Amidex 1 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Anastrozole
Available from:
Clonmel Healthcare Ltd
ATC code:
L02BG; L02BG03
INN (International Name):
Anastrozole
Dosage:
1 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Aromatase inhibitors; anastrozole
Authorization status:
Marketed
Authorization number:
PA0126/189/001
Authorization date:
2009-07-24

Page 1 of 5

Package leaflet: Information for the user

Amidex 1 mg film-coated tablets

Anastrozole

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

In this leaflet

What Amidex is and what it is used for

What you need to know before you take Amidex

How to take Amidex

Possible side effects

How to store Amidex

Contents of the pack and other information

1. What Amidex is and what it is used for

Amidex contains a substance called anastrozole. This belongs to a group of medicines called

‘aromatase inhibitors’. Amidex is used to treat breast cancer in women who have gone through the

menopause.

Amidex works by cutting down the amount of the hormone called oestrogen that your body makes. It

does this by blocking a natural substance (an enzyme) in your body called ‘aromatase’.

2. What you need to know before you take Amidex

DO NOT take Amidex:

if you are allergic to anastrozole or any of the other ingredients of this medicine (listed in section 6).

if you are pregnant or breast-feeding (see the section called ‘Pregnancy and breast-feeding’).

Do not take Amidex if any of the above applies to you. If you are not sure, talk to your doctor or

pharmacist before taking Amidex.

Warnings and precautions

Talk to your doctor or pharmacist before taking Amidex

if you still have menstrual periods and have not yet gone through the menopause.

if you are taking a medicine that contains tamoxifen or medicines that contain oestrogen (see the

section called ‘Other medicines and Amidex’).

if you have ever had a condition that affects the strength of your bones (osteoporosis).

if you have problems with your liver or kidneys.

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking

Amidex .

If you go into the hospital, let the medical staff know you are taking Amidex.

Other medicines and Amidex

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines. This includes medicines that you buy without a prescription and herbal medicines. This is

Page 2 of 5

because Amidex can affect the way some medicines work and some medicines can have an effect on

Amidex.

Do not take Amidex if you are already taking any of the following medicines:

Certain medicines used to treat breast cancer (selective oestrogen receptor modulators), e.g.,

medicines that contain tamoxifen. This is because these medicines may stop Amidex from working

properly.

Medicines that contain oestrogen, such as hormone replacement therapy (HRT).

If this applies to you, ask your doctor or pharmacist for advice.

Tell your doctor or pharmacist if you are taking the following:

A medicine known as an ‘LHRH analogue’. This includes gonadorelin, buserelin, goserelin,

leuprorelin and triptorelin. These medicines are used to treat breast cancer, certain female health

(gynaecological) conditions, and infertility.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

Do not take Amidex if you are pregnant or breast-feeding. Stop Amidex if you become pregnant and

talk to your doctor.

Driving and using machines

Amidex is not likely to affect your ability to drive or use any tools or machines. However, some

people may occasionally feel weak or sleepy while taking Amidex. If this happens to you, ask your

doctor or pharmacist for advice.

Amidex contains lactose

Amidex contains lactose which is a type of sugar. If you have been told by your doctor that you have

an intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take Amidex

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

The recommended dose is one tablet once a day.

Try to take your tablet at the same time each day.

Swallow the tablet whole with a drink of water.

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

Keep taking Amidex for as long as your doctor tells you to. It is a long-term treatment and you may

need to take it for several years.

Use in children

Amidex should not be given to children and adolescents.

If you take more Amidex than you should

If you take more Amidex than you should, talk to a doctor straight away.

If you forget to take Amidex

If you forget to take a dose, just take your next dose as normal.

Do not take a double dose (two doses at the same time) to make up for a forgotten dose.

If you stop taking Amidex

Do not stop taking your tablets unless your doctor tells you to.

Page 3 of 5

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common side effects (may affect more than 1 in 10 people)

Headache.

Hot flushes.

Feeling sick (nausea).

Skin rash.

Pain or stiffness in your joints.

Inflammation of the joints (arthritis).

Feeling weak.

Bone loss (osteoporosis).

Common side effects (may affect up to 1 in 10 people)

Loss of appetite.

Raised or high levels of a fatty substance known as cholesterol in your blood. This would be seen

in a blood test.

Feeling sleepy.

Carpal tunnel syndrome (tingling, pain, coldness, weakness in parts of the hand).

Tickling, tingling or numbness of skin, loss/lack of taste.

Diarrhoea.

Being sick (vomiting).

Changes in blood tests that show how well your liver is working.

Thinning of your hair (hair loss).

Allergic (hypersensitivity) reactions including face, lips, or tongue.

Bone pain.

Vaginal dryness.

Bleeding from the vagina (usually in the first few weeks of treatment – if the bleeding continues,

talk to your doctor).

Muscle pain.

Uncommon side effects (may affect up to 1 in 100 people)

Changes in special blood tests that show how your liver is working (gamma-GT and bilirubin).

Inflammation of the liver (hepatitis).

Hives or nettle rash.

Trigger finger (a condition in which your finger or thumb catches in a bent position).

Increased amounts of calcium in your blood. If you experience nausea, vomiting and thirst, you

should tell your doctor or pharmacist or nurse as you may need to have blood tests.

Rare side effects (may affect up to 1 in 1,000 people)

Rare inflammation of your skin that may include red patches or blisters.

Skin rash caused by hypersensitivity (this can be from allergic or anaphylactoid reaction).

Inflammation of the small blood vessels causing red or purple colouring of the skin. Very rarely

symptoms of joint, stomach, and kidney pain may occur; this is known as ‘Henoch-Schönlein

purpura’.

Very rare side effects (may affect up to 1 in 10,000 people)

An extremely severe skin reaction with ulcers or blisters on the skin. This is known as ‘Stevens-

Johnson syndrome’.

Allergic (hypersensitivity) reactions with swelling of the throat that may cause difficulty in

swallowing or breathing. This is known as ‘angio-oedema’.

Page 4 of 5

If any of these happen to you, call an ambulance or see a doctor straight away – you may need urgent

medical treatment.

Effects on your bones

Anastrozole lowers the amount of the hormone called oestrogen that is in your body. This may lower

the mineral content of your bones. Your bones may be less strong and may be more likely to fracture.

Your doctor will manage these risks according to treatment guidelines for managing bone health in

women who have gone through the menopause. You should talk to your doctor about the risks and

treatment options.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance,

Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie;

E-mail: medsafety@hpra.ie. By reporting side effects you can help provide more information on the

safety of this medicine.

5. How to store Amidex

Keep this medicine out of the sight and reach of children. Keep your tablets in a safe place where

children cannot see or reach them. Your tablets could harm them.

Do not use this medicine after the expiry date which is stated on the outer carton and the blister

packaging (strips of tablets)

after ‘EXP’. The expiry date refers to the last day of that month.

Keep your tablets in the container they came in.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Amidex 1 mg film-coated tablets contains:

The active substance is: anastrozole.

One film-coated tablet contains 1 mg anastrozole.

The other ingredients are:

Tablet core:

Lactose monohydrate

Sodium starch glycolate (type A)

Povidone K25

Magnesium stearate

Film coating:

Hypromellose

Macrogol 6000

Cottonseed oil, hydrogenated

Starch, pregelatinised modified (origin: maize)

Titanium dioxide

What Amidex 1 mg film-coated tablets look like and contents of the pack

Amidex 1 mg are white, round, film-coated tablets imprinted with an ‘A1’ on one side.

Amidex 1 mg film-coated tablets are available in packs of 28, 30, 50, 90, 98, 100 film coated tablets.

Not all pack sizes may be marketed.

Marketing authorisation holder

Page 5 of 5

Clonmel Healthcare Ltd, Waterford Road, Clonmel, Co. Tipperary, Ireland

Manufacturer:

STADAPHARM GmbH, Stadastrasse 2–18, 61118 Bad Vilbel, Germany

STADA Arzneimittel AG, Stadastrasse 2–18, 61118 Bad Vilbel, Germany

Centrafarm Services B.V., Nieuwe Donk 9, 4879 AC Etten Leur, The Netherlands

Clonmel Healthcare Ltd, Waterford Road, Clonmel, Co. Tipperary, Ireland

This medicinal product is authorised in the Member States of the European Economic Area

(EEA) under the following names:

Germany:

ANASTRO-cell 1 mg Filmtabletten

Denmark:

Anastelb

Finland:

Anastelb 1 mg kalvopäällysteiset tabletit

France:

Anastrozole EG 1 mg, comprimé pelliculé

Hungary:

Anastrozol STADA 1 mg filmtabletta

Ireland:

Amidex 1 mg film-coated tablets

Romania:

Anastelb 1 mg, comprimate filmate

Sweden:

Anastelb 1 mg filmdragerade tabletter

This leaflet was last revised in December 2017.

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amidex 1 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 1 mg of anastrozole.

Excipient with known effect: Lactose monohydrate 92.75 mg

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet.

White, round, biconvex tablet with logo on one side and strength on the other.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Amidex is indicated for the:

Treatment of hormone receptor-positive advanced breast cancer in postmenopausal women.

Adjuvant treatment of hormone receptor-positive early invasive breast cancer in postmenopausal women.

Adjuvant treatment of hormone receptor-positive early invasive breast cancer in postmenopausal women who

have received 2 to 3 years of adjuvant tamoxifen.

4.2 Posology and method of administration

Posology

The recommended dose of Amidex for adults including the elderly is one 1 mg tablet once a day.

For postmenopausal women with hormone receptor-positive early invasive breast cancer, the recommended duration of

adjuvant endocrine treatment is 5 years.

Special populations

Paediatric population

Amidex is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see

sections 4.4 and 5.1).

Renal impairment

No dose change is recommended in patients with mild or moderate renal impairment. In patients with severe renal

impairment, administration of Amidex should be performed with caution (see section 4.4 and 5.2).

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Hepatic impairment

No dose change is recommended in patients with mild hepatic disease. Caution is advised in patients with moderate to

severe hepatic impairment (see section 4.4).

Method of administration

Amidex should be taken orally.

4.3 Contraindications

Anastrozole is contraindicated in:

Pregnant or breast-feeding women.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

General

Anastrozole should not be used in premenopausal women. 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. There are no data to support the use of Amidex with LHRH analogues.

Co-administration of tamoxifen or oestrogen-containing therapies with Amidex should be avoided as this may diminish

its pharmacological action (see sections 4.5 and 5.1).

Effect on bone mineral density

As Amidex lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible

consequent increased risk of fracture (see section 4.8).

Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed at the

commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be

initiated as appropriate and carefully monitored. The use of specific treatments, e.g., bisphosphonates, may stop further

bone mineral loss caused by Amidex in postmenopausal women and could be considered (see section 4.8).

Hepatic impairment

Amidex has not been investigated in breast cancer patients with moderate or severe hepatic impairment. Exposure to

anastrozole can be increased in subjects with hepatic impairment (see section 5.2); administration of anastrozole in

patients with moderate and severe hepatic impairment should be performed with caution (see section 4.2). Treatment

should be based on a benefit-risk evaluation for the individual patient.

Renal impairment

Anastrozole has not been investigated in breast cancer patients with severe renal impairment. Exposure to anastrozole

is not increased in subjects with severe renal impairment (GRF<30ml/min, see section 5.2); in patients with severe

renal impairment, administration of Amidex should be performed with caution (see section 4.2).

Paediatric population

Anastrozole is not recommended for use in children and adolescents as safety and efficacy have not been established in

this group of patients (see section 5.1).

Amidex should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In the

pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole

reduces estradiol levels, Amidex 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.

Hypersensitivity to lactose

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This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Anastrozole inhibits CYPs 1A2, 2C8/9 and 3A4 in vitro. Clinical studies with antipyrine and warfarin showed that

anastrozole at a 1 mg dose did not significantly inhibit the metabolism of antipyrine and R– and S-warfarin indicating

the co-administration of Arimidex with other medicinal products is unlikely to result in clinically significant medicinal

product interactions mediated by CYP enzymes.

The enzymes mediating metabolism of anastrozole have not been identified. Cimetidine, a weak, unspecific inhibitor of

CYP enzymes, did not affect the plasma concentrations of anastrozole. The effect of potent CYP inhibitors is unknown.

A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients

treated with Arimidex who also received other commonly prescribed medicinal products. There were no clinically

significant interactions with bisphosphonates (see section 5.1).

Co-administration of tamoxifen or estrogen-containing therapies with Arimidex should be avoided as this may diminish

its pharmacological action (see section 4.4 and 5.1).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Amidex in pregnant women. Studies in animals have shown reproductive toxicity

(see section 5.3). Anastrozole is contraindicated during pregnancy (see section 4.3).

Breast-feeding

There are no data on the use of Amidex during lactation. Anastrozole is contraindicated during breast-feeding (see

section 4.3).

Fertility

The effects of Amidex on fertility in humans have not been studied. Studies in animals have shown reproductive

toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

Anastrozole has no or negligible influence on the ability to drive and use machines. However, asthenia and somnolence

have been reported with the use of Amidex and caution should be observed when driving or operating machinery while

such symptoms persist.

4.8 Undesirable effects

The following table presents adverse reactions from clinical trials, post-marketing studies or spontaneous reports.

Unless specified, the frequency categories were calculated from the number of adverse events reported in a large phase

III study conducted in 9,366 postmenopausal women with operable breast cancer given adjuvant treatment for five

years (the Anastrozole, Tamoxifen, Alone or in Combination [ATAC] study).

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency

groupings are defined according to the following convention: very common (

1/10), common (

1/100 to < 1/10),

uncommon (

1/1,000 to < 1/100), rare (

1/10,000 to <1/1,000), and very rare (<1/10,000). The most frequently

reported adverse reactions were headache, hot flushes, nausea, rash, arthralgia, joint stiffness, arthritis, and asthenia.

Table 1 Adverse reactions by System Organ Class and frequency

Adverse reactions by SOC and frequency

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* Events of Carpal Tunnel Syndrome have been reported in patients receiving anastrozole treatment in clinical trials in

greater numbers than those receiving treatment with tamoxifen. However, the majority of these events occurred in

patients with identifiable risk factors for the development of the condition.

** Since cutaneous vasculitis and Henoch-Schönlein purpura was not observed in ATAC, the frequency category for

these events can be considered as ‘Rare’ (

0.01% and < 0.1%) based on the worst value of the point estimate.

*** Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few

weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further

evaluation should be considered.

The table below presents the frequency of pre-specified adverse events in the ATAC study after a median follow-up of

68 months, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial

therapy.

Table 2 ATAC study pre-specified adverse events

Metabolism and nutrition

disorders

Common

Anorexia

Hypercholesterolaemia

Uncommon

Hypercalcaemia (with or without an

increase in parathyroid hormone)

Nervous system disorders

Very common

Headache

Common

Somnolence

Carpal Tunnel Syndrome*

Sensory disturbances (including

paraesthesia, taste loss and taste perversion)

Vascular disorders

Very common

Hot flushes

Gastrointestinal disorders

Very common

Nausea

Common

Diarrhoea

Vomiting

Hepatobiliary disorders

Common

Increases in alkaline phosphatase, alanine

aminotransferase and aspartate

aminotransferase

Uncommon

Increases in gamma-GT and bilirubin

Hepatitis

Skin and subcutaneous tissue

disorders

Very common

Rash

Common

Hair thinning (alopecia)

Allergic reactions

Uncommon

Urticaria

Rare

Erythema multiforme

Anaphylactoid reaction

Cutaneous vasculitis (including some

reports of Henoch-Schönlein purpura)**

Very rare

Stevens-Johnson syndrome

Angio-oedema

Musculoskeletal and

connective tissue disorders

Very common

Arthralgia/joint stiffness

Arthritis

Osteoporosis

Common

Bone pain

Myalgia

Uncommon

Trigger fingers

Reproductive system and breast

disorders

Common

Vaginal dryness

Vaginal bleeding***

General disorders and

administration site conditions

Very common

Asthenia

Adverse events

Anastrozole

(N=3,092)

Tamoxifen

(N=3,094)

Hot flushes

1,104 (35.7%)

1,264 (40.9%)

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Fracture rates of 22 per 1,000 patient-years and 15 per 1,000 patient-years were observed for the anastrozole and

tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is

similar to the range reported in age-matched postmenopausal populations. The incidence of osteoporosis was 10.5% in

patients treated with anastrozole and 7.3% in patients treated with tamoxifen.

It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole

treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

There is limited clinical experience of accidental overdose. In animal studies, anastrozole demonstrated low acute

toxicity. Clinical trials have been conducted with various dosages of Amidex, 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 Amidex that results in life-threatening symptoms has not been

established. There is no specific antidote to overdose 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 Amidex is not highly protein

bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is

indicated.

Joint pain/stiffness

1,100 (35.6%)

911 (29.4%)

Mood disturbances

597 (19.3%)

554 (17.9%)

Fatigue/asthenia

575 (18.6%)

544 (17.6%)

Nausea and vomiting

393 (12.7%)

384 (12.4%)

Fractures

315 (10.2%)

209 (6.8%)

Fractures of the spine, hip, or wrist/Colles

133 (4.3%)

91 (2.9%)

Wrist/Colles fractures

67 (2.2%)

50 (1.6%)

Spine fractures

43 (1.4%)

22 (0.7%)

Hip fractures

28 (0.9%)

26 (0.8%)

Cataracts

182 (5.9%)

213 (6.9%)

Vaginal bleeding

167 (5.4%)

317 (10.2%)

Ischaemic cardiovascular disease

127 (4.1%)

104 (3.4%)

Angina pectoris

71 (2.3%)

51 (1.6%)

Myocardial infarct

37 (1.2%)

34 (1.1%)

Coronary artery disorder

25 (0.8%)

23 (0.7%)

Myocardial ischaemia

22 (0.7%)

14 (0.5%)

Vaginal discharge

109 (3.5%)

408 (13.2%)

Any venous thromboembolic event

87 (2.8%)

140 (4.5%)

Deep venous thromboembolic events including PE

(pulmonary embolism)

48 (1.6%)

74 (2.4%)

Ischaemic cerebrovascular events

62 (2.0%)

88 (2.8%)

Endometrial cancer

4 (0.2%)

13 (0.6%)

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5

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Enzyme inhibitors, ATC code: L02B G03

Mechanism of action and pharmacodynamic effects

Arimidex is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is

produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in

peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown

to produce a beneficial effect in women with breast cancer. In postmenopausal women, Arimidex at a daily dose of 1

mg produced estradiol suppression of greater than 80% using a highly sensitive assay.

Arimidex does not possess any progestogenic, androgenic, or estrogenic activity.

Daily doses of Arimidex up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or

after standard adrenocorticotrophic hormone (ACTH) challenge testing. Corticoid supplements are therefore not

needed.

Clinical efficacy and safety

Advanced breast cancer

First-line therapy in postmenopausal women with advanced breast cancer

Two double-blind, controlled clinical studies of similar design (Study 1033IL/0030 and Study 1033IL/0027) were

conducted to assess the efficacy of Arimidex compared with tamoxifen as first-line therapy for hormone receptor-

positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women. A total

of 1,021 patients were randomised to receive 1 mg of Arimidex once daily or 20 mg of tamoxifen once daily. The

primary endpoints for both trials were time to tumour progression, objective tumour response rate, and safety.

For the primary endpoints, Study 1033IL/0030 showed that Arimidex had a statistically significant advantage over

tamoxifen for time to tumour progression (Hazard ratio (HR) 1.42, 95% Confidence Interval (CI) [1.11, 1.82], Median

time to progression 11.1 and 5.6 months for Arimidex and tamoxifen respectively, p=0.006); objective tumour response

rates were similar for Arimidex and tamoxifen. Study 1033IL/0027 showed that Arimidex and tamoxifen had similar

objective tumour response rates and time to tumour progression. Results from the secondary endpoints were supportive

of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both

trials to draw conclusions on overall survival differences.

Second-line therapy in postmenopausal women with advanced breast cancer

Arimidex was studied in two controlled clinical trials (Study 0004 and Study 0005) in postmenopausal women with

advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast

cancer. A total of 764 patients were randomised to receive either a single daily dose of 1 mg or 10 mg of Arimidex or

megestrol acetate 40 mg four times a day. Time to progression and objective response rates were the primary efficacy

variables. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also

calculated. In both studies there were no significant differences between treatment arms with respect to any of the

efficacy parameters.

Adjuvant treatment of early invasive breast cancer for hormone receptor-positive patients

In a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer treated for 5 years

(see below), Arimidex was shown to be statistically superior to tamoxifen in disease-free survival. A greater magnitude

of benefit was observed for disease free survival in favour of Arimidex versus tamoxifen for the prospectively defined

hormone receptor-positive population.

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Table 3 ATAC endpoint summary: 5-year treatment completion analysis

a Disease-free survival includes all recurrence events and is defined as the first occurrence of loco-regional recurrence, contralateral new breast

cancer, distant recurrence or death (for any reason).

b Distant disease-free survival is defined as the first occurrence of distant recurrence or death (for any reason).

c Time to recurrence is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death

due to breast cancer.

d Time to distant recurrence is defined as the first occurrence of distant recurrence or death due to breast cancer.

e Number (%) of patients who had died.

The combination of Arimidex and tamoxifen did not demonstrate any efficacy benefits in comparison with tamoxifen

in all patients as well as in the hormone receptor-positive population. This treatment arm was discontinued from the

study.

With an updated follow-up at a median of 10 years, long term comparison of the treatment effects of Arimidex relative

to tamoxifen were shown to be consistent with previous analyses.

Adjuvant treatment of early invasive breast cancer for hormone receptor-positive patients being treated with adjuvant

tamoxifen

In a phase III trial (Austrian Breast and Colorectal Cancer Study Group [ABCSG] 8) conducted in 2,579

postmenopausal women with hormone receptor-positive early breast cancer who had received surgery with or without

radiotherapy and no chemotherapy (see below), switching to Arimidex after 2 years adjuvant treatment with tamoxifen

was statistically superior in disease-free survival when compared to remaining on tamoxifen, after a median follow-up

Efficacy endpoints

Number of events (frequency)

Intention-to-treat population

Hormone receptor-positive

tumour status

Anastrozole

(N=3,125)

Tamoxifen

(N=3,116)

Anastrozole

(N=2,618)

Tamoxifen

(N=2,598)

Disease-free survival

575 (18.4)

651 (20.9)

424 (16.2)

497 (19.1)

Hazard ratio

0.87

0.83

2-sided 95% CI

0.78 to 0.97

0.73 to 0.94

p-value

0.0127

0.0049

Distant disease-free survival

500 (16.0)

530 (17.0)

370 (14.1)

394 (15.2)

Hazard ratio

0.94

0.93

2-sided 95% CI

0.83 to 1.06

0.80 to 1.07

p-value

0.2850

0.2838

Time to recurrence

402 (12.9)

498 (16.0)

282 (10.8)

370 (14.2)

Hazard ratio

0.79

0.74

2-sided 95% CI

0.70 to 0.90

0.64 to 0.87

p-value

0.0005

0.0002

Time to distant recurrence

324 (10.4)

375 (12.0)

226 (8.6)

265 (10.2)

Hazard ratio

0.86

0.84

2-sided 95% CI

0.74 to 0.99

0.70 to 1.00

p-value

0.0427

0.0559

Contralateral breast primary

35 (1.1)

59 (1.9)

26 (1.0)

54 (2.1)

Odds ratio

0.59

0.47

2-sided 95% CI

0.39 to 0.89

0.30 to 0.76

p-value

0.0131

0.0018

Overall survival

411 (13.2)

420 (13.5)

296 (11.3)

301 (11.6)

Hazard ratio

0.97

0.97

2-sided 95% CI

0.85 to 1.12

0.83 to 1.14

p-value

0.7142

0.7339

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of 24 months.

Table 4 ABCSG 8 trial endpoint and results summary

Two further similar trials (GABG/ARNO 95 and ITA), in one of which patients had received surgery and

chemotherapy, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results.

The Arimidex safety profile in these 3 studies was consistent with the known safety profile established in

postmenopausal women with hormone receptor-positive early breast cancer.

Bone mineral density (BMD)

In the phase III/IV study (Study of Anastrozole with the Bisphosphonate Risedronate [SABRE]), 234 postmenopausal

women with hormone receptor-positive early breast cancer scheduled for treatment with anastrozole 1 mg/day were

stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. The primary

efficacy parameter was the analysis of lumbar spine bone mass density using DEXA scanning. All patients received

treatment with vitamin D and calcium. Patients in the low risk group received anastrozole alone (N=42), those in the

moderate group were randomised to anastrozole plus risedronate 35 mg once a week (N=77) or anastrozole plus

placebo (N=77) and those in the high risk group received anastrozole plus risedronate 35 mg once a week (N=38). The

primary endpoint was change from baseline in lumbar spine bone mass density at 12 months.

The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture showed no

decrease in their bone mass density (assessed by lumbar spine bone mineral density using DEXA scanning) when

managed by using anastrozole 1 mg/day in combination with risedronate 35 mg once a week.

In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with

anastrozole 1 mg/day alone. These findings were mirrored in the secondary efficacy variable of change from baseline in

total hip BMD at 12 months.

Efficacy endpoints

Number of events (frequency)

Anastrozole (N=1,297)

Tamoxifen (N=1,282)

Disease-free survival

65 (5.0)

93 (7.3)

Hazard ratio

0.67

2-sided 95% CI

0.49 to 0.92

p-value

0.014

Time to any recurrence

36 (2.8)

66 (5.1)

Hazard ratio

0.53

2-sided 95% CI

0.35 to 0.79

p-value

0.002

Time to distant recurrence

22 (1.7)

41 (3.2)

Hazard ratio

0.52

2-sided 95% CI

0.31 to 0.88

p-value

0.015

New contralateral breast

cancer

7 (0.5)

15 (1.2)

Odds ratio

0.46

2-sided 95% CI

0.19 to 1.13

p-value

0.090

Overall survival

43 (3.3)

45 (3.5)

Hazard ratio

0.96

2-sided 95% CI

0.63 to 1.46

p-value

0.840

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This study provides evidence that the use of bisphosphonates could be considered in the management of possible bone

mineral loss in postmenopausal women with early breast cancer scheduled to be treated with Arimidex.

Paediatric population

Arimidex is not indicated for use in children and adolescents. Efficacy has not been established in the paediatric

populations studied (see below). The number of children treated was too limited to draw any reliable conclusions on

safety. No data on the potential long-term effects of Arimidex treatment in children and adolescents are available (see

also section 5.3).

The European Medicines Agency has waived the obligation to submit the results of studies with Arimidex in one or

several subsets of the paediatric population in short stature due to growth hormone deficiency (GHD), testotoxicosis,

gynaecomastia, and McCune-Albright syndrome (see section 4.2).

Short stature due to Growth Hormone Deficiency

A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11 to 16 years inclusive) with GHD

treated for 12 to 36 months with Arimidex 1 mg/day or placebo in combination with growth hormone. Only 14 subjects

on Arimidex completed 36 months.

No statistically significant difference from placebo was observed for the growth related parameters of predicted adult

height, height, height SDS (standard deviation score), and height velocity. Final height data were not available. While

the number of children treated was too limited to draw any reliable conclusions on safety, there was an increased

fracture rate and a trend towards reduced bone mineral density in the Arimidex arm compared to placebo.

Testotoxicosis

An open-label, non-comparative, multi-centre study evaluated 14 male patients (aged 2 to 9 years) with familial male-

limited precocious puberty, also known as testotoxicosis, treated with combination of Arimidex and bicalutamide. The

primary objective was to assess the efficacy and safety of this combination regimen over 12 months. Thirteen out of the

14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). There was no

significant difference in growth rate after 12 months of treatment, relative to the growth rate during the 6 months prior

to entering the study.

Gynaecomastia studies

Trial 0006 was a randomised, double-blind, multi-centre study of 82 pubertal boys (aged 11-18 years inclusive) with

gynaecomastia of greater than 12 months duration treated with Arimidex 1 mg/day or placebo daily for up to 6 months.

No significant difference in the number of patients who had a 50% or greater reduction in total breast volume after 6

months of treatment was observed between the Arimidex 1 mg treated group and the placebo group.

Trial 0001 was an open-label, multiple-dose pharmacokinetic study of Arimidex 1 mg/day in 36 pubertal boys with

gynaecomastia of less than 12 months duration. The secondary objectives were to evaluate the proportion of patients

with reductions from baseline in the calculated volume of gynaecomastia of both breasts combined of at least 50%

between day 1 and after 6 months of study treatment, and patient tolerability and safety. A decrease in 50% or more of

total breast volume was seen in 56% (20/36) of the boys after 6 months.

McCune-Albright Syndrome study

Trial 0046 was an international, multi-centre, open-label exploratory trial of Arimidex in 28 girls (aged 2 to

10 years)

with McCune-Albright Syndrome (MAS). The primary objective was to evaluate the safety and efficacy of Arimidex 1

mg/day in patients with MAS. The efficacy of study treatment was based on the proportion of patients fulfilling defined

criteria relating to vaginal bleeding, bone age, and growth velocity.

No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. There were no

clinically significant changes in Tanner staging, mean ovarian volume, or mean uterine volume. No statistically

significant change in the rate of increase in bone age on treatment compared to the rate during baseline was observed.

Growth rate (in cm/year) was significantly reduced (p<0.05) from pre-treatment through month 0 to month 12, and

from pre-treatment to the second 6 months (month 7 to month 12).

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5.2 Pharmacokinetic properties

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 Arimidex tablets. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are

attained after 7 daily doses, and accumulation is 3- to 4-fold. There is no evidence of time or dose-dependency of

anastrozole pharmacokinetic parameters.

Anastrozole pharmacokinetics are independent of age in postmenopausal women.

Anastrozole is only 40% bound to plasma proteins.

Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. 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, the major metabolite in plasma, does not inhibit aromatase.

Renal or hepatic impairment

The apparent clearance (CL/F) of anastrozole, following oral administration, was approximately 30% lower in

volunteers with stable hepatic cirrhosis than in matched controls (Study 1033IL/0014). However, plasma anastrozole

concentrations in the volunteers with hepatic cirrhosis were within the range of concentrations seen in normal subjects

in other trials. Plasma anastrozole concentrations observed during long-term efficacy trials in patients with hepatic

impairment were within the range of plasma anastrozole concentrations seen in patients without hepatic impairment.

The apparent clearance (CL/F) of anastrozole, following oral administration, was not altered in volunteers with severe

renal impairment (GFR <30ml/min) in Study 1033IL/0018, consistent with the fact that anastrozole is eliminated

primarily by metabolism. Plasma anastrozole concentrations observed during long-term efficacy trials in patients with

renal impairment were within the range of plasma anastrozole concentrations seen in patients without renal impairment.

In patients with severe renal impairment, administration of Arimidex should be performed with caution (see section 4.2

and 4.4).

Paediatric population

In boys with pubertal gynaecomastia (10-17 years), anastrozole was rapidly absorbed, was widely distributed, and was

eliminated slowly with a half-life of approximately 2 days. Clearance of anastrozole was lower in girls (3-10 years)

than in the older boys and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated

dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction for the indicated population.

Acute toxicity

In animal studies toxicity was only seen at high doses. In acute toxicity studies in rodents, the median lethal dose of

anastrozole was greater than 100 mg/kg/day by the oral route and greater than 50 mg/kg/day by the intraperitoneal

route. In an oral acute toxicity study in the dog, the median lethal dose was greater than 45 mg/kg/day.

Chronic toxicity

In animal studies adverse effects were only seen at high doses. 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.

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Mutagenicity

Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen.

Reproductive toxicology

In a fertility study weanling male rats were dosed orally with 50 or 400 mg/l anastrozole via their drinking water for 10

weeks. Measured mean plasma concentrations were 44.4 (±14.7) ng/ml and 165 (±90) ng/ml respectively. Mating

indices were adversely affected in both dose groups, whilst a reduction in fertility was evident only at the 400 mg/l

dose level. The reduction was transient as all mating and fertility parameters were similar to control group values

following a 9 week treatment-free recovery period.

Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased

pre-implantation loss at 0.02 mg/kg/day. These effects occurred at clinically relevant doses. An effect in man cannot be

excluded. These effects were related to the pharmacology of the compound and were completely reversed after a 5-

week compound withdrawal period.

Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2

mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits)

were related to the pharmacology of the compound.

The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above (from Day 17 of pregnancy to Day 22

post-partum) was compromised. These effects were related to the pharmacological effects of the compound on

parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring

attributable to maternal treatment with anastrozole.

Carcinogenicity

A two-year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps

in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose

which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be

clinically relevant to the treatment of patients with anastrozole.

A two-year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the

incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of

lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically

relevant to the treatment of patients with anastrozole.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate

Sodium starch glycolate (Type A)

Povidone K-25

Magnesium stearate

Film coating:

Hypromellose

Macrogol 6000

Cottonseed oil, hydrogenated

Starch, pregelatinised modified (origin: maize)

Titanium dioxide E171

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6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/Aluminium blister

Pack sizes: 28, 30, 50, 90, 98, 100 film coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Clonmel Healthcare Ltd

Waterford Rd

Clonmel

Co. Tipperary

8 MARKETING AUTHORISATION NUMBER

PA0126/189/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 24

July 2009

Date of Last renewal: 17th December 2013

10 DATE OF REVISION OF THE TEXT

April 2017

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