Treatment for advanced breast cancer in post-menopausal women. Its efficacy has not been
demonstrated in oestrogen receptor-negative patients except for those who have shown
a positive clinical response to tamoxifen.

Posology:
Adults, including the elderly.
One 1 mg tablet once a day.
Paediatric population.
Its use in this population is not recommended due to the limited safety and efficacy data
(see sections 4.4 and 5.1).
Renal failure.
Dose adjustment is not recommended in patients with mild or moderate renal failure.
Hepatic failure.
Dose adjustment is not recommended in patients with mild hepatic failure.
In initial stages, the recommended duration of treatment is 5 years.
Method of administration:
Oral route.

Premenopausal women. - Pregnant or breast-feeding women. - Severe renal failure (creatinine clearance < 20 mL/min) - Moderate or severe hepatic failure. - Hypersensitivity to anastrozole or to any of the excipients. Co-administration of anastrozole with oestrogen-containing treatments should be avoided as this may reduce its pharmacological action. Concomitant treatment with tamoxifen (see section 4.5).

Administration of anastrozole in the paediatric population is not recommended as its safety
and efficacy in this group of patients has not been established (see section 5.1).
This medicinal product should not be administered jointly with growth hormone treatment in
boys with a deficiency in this hormone. In the pivotal clinical trial, efficacy was not
demonstrated and safety was not established (see section 5.1). Anastrozole should not be used
together with growth hormone treatment in girls with a deficiency in this hormone as anastrozole
reduces oestradiol levels. No long-term safety data in children and adolescents are available.
Menopause should be confirmed biochemically in patients for whom doubts regarding their
hormonal status exist.
Data supporting the safe use of anastrozole in patients with moderate or severe hepatic impairment
or in patients with severe renal impairment (creatinine clearance < 20 mL/min) are not available.
Bone density in women with osteoporosis or at risk of suffering from it should be assessed by
bone densimetry, for example using a DEXA scanner, in a protocolised manner at the onset of
treatment and at regular intervals subsequently. Osteoporosis treatment or prophylaxis should
be initiated when required and monitored carefully.
There are no data regarding the use of anastrozole with LHRH analogs. This combination
should not be used outside the scope of clinical trials.
As anastrozole reduces circulating oestrogen levels, it may provoke a reduction in bone
mineral density and therefore an increased risk of fracture. The use of bisphosphonates may
inhibit the additional bone mineral loss provoked by anastrozole in postmenopausal women
and should therefore be considered.
Warnings on excipients:
This medicine contains lactose. Patients with a hereditary galactose intolerance, Lapp lactase
deficiency (deficiency observed in some towns in Lapland) or glucose-galactose
malabsorption should not take this medicinal product.

Clinical interaction studies with antipyrine and cimetidine suggest that co-administration of
anastrozole with other drugs is unlikely to produce clinically significant drug interactions
mediated by cytochrome P450.
A review of the clinical safety trials database found no evidence for clinically significant
interaction in patents treated simultaneously with anastrozole and drugs prescribed normally.
There were no clinically significant interactions with bisphosphonates (see section 5.1).
Oestrogen-based therapies should not be administered jointly with anastrozole as they may
cancel out its pharmacological effect.
Tamoxifen should not be co-administered with anastrozole as this may reduce its pharmacological action (see section 4.3).

Pregnancy
Anastrozole is contraindicated during pregnancy.
Breast-feeding
Anastrozole is contraindicated in breast-feeding women.

The influence of anastrozole on the ability to drive and operate machinery is negligible.
However, asthenia and somnolence have been reported during treatment with anastrozole,
therefore caution should be observed when driving or operating machinery while such
symptoms persist.

Unless otherwise specified, the following frequency categories have been calculated on the basis
of the number of adverse events reported in a large phase-III trial performed in 9366
postmenopausal women with operable breast cancer receiving treatment for 5 years (ATAC study)
Frequency Classification by system
organ class
Adverse Reaction
Very common (≥ 1/10) Vascular disorders Hot flushes, usually mild or
moderate in nature.
General disorders Asthenia, usually mild or
moderate in nature.
Musculoskeletal and connective
tissue disorders
Joint pain/stiffness, usually
mild or moderate in nature.
Nervous system disorders Headache, usually mild or
moderate in nature.
Gastrointestinal disorders Nausea, usually mild or
moderate in nature.
Skin and subcutaneous tissue
disorders
Skin rash, usually mild or
moderate in nature.
Common
(≥ 1/100 to < 1/10)
Skin and subcutaneous tissue
disorders
Hair thinning (alopecia), usually
mild or moderate in nature.
Allergic reactions.
Gastrointestinal disorders Diarrhoea, usually mild or
moderate in nature.
Vomiting, usually mild or
moderate in nature.
Nervous system disorders Drowsiness, usually mild or
moderate in nature.
Carpal tunnel syndrome.
Hepatobiliary disorders Increased alkaline phosphatase,
alanine aminotransferase,
aspartate aminotransferase.
Reproductive system and breast
disorders
Vaginal dryness, usually mild
or moderate in nature.
Vaginal bleeding, usually mild
or moderate in nature*.
Metabolism and nutrition
disorders
Anorexia, usually mild in nature.
Hypercholesterolaemia, usually
mild or moderate in nature.
Uncommon
(≥1/1000 to <1/100)
Hepatobiliary disorders Increased gamma-GT and
bilirubin.
Hepatitis.
Skin and subcutaneous tissue
disorders
Urticaria
Musculoskeletal and connective
tissue disorders
Trigger finger
Rare
(≥1/10,000 to <1/1000)
Skin and subcutaneous tissue
disorders
Erythema multiforme.
Anaphylactic type reaction.
Frequency not known Skin and subcutaneous tissue
disorders
Stevens-Johnson
syndrome**.
Angioedema**.
* 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.
** Cannot be estimated from the available information.
As anastrozole reduces circulating oestrogen levels, it may provoke a reduction in bone
mineral density and therefore an increased risk of fracture in some patients (see section 4.4).
The table below presents the frequency of pre-specified adverse events in the ATAC study,
irrespective of causality, reported in patients receiving trial therapy and up to 14 days after
cessation of trial therapy.
Undesirable effects Anastrazole
(N=3092)
Tamoxifen
(N=3094)
Hot flushes 1104 (35.7%) 1264 (40.9%)
Joint pain/stiffness 1100 (35.6%) 911 (29.4%)
Mood swings 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%)
Spinal, hip or wrist/Colles fractures 133 (4.3%) 91 (2.9%)
- Wrist/Colles fractures 67 (2.2%) 50 (1.6%)
- Spinal 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 infarction 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 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%)
Fracture rates of 22 per 1000 patient-years and 15 per 1000 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. It has not been determined whether the fracture and osteoporosis
rates for patients in the ATAC trial treated with anastrozole suggest a protective effect of
tamoxifen, a specific effect of anastrozole, or both.
The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3%
in patients treated with tamoxifen.

The experience of accidental overdose is limited.
In animal studies, anastrozole showed 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.
As there is no specific antidote to overdose, treatment should 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 of use as anastrozole does not bind strongly to proteins.
General supportive care, including frequent monitoring of vital signs and close observation
of the patient, is indicated

Pharmacotherapeutic group: Enzyme inhibitors. ATC code: L02B G03
Anastrazole is a potent, nonsteroidal, highly selective aromatase inhibitor. In postmenopausal
women, oestradiol is mainly produced by the conversion of androstenedione to oestrone
through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently
converted into oestradiol. It has been demonstrated that a reduction in circulating oestradiol
levels has a beneficial effect in women with breast cancer.
Using a highly sensitive method, a daily dose of 1 mg of anastrozole in postmenopausal
women suppressed oestroadiol by more than 80%.
Anastrozole has no progestogenic, androgenic or oestrogenic activity.
A daily dose of 10 mg of anastrozole has no effect on cortisol or aldosterone secretion, as
determined before or after standard ACTH stimulation testing. Cortocoid supplements are
therefore not required.

The pharmacokinetics of anastrozole are age-independent in postmenopausal women.
Absorption
Anastrozole is absorbed rapidly, with peak plasma concentrations normally being reached
within two hours post-administration (under fasting conditions).
Food decreases the absorption rate slightly but not the degree of absorption. This minor
change in the absorption rate is not expected to have a clinically significant effect on the
steady-state plasma concentrations during daily treatment with 1 mg anastrozole tablets.
Steady-state anastrozole plasma concentrations of approximately 90–95% are achieved after 7
daily doses. There is no evidence that the pharmacokinetic parameters of anastrozole are
time-or dose-dependent.
Distribution
Only 40% of anastrozole is bound to plasma proteins.
Biotransformation
Postmenopausal women metabolise anastrozole extensively, with less than 10% of the dose
being excreted unaltered in urine during the 72 hours post-administration. Anastrozole
metabolism involves N-dealkylation, hydroxylation and glucuronidation. The metabolites are
mainly excreted in urine. Triazole, the main metabolite is plasma and urine, does not inhibit
aromatase.
Elimination
Anastrozole is eliminated slowly, with an elimination half-life in plasma of 40–50 hours.
The apparent clearance of anastrozole after oral administration in volunteers with stable
hepatic cirrhosis or renal impairment was in the range observed for healthy volunteers.
In males with pubertal gynaecomastia, anastrozole was rapidly absorbed, widely distributed
and eliminated slowly, with a half-life of approximately 2 days. Anastrozole clearance was
lower in girls than in these males, and exposure was greater. Anastrozole was widely
distributed and slowly eliminated in girls, with a half-life of approximately 0.8 days.

Acute toxicity: The mean lethal dose of anastrozole in acute toxicity studies in rodents was
greater than 100 mg/kg/day orally and 50 mg/kg/day intraperitoneally. The mean lethal dose
in an acute toxicity study in dog was greater than 45 mg/kg/day.
Chronic toxicity: Multiple dose toxicity studies were performed in rat and dog. No no-effect
levels were established for anastrozole in the toxicity studies, but those effects observed at the
low (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 not accompanied
by significant toxic or degenerative changes.
Mutagenicity: Genetic toxicology studies with anastrozole show that it is not mutagenic
or clastogenic.
Reproductive toxicology: In a fertility study, weanling male rats were dosed orally with 50
or 400 mg/L of anastrozole via their drinking water for 10 weeks. Measured mean plasma
concentrations were 44.4 (±14.7) and 165 (±90) ng/mL respectively. Mating indices were
adversely affected in both dose groups, although a reduction in fertility was evident only at the
400 mg/L dose level. This reduction was transient as all mating and fertility parameters were
similar to control group values following a nine-week treatment-free recovery period.
Oral administration of anastrozole to female rats produced a high incidence of infertility and
increased pre-implantation loss at a dose of 1 and 0.02 mg/kg/day, respectively. As these
effects occurred at clinically relevant doses, an effect in humans cannot be excluded.
These effects were related to the pharmacology of the compound and disappeared completely
after a five-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. The effects observed (placental enlargement
in rats and pregnancy failure in rabbits) were related to the pharmacological activity of the
compound.
The survival of litters born to rats given anastrozole at a dose of 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 the 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). These changes occurred at a dose which represents a 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 lymphoma-related deaths). These changes are considered to be mousespecific
effects of aromatase inhibition and not clinically relevant to the treatment of patients

Tablet core:
Lactose monohydrate, anhydrous lactose, sodium carboxymethyl starch from potato,
microcrystalline cellulose (E460), anhydrous colloidal silica and magnesium stearate.
Tablet coating:
Hypromellose (E464), titanium dioxide (E171) and Macrogol 6000.

Not applicable.

30 months

This medicine does not require any special storage conditions. Store in the original package.

PVC/aluminium blisters
Packages containing 28 and 100 tablets

No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with
local requirements.