Novartis Pharmaceuticals UK Ltd

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.

In experimental animals oestradiol or oestradiol valerate displayed an embryolethal effect already at relatively low oral doses; malformations of the urogenital tract and feminisation of male fetuses were observed.

Norethisterone, like other progestagens, caused virilisation of female fetuses in rats and monkeys.  After high oral doses of norethisterone, embryolethal effects were observed.

Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential revealed no particular human risks beyond those discussed in other sections of the SmPC. Long-term, continuous administration of natural and synthetic oestrogens and norethisterone in some animal species increases the frequency of tumours in certain hormone dependent tissues.

In Sections 2, 3, 4.1, 4.2, 4.5, 5.1, 5.2, 5.3 and 6.1 minor typographical updates have been made ie. estrogen changed to oestrogen. estradiol changed to oestradiol  and progestogen changed to progestagen.

In Sections 4.3, 4.4 and 4.8 the following updates have been made:

Section 4.3

·         Known, past or suspected breast cancer,

·         Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer),

·         Undiagnosed genital bleeding,

·         Untreated endometrial hyperplasia,

·         Severe renal disease,

·         Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal,

·         Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism),

·         Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4),

·         Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction),

·         Known hHypersensitivity to the active substances or to any of the excipients,

·         Porphyria.

Section 4.4

1st two paragraphs remain unchanged.....

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.

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken.  Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use.  During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman.  Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast cancer’ below).  Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified according to the clinical needs of the individual. 

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Climagest, in particular:

·         leiomyoma (uterine fibroids) or endometriosis,

·         a history of, or risk factors for, thromboembolic disorders (see below),

·         risk factors for oestrogen dependent tumours, e.g. 1^st-degree heredity for breast cancer,

·         hypertension,

·         liver disorders (e.g. liver adenoma) – patients with mild chronic disease should have their liver function checked every 8-12 weeks,

·         diabetes mellitus with or without vascular involvement,

·         cholelithiasis,

·         migraine or (severe) headache,

·         systemic lupus erythematosus (SLE),

·         a history of endometrial hyperplasia (see below),

·         epilepsy,

·         asthma,

·         otosclerosis.

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

·         jaundice or deterioration in liver function,

·         significant increase in blood pressure,

·         new onset of migraine-type headache, or any other symptoms that are a possible prodromata of vascular occlusion,

·         pregnancy.

Endometrial hyperplasia and carcinoma

In women with an intact uterus the The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8). 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 at least 10 years.  The addition of a progestaogen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess greatly reduces this risk associated with oestrogen-only HRT.

greatly reduces this

Break-through bleeding and spotting may occur during the first months of treatment.  If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

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.

Combined oestrogen-progestagen therapy

TheA randomised placebo-controlled trial, the Women’s Health Initiative study (WHI) and epidemiological studies, are consistent in finding including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking combined estrogens or oestrogen-progestaogen for combinations or tibolone for HRT that becomes apparent after for about 3several years (see section 4.8).

including the Million Women Study (MWS), have reported for seOestrogen-only therapy

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestagen combinations (see section 4.8).

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen.  There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

TFor all HRT, anhe excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen.  There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

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

Venous thromboembolism

HRT is associated with a 1.3 -to 3-fold  higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.  The occurrence of such an event is more likely in the first year of HRT than later (see Section 4.8).

One randomised controlled trial and epidemiological studies found a 2-3 fold higher risk for users compared with non-users.

For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years.  The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include , use of oestrogens, older age, major surgery, prolonged immobilisation, a personal history or family history, severe obesity (Body Mass Index >30 kg/m²), pregnancy/ postpartum period, and systemic lupus erythematosus (SLE). and cancer.

There is no consensus about the role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE and. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition.  Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contra-indicated. HRT is therefore contraindicated in these patients (see section 4.3). Those wWomen already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all post-operative patients, scrupulous attention should be given to prophylactic measures need to be considered to prevent VTE following surgery. IfWhere prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT four to six weeks earlier is recommended, if possible.  Treatment should not be restarted until the woman is completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at 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.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRT.cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA).  Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit.  For other HRT products there are only limited data from randomised controlled trials to date examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Combined oestrogen-progestagen therapy

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.

Oestrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

Ischaemic Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA.  For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years.  It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate=1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate=4) per 1000 users aged 60-69 years.  It is unknown whether the increased risk also extends to other HRT products.

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).

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5 to 10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an slightly increased risk of ovarian cancer (see section 4.8) in some epidemiological studies.  It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.

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).

Other conditions

OeEstrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Climagest is increased.

Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

OeEstrogens 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 radio-immunoassay) or T3 levels (by radio-immunoassay). 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, ceruloplasmin).

HRT use does not improve There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

Patients with rare hereditary problems of galactose intolerance, of Lapp lactase deficiency or of glucose-galactose malabsorption should not take this medicine.

Section 4.8

Reproductive system and breast disorders

Breast tension and pain, breast cancer*, mucous vaginal discharge.

Nervous system disorders

Headaches, dizziness, vertigo, changes in libido, depressive mood.

Cardiac disorders

Hypertension, palpitations, thrombophlebitis, oedema, epistaxis.

Gastrointestinal disorders

Dyspepsia, flatulence, nausea, vomiting, abdominal pain and bloating, biliary stasis.

Skin and subcutaneous tissue disorders

General pruritus, alopecia, urticaria and other rashes.

Metabolism and nutrition disorders

Decrease in glucose tolerance.

General disorders and administration site reactions

Weight gain.

*Breast cancer risk

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women’s Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

-          For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

-         For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be :

For users of estrogen-only replacement therapy

o          between 0 and 3 (best estimate = 1.5) for 5 years’ use

o          between 3 and 7 (best estimate = 5) for 10 years’ use.

For users of estrogen plus progestogen combined HRT

o          between 5 and 7 (best estimate = 6) for 5 years’ use

o          between 18 and 20 (best estimate = 19) for 10 years’ use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

-           For 1000 women in the placebo group,

-           about 16 cases of invasive breast cancer would be diagnosed in 5 years.

-           For 1000 women who used estrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be

-           between 0 and 9 (best estimate = 4) for 5 years’ use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

-     An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years,

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

-     The level of risk is dependent on the duration of use (see section 4.4),

-     Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.

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

* Taken from baseline incidence rates in developed countries.

US WHI studies - additional risk of breast cancer after 5 years’ use

‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

* WHI study in women with no uterus, which did not show an increase in risk of breast cancer.

Endometrial cancer risk

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2- to 12-fold greater compared with non-users.  Adding a progestogen to estrogen-only therapy greatly reduces this increased risk.

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8 - 1.2)).

Ovarian cancer

Long-term use of oestrogen-only and combined oestrogen-progestagen 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 2500 users.

Risk of venous thromboembolism

HRT is associated with a 1.3 -to 3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HRT (see section 4.4). Results of the WHI studies are presented:

WHI Studies - Additional risk of VTE over 5 years’ use

* Study in women with no uterus.

Risk of coronary artery disease

-  The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

-  The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5 -fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT,

-  This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined - Additional risk of ischaemic stroke* over 5 years’ use

* No differentiation was made between ischaemic and haemorrhagic stroke.

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

-            Estrogen-dependent neoplasms benign and malignant (e.g. endometrial cancer),

-            venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see Section 4.3 and 4.4.

-            myocardial infarction and stroke,

-          gall bladder disease,

-          skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura,

-          probable dementia over the age of 65 (see section 4.4).