Consumer medicine information

APO-Anastrozole Tablets

Anastrozole

BRAND INFORMATION

Brand name

APO-Anastrozole

Active ingredient

Anastrozole

Schedule

What is in this leaflet

This leaflet answers some common questions about anastrozole. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What this medicine is used for

Anastrozole is used to treat breast cancer in women who no longer have their menstrual periods either naturally, due to their age or after surgery, radiotherapy or chemotherapy.

How it works

Anastrozole is a non-steroidal aromatase inhibitor, which reduces the amount of oestrogen (female sex hormone) made by the body. In some types of breast cancer, oestrogen can help the cancer cells grow. By blocking oestrogen, anastrozole may slow or stop the growth of cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

This medicine is not addictive.

Anastrozole is not recommended for use in children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

anastrozole
any of the ingredients listed at the end of this leaflet.
Other anti-oestrogen medicines.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue, throat or other parts of the body
rash, itching or hives on the skin.

Do not take anastrozole if you are still having menstrual periods.

Anastrozole should only be taken by women who are no longer having menstrual periods.

Do not take anastrozole if you are a man. Men are not normally treated with anastrozole.

Do not take this medicine if you are pregnant, plan to become pregnant or are breastfeeding. Anastrozole may affect your developing baby if you take it during pregnancy. It may also pass into human breast milk.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

liver or kidney problems
osteoporosis, a family history of osteoporosis or risk factors for developing osteoporosis (such as smoking, a diet low in calcium, poor mobility, a slight build or treatment with steroid medicines)

Aromatase inhibitors may decrease bone mineral density (BMD) in women who have been through menopause, with a possible increased risk of fractures. Your doctor should discuss with you your treatment options for managing this possible increased risk of fractures.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interact with anastrozole. These include:

tamoxifen, used to treat breast cancer
any medicine that contains oestrogen (e.g. hormone replacement therapy (HRT) or oral contraceptives)
any health food products that contain natural oestrogens used for post-menopausal symptoms.
luteinising hormone releasing hormone (LHRH) agonists (e.g. goserelin or leuprorelin)

If you are taking any of these, you may need a different dose, or you may need to take different medicines.

Other medicines not listed above may also interact with anastrozole.

How to take this medicine

Follow carefully all directions given to you by your doctor or pharmacist. They may differ to the information contained in this leaflet.

Your doctor or pharmacist will tell you how many tablets you will need to take each day. This depends on your condition and whether or not you are taking any other medicines.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The usual dose is one tablet taken once each day.

How to take it

Swallow anastrozole tablets whole, with a glass of water.

When to take it

Take this medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take anastrozole with or without food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Anastrozole helps to control your condition, but does not cure it.

Do not stop taking it unless your doctor tells you to, even if you feel better.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time.

Otherwise take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to the Emergency department at your nearest hospital if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, tell your doctor that you are taking this medicine.

If you become pregnant whilst taking anastrozole, tell your doctor immediately.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor tells you to.

Do not stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how anastrozole affects you. Some patients may occasionally feel weak or sleepy.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking anastrozole.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following:

hot flushes
feeling weak or sleepy, lack of energy
joint pain or stiffness, bone pain or arthritis
vaginal dryness or bleeding
hair thinning or hair loss
mild skin rash
nausea, vomiting, loss of appetite (anorexia), diarrhoea
headache
carpal tunnel syndrome (tingling, pain, coldness, weakness in parts of hand)
pins and needles
toss of taste or changing taste of food or drink
feelings of sadness or depression

The above list includes the more common side effects. Mostly, these are mild.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Emergency department at your nearest hospital:

Sudden signs of allergy such as shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; rash, itching or hives on the skin.
severe skin reactions with lesions, ulcers or blisters.
liver pain or swelling and/or a general feeling of unwell with or without jaundice (yellowing of the skin and eyes)

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Anastrozole may be associated with changes in your blood, urine or liver.

Your doctor may want to perform tests from time to time to check on your progress and detect any side effects.

Uncommon side effects can include, trigger finger which is a condition in which one of your fingers or your thumb catches in a bent position.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

Keep your medicine in its pack until it is time to take it. If you take your medicine out of its pack it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it looks like

White, round, biconvex tablet, with '1' on one side.

Blister pack of 30 film-coated tablets. AUST R 266676

Ingredients

Each tablet contains 1 mg of anastrozole as the active ingredient.

It also contains the following:

lactose
magnesium stearate
sodium starch glycollate type A
Opadry II white 85F18422.

This medicine does not contain gluten, sucrose, tartrazine or any other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was prepared in August 2021.

Published by MIMS September 2021

BRAND INFORMATION

Brand name

APO-Anastrozole

Active ingredient

Anastrozole

Schedule

1 Name of Medicine

Anastrozole.

2 Qualitative and Quantitative Composition

Each tablet contains 1 mg of anastrozole as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Anastrozole 1 mg.

A round, white, biconvex film-coated tablet with "1" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Early breast cancer.

Adjuvant treatment of early breast cancer in postmenopausal women with oestrogen/progesterone-receptor-positive disease.

Advanced breast cancer.

First line treatment of advanced breast cancer in postmenopausal women with oestrogen/progesterone receptor positive disease.
Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with oestrogen receptor negative disease and patients who have not responded to previous tamoxifen therapy rarely respond to anastrozole.

4.2 Dose and Method of Administration

APO-Anastrozole tablets are intended for oral administration.

Dosage.

Adults including the elderly.

One tablet (1 mg) to be taken orally once a day.
For early breast cancer, the recommended total duration of hormonal therapy is 5 years. For patients being switched to anastrozole from tamoxifen, the switch should occur after completion of 2 to 3 years of tamoxifen therapy. There are no data to support switching at earlier or later time points.

Children.

Not recommended for use in children.

Renal impairment.

No dose change is recommended.

Hepatic impairment.

No dose change is recommended.

4.3 Contraindications

Anastrozole must not be administered during pregnancy or lactation.
Known hypersensitivity to the active substance or to any of the excipients of this product (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Use in premenopausal women.

Anastrozole is not recommended for use in premenopausal women as safety and efficacy have not been established in these groups of patients.

Use in renal impairment.

The apparent oral clearance of anastrozole in volunteers with renal impairment (creatinine clearance less than 30 mL/min/1.73 m²) was in the range observed in healthy volunteers. Dosage adjustment is therefore not necessary. Anastrozole has not been investigated in patients with severe renal impairment. The potential risk/benefit to such patients should be carefully considered before administration of anastrozole.

Use in hepatic impairment.

The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis was in the range observed in healthy volunteers. Dosage adjustment is therefore not necessary. Anastrozole has not been investigated in patients with severe hepatic impairment. The potential risk/benefit to such patients should be carefully considered before administration of anastrozole.

Bone mineral density.

As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture. Women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated and monitored as appropriate.
In the phase III/IV SABRE study, 234 postmenopausal women with hormone receptor positive early breast cancer scheduled for treatment with anastrozole were stratified to low, moderate and high-risk groups according to their existing risk of fragility fracture. All patients received treatment with vitamin D and calcium. Patients in the low risk group received anastrozole alone, those in the moderate group were randomised to anastrozole plus bisphosphonate or anastrozole plus placebo and those in the high risk group received anastrozole plus bisphosphonate.
The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture had their bone health (assessed by bone mineral density and bone formation and resorption markers) successfully managed by using anastrozole in combination with a bisphosphonate. These findings were mirrored in the secondary efficacy variable of change from baseline in total hip BMD at 12 months.

Combination with LHRH agonists.

There are no data available for the use of anastrozole with LHRH agonists. This combination should not be used outside clinical trials.

Use in the elderly.

Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age related effects were seen over the range < 50 to > 80 years.

Paediatric use.

Anastrozole is not recommended for use in children as safety and efficacy have not been established in these groups of patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Anastrozole inhibited reactions catalysed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state C_max values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalysed by cytochrome P450 2A6 or 2D6 in vitro. Based on these in vitro and the in vivo results with antipyrine and cimetidine, it is unlikely that coadministration of anastrozole 1 mg with other drugs will result in clinically significant inhibition of cytochrome P450 mediated metabolism.

Other medicines that affect anastrozole.

Demonstrated interactions.

On the basis of clinical and pharmacokinetic data from the ATAC trial, tamoxifen must not be administered with anastrozole. Co-administration of anastrozole and tamoxifen resulted in a reduction of anastrozole plasma levels by 27% compared with those achieved with anastrozole alone.

Theoretical interactions.

Oestrogen containing therapies should not be coadministered with anastrozole as they would negate its pharmacological action.

Potential interactions that have been excluded.

A review of the clinical trial safety database did not reveal evidence of any clinically significant interaction in patients treated with anastrozole who also received commonly prescribed drugs. There were no clinically significant interactions with bisphosphonates (see Section 4.4 Special Warnings and Precautions for Use, Bone mineral density).

Effects of anastrozole on other medicines.

Potential interactions that have been excluded.

Antipyrine.

Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.

Cimetidine.

Pretreatment with cimetidine, at a dose of 300 mg every six hours for four days, in normal postmenopausal women had no effect on the single dose pharmacokinetics of anastrozole (10 mg).

Warfarin.

An interaction study with warfarin showed no clinically significant effect of anastrozole on warfarin pharmacokinetics or anticoagulant activity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In female rats treated orally with anastrozole for 14 days prior to mating up to day 7 of gestation, the fertility index (pregnancies/matings) was reduced after oral doses of 1 mg/kg and above [9 times the maximum recommended clinical dose, based on body surface area (BSA)]. Preimplantation loss was increased, and the number of implantations decreased, at doses of 0.02 mg/kg and above (0.2 times the maximum recommended clinical dose, based on BSA). It is not known whether anastrozole impairs fertility in humans.
(Category C)
Anastrozole is contraindicated in pregnant women.
After oral administration of anastrozole to pregnant rats and rabbits, the drug was shown to cross the placenta and was detectable in foetal tissues at concentrations approximately 40% of corresponding maternal plasma drug concentrations. Anastrozole showed no evidence for teratogenic activity and had no effects on pregnancy parameters at oral doses of up to 1 mg/kg/day in rats and up to 0.2 mg/kg/day in rabbits (9 and 3 times the maximum recommended clinical dose, based on BSA, respectively). However, enlargement of the placenta was seen in rats and treatment of rabbits with anastrozole at doses greater than 0.2 mg/kg/day caused abortion in 100% of animals. These effects are consistent with disruption of oestrogen dependent events during pregnancy and are not unexpected with a drug of this class.
In a peripostnatal study (administration from day 17 of gestation to day 21 postpartum) in rats, increased resorption was observed at 0.5 mg/kg/day. Increased stillbirths and evidence for dystocia (increased variability in the length of gestation and/or vaginal bleeding at birth) were reported at doses of 0.1 mg/kg/day or greater. Pup survival was reduced at all doses tested (0.02 mg/kg/day and above, 0.2 times the maximum recommended clinical dose, based on BSA). There was no evidence of adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole.
Anastrozole is contraindicated in breastfeeding 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 Adverse Effects (Undesirable Effects)

Anastrozole has generally been well tolerated. Adverse events have usually been mild to moderate with only few withdrawals from treatment due to undesirable events. 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 and unless specified, no account was taken of the frequency within the comparative treatment group or whether the investigator considered it to be related to study medication. See Table 1.
In a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years, ischaemic cardiovascular events (consisting mainly of angina pectoris) in the on treatment period were reported more frequently in patients treated with anastrozole compared to those treated with tamoxifen (mainly associated with patients with pre-existing ischaemic heart disease), although the difference was not statistically significant (p = 0.1224).
In studies in the adjuvant setting, anastrozole has been associated with an increased incidence of fractures compared to tamoxifen treatment during the active treatment phase. At the 100 month analysis of a large phase III study the off treatment fracture episode rate was no different between the anastrozole and tamoxifen treatment arms (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

There is limited clinical experience of overdose of anastrozole. There are no reports where a patient has taken a dose exceeding 60 mg. No toxicity was observed and no clinically relevant adverse effects have been seen.
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 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 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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Anastrozole is a potent and highly selective nonsteroidal aromatase inhibitor. It significantly lowers serum oestradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
Many breast cancers have oestrogen receptors and growth of these tumours can be stimulated by oestrogen. 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. Many breast cancers also contain aromatase; the importance of tumour generated oestrogens is uncertain.
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 1 mg 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 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.
In a phase III/IV study there was a neutral effect on plasma lipids in those patients treated with anastrozole.

Clinical trials.

Switching in treatment of early breast cancer.

A combined analysis of 2 multicentre, open-label, randomised controlled trials (ABCSG trial 8 and ARNO 95) was conducted to examine the efficacy of switching postmenopausal patients with hormone-receptor positive early breast cancer receiving tamoxifen (20 or 30 mg daily), to anastrozole (1 mg daily). A total of 3224 patients who had completed 2 years adjuvant treatment with tamoxifen and had remained disease-free, were randomised to receive anastrozole for 3 years (n = 1618) or to continue on tamoxifen for 3 years (20 to 30 mg daily; n = 1606). The total duration of hormonal therapy was 5 years. Patients did not receive adjuvant chemotherapy. 74% of patients had lymph-node negative disease at commencement of hormonal therapy.
The primary endpoint was event-free survival, with an event being defined as loco-regional or distant recurrence or the development of contralateral breast cancer. Overall survival was a secondary end-point. Median follow-up after randomisation was 28 months, and 55% of patients in each group had completed the planned 5 years of hormonal therapy. Results are presented in Table 2.

Compared with tamoxifen, anastrozole treatment was associated with a significantly increased incidence of fractures - 34 cases vs. 16 cases; odds ratio (OR) = 2.14 (95% CI: 1.14-4.17; p = 0.015), but with a reduced incidence of thromboses (3 vs. 12 cases; OR = 0.25 (95% CI: 0.04-0.92; p = 0.034).
Another open-label, randomised controlled trial (the ITA study) enrolled 448 postmenopausal patients with oestrogen receptor positive early breast cancer. All patients had lymph node involvement. Patients who remained disease-free after receiving 2 to 3 years of tamoxifen therapy were randomly assigned to receive anastrozole (1 mg daily; n = 233) or to continue therapy with tamoxifen (20 mg daily, n = 225) for a total of 5 years hormonal therapy in each arm. 67% of patients in each arm received adjuvant chemotherapy.
The primary endpoint was disease recurrence, with a recurrence being defined as loco-regional or distant recurrence. Event-free survival was a secondary end-point with an event being defined as loco-regional or distant recurrence, the development of contralateral breast cancer, the development of a second primary cancer, or death occurring without disease recurrence. Overall survival was also a secondary end-point. Median follow-up after randomisation was 36 months. Results are presented in Table 3.

Anastrozole was associated with an increased incidence of lipid disorders and gastrointestinal events, but with a reduced incidence of gynaecological events, when compared with tamoxifen.

Adjuvant treatment of early breast cancer in postmenopausal women.

In a multicentre, double-blind trial, 9,366 postmenopausal women aged 33 to 95 years old with early breast cancer were randomised to receive adjuvant treatment with anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of disease.
The primary endpoint was disease-free survival (i.e. time to occurrence of a distant or local recurrence, new contralateral breast cancer or death from any cause). Secondary and additional prospectively defined endpoints included time to distant recurrence, the incidence of contralateral breast cancer, overall survival, time to recurrence and time to death following recurrence.
Demographic and other baseline characteristics were similar among the two treatment arms, with approximately 84% of patients with hormone receptor positive disease. The median follow-up was 100 months.
Treatment with anastrozole was superior to tamoxifen in the Intention-To-Treat (ITT) group with statistically significant risk reductions in disease-free survival and time to recurrence of 10% and 19%, respectively (see Table 4). In the clinically relevant hormone-receptor-positive sub-group, statistically significant benefits of anastrozole compared to tamoxifen were also observed for disease-free survival and time to recurrence, with risk reductions of 15% and 24%, respectively (see Figures 1-4 and Table 4). The absolute benefit in recurrence rates of anastrozole over tamoxifen increased over the entire 100 month follow up period. The gain in absolute benefit during the off-treatment period demonstrates a superior carryover effect to that already demonstrated with 5 years of tamoxifen treatment (see Figure 2).

Hazard ratios of < 1.00 indicate that treatment with anastrozole is favourable relative to tamoxifen.

Overall survival was a secondary endpoint in the ATAC study. The 100 month analysis of this study demonstrated that overall survival in the anastrozole arm and the tamoxifen arm were not significantly different. Similar overall survival was observed for both the ITT group and hormone-receptor-positive sub-group (see Table 4). At the 100 month follow up the mean age of the surviving population was 72 years, with non-breast cancer deaths accounting for 42 and 46% of total mortality in the ITT and hormone-receptor positive subgroup respectively.
Other secondary and additional outcome variables were all either significantly in favour of anastrozole or with trends evident in favour of anastrozole when compared to tamoxifen (see Table 4).
Overall, anastrozole was well tolerated. Withdrawals due to drug-related adverse events were less common with anastrozole compared to tamoxifen (6.5% vs 8.9%; odds Ratio 0.71, 95% CI: 0.59 - 0.86; p = 0.0004). The following adverse events were reported regardless of causality. Patients receiving anastrozole had a significant decrease in hot flushes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischaemic cerebrovascular events compared to patients receiving tamoxifen. Patients receiving anastrozole also had an increase in joint disorders (including arthritis, arthrosis and arthralgia) and total number of fractures compared with patients receiving tamoxifen. Although the incidences of fractures (both serious and non-serious, occurring either during or after treatment) were higher in the anastrozole compared to the tamoxifen treatment group, the incidences of hip fractures were similar between the groups. The fracture rate for anastrozole whilst on treatment falls within the broad range of fracture rates reported in an age-matched postmenopausal population.
A plot of the annual first fracture rates, throughout the study, shows that following the end of treatment the annual first event rates were similar in the anastrozole and tamoxifen treatment groups and the increased first fracture rate seen during treatment was not continued in the post-treatment follow-up period (see Figure 5).

Serious adverse events continued to be collected during the off-treatment follow-up. Overall the number of treatment-related serious adverse events remained lower with anastrozole than with tamoxifen for the active follow-up period, and was significantly lower during treatment and similar after treatment completion. The incidence of cardiovascular events reported was similar in the anastrozole and tamoxifen arms (3.9% vs. 3.7%, respectively) in the 100 month analysis.
Ischaemic cardiovascular events (consisting mainly of angina pectoris) in the on-treatment period were reported more frequently in patients treated with anastrozole compared to those treated with tamoxifen (mainly associated with patients with pre-existing ischaemic heart disease), although the difference was not statistically significant (p = 0.1224).
At a median follow-up of 33 months, the combination arm did not demonstrate any efficacy benefit when compared with tamoxifen in either the ITT group or the hormone-receptor-positive sub-group. This treatment arm was discontinued from the trial.

First line therapy in postmenopausal women with advanced breast cancer.

In two similar controlled trials (trials 0027 and 0030), 1021 postmenopausal women aged 30 to 92 years old, with advanced breast cancer [stage IV (metastatic disease) and stage III (locally advanced disease)] were randomised to receive anastrozole 1 mg (n = 511) or tamoxifen 20 mg (n = 510) once daily as first line therapy.
The primary end points for both trials were time to progression, objective response rate and safety. The trials were designed to allow data to be pooled. The median duration of follow up was 18.8 and 17.7 months in trial 0027 and trial 0030 respectively. The number of patients still on trial treatment at the end of the follow-up period was as follows (see Table 5).

Demographics and other baseline characteristics were similar for the two treatment groups for both trials. The hormone receptor status at entry for all randomised patients in trials 0027 and 0030 is summarised in Table 6.
Anastrozole was at least as effective as tamoxifen for the primary endpoints of time to progression and objective response rate. A comparison of the results for the primary endpoints, for both trials, is provided in Table 6. Positive oestrogen/ progesterone receptor status had an impact on the primary efficacy parameters and this may partly explain the difference in results between the two trials.

Second line therapy in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy.

In two similar controlled trials (trials 0004 and 0005), 764 postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either early or advanced breast cancer were randomised to receive anastrozole 1 mg daily, anastrozole 10 mg daily or megestrol acetate 40 mg four times daily. Some of the patients had also received previous cytotoxic treatment. Patients were either ER positive or unknown status (with about 5% being ER negative) and had responded to previous treatment with tamoxifen.
At a median follow up of approximately 30 months and with approximately 60% of patients having died, the data from both studies combined demonstrated significant prolongation of survival with anastrozole 1 mg compared to megestrol acetate. The median time to death for anastrozole 1 mg was 26.7 months compared to 22.5 months for megestrol acetate, with a 2 year survival rate for anastrozole 1 mg of 56.1% compared to 46.3% for megestrol acetate. The hazard ratio of risk of death of patients on anastrozole 1 mg compared to megestrol acetate was 0.78, and there was a statistically significant difference in time to death (p < 0.025).

5.2 Pharmacokinetic Properties

Absorption.

Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). 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.

Distribution.

Anastrozole is only 40% bound to plasma proteins. The pharmacokinetics of anastrozole are linear over the dose range of 1 mg to 20 mg and do not change with repeated dosing.
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.

Metabolism.

Anastrozole is extensively metabolised by postmenopausal 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.

Excretion.

Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours.

Paediatric pharmacokinetics.

In boys with pubertal gynecomastia, anastrozole was rapidly absorbed, was widely distributed, and was eliminated slowly with a half-life of approximately 2 days. Pharmacokinetic parameters in boys were comparable to those of postmenopausal women. Clearance of anastrozole was lower in girls than in boys and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated, with an estimated half-life of approximately 0.8 days.

5.3 Preclinical Safety Data

Preclinical 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. Plasma levels of anastrozole at these doses in rats and dogs were at least 3 and 12 times greater, respectively, than those expected in human postmenopausal women during treatment with anastrozole. At higher doses of anastrozole, nephropathy was observed in rats, ECG changes were observed in dogs, and changes in cholesterol levels were observed in both animal species.

Genotoxicity.

Anastrozole did not show evidence of genotoxicity in assays for gene mutations in vitro and chromosomal damage in vitro and in vivo.

Carcinogenicity.

In a two year rat oncogenicity study, anastrozole caused an increase in incidence of hepatic adenomas and carcinomas and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day), where exposure (AUC) was approximately 100-fold that which occurs at the maximum recommended clinical dose. At the no tumourigenic effect level (5 mg/kg/day), exposure (AUC) was approximately 20-fold that which occurs at the maximum recommended clinical dose.
In a two year mouse oncogenicity study, anastrozole induced 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). The benign tumourigenic effect on the ovary occurred at all doses including the lowest dose tested (5 mg/kg/day) [exposure (AUC) was approximately 1 to 2-fold that which occurs at the maximum recommended clinical dose]. The clinical relevance of these findings in the mouse are not clear.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, magnesium stearate, sodium starch glycollate type A, Opadry II complete film coating system 85F18422 White.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

APO-Anastrozole 1 mg.

Blister pack (PVC/PVDC/Al) of 30 tablets: AUST R 266676.
APO and APOTEX are registered trade marks of Apotex Inc.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

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

Chemical structure.

Chemical Name: 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis (2-methylpropiononitrile).
Molecular Formula: C₁₇H₁₉N₅.
Molecular Weight: 293.37.

CAS number.

120511-73-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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APO-Anastrozole 1 mg Tablets