Section 7-MA Holder updated

Section 8 -New PA number

Section 10- Date of revision updated

MA transfer form AstraZenca UK to AstraZeneca AB Sweden.

Section 3 – Clarification of tablet appearance.

Section 4.8 – Update to AE reporting statement and address in line with latest QRD template.

Section 10 – Update to "Date of Revision"

Section 4.6 – Editorial change to heading.

Section 4.8 – Addition of side effect “Sensory disturbances (including paraesthesia, taste loss and taste perversion)”
Section 4.8 - Reporting of suspected adverse reactions statement.

Section 10 – Update to "Date of Revision"

- Section 4.8 - addition of myalgia and hypercalcaemia
-Section 10 - updated date of revision of text

Section 4.8

update section in line with current SPC guidelines (medDRA classification).

Also in the table under ‘Musculoskeletal and connective tissue disorders’

Very Common: Change of text to: ‘Arthralgia/Joint stiffness’ and the addition of ‘Arthritis’

Section 10

Revision date of text: 6 December 2010

Section 4.8

Changes in side effects table:

Addition of “Arthritis”

“Joint pain/stiffness, mainly mild or moderate in nature” has been amended to “Arthralgia/Joint stiffness”

Addition of “Cutaneous vasculitis (including some reports of Henoch-Schönlein purpura).”

Section 10

Revision date of text: 26 November 2010

Section 2

Excipients included in section

Excipients: each film-coated tablet contains 93 mg lactose monohydrate.

Section 6.4

Deletion of text: Store in original package.

 

Section 9

Renewal date 11 August 2010

 

Section 10

Revision date of text: 29 October 2010

Section 4.2

Change of text for heading ‘Children’:

Arimidex is not recommended for use in children due to insufficient data on safety and efficacy (see sections 4.4 and 5.1)

Section 4.4

New text second paragraph

Arimidex 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, Arimidex 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.

Section 5.1

New additional text

Arimidex is not indicated for use in children. 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 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.

Short stature due to Growth Hormone Deficiency

A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11-16 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 anastrozole completed 36 months.

After 3 years anastrozole was found to statistically significantly slow bone maturation in pubertal boys on growth hormone therapy. No statistically significant difference with placebo was observed for the growth related parameters of predicted adult height, height, height SDS, 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 2-9) 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.

Section 5.3

New additional text:

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.

Section 10

Revision date of text: 22 December 2009

Section 4.2

Change of text regarding children:

The use of Arimidex is not recommended in children, as efficacy has not been established (see sections 5.1 and 5.2).

Section 4.4

Change of text in 3^rd paragraph:

As Arimidex lowers circulating oestrogen levels, it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture. This possible increased risk should be managed according to treatment guidelines for managing bone health in postmenopausal women.

Section 4.8

Additional text before table:

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years and unless specified, no account was taken of the frequency within the comparative treatment group or whether the investigator considered it to be related to study medication.

Table -  Changed text:

Reference under table regarding Carpal Tunnel Syndrome:

Events of Carpal Tunnel Syndrome have been reported in patients receiving Arimidex 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.

Reference under table change of text to the word commonly

** Vaginal bleeding has been reported commonly, mainly in patients.

Deletion of text at end of section:

Elevated gamma-GT and alkaline phosphatase have been reported uncommonly ( 0.1% and < 1%). A causal relationship for these changes has not been established.

Section 5.1

Additional text at end of section:

Study of anastrozole with the bisphosphonate risedronate (SABRE)

Bone Mineral Density (BMD)

In the phase III/IV SABRE study, 234 postmenopausal women with hormone receptor positive early breast cancer scheduled for treatment with Arimidex were stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. All patients received treatment with vitamin D and calcium. Patients in the low risk group received Arimidex alone, those in the moderate group were randomised to Arimidex plus bisphosphonate or Arimidex plus placebo and those in the high risk group received Arimidex plus bisphosphonate.

The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture had their bone health (assessed by bone mineral density and bone formation and resorption markers) successfully managed by using Arimidex in combination with a bisphosphonate. In addition, no changes in BMD were seen in the low risk group treated with Arimidex alone and given vitamin D and calcium. 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 postmenopausal women with early breast cancer scheduled to be treated with Arimidex should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.

Lipids

In the SABRE study, there was a neutral effect on plasma lipids both in those patients treated with Arimidex alone, and in those treated with Arimidex plus a bisphosphonate.

Paediatrics

Three clinical trials were conducted in paediatric patients (2 in pubertal boys with gynaecomastia and 1 in girls with McCune-Albright Syndrome).

Gynaecomastia study

Trial 0006 was a randomised, double-blind, multi-centre study of 80 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. A decrease of ≥50% in total breast volume measured by ultrasound was seen in 38.5% (15/39) of the Arimidex and 31.4% (11/35) of the placebo treated group (odds ratio = 1.513, 95% CI 0.496 to 4.844, p=0.4687).

Trial 0001 was an open label, multiple-dose pharmacokinetic (PK) study of Arimidex 1 mg/day in 36 pubertal boys with gynaecomastia of less than 12 months duration. A decrease in total breast volume of 50% or greater at 6 months was seen in 55.6% (20/36) of the boys.

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. No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. Of the patients with baseline vaginal bleeding, 28% experienced a ≥50% reduction in the frequency of bleeding days on treatment; 40% experienced a cessation over a 6 month period and 12% experienced a cessation over a 12 month period. 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).

The overall assessment of the adverse events in children less than 18 years of age raised no safety and tolerability concerns.

Section 5.2

Deleted text: 

Pharmacokinetics have not been studied in children.

New text:

In boys with pubertal gynaecomastia, anastrozole was rapidly absorbed, was widely distributed and was eliminated slowly with a half-life of approximately 2 days. Pharmacokinetic parameters in boys were comparable to those of postmenopausal women. Clearance of anastrozole was lower in girls than in boys and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated, with an estimated half-life of approximately 0.8 days.

Section 10

Revision date of text: 15 October 2008

Section 4.8

In the table under ‘common’ side effects – the addition of Carpal Tunnel Syndrome*

In the table under ‘common’ side effects – the addition of Hepatobiliary disorders - Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

In the table under ‘uncommon’ side effects – the addition of Hepatobiliary disorders –

Increases in gamma-GT and bilirubin

Hepatitis

Immediately under the table a new reference for Carpal Tunnel Syndrome -

* Events of Carpal Tunnel Syndrome have been reported in patients receiving Arimidex 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.

The last paragraph of section 4.8 has been deleted.

Elevated gamma-GT and alkaline phosphatase have been reported uncommonly (³ 0.1% and < 1%). A causal relationship for these changes has not been established.

Section 10

Section 5.1 Pharmacodynamic properties

Addition of text after 5^th paragraph

Primary adjuvant treatment of early breast cancer

Addition of text after 12^th paragraph

Adjuvant treatment of early breast cancer for patients being treated with adjuvant tamoxifen

In a phase III trial (ABCSG 8) conducted in 2579 postmenopausal women with hormone receptor positive early breast cancer being treated with adjuvant tamoxifen, patients had a superior disease-free survival when switched to Arimidex compared with those continuing on tamoxifen, after a median follow-up of 24 months.

Time to any recurrence, time to local or distant recurrence and time to distant recurrence confirmed a statistical advantage for Arimidex, consistent with the results of disease free survival. The incidence of contralateral breast cancer was very low in the two treatment arms with a numerical advantage for Arimidex. Overall survival was similar for the two treatment groups.

Two further similar trials (GABG/ARNO 95 and ITA) with Arimidex, 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.