Consumer medicine information

ANASTROL

Anastrozole

BRAND INFORMATION

Brand name

Anastrol Tablets

Active ingredient

Anastrozole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using ANASTROL.

What is in this leaflet

This leaflet answers some of the common questions people ask about Anastrol. It does not contain all the information that is known about Anastrol.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you taking Anastrol 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 need to read it again.

What ANASTROL is used for

Anastrol 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.

Anastrol 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, Anastrol may slow or stop the growth of cancer.

Ask your doctor if you have any questions about why Anastrol has been prescribed for you.

Your doctor may have prescribed it for another reason.

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

Anastrol is not addictive.

Before you take it

When you must not take it

Do not take Anastrol if you are pregnant or intend to become pregnant.

It may affect your developing baby if you take it during pregnancy.

Do not breastfeed while taking Anastrol.

Your baby can take in Anastrol from breast milk if you are breastfeeding.

Do not take Anastrol if you have an allergy to:

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

Symptoms of an allergic reaction may include 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.

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

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

Do not take Anastrol if you are a man.

Men are not normally treated with it.

Do not give Anastrol to a child.

It is not recommended for use in children.

Do not take Anastrol after the expiry date printed on the pack.

Do not take Anastrol if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

Do not use it to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else.

Before you start to take it

Tell your doctor if you are allergic to any other medicines or any foods, dyes or preservatives.

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

  • liver problems
  • 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).

Medicines such as Anastrol 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 him/her before you start taking Anastrol.

Taking other medicines

Tell your doctor or pharmacist 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 should not be taken with Anastrol. These include:

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

Talk to your doctor or pharmacist if you have any concerns or questions about taking Anastrol.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

How to take it

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

Your doctor 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 every day.

When to take it

Take Anastrol 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.

How to take it

Swallow the tablet whole with a glass of water.

It does not matter if you take Anastrol before, with or after food.

How long to take it

Continue taking it for as long as your doctor or pharmacist tells you.

Anastrol helps to control your condition, but does not cure it. Therefore you must take this medicine every day.

Do not miss any doses and do not stop taking the medicine even if you feel better.

If you forget to take it

If you miss a dose, take it as soon as you remember, as long as it is 12 hours before the next dose is due. If it is less than 12 hours to the next dose, do not take the dose you have missed.

Do not double the dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when 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 Accident and Emergency at the nearest hospital if you think that you or anyone else may have taken too much Anastrol. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking it

Things you must do

Be sure to keep all your appointments with your doctor so your progress can be checked.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking Anastrol.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking Anastrol.

If you go into hospital, tell the medical staff that you are taking Anastrol.

Things you must not do

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

Do not take it to treat any other complaints unless your doctor tells you to.

Do not stop taking this medicine unless you have discussed it with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Anastrol 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 Anastrol.

This medicine helps most postmenopausal women who have breast cancer, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. Side effects may happen at the start of treatment or they may happen after you have been taking your medicine for some time. You may need medical treatment if you get some of the side effects.

If you get any side effects do not stop taking Anastrol without first talking to your doctor or pharmacist.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • hot flushes
  • feeling weak or a lack of energy
  • feeling sleepy
  • joint pain or stiffness
  • arthritis
  • aching muscles, muscle tenderness or weakness, not caused by exercise
  • bone pain
  • high calcium levels in the blood
  • swelling of the blood vessels
  • vaginal dryness
  • vaginal bleeding
  • thinning of hair (hair loss)
  • mild skin rash
  • feeling sick (nausea)
  • diarrhoea
  • headache
  • loss of appetite (anorexia)
  • vomiting
  • carpal tunnel syndrome (tingling, pain, coldness, weakness in parts of hand).

These are the more common side effects of Anastrol. Mostly these are mild to moderate in nature.

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 immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following symptoms:

  • 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).

These are serious side effects. You may need urgent medical attention or hospitalisation.

Serious side effects are uncommon.

Anastrol 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 unwanted side effects.

Tell your doctor if you notice anything else that is making you feel unwell.

Other side effects not listed above may occur in some people.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After taking it

Storage

Keep your tablets in the blister pack until it is time to take them.

If you take Anastrol out of the blister pack it will not keep well.

Keep it in a cool dry place where the temperature stays below 30 degrees C.

Do not store it or any other medicine in the bathroom or near a sink.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not leave it on a window-sill or in the car on hot days.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking it or you find that the expiry date has passed, ask your pharmacist what to do with any tablets you have left over.

Product description

What it looks like

Anastrol is a round, white to off-white film-coated tablet with “93” debossed on one side and “A10” on the other.

It is available in a blister pack containing 30, 60, 90 or 100 tablets.

Ingredients

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

It also contains the following inactive ingredients:

  • lactose
  • povidone
  • sodium starch glycollate
  • magnesium stearate
  • hypromellose
  • macrogol 400
  • macrogol 6000
  • titanium dioxide.

Sponsor

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065

Australian Registration Number: AUST R 170001

This leaflet was updated in November 2012

BRAND INFORMATION

Brand name

Anastrol Tablets

Active ingredient

Anastrozole

Schedule

S4

 

1 Name of Medicine

Anastrozole.

6.7 Physicochemical Properties

Anastrozole is a fine white to off-white powder. It is very slightly soluble in water and freely soluble in methanol, acetone, ethanol and tetrahydrofuran and very soluble in acetonitrile.

Chemical structure.

Chemical name: α,α,α',α'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-benzene-diacetonitrile.
Molecular weight: 293.4. Molecular formula: C17H19N5.

CAS number.

120511-73-1.

2 Qualitative and Quantitative Composition

Anastrol tablets contain the active 1 mg anastrozole.

List of excipients with known effects.

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

3 Pharmaceutical Form

Anastrol is a round, white to off white, film-coated tablet debossed with "93" on one side and "A10" on the other.

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 prospectively planned, 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 locoregional or distant recurrence or the development of contralateral breast cancer. Overall survival was a secondary endpoint. 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 locoregional or distant recurrence. Event free survival was a secondary endpoint with an event being defined as locoregional 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 endpoint. 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 (ATAC; trial 0029) 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 subgroup, 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, 2 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 subgroup (see Table 4). At the 100 month follow-up the mean age of the surviving population was 72 years, with nonbreast 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 nonserious, 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 subgroup. 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

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.

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.

4.3 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.

4.4 Special Warnings and Precautions for Use

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.

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.

Use in renal and hepatic impairment.

The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment (creatinine clearance less than 30 mL/min/1.73m2) was in the range observed in healthy volunteers. Dosage adjustment is therefore not necessary. Anastrozole 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 anastrozole.

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 and use in pre-menopausal women.

Anastrozole 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.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed 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. Coadministration 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 peri postnatal 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.

4.8 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.

4.2 Dose and Method of Administration

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 Anastrol 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.

Use in adults with renal impairment.

No dose change is recommended.

Use in adults with hepatic impairment.

No dose change is recommended.

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.

4.9 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 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Anastrol tablets contain the following excipients: lactose monohydrate, povidone, sodium starch glycollate, magnesium stearate, hypromellose, macrogol 400, macrogol 6000 and titanium dioxide.

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

Anastrol tablets are presented in a blister pack containing 30, 60, 90 and 100 tablets.

6.6 Special Precautions for Disposal

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

Summary Table of Changes