When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women with more than 1 year since last menses. 4.3 Contraindications Sentence added: Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency (see section 4.4)) 4.4 Special warnings and precautions for use Sentences added: Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women. Endometrial hyperplasia and carcinoma In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment risk may remain elevated for more than 10 years. Breast Cancer Sentence added and information deleted Breast cancer The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT. Added: Ovarian cancer Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies, including the WHI trial, suggest that the long-term use of combined HRTs may confer a similar or slightly smaller risk (see section 4.8). Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated. Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. Coronary artery disease (CAD) - information added and deleted The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age. Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8). Venous thromboembolism information added and deleted Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated. Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. Coronary artery disease (CAD) information added dn deleted The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age. Ischaemic stroke Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8). Revision date: June 2011
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency (see section 4.4))
4.4 Special warnings and precautions for use
Sentences added:
Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.
Endometrial hyperplasia and carcinoma
In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment risk may remain elevated for more than 10 years.
Breast Cancer Sentence added and information deleted
Breast cancer
The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.
Added: Ovarian cancer
Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies, including the WHI trial, suggest that the long-term use of combined HRTs may confer a similar or slightly smaller risk (see section 4.8). Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated. Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. Coronary artery disease (CAD) - information added and deleted The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age. Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8). Venous thromboembolism information added and deleted Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated. Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. Coronary artery disease (CAD) information added dn deleted The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age. Ischaemic stroke Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8). Revision date: June 2011
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).
If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
Coronary artery disease (CAD) - information added and deleted
The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.
Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).
Venous thromboembolism information added and deleted
Coronary artery disease (CAD) information added dn deleted
Ischaemic stroke
Revision date: June 2011
Section 4.4 Special Warnings and Precautions for Use
Previous wording: Long term (at least 5-10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than oestrogen-only products.
New wording: Long-term (at least 5 or 10 years) use of oestrogen-only HRTs and oestrogen plus progestogen HRTs has been associated with an increased risk of ovarian cancer in some epidemiological studies.
Section 4.8 Undesirable effects
Ovarian cancer
New addition: Long-term use of oestrogen-only and combined oestrogen-progestogen HRT may slightly increase the risk of ovarian cancer, as reported in some epidemiological studies (see Section 4.4)
New addition: Immune system disorder: Hypersensitivity (to post marketing experience) Section 10 Amendment of date to January 2009.
Change to section 1
“Film-coated tablet” added
Change to section 2
The following has been added:
Each film-coated tablet contains:
For excipients, see 6.1”
Change to section 3
White film-coated, round, biconvex tablets with a diameter of 6 mm. The tablets are engraved with NOVO 288 on one side and the APIS on the other.
Change to section 4.1
Addition of the following statement on osteoporosis:
Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.
Change to section 4.2
Addition of statements regarding revised SPC guidelines.
Change to section 4.3
Pregnancy moved to section 4.6
Arterial thromboembolic disease and Porphyria added.
Change to section 4.4
This section has been updated in line with revised SPC guidelines.
Inclusion of statement on lactose.
Change to section 4.5
Change to section 4.6
Further information on pregnancy and lactation included.
Change to section 4.8
Change to section 5.1
Editorial changes.
Change to section 5.3
Additional preclinical data included.
Change to section 6.3
Shelf-life increased from 2 years to 3 years.
Change to section 6.4
Updated inline with use of standard terms.
Change to section 6.6
Instructions for use removed and new statement “No special requirements” added.
Change to section 9
Date of renewal included
Change to section 10
Date of revision of the text amended