Agerdex 1mg Film Coated Tablets

6.3 Shelf life
30 48 months.

section 2  - 'with known effect' added
section 4.3 - hypersensitivity to anastrazole - wording changed
section 4.4 - spelling of estorgen chanhed to oestrogen, caps lock removed from Anaztrazole, luteinizing changed to luteinising
section 4.5 - oestrogen spelling correction
section 4.8 - refer to table 1
section 5.1 - Hormone Antagonists and Related Agents Aromatase added instead of 'Enzyme' and spelling of estorgen chanhed to oestrogen, caps lock removed from Anaztrazole
section 5.2 - underline added on sub headings
section 10 - Date of revision changed

 

 

Harmonisation of the product information in line with Article 30 Referral.

Sections 4 & 5 updated.
New text added.

SmPC updated to remove Patented Indication

4.1            Therapeutic indications

Treatment of advanced breast cancer in postmenopausal women. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen.

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

Adjuvant treatment of early breast cancer in hormone receptor positive postmenopausal women who have received 2 to 3 years of adjuvant tamoxifen.

5.1            Pharmacodynamic properties

Pharmacotherapeutic group: Enzyme inhibitors

ATC Code: L02B G03

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily by the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Lowering circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer.

In postmenopausal women, a daily dose of 1 mg of anastrozole produced oestradiol suppression of greater than 80% using a highly sensitive assay.

Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity.

Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.

Primary adjuvant treatment of early breast cancer

In aA large phase III study showed that anastrozole is an effective treatment conducted in 9366 for postmenopausal women with operable breast cancer treated for 5 years, anastrozole 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 anastrozole versus tamoxifen for the prospectively defined hormone receptor positive population Anastrozole was statistically superior to tamoxifen in time to recurrence. The difference was of even greater magnitude than in disease free survival for both the Intention To Treat (ITT) population and hormone receptor positive population. Anastrozole was statistically superior to tamoxifen in terms of time to distant recurrence. The incidence of contralateral breast cancer was statistically reduced for anastrozole compared to tamoxifen. Following 5 years of therapy, anastrozole is at least as effective as tamoxifen in terms of overall survival. However, due to low death rates, additional follow-up is required to determine more precisely the long-term survival for anastrozole relative to tamoxifen. With 68 months median follow-up, patients in the ATAC study have not been followed up for sufficient time after 5 years of treatment, to enable a comparison of long-term post treatment effects of anastrozole relative to tamoxifen.

ATAC endpoint summary: 5- year treatment completion analysis
Efficacy endpoints	Number of events (frequency)
	Intention to treat population		Hormone-receptor-positive tumour status
	anastrozole (n=3125)	tamoxifen (n=3116)	anastrozole (n=2618)		tamoxifen (n=2598)
Disease-free survivala	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 survivalb	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 recurrencec	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 recurrenced	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 survivale	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

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.

As with all treatment decisions, women with breast cancer and their physician should assess the relative benefits and risks of the treatment.

 

When anastrozole and tamoxifen were co-administered, the efficacy and safety were similar to tamoxifen when given alone, irrespective of hormone receptor status. The exact mechanism of this is not yet clear. It is not believed to be due to a reduction in the degree of estradiol suppression produced by anastrozole.

 

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

In aA phase III trial (ABCSG 8) conducted in 2579 showed that anastrozole is an effective treatment of hormone receptor positive early breast in postmenopausal women with hormone receptor positive early breast cancer who had received surgery with or without radiotherapy and no chemotherapy, switching to anastrozole 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 of 24 months.

Time to any recurrence, time to local or distant recurrence and time to distant recurrence confirmed a statistical advantage for anastrozole, 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 anastrozole. Overall survival was similar for the two treatment groups.

ABCSG 8 trial endpoint and results summary
Efficacy endpoints	Number of events (frequency)
	anastrozole (n=1297)	tamoxifen (n=1282)
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 local or distant recurrence	29 (2.2)	51 (4.0)
Hazard ratio	0.55
2-sided 95% CI	0.35 to 0.87
p-value	0.011
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

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 anastrozole safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor positive early breast cancer.

None provided