatment for five years (the Arimidex, Tamoxifen, Alone or in Combination [ATAC] study).
Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency groupings are defined according to the following convention: very common (
Table 1 Adverse reactions by System Organ Class and frequency
| ||
|
|
|
|
|
|
|
| |
|
|
|
|
|
|
|
| |
|
|
|
|
| |
|
|
|
|
| |
|
| |
|
| |
|
| |
|
|
|
|
| |
|
| |
|
|
|
|
|
|
*Events of Carpal Tunnel Syndrome have been reported in patients receiving Arimidex treatment in clinical trials in greater numbers than those receiving treatment with tamoxifen. However, the majority of these events occurred in patients with identifiable risk factors for the development of the condition.
**Since cutaneous vasculitis and Henoch-Schönlein purpura was not observed in ATAC, the frequency category for these events can be considered as 'Rare' (
***Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with Arimidex. If bleeding persists, further evaluation should be considered.
The table below presents the frequency of pre-specified adverse events in the ATAC study after a median follow-up of 68 months, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.
Table 2 ATAC study pre-specified adverse events
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Fracture rates of 22 per 1,000 patient-years and 15 per 1,000 patient-years were observed for the Arimidex and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for Arimidex is similar to the range reported in age-matched postmenopausal populations. The incidence of osteoporosis was 10.5% in patients treated with Arimidex and 7.3% in patients treated with tamoxifen.
It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on Arimidex treatment reflect a protective effect of tamoxifen, a specific effect of Arimidex, or both.
4.9 Overdose
There is limited clinical experience of accidental overdose. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of Arimidex, 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 Arimidex that results in life-threatening symptoms has not been established. There is no specific antidote to overdose 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 Arimidex is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Enzyme inhibitors, ATC code: L02B G03
Mechanism of action and pharmacodynamic effects
Arimidex is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, Arimidex at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay.
Arimidex does not possess any progestogenic, androgenic, or estrogenic activity.
Daily doses of Arimidex up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard adrenocorticotrophic hormone (ACTH) challenge testing. Corticoid supplements are therefore not needed.
Clinical efficacy and safety
Advanced breast cancer
First-line therapy in postmenopausal women with advanced breast cancer
Two double-blind, controlled clinical studies of similar design (Study 1033IL/0030 and Study 1033IL/0027) were conducted to assess the efficacy of Arimidex 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 1,021 patients were randomised to receive 1 mg of Arimidex once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumour progression, objective tumour response rate, and safety.
For the primary endpoints, Study 1033IL/0030 showed that Arimidex had a statistically significant advantage over tamoxifen for time to tumour progression (Hazard ratio (HR) 1.42, 95% Confidence Interval (CI) [1.11, 1.82], Median time to progression 11.1 and 5.6 months for Arimidex and tamoxifen respectively, p=0.006); objective tumour response rates were similar for Arimidex and tamoxifen. Study 1033IL/0027 showed that Arimidex and tamoxifen had similar objective tumour response rates and time to tumour progression. 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.
Second-line therapy in postmenopausal women with advanced breast cancer
Arimidex was studied in two controlled clinical trials (Study 0004 and Study 0005) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. A total of 764 patients were randomised to receive either a single daily dose of 1 mg or 10 mg of Arimidex or megestrol acetate 40 mg four times a day. Time to progression and objective response rates were the primary efficacy variables. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters.
Adjuvant treatment of early invasive breast cancer for hormone receptor-positive patients
In a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer treated for 5 years (see below), Arimidex was shown to be statistically superior to tamoxifen in disease-free survival. A greater magnitude of benefit was observed for disease-free survival in favour of Arimidex versus tamoxifen for the prospectively defined hormone receptor-positive population.
Table 3 ATAC endpoint summary: 5-year treatment completion analysis
|
| |||
|
| |||
|
|
|
| |
|
|
|
|
|
Hazard ratio |
|
| ||
2-sided 95% CI |
|
| ||
p-value |
|
| ||
Distant disease-free survivalb |
|
|
|
|
Hazard ratio |
|
| ||
2-sided 95% CI |
|
| ||
p-value |
|
| ||
Time to recurrencec |
|
|
|
|
Hazard ratio |
|
| ||
2-sided 95% CI |
|
| ||
p-value |
|
| ||
|
|
|
|
|
Hazard ratio |
|
| ||
2-sided 95% CI |
|
| ||
p-value |
|
| ||
|
|
|
|
|
Odds ratio |
|
| ||
2-sided 95% CI |
|
| ||
p-value |
|
| ||
|
|
|
|
|
Hazard ratio |
|
| ||
2-sided 95% CI |
|
| ||
p-value |
|
|
a Disease-free survival includes all recurrence events and is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death (for any reason).
b Distant disease-free survival is defined as the first occurrence of distant recurrence or death (for any reason).
c Time to recurrence is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death due to breast cancer.
d Time to distant recurrence is defined as the first occurrence of distant recurrence or death due to breast cancer.
e Number (%) of patients who had died.
The combination of Arimidex and tamoxifen did not demonstrate any efficacy benefits in comparison with tamoxifen in all patients as well as in the hormone receptor-positive population. This treatment arm was discontinued from the study.
With an updated follow-up at a median of 10 years, long term comparison of the treatment effects of Arimidex relative to tamoxifen were shown to be consistent with previous analyses.
Adjuvant treatment of early invasive breast cancer for hormone receptor-positive patients being treated with adjuvant tamoxifen
In a phase III trial (Austrian Breast and Colorectal Cancer Study Group [ABCSG] 8) conducted in 2,579 postmenopausal women with hormone receptor-positive early breast cancer who had received surgery with or without radiotherapy and no chemotherapy (see below), switching to Arimidex after 2 years adjuvant treatment with tamoxifen was statistically superior in disease-free survival when compared to remaining on tamoxifen, after a median follow-up of 24 months.
Table 4 ABCSG 8 trial endpoint and results summary
|
| |
|
| |
|
|
|
|
| |
|
| |
|
| |
|
|
|
|
| |
|
| |
|
| |
|
|
|
|
| |
|
| |
|
| |
|
|
|
|
| |
|
| |
|
| |
|
|
|
|
| |
|
| |
|
|
Two further similar trials (GABG/ARNO 95 and ITA), in one of which patients had received surgery and chemotherapy, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results.
The Arimidex safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor-positive early breast cancer.
Bone mineral density (BMD)
In the phase III/IV study (Study of Anastrozole with the Bisphosphonate Risedronate [SABRE]), 234 postmenopausal women with hormone receptor-positive early breast cancer scheduled for treatment with Arimidex 1 mg/day were stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. The primary efficacy parameter was the analysis of lumbar spine bone mass density using DEXA scanning. All patients received treatment with vitamin D and calcium. Patients in the low risk group received Arimidex alone (N=42), those in the moderate group were randomised to Arimidex plus risedronate 35 mg once a week (N=77) or Arimidex plus placebo (N=77) and those in the high risk group received Arimidex plus risedronate 35 mg once a week (N=38). The primary endpoint was change from baseline in lumbar spine bone mass density at 12 months.
The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture showed no decrease in their bone mass density (assessed by lumbar spine bone mineral density using DEXA scanning) when managed by using Arimidex 1 mg/day in combination with risedronate 35 mg once a week. In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with Arimidex 1 mg/da
Thanks for sharing the Valuable information, Anastrozole helps lower estrogen hormone and is taken in the steroid cycle to fight estrogen. for best Arimidex try Alpha Pharmaceuticals.
ReplyDelete