Apo-Anastrozole

Each film coated tablet contains 1 mg Anastrozole.
Excipients/Inactive Ingredients: Anhydrous lactose, Microcrystalline Cellulose, Croscarmellose Sodium, Magnesium Stearate, Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose, Polyethylene Glycol 8000, Titanium Dioxide, Purified Water.

Pharmacotherapeutic Group: Enzyme Inhibitors. ATC Code: L02B G03.
Pharmacology: Pharmacodynamics: Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily from the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Reducing circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1mg produced oestradiol suppression of greater than 80% using a highly sensitive assay.
Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity.
Daily doses of anastrozole up to 10mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.
Pharmacokinetics: Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of anastrozole tablets. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose-dependency of anastrozole pharmacokinetic parameters.
Anastrozole pharmacokinetics are independent of age in postmenopausal women.
Anastrozole is only 40% bound to plasma proteins.
Anastrozole is extensively metabolised by post-menopausal women with less than 10% of the dose excreted in the urine unchanged 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 in plasma, does not inhibit aromatase.
The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.
Toxicology: 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 utilised rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low dose (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: Oral administration of anastrazole 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 anastrazole.
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.

Treatment of advanced breast cancer in postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen.

Adults (including elderly): One 1 mg tablet to be taken orally, once a day.
Children: Not recommended for use in children.
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.

There is limited 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 lifethreatening 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.

Patients who are hypersensitive to Apo-Anastrozole (anastrozole) or to any ingredient in the formulation.
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.
Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.
Concurrent tamoxifen therapy (see Interactions).

Anastrozole tablet is not recommended for use in children as safety and efficacy have not been established in these patients.
The menopause should be defined biochemically in any patient where there is doubt about menopausal status.
There are no data to support the safe use of anastrozole tablet in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min).
Women with osteoporosis or at risk of osteoporosis 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. This combination should not be used outside clinical trials.
As anastrozole tablet lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fractures. The use of bisphosphonates may stop further bone mineral loss caused by anastrozole tablet in postmenopausal women and could be considered.
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.

Anastrozole tablet is contraindicated in pregnant or lactating women.

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years (ATAC Study). (See Table 1.)

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The table as follows 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. (See Table 2.)

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The ATAC trial data showed that patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis, and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in the incidence of fractures (including fractures of spine, hip and wrist) compared with patients receiving tamoxifen.
These differences were statistically significant. 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.
Patients receiving anastrozole had a decrease in hot flushes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events (including deep venous thrombosis) and ischaemic cerebrovascular events compared with patients receiving tamoxifen. These differences were statistically significant.
Results from the ATAC trial bone substudy, at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.
Slight increases in total cholesterol have also been observed in clinical trials with anastrozole, although the clinical significance has not been determined.

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.
A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed drugs. There were no clinically significant interactions with biphosphonates (see Pharmacology: Pharmacodynamics under Actions).
Oestrogen-containing therapies should not be co-administered with anastrozole as they may counteract the goal of achieving estrogen suppression.
Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see Contraindications). Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the co-administration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen.

Store at or below 30°C.

Cancer Hormone Therapy

L02BG03 - anastrozole ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.

POM