posted July 20, 2000 01:28 AM            

later,
WCP

Data Sheet

ARIMIDEX
Anastrozole
Description
Anastrozole is a fine white to off white powder. It has moderate aqueous solubility (0.53mg/mL at 25oC) which is dependent on pH from pH 1 to 4 but independent of pH thereafter.

ARIMIDEX 1mg is a round, white, biconvex film-coated tablet containing 1mg anastrozole and includes the following excipients: lactose, povidone, sodium starch glycollate, magnesium stearate, hypromellose, macrogol 300 and titanium dioxide.

Uses
Actions
ARIMIDEX is a potent and highly selective non-steroidal aromatase inhibitor. In post-menopausal 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 post-menopausal women, ARIMIDEX at a daily dose of 1mg produced oestradiol suppression of greater than 80% using a highly sensitive assay. Oestradiol suppression is maintained during the whole treatment period.

In clinical trials treatment with ARIMIDEX at a dose of 1mg has demonstrated significant prolongation of survival time.

ARIMIDEX does not possess any progestogenic, androgenic or oestrogenic activity.

Daily doses of ARIMIDEX 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 ARIMIDEX 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 post-menopausal women.

Pharmacokinetics have not been studied in children.

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, a major metabolite in plasma and urine, 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.

Indications
Treatment of advanced breast cancer in post-menopausal women.

Dosage and Administration
Adults Including The Elderly
One tablet (1mg) to be taken orally once a day.

Children
Not recommended for use in children.

Use In Adults With Renal Impairment
No dose change is recommended.

Use In Adults With Hepatic Impairment
No dose change is recommended.

Contraindications
ARIMIDEX must not be administered during pregnancy or lactation.

Warnings and Precautions
ARIMIDEX is not recommended for use in children or in pre-menopausal women as safety and efficacy have not been established in these groups of patients.

ARIMIDEX has not been investigated in patients with severe hepatic or severe renal impairment. The potential risk/benefit to such patients should be carefully considered before administration of ARIMIDEX.

Use in Pregnancy
ARIMIDEX is contraindicated in pregnant women.

Use in Lactation
ARIMIDEX is contraindicated in breast-feeding women.

Interaction with Other Drugs
Antipyrine and cimetidine clinical interaction studies indicate that the co-administration of ARIMIDEX 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 ARIMIDEX who also received other commonly prescribed drugs.

There is no clinical information to date on the use of ARIMIDEX in combination with other anti-cancer agents.

Oestrogen-containing therapies should not be co-administered with ARIMIDEX as they would negate its pharmacological action.

Effects on Ability to Drive and Use Machines
ARIMIDEX is unlikely to impair the ability of patients to drive and operate machinery. 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.

Adverse Effects
ARIMIDEX has generally been well tolerated. Adverse events have usually been mild to moderate with only few withdrawals from treatment due to undesirable events.

The pharmacological action of ARIMIDEX may give rise to certain expected effects. These include hot flushes, vaginal dryness and hair thinning. ARIMIDEX may also be associated with gastrointestinal disturbances (anorexia, nausea, vomiting, and diarrhoea), asthenia, joint pain/stiffness, somnolence, headache or rash.

Vaginal bleeding has been reported infrequently, mainly in patients during the first few weeks after changing from existing hormonal therapy to treatment with ARIMIDEX. If bleeding persists, further evaluation should be considered.

Hepatic changes (elevated gamma-GT or less commonly alkaline phosphatase) have been reported in patients with advanced breast cancer, many of whom had liver and/or bone metastases. A casual relationship for these changes has not been established. Slight increases in total cholesterol have also been observed in clinical trials with ARIMIDEX.

Overdosage
There is no clinical experience of accidental overdosage. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of ARIMIDEX, up to 60mg in a single dose given to healthy male volunteers and up to 10mg daily given to post-menopausal 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 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 ARIMIDEX is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

Pharmaceutical Precautions
Store below 30oC.

Package Quantities
ARIMIDEX is presented as a round, white, biconvex film-coated tablet containing 1mg of anastrozole. The tablets are 6mm in diameter and are compressed to a weight of 100mg. A logo consisting of the letter 'A' with an arrow head attached to the foot of the extended right leg of the 'A' is impressed on one side and a tablet strength marking ('Adx1') is impressed on the other side. ARIMIDEX tablets are presented in a PVC blister/aluminium foil blister pack containing 28 tablets.

Further Information
Pre-clinical Safety Data
Acute Toxicity

In acute toxicity studies in rodents the median lethal dose of anastrozole was greater than 100mg/kg/day by the oral route and greater than 50mg/kg/day by the intraperitoneal route.

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 (1mg/kg/day) and mid doses (dog 3mg/kg/day; rat 5mg/kg/day) were related to either the pharmacological or enzyme inducing properties of anastrozole and were unaccompanied by 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 anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2mg/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.

Carcinogenicity

No carcinogenicity studies have been conducted using anastrozole.

CPI 08/99

ARIMIDEX is a trade mark, the property of ZENECA Limited.