Consumer medicine information

Anastrozole Sandoz

Anastrozole

BRAND INFORMATION

Brand name

Anastrozole Sandoz

Active ingredient

Anastrozole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Anastrozole Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Anastrozole Sandoz. 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 risk of you taking Anastrozole Sandoz against the benefits it is expected to 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 ANASTROZOLE SANDOZ IS USED FOR

Anastrozole Sandoz 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.

Anastrozole Sandoz 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 Sandoz may slow or stop the growth of cancer.

Follow all directions given by your doctor. They may differ from the information contained in this leaflet.

Ask your doctor if you have any questions about why Anastrozole Sandoz was prescribed for you. Your doctor may have prescribed Anastrozole Sandoz for another reason.

Anastrozole Sandoz is only available with a doctor’s prescription.

Anastrozole Sandoz is not addictive.

BEFORE YOU TAKE ANASTROZOLE SANDOZ

When you must not take it

Do not take Anastrozole Sandoz if you have an allergy to:

  • any medicine containing 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 or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you are pregnant or intend to become pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine. Your baby can take in Anastrozole Sandoz from breast milk if you are breastfeeding.

Do not take Anastrozole Sandoz if you are still having menstrual periods. Anastrozole Sandoz should only be taken by women who are no longer having menstrual periods.

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

Do not give Anastrozole Sandoz to a child. Anastrozole Sandoz is not recommended for use in children.

Do not take Anastrozole Sandoz after the use by (expiry) date printed on the pack. Do not take Anastrozole Sandoz 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.

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, especially if they are in the same drug class as anastrozole
  • any other substances, including foods, preservatives or dyes.

Tell your doctor if you plan on becoming pregnant or will be breastfeeding while you are using Anastrozole Sandoz.

Tell your doctor if you have or have had any medical conditions, especially 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).

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 him/her before you start taking Anastrozole Sandoz.

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.

In particular, tell your doctor if you take any of the following:

  • 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”, such as goserelin or leuprorelin.

These medicines may be affected by Anastrozole Sandoz, or may affect how well it works. You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

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

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

HOW TO TAKE ANASTROZOLE SANDOZ

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from 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 every day.

When to take it

Take Anastrozole Sandoz 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.

Swallow Anastrozole Sandoz tablets whole, with a glass of water.

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

How long to take it

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

Anastrozole Sandoz helps to control your condition, but does not cure it. Therefore you must take Anastrozole Sandoz every day. Do not stop taking it unless your doctor tells you to - even if you feel better.

If you forget to take your dose

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 take a double dose to make up for the dose 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

Immediately telephone your doctor, or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) or go to Accident and Emergency at your nearest hospital, if you think you or anyone else has taken too much Anastrozole Sandoz. Do this even if there are no signs of discomfort or poisoning.

WHILE YOU ARE TAKING ANASTROZOLE SANDOZ

Things you must do

  • Always follow your doctor's instructions carefully.
  • Tell your doctor if you become pregnant while taking Anastrozole Sandoz.
  • 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 Anastrozole Sandoz.
  • If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking Anastrozole Sandoz.
  • If you go into hospital, please let the medical staff know that you are taking Anastrozole Sandoz.

Things you must not do

  • Do not stop taking Anastrozole Sandoz unless you have discussed it with your doctor.
  • Do not take Anastrozole Sandoz to treat any other complaints unless your doctor tells you to.
  • Do not give this medication to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how Anastrozole Sandoz affects you. This medicine may occasionally cause some people to 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 Sandoz.

This medicine helps most postmenopausal women with 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 attention if you get some of the side effects.

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

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

If any of the following happen, tell your doctor immediately or go to Accident and Emergency 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 (Stevens-Johnson syndrome) 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. These side effects are uncommon or rare.

Tell your doctor or pharmacist 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
  • 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)
  • pins and needles
  • loss of taste or changing taste of food or drink
  • feeling depressed.

Anastrozole Sandoz 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.

These are the more common side effects of the medicine. 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 or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

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

AFTER USING ANASTROZOLE SANDOZ

Storage

Keep Anastrozole Sandoz in the original packaging until you need to take it.

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

Disposal

Return any unused or out of date medicine to your pharmacist.

PRODUCT DESCRIPTION

What Anastrozole Sandoz looks like

Anastrozole Sandoz 1 mg: white, round, biconvex film coated tablet without breaking notch and embossment 'A1' on one side. Available in PVC/Al blisters of 30 tablets.

Ingredients

Active Ingredient
Each Anastrozole Sandoz 1 mg tablet contains 1 mg anastrozole.

Inactive Ingredients
Each Anastrozole Sandoz 1 mg tablet also contains: lactose monohydrate, cellulose - microcrystalline, sodium starch glycollate type A, magnesium stearate, silica - colloidal anhydrous, hyprolose and Opadry II white [lactose monohydrate, hypromellose, titanium dioxide and macrogol 4000].

Supplier

Anastrozole Sandoz is supplied in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road,
Macquarie Park,
NSW 2113, AUSTRALIA
Tel: 1800 726 369

This leaflet was revised in February 2022.

Australian Register Number

Anastrozole Sandoz 1 mg tablet: AUST R 142746 (blisters)

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Anastrozole Sandoz

Active ingredient

Anastrozole

Schedule

S4

 

1 Name of Medicine

Anastrozole.

2 Qualitative and Quantitative Composition

Excipients of known effect.

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

3 Pharmaceutical Form

Anastrozole Sandoz 1 mg: white, round, biconvex film coated tablet without breaking notch and embossment 'A1' on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Early breast cancer.

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

Advanced breast cancer.

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

4.2 Dose and Method of Administration

Dosage.

Adults (including the elderly).

One tablet (1 mg) to be taken orally once daily.
For early breast cancer, the recommended duration of treatment should be five years. For patients being switched to anastrozole from tamoxifen, the switch should occur after completion of two to three years of tamoxifen therapy. There are no data to support switching at earlier or later time points.

Infants and children.

Not recommended for use in children.

Dosage adjustment.

Renal impairment.

No dose change is recommended for patients with renal impairment.

Hepatic impairment.

No dose change is recommended for patients with hepatic impairment.

4.3 Contraindications

Anastrozole must not be administered during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in 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

Paediatric use and use in premenopausal women.

Anastrozole is not recommended for use in children or in premenopausal women, as safety and efficacy have not been established in these groups of patients. The menopause should be defined biochemically (luteinizing hormone (LH), follicle stimulating hormone (FSH), and/or estradiol levels) in any patient where there is doubt about menopausal status.
Coadministration of tamoxifen or estrogen containing therapies with anastrozole should be avoided as this may diminish its pharmacological action.

Bone mineral density.

As anastrozole lowers circulating estrogen 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. The use of specific treatments, e.g. bisphosphonates, may stop further bone mineral loss caused by anastrozole in postmenopausal women and could be considered.

Combination with luteinising hormone releasing hormone (LHRH) agonist.

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

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.

Use in renal impairment.

The apparent oral clearance of anastrozole in volunteers with stable renal impairment (creatinine clearance less than 30 mL/minute/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 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.

See Paediatric use and use in premenopausal women, above.
Anastrozole is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients.
Anastrozole should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. Since anastrozole reduces estradiol levels, anastrozole must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available.

Effects on laboratory tests.

Preclinical 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 doses (1 mg/kg/day) and mid doses (dogs 3 mg/kg/day; rats 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 species.

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 Cmax 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 medicines 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.

Estrogen 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 bisphosphonates or other commonly prescribed medicines. 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 (nine 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 medicine was shown to cross the placenta and was detectable in foetal tissues at concentrations approximately 40% of corresponding maternal plasma medicine 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 (nine and three 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 estrogen dependent events during pregnancy and are not unexpected with a medicine of this class.
In a perinatal/ 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.

4.7 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. Adverse effects which have been associated with anastrozole are provided in Table 1.
In a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer treated for five 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).

Post-marketing experience.

In addition to the above, the following adverse events have been reported during post marketing experience for anastrozole.

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.

4.9 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.

Treatment.

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 estrogen receptors and growth of these tumours can be stimulated by estrogen. 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 estrogens 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 estrogenic 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 two 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 3,224 patients who had completed two years of adjuvant treatment with tamoxifen and had remained disease free were randomised to receive anastrozole for three years (n = 1,618) or to continue on tamoxifen for three years (20 to 30 mg daily; n = 1,606). The total duration of hormonal therapy was five 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 five years of hormonal therapy (see Table 2).
Compared with tamoxifen, anastrozole treatment was associated with a significantly increased incidence of fractures (34 versus 16 cases; odds ratio (OR) = 2.14 (95% CI: 1.14 to 4.17; p = 0.015)) but with a reduced incidence of thromboses (three versus 12 cases; OR = 0.25 (95% confidence interval (CI): 0.04 to 0.92; p = 0.034)).
Another open label, randomised controlled trial (the ITA study) enrolled 448 postmenopausal patients with estrogen receptor positive early breast cancer. All patients had lymph node involvement. Patients who remained disease free after receiving two to three 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 five 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 (see 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 68 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 13 and 21%, 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 17 and 26%, respectively (see Figure 1 and Figure 2, and Table 4). The absolute difference in recurrence rates increased over time, even beyond the five years of scheduled treatment (see Figure 2).
The primary survival analysis was for noninferiority. The overall survival benefit of tamoxifen was maintained with anastrozole. Similar overall survival was observed for both the ITT group and hormone receptor positive subgroup (see Table 4). The absence of a statistically significant survival benefit at this point in the study was anticipated and could be predicted from previous experience in a similar population.
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 medicine related adverse events were less common with anastrozole compared to tamoxifen (6.5 versus 8.9%, odds ratio 0.71, 95% CI 0.59 to 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 had an increase in joint disorders (including arthritis, arthrosis and arthralgia) and total number of fractures compared with patients receiving tamoxifen, although the incidence of hip fractures (generally associated with greater morbidity) was similar for the two treatment groups. A fracture rate for all fractures (both on treatment and off treatment events) of 22 per 1,000 patient years was observed with anastrozole and 15 per 1,000 patient years with tamoxifen with a median follow-up of 68 months. The fracture rate for anastrozole falls within the broad range of fracture rates reported in an age matched postmenopausal population. Ischaemic cardiovascular events (consisting mainly of angina pectoris) 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), 1,021 postmenopausal women between the ages of 30 and 92 years old with advanced breast cancer (stage IV (metastatic disease) and stage III (locally advanced disease)) were randomised to receive anastrozole 1 mg daily (n = 511) or tamoxifen 20 mg once daily (n = 510) as first line therapy.
The primary endpoints 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 in trial 0030, respectively. The number of patients still on trial treatment at the end of the follow-up period was as follows.

Anastrozole 1 mg.

Trial 0027: 101 out of 340 (29.7%); trial 0030: 48 out of 171 (28.1%); pooled trials: 149 out of 511 (29.2%).

Tamoxifen 20 mg.

Trial 0027: 88 out of 328 (26.8%); trial 0030: 40 out of 182 (22.0%); pooled trials: 128 out of 510 (25.1%).
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 5.
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 5. Positive estrogen/ 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 or 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 estrogen receptor positive or unknown status (with about 5% being estrogen receptor 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 two 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 seven daily doses. There is no evidence of time or dose dependency of anastrozole pharmacokinetic parameters.
Anastrozole pharmacokinetics are independent of age in postmenopausal women.
Pharmacokinetics have not been studied in children.

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.

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 tumorigenic 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 tumorigenic effect on the ovary occurred at all doses including the lowest dose tested (5 mg/kg/day) (exposure (AUC) was approximately one to twofold 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, microcrystalline cellulose, sodium starch glycollate type A, magnesium stearate, colloidal anhydrous silica, hyprolose and Opadry II complete film coating system OY-L-28900 White [lactose monohydrate, hypromellose, titanium dioxide and Macrogol 4000].

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Anastrozole Sandoz should be stored below 30°C.

6.5 Nature and Contents of Container

Anastrozole Sandoz 1 mg is available in PVC/Al blisters of 30 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

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: 293.4.

CAS number.

120511-73-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes