Activelle

HRTs Safety update

Angiodema

Hepatitis C virus information

Addition of angiodema

Medicines for Hep C virus

Section 2 – Warnings and Precautions

Breast cancer

Evidence suggests shows that taking combined oestrogen-progestagen and or possibly also oestrogen-only hormone replacement therapy (HRT) increases the risk of breast cancer. The extra risk depends on how long you take use HRT. The additional risk becomes clear within a few 3 years of use. After stopping HRT the extra risk will decrease with time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years. However, it returns to normal within a few years (at most 5) after stopping treatment.

Compare

Women aged 50 to 54 79who are not taking HRT, on average, 13 9 to 17 in 1,000 will be diagnosed with breast cancer over a 5-year period.

For women aged 50 who start taking oestrogen-only HRT for 5 years, there will be 16-17 cases in 1,000 users (i.e. an extra 0 to 3 cases).

For women aged 50 to 79 who are start taking oestrogen-progestagen HRT over for 5 years, there will be 13 21 to 23 cases in 1,000 users (i.e. an extra 4 to 6 8 extra cases).

Women aged 50 to 59 who are not taking HRT, on average, 27 in 1,000 will be diagnosed with breast cancer over a 10-year period.

For women aged 50 who start taking oestrogen-only HRT for 10 years, there will be 34 cases in 1,000 users (i.e. an extra 7 cases).

For women aged 50 who start taking oestrogen-progestagen HRT for 10 years, there will be 48 cases in 1,000 users (i.e. an extra 21 cases).

Section 4 – Reporting of side effects

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL Dublin 2

Tel: +353 1 6764971

Tel: +353 1 6762517

Website: www.hpra.ie

Email: medsafety@hpra.ie

Section 4.4:

Breast Cancer

The overall evidence shows suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen or , and possibly oestrogen-only HRT that is dependent on the duration of taking HRT.

The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen HRT that becomes apparent after about 3 (1-4) years (see section 4.8).

The excess risk becomes apparent after about 3 years of use but returns to baseline within a few (at most 5) years  Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Section 4.8:

Text update in section 'Breast cancer risk'.

The Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations.

Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented below:

Largest meta-analysis of prospective epidemiological studies

Data update for 'Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m²)' - refer to table in SmPC.

 New data added for 'Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m²)' - refer to table in SmPC.

Section 4.8 - how to report a side effect:

Reporting details for the HPRA shortened to 'HPRA Pharmacovigilance, Website: www.hpra.ie'

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Ireland

HPRA Pharmacovigilance IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie   www.imb.ie

e-mail: medsafety@hpra.ie   imbpharmacovigilance@imb.ie .

10.     DATE OF REVISION OF THE TEXT

March 2015 July 2014

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains:

Estradiol 1 mg (as estradiol hemihydrate) and norethisterone acetate 0.5 mg.

Excipient with known effect: lactose monohydrate.

For thea full list of excipients, see section 6.1.

3.       PHARMACEUTICAL form

Film-coated tablets.

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, the risk may remain elevated for more than 10 years.

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.

The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen for HRT becomes apparent after about 3 years (see section 4.8).

The excess risk becomes apparent after about 3 within a few years of use, but returns to baseline within a few (at most 5) years after stopping treatment.

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by radioimmunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin and ceruloplasmin).

HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

Activelle contains tablets contain lactose monohydrate. Patients with rare hereditary heredity problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

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Ritonavir, telaprevir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John’s Wort (Hypericum perforatum) may induce the metabolism of oestrogens and progestagens.

If pregnancy occurs during medication with Activelle, treatment should be withdrawn immediately.

Clinically, data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than those normally used in OC and HRT formulations, masculinisation of female foetuses was observed.

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Fertility

No data available.

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-    Neoplasms benign and malignant (including cysts and polyps): Endometrial cancer

–        Immune system disorders: Generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock)

–        Psychiatric disorders: Insomnia, anxiety, libido decreased, libido increased

–        Nervous system disorders: Dizziness, stroke

–        Eye disorders: Visual disturbances

–        Cardiac disorders: Myocardial infarction

–        Vascular disorders: Hypertension aggravated

–        Gastrointestinal disorders: Dyspepsia, vomiting

–        Hepatobiliary Hepatobilitary disorders: Gallbladder disease, cholelithiasis, cholelithiasis aggravated, cholelithiasis recurrence reoccurrence

–        Skin and subcutaneous tissue disorders: Seborrhoea, rash, angioneurotic oedema

–        Reproductive system and breast disorders: Hyperplasia endometrial Endometrial hyperplasia, vulvovaginal pruritus

–        Investigations: Weight decreased, blood pressure increased.

Other adverse reactions have been reported in association with oestrogen/progestagen treatment:

–        Skin and subcutaneous disorders: Alopecia, chloasma, erythema multiforme, erythema nodosum, vascular purpura

–        Probable dementia over the age of 65 (see section 4.4).

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Million Women Study – Estimated additional risk of breast cancer after 5 years’ use

* Taken from baseline incidence rates in developed countries.

** Overall risk ratio. The risk ration is not constant but will increase with increasing duration on use.

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionatelyproportionally.

US WHI Studies – Additional risk of breast cancer after 5 years’ use

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Ovarian cancer risk

Long-term use of oestrogen-only and combined oestrogen-progestagenprogestogen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study, 5 years of HRT resulted in 1 extra case per 2,500 users.

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Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Ireland

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

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5.1     Pharmacodynamic properties

Pharmacotherapeutic group: progestagenprogestogen and oestrogens, fixed combinations, ATC code: G03FA01.

Mechanism of action

Estradiol: The active ingredient, synthetic 17betaβ-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in postmenopausal women, and alleviates menopausal symptoms.

Oestrogens prevent bone loss following menopause or ovariectomy.

Norethisterone acetate: Synthetic progestagen with actions similar to those of progesterone, a natural female sex hormone. As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Pharmacodynamic effects

In clinical trials with Activelle, the addition of the norethisterone acetate component enhanced the vasomotor symptom relieving effect of 17betaβ-estradiol.

Relief of menopausal symptoms is achieved during the first few weeks of treatment.

Activelle is a continuous combined HRT given with the intent of avoiding the regular withdrawal bleeding associated with cyclic or sequential HRT. Amenorrhoea (no bleeding or spotting) was seen in 90% of the women during months 9-12 of treatment. Bleeding and/or spotting appearedwas observed in 27% of the women during the first 3 months of treatment and in 10% during months 10-12 of treatment.

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Absorption and distribution of 17β-estradiol

Following oral administration of 17betaβ-estradiol in microniszed form, rapid absorption from the gastrointestinal tract occurs. It undergoes extensive first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration of approximately 35 pg/ml (range 21-52 pg/ml) within 5-8 hours. The half-life of 17betaβ-estradiol is about 12-14 hours. It circulates bound to SHBG (37%) and to albumin (61%), while only approximately 1-2% is unbound.

Biotransformation and elimination of 17β-estradiol

Metabolism of 17β-estradiol, occurs mainly in the liver and the gut but also in target organs, and involves the formation of less active or inactive metabolites, including oestrone, catecholoestrogens and several oestrogen sulfphates and glucuronides. Oestrogens are excreted withby the bile, where they are hydrolysed and reabsorbed (enterohepatic circulation), and mainly eliminated in urine in biologically inactive form.

Absorption and distribution of norethisterone acetate

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Biotransformation and elimination of norethisterone acetate

The most important metabolites are isomers of 5α-dihydro-NET and of tetrahydro-NET, which are excreted mainly in the urine as sulfphate or glucuronide conjugates.

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The acute toxicity of oestrogens is low. Because of marked differences between animal species and between animals and humans, preclinical results possess a limited predictive value for the application of oestrogens in humans.

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Date of latest renewal: 6th March 2013 6th March 2008

10.     DATE OF REVISION OF THE TEXT

July 2014

2            Qualitative and Quantitative Composition
        word "anhydros" deleted
4.1       Therapeutic indications

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

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

The following has been added:

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

This section has been updated in line with revised SPC guidelines.

Change to section 4.6

Further information on pregnancy and lactation included.

Change to section 4.8

This section has been updated in line with revised SPC guidelines.

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