Anastrozole 1mg Film Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Anastrozole 1 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 1 mg anastrozole.
Excipient(s): Each tablet contains 65 mg of Lactose monohydrate For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
White, round film-coated tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of advanced breast cancer in postmenopausal women. The efficacy of anastrozole has not been demonstrated in oestrogen-receptor negative patients, unless they have had a previous positive clinical response to tamoxifen.
4.2 Posology and method of administration
Adults including the elderly:
One film-coated tablet (1 mg) to be taken orally once a day.
Children: Not recommended for use in children 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.
Hepatic impairment: No dose change is recommended in patients with mild hepatic disease.
For early disease, the recommended duration of treatment should be 5 years.
4.3 Contraindications
Anastrozole is contraindicated in:
- premenopausal women.
- pregnant or lactating women.
- patients with severe renal impairment (creatinine clearance less than 20 ml/min).
- patients with moderate or severe hepatic disease.
- patients with hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.
Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.
Concurrent tamoxifen therapy (see section 4.5).
4.4 Special warnings and precautions for use
The use of anastrozole is not recommended in children as its safety and efficacy have not been established yet in this group of patients.
The onset of the menopause must be confirmed biochemically if the hormonal status of the patient cannot be established with clinical methods.
There are no data to support the safe use of anastrozole in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance below 20 ml/min).
Women with osteoporosis or at risk of that disease, should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.
There are no data available for the use of anastrozole with LHRH analogues; therefore, this combination is restricted for use only in clinical studies.
Anastrozole should not be used in addition to growth hormone treatment in boys with growth hormone deficiency. In the pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces oestradiol levels, it 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.
As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density. Adequate data to show the effect of bisphosphonates on bone mineral density loss caused by anastrozole, or their utility when used prophylactically, are not currently available
Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.
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 inhibited cytochrome P450 1A2, 2C8/9 and 3A4 in vitro, but a clinical interaction study with warfarin indicated that anastrozole at a 1 mg dose does not significantly inhibit the metabolism of substances that are metabolised via cytochrome P450.
No clinically significant interactions between anastrozole and biphosphonates have been identified.
Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see section 4.3).
4.6 Pregnancy and lactation
Anastrozole is contraindicated in pregnant and lactating women (see section 4.3). Pregnancy
There are no data on the use of anastrozole in pregnant patients. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Anastrozole is contraindicated in pregnant women.
Lactation
It is unknown whether anastrozole is excreted in human milk. Anastrozole is contraindicated in lactating women.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
|
Very common ( >10%) |
Vascular |
Hot flushes, mainly mild or moderate in nature |
|
Common (>1% and <10%) |
General |
Asthenia, mainly mild or moderate |
|
Musculoskeletal, connective tissue and bone |
Joint pain/stiffness, mainly mild or moderate in nature |
|
Reproductive system and breast |
Vaginal dryness, mainly mild or moderate in nature | |
|
Skin and subcutaneous tissues |
Hair thinning, mainly mild or moderate in nature Rash, mainly mild or moderate in nature | |
|
Gastrointestinal system |
Nausea, mainly mild or moderate in nature Diarrhoea, mainly mild or moderate in nature | |
|
Nervous system |
Headache, mainly mild or moderate in nature carpal tunnel syndrome | |
|
Hepatobiliary disorders |
Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase | |
|
Reproductive system and breast disorders |
*Vaginal bleeding, mainly mild or moderate in nature | |
|
Metabolism, nutrition |
Anorexia, mainly mild in nature Hypercholesterolaemia, mainly mild or moderate in nature | |
|
Uncommon (>0.1% and <1%) |
Gastrointestinal system |
Vomiting, mainly mild or moderate in nature |
|
Nervous system |
Somnolence, mainly mild or moderate in nature | |
|
Hepatobiliary disorders |
Elevated gamma-GT & bilirubin | |
|
Hepatitis | ||
|
Very rare (<0.01%) |
Skin and subcutaneous tissue |
Erythema multiforme, Stevens-Johnson syndrome Allergic reactions, including angioedema, urticaria and anaphylaxis |
*Vaginal bleeding has been reported uncommonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.
As Anastrozole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing some patients at a higher risk of fracture (see section 4.4).
Due to the pharmacological actions of anastrozole, hot flushes, vaginal dryness and hair thinning may develop. During the use of anastrozole gastrointestinal complaints (anorexia, nausea, vomiting and diarrhoea), asthenia, joint pain/stiffness, somnolence, headache and mild rashes may occur, including rare forms of mucodermal disorders, such as erythema multiforme and Stevens-Johnson syndrome.
The table below presents the frequency of pre-specified adverse events in the ATAC study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.
|
Adverse effects |
Anastrozol e (N=3092) |
Tamoxifen (N=3094) |
|
Hot flushes |
1104 (35.7%) |
1264 (40.9%) |
|
Joint pain/stiffness |
1100 (35.6%) |
911 (29.4%) |
|
Mood disturbances |
597 (19.3%) |
554 (17.9%) |
|
Fatigue/asthenia |
575 (18.6%) |
544 (17.6%) |
|
Nausea and vomiting |
393 (12.7%) |
384 (12.4%) |
|
Fractures |
315 (10.2%) |
209 (6.8%) |
|
Fractures of the spine, hip, or wrist/Colles |
133 (4.3%) |
91 (2.9%) |
|
Wrist/Colles fractures |
67 (2.2%) |
50 (1.6%) |
|
Spine fractures |
43 (1.4%) |
22 (0.7%) |
|
Hip fractures |
28 (0.9%) |
26 (0.8%) |
|
Cataracts |
182 (5.9%) |
213 (6.9%) |
|
Vaginal bleeding |
167 (5.4%) |
317 (10.2%) |
|
Ischaemic cardiovascular disease |
127 (4.1%) |
104 (3.4%) |
|
Angina pectoris |
71 (2.3%) |
51 (1.6%) |
|
Myocardial infarct |
37 (1.2%) |
34 (1.1%) |
|
Coronary artery disorder |
25 (0.8%) |
23 (0.7%) |
|
Myocardial ischaemia |
22 (0.7%) |
14 (0.5%) |
|
Vaginal discharge |
109 (3.5%) |
408 (13.2%) |
|
Any venous thromboembolic event |
87 (2.8%) |
140 (4.5%) |
|
Deep venous thromboembolic events including PE |
48 (1.6%) |
74 (2.4%) |
|
Ischaemic cerebrovascular events |
62 (2.0%) |
88 (2.8%) |
|
Endometrial cancer |
4 (0.2%) |
13 (0.6%) |
Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months.
The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.
The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.
4.9 Overdose
There is limited clinical experience of overdose of anastrozole.
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 an overdose and treatment must be symptomatic.
Absorption may be prevented by gastric lavage followed by administration of activated charcoal (adsorbant) or activated charcoal alone
In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken simultaneously. If the patient is alert, it is recommended to induce vomiting.
Dialysis may be helpful for the elimination of the medicine that has been absorbed already because anastrozole is not highly protein bound.
General supportive care, including frequent monitoring of vital signs and close observation of the patient, is recommended.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Enzyme Inhibitors, ATC code: L02BG03 Anastrozole 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 present in peripheral tissues. Estrone is subsequently converted to estradiol.
Reducing the levels of circulating estradiol has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg suppressed estradiol levels by more than 80%.
Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity. Regular daily doses of anastrozole up to 10 mg did not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed during its administration.
Two further, similar studies performed with anastrozole (GABG/ARNO 95 and ITA), as well as a combined analysis of the ABCSG 8 and GABG/ARNO 95 studies, supported these results.
The safety profile of anastrozole obtained in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor positive, early-stage breast cancer.
Paediatrics
Anastrozole is not indicated for use in children. Efficacy has not been established in the paediatric populations studied (see below). The number of children treated was too limited to draw any reliable conclusions on safety. No data on the potential longterm effects of anastrozole treatment in children are available (see also section 5.3).
The European Medicines Agency has waived the obligation to submit the results of studies with anastrozole in one or several subsets of the paediatric population in short stature due to growth hormone deficiency (GHD), testotoxicosis, gynaecomastia, and McCune-Albright syndrome.
Short stature due to growth hormone deficiency
A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 1116 years inclusive) with GHD treated for 12 to 36 months with anastrozole 1 mg/day or placebo in combination with growth hormone. Only 14 subjects on anastrozole completed 36 months.
After 3 years anastrozole was found to statistically significantly slow bone maturation in pubertal boys on growth hormone therapy. No statistically significant difference with placebo was observed for the growth related parameters of predicted adult height, height, height SDS, and height velocity. Final height data were not available. While the number of children treated was too limited to draw any reliable conclusions on safety, there was an increased fracture rate and a trend towards reduced bone mineral density in the anastrozole arm compared to placebo.
Testotoxicosis
An open-label, non-comparative, multi-centre study evaluated 14 male patients (aged 2-9) with familial male-limited precocious puberty, also known as testotoxicosis, treated with combination of anastrozole and bicalutamide. The primary objective was to assess the efficacy and safety of this combination regimen over 12 months. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). There was no significant difference in growth rate after 12 months of treatment, relative to the growth rate during the 6 months prior to entering the study.
5.2 Pharmacokinetic properties
Absorption of anastrozole, the active substance of Anastrozole, is rapid. Maximum plasma concentrations typically occur within two hours of dosing if the medicine is given under fasting conditions.
Anastrozole is eliminated slowly with a plasma elimination half-life of 40-50 hours. Food causes a slight decrease in the rate but not in the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on the steady-state plasma concentrations during once daily dosing of Anastrozole tablets.
After 7 daily doses, the plasma anastrozole concentrations attained are 90-95% of the steady-state concentration.
There is no evidence of a time or dose-dependency of the pharmacokinetic parameters of anastrozole.
The pharmacokinetics of anastrozole are independent of age in postmenopausal women.
Pharmacokinetics have not been studied in children.
Anastrozole is 40% bound to plasma proteins.
Anastrozole is extensively metabolised by postmenopausal women, with less than 10% of the dose excreted unchanged in the urine within 72 hours of dosing. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine.
Triazole, the major metabolite of anastrozole in plasma, does not inhibit the aromatase enzyme.
In volunteers with stable hepatic cirrhosis or renal impairment, the oral clearance of anastrozole remained in the range observed in healthy volunteers.
5.3 Preclinical safety data
Acute toxicity
In acute toxicity studies in rodents, the median lethal dose of anastrozole was greater than 100 mg/kg/day by the oral route and greater than 50 mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog, the median lethal dose was greater than 45 mg/kg/day.
Chronic toxicity
Multiple dose toxicity studies utilized rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low doses (1 mg/kg/day) and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme inducing properties of anastrozole and were unaccompanied by significant toxic or degenerative changes. Mutagenicity
Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen.
Reproductive toxicology
In a fertility study weanling male rats were dosed orally with 50 or 400 mg/l anastrozole via their drinking water for 10 weeks. Measured mean plasma concentrations were 44.4 (± 14.7) ng/ml and 165 (±90) ng/ml respectively. Mating indices were adversely affected in both dose groups, whilst a reduction in fertility was evident only at the 400 mg/l dose level. The reduction was transient as all mating and fertility parameters were similar to control group values following a 9-week treatment-free recovery period.
Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects occurred at clinically relevant doses. An effect in man cannot be excluded. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.
Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound.
The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above (from day 17 of pregnancy to day 22 post-partum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole. Carcinogenicity
A two year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with anastrozole.
A two year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with anastrozole.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Maize starch Povidone
Microcrystalline cellulose Sodium starch glycolate Type A Colloidal anhydrous silica Magnesium stearate Talc
Film-coating:
Hypromellose
Macrogol
Titanium dioxide (E171)
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
PVC/Aluminium blisters of 14 tablets. 28 film-coated tablets
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Waymade PLC
Trading as Sovereign Medical
Sovereign House
Miles Gray Road
Basildon
Essex
SS14 3FR
8 MARKETING AUTHORISATION NUMBER(S)
PL 06464/2827
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/03/2009
10 DATE OF REVISION OF THE TEXT
27/04/2012