Anastrozole Bluefish 1 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Anastrozole
Available from:
Bluefish Pharmaceuticals AB
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:
PA1436/010/001
Authorization date:
2011-03-25

PACKAGE LEAFLET: INFORMATION FOR THE USER

Anastrozole Bluefish 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

or nurse

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

or nurse

.This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

What Anastrozole Bluefish is and what it is used for

What you need to know before you take Anastrozole Bluefish

How to take Anastrozole Bluefish

Possible side effects

How to store Anastrozole Bluefish

Contents of the pack and other information

1.

WHAT ANASTROZOLE BLUEFISH IS AND WHAT IT IS USED FOR

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

called ‘aromatase inhibitors’. Anastrozole Bluefish is used to treat breast cancer in women who

have gone through the menopause.

Anastrozole Bluefish works by cutting down the amount of the hormone called estrogen that your

body makes. It does this by blocking a natural substance (an enzyme) in your body called

‘aromatase’.

You must talk to a doctor if you do not feel better or if you feel worse.

2.

WHAT YOU NEED TO KNOW BEFORE YOU TAKE ANASTROZOLE BLUEFISH

Do not take Anastrozole Bluefish

if you are allergic (hypersensitivity) 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 Anastrozole Bluefish if any of the above apply to you. If you are not sure, talk to your

doctor or pharmacist before taking Anastrozole Bluefish.

Warnings and precautions

Talk to your doctor or pharmacist

or nurse

before takingAnastrozole Bluefish

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 estrogen (see

the section called ‘Other medicines and Anastrozole Bluefish).

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

Anastrozole Bluefish.

If you go to the hospital, let the medical staff know you are taking Anastrozole Bluefish.

Other medicines and Anastrozole Bluefish

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 because Anastrozole Bluefish can affect the way some medicines work and some medicines can

have an effect on Anastrozole Bluefish.

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

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

medicines that contain tamoxifen. This is because these medicines may stop Anastrozole

Bluefish from working properly.

Medicines that contain estrogen, 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 and fertility

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.

Stop taking Anastrozole Bluefish if you become pregnant and talk to your doctor.

Driving and using machines

Anastrozole Bluefish 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 Anastrozole Bluefish. If

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

Anastrozole Bluefish contains lactose

Anastrozole Bluefish 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 medicinal

product.

Anastrazole Bluefish contains sodium

Anastrozole Bluefish contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’

3.

HOW TO TAKE ANASTROZOLE BLUEFISH

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

doctor or pharmacist if you are not sure.

The recommendeddose 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 Anastrozole Bluefish before, with or after food.

Keep taking Anastrozole Bluefish 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. Check with your doctor or pharmacist if you are not

sure.

Use in children and adolescents

Anastrozole Bluefish should not be given to children and adolescents.

If you take more Anastrozole Bluefish than you should

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

If you forget to take Anastrozole Bluefish

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 Anastrozole Bluefish

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

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

or nurse

4.

POSSIBLE SIDE EFFECTS

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

Tell your doctor immediately:

If you experience any of the following very rare symptoms after taking this medicine, these

symptoms can be serious:

Swollen

face,

tongue

pharynx,

difficulty

swallow,

hives

difficulties

breath

(angioedema).

Serious allergic reactions with blistering of the skin, mouth, eyes and genitals (Stevens-Johnsons

syndrome).

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 in10 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).

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

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, 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’.

Effects on your bones

Anastrozole Bluefish lowers the amount of the hormone called estrogen 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 of the side effects, talk to your doctor or 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 ANASTROZOLE BLUEFISH

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 carton and blister strip

after

EXP:

. The expiry date refers to the last day of that month.

This medicine does not required any special storage conditions.

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 Anastrozole Bluefish contains

The active substance is Anastrozole. Each film-coated tablet contains 1mg Anastrozole.

The other ingredients are Lactose monohydrate 93 mg, Povidone (K30), Sodium starch glycolate,

Magnesium stearate. The tablets are coated with Hypromellose, Macrogol 300, Titanium dioxide

(E171).

What Anastrozole Bluefish looks like and contents of the pack

Anastrozole Bluefish are white and round film-coated tablets of diameter 6.0 - 6.2mm. The tablets

are packed in blister packs containing 28, 30, 98 & 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and manufacturer

Marketing Authorisation Holder

Bluefish Pharmaceuticals AB

P.O. Box 49013

100 28 Stockholm

Sweden

Manufacturer

Bluefish Pharmaceuticals AB, Gävlegatan 22, 113 30 Stockholm, Sweden.

Genepharm S.A., 18th km Marathonos Avenue, 153 51 Pallini Attikis, Greece

This medicinal product is authorised in the Member States of the EEA under the following

names:

Anastrozol Bluefish 1 mg Filmtabletten

Anastrozole

Bluefish

comprimidos

recubiertos

película EFG

Anastrozole Bluefish 1 mg comprimés peliculés

Anastrozole Bluefish 1 mg film-coated tablets

Adiunastrol 1 mg compresse rivestite con film

Anastrozole Bluefish, 1 mg, tabletki powlekane

Anastrozole Bluefish 1 mg filmdragerade tabletter

IS Anastrozole Bluefish 1 mg filmuhúðaðar töflur

This leaflet was last revised in April 2020.

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Anastrozole Bluefish 1 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1 mg anastrozole

Excipient with known effect:

Each tablet contains 93 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White, round, biconvex tablet of diameter 6.0 - 6.2mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Anastrozole Bluefish is indicated for the:

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

4.2 Posology and method of administration

Posology

The recommended dose of Anastrozole Bluefish for adults including the elderly is 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 population

Paediatric population

Anastrozole Bluefish 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 and moderate renal impairment.In patients with severe renal

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

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

Anastrozole should be taken orally.

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4.3 Contraindications

Anastrozole Bluefish 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 anastrozole with LHRH analogues.

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

pharmacological action (see section 4.5 and 5.1).

Effect on 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 (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 anastrozole in postmenopausal women and could be considered (see section 4.8).

Hepatic impairment

Anastrozole 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 Anastrozole 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).

Anastrozole 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, 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.

Hypersensitivity to lactose

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or

glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per 1mg tablet, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

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

anastrozole with other medicinal products is unlikely to result in clinically significant medicinal product interactions mediated

by CYP enzymes.

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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

anastrozole 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 anastrozole 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 on the use of anastrozole 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 anastrozole during lactation. Anastrozole is contraindicated during breast-feeding (see section

4.3).

Fertility

The effects of anastrozole 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 anastrozole 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 1Adverse reactions by System Organ Class and frequency

Adverse reactions by SOC and frequency

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*

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

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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

Angioedema

Musculoskeletal and connective tissue disorders

Very common

Arthralgia/joint stiffness

Arthritis

Osteoporosis

Common

Bone pain

Myalgia

Uncommon

Trigger finger

Reproductive system and breast disorders

Common

Vaginal dryness

Vaginal bleeding ***

General disorders and administration site conditions

Very common

Asthenia

* 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

Undesirable effect

Anastrozole

(N = 3,092)

Tamoxifen

(N = 3,094)

Hot flushes

1,104 (35.7 %)

1,264 (40.9 %)

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 fractures

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 %)

Ischemic 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 ischemia

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 %)

Ischemic cerebrovascular events

62 (2.0 %)

88 (2.8 %)

Endometrial cancer

4 (0.2 %)

13 (0.6 %)

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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 in 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

medicinal

product

important.

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 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 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 anastrozole is not highly protein bound.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Enzyme inhibitors

ATC Code: L02B G03

Mechanism of action and pharmacodynamic effects

Anastrozole 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, Anastrozole at a daily dose of 1 mg of produced

estradiol 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 adrenocorticotropic 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 anastrozole 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 anastrozole 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.

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For the primary endpoints, Study 1033IL/0030 showed that anastrozole 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 anastrozole and tamoxifen respectively, p=0.006); objective tumour response rates were similar for

anastrozole and tamoxifen. Study 1033IL/0027 showed that anastrozole 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

Anastrozole 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 anastrozole 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.

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.

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 anastrozole.

Paediatric population

Anastrozole Bluefish 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 anastrozole 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 Anastrozole 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 randomized, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11-16 years inclusive) with GHD treated for

12 to 36 months with anastrozole 1 mg/day or placebo in combination with growth hormone. Only 14 subjects on anastrozole

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 anastrozole 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 anastrozole 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

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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 anastrozole 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 anastrozole 1 mg treated group and the placebo group.

Trial 0001 was an open-label, multiple-dose pharmacokinetic study of anastrozole 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 anastrozole in 28 girls (aged 2 to ≤ 10 years) with

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

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. 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.

Distribution

Anastrozole is only 40% bound to plasma proteins.

Elimination

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, a 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 Anastrozole should be performed with caution (see section 4.2 and 4.4).

Paediatric population

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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.

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 introduction 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

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Lactose monohydrate

Povidone (K30)

Sodium starch glycolate

Magnesium stearate

Hypromellose

Macrogol 300

Titanium dioxide (E171)

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 condition.

6.5 Nature and contents of container

PVC/Aluminium blister

Pack sizes 28, 30, 98 and 100 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Bluefish Pharmaceuticals AB

P.O. Box 49013

100 28 Stockholm

Sweden

8 MARKETING AUTHORISATION NUMBER

PA1436/010/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25

March 2011

Date of last renewal: 25

January 2015

10 DATE OF REVISION OF THE TEXT

June 2020

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