Kliogest 2 mg/1 mg film-coated tablets

Section 4.5: Addition of paragraph regarding the effects of Hormone contraceptives containing oestrogens on plasma concentrations of lamotrigine.

Minor formatting changes throughout document.

Section 2 - Using other medicines sub-section:

• Addition of bullet point for medicines for hepatitis C infections (such as telaprevir)
• Addition of bullet point for lamotrigine

Adding 'Package leaflet: Information for the user' to the PIL as it was accidently removed during last update.

Local Affiliate Lo-call phone number (1850) removed from Section 6.

Date of revision updated to 06/2022.

Section 2. Qualitative and quantitative composition

Estradiol updated to estradiol in: 'estradiol 2 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg.'

Section 4.4 Special warnings and precautions for use

1) Sentence removed:

'Angioedema

Oestrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.'

2) Sentence added: 'Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.'

3) Text added:

'ALT elevations

During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See section 4.5.'

4) Excipients text updated to: 'Kliogest tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.'

Section 4.5 Interaction with other medicinal products and other forms of interaction 

Text added:

'Pharmacodynamic interactions

 During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see section 4.4).'

Section 10. Date of revision of the text

Date updated to 05/2022

Section 2. Warnings and Precautions

Sentence removed: 'Hereditary and acquired angioedema'

Sentence removed: 'a hereditary condition causing recurrent episodes of severe swelling (hereditary angioedema) or if you have had episodes of rapid swelling of the hands, face, feet, lips, eyes, tongue, throat (airway blockage) or digestive tract'

Section 2. Stop taking Kliogest and see a doctor immediately

Sentence added 'a hereditary condition causing recurrent episodes of severe swelling (hereditary angioedema) or if you have had episodes of rapid swelling of the hands, face, feet, lips, eyes, tongue, throat (airway blockage) or digestive tract'

Section 2. Using other medicines

Text for Medicines for Hepatitis C virus updated to: 'Medicines for Hepatitis C virus (HCV) (such as combination regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir as well as a regimen with glecaprevir/pibrentasvir) may cause increases in liver function blood test results (increase in ALT liver enzyme) in women using CHCs containing ethinylestradiol. Kliogest contains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using Kliogest with this HCV combination regimen. Your doctor will advise you.'

Section 2. Kliogest contains lactose monohydrate

Lactose monohydrate text updated to:

'Kliogest contains lactose monohydrate

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.'

Section 6.

1) Removed reference to names of this medicinal products in other Member States of the EEA.

2) Revision date updated to 05/2022.

3) Added sentence:

'Other sources of information

Detailed information on this medicine is available on the website of: HPRA'

4) Copyright year updated to 2022

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'.

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'

Section 2

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.

For women who have had their womb removed and who are using oestrogen only HRT for 5 years, little or no increase in breast cancer risk is shown.

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

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

The overall evidence shows suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also  or 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'.

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'

4.4     Special warnings and precautions for use

            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 HRT may confer a similar or slightly smaller risk (see section 4.8).

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see Section 4.8).

4.8     Undesirable effects

Ovarian cancer risk

Long-term useUse  of oestrogen-only andor combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer. In the Million Women Study diagnosed (see Section 4.4).

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31- 1.56). For women aged 50 to 54 years taking, 5 years of HRT,  resulted this results in about 1 extra case per 2,5002,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period.

10        Date of revision of the text

Sections without changes have been omitted and marked with .......


2.       Qualitative and quantitative composition

Each film-coated tablet contains:

Estradiol 2 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg.

Excipient with known effect: lactose monohydrate.

Each white film-coated tablet contains lactose monohydrate 36.3 mg per tablet.

For the full list of excipients, see section 6.1.

……

4.4     Special warnings and precautions for use

……

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.

... Indicates unchanged text that has been omitted

2.       Qualitative and quantitative composition

Each film-coated tablet contains:

Estradiol 2 mg (as estradiol hemihydrate) and .

Nnorethisterone acetate 1 mg.

 Excipient with known effect: lLactose monohydrate 36.3 mg per tablet.

For thea full list of excipients, see section 6.1.

3.       Pharmaceutical Form

            Film- coated tablets.

             White, film-coated, biconvex tablets, engraved with NOVO 281. Diameter 6 mm.

... 

4.2     Posology and method of administration

Kliogest is a continuous combined hormone replacementHRT  product intended for use in women with an intact uterus. One tablet should be taken orally once a day without interruption, preferably at the same time every day.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest  effective dose for the shortest duration (see also section 4.4) should be used.

In women with amenorrhoea and not taking HRT or women in transition transferring from another continuous combined HRT product, treatment with Kliogest may be started on any convenient day. In women in transitiontransferring from a sequential HRT regimens, treatment should start right after their withdrawal bleeding has ended.

If the patient has forgotten to take a tablet, the tablet should be taken as soon as possible within the next 12 hours. If more than 12 hours have passed, the tablet should be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

4.3     Contraindications

–                     Known, past or suspected breast cancer

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

–                     Undiagnosed genital bleeding

–                     Untreated endometrial hyperplasia

–                    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 previous arterial thromboembolic disease (e.g. angina, myocardial infarction)

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

–                     Known hypersensitivity to the active substances or to any of the excipientsingredients

–                     Porphyria.

4.4     Special warnings and precautions for use

... 

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 a number of years. In some studies the risk remained elevated more than 10 years off oestrogen.

The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting continues after the first months of treatment, appears after some time during 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.

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 HRT that becomes apparent after about 3 years (see section 4.8).

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

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

            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 HRT may confer a similar, or slightly smaller risk (see section 4.8).

Venous thromboembolism

HRT is associated with a 1.3- to 3-fold 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).

            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).

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer.  There is no consensus about the possible role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery, temporarily stopping HRT 4 to 6 weeks earlier, is recommended. 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             venous thromboembolismosis 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 venous thromboembolismsis 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.

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-s progestagen or oestrogen-only HRT.

            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).

Other conditions

Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

            Oestrogens may induce or exacerbate symptoms of angioedema, in particular in women with             hereditary angioedema.

Women with pre-existing hypertriglyceridaemia 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.

            Patients who require thyroid hormone replacement therapy should have their thyroid function             monitored regularly while on HRT to ensure that thyroid hormone levels remain in an        acceptable range.

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 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 biologically active hormone concentrations are unchanged.  Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I1-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.

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

4.5     Interaction with other medicinal products and other forms of interactions

The metabolism of oestrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as meprobamate, phenylbutazone, anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz, telaprevir).

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.

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

Drugs that inhibit the activity of hepatic microsomal drug metabolising enzymes, e.g. ketoconazole, may increase circulating levels of the active substances in Kliogest .

Oral contraceptives (OC) containing ethinylestradiol have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered. Similar interaction may exist between HRT containing estradiol and lamotrigine. Therefore, dosage adjustment of lamotrigine may be necessary for seizure control.

Concomitant administration of cyclosporine may cause increased blood levels of cyclosporine, creatinine and transaminases due to decreased metabolism of cyclosporine in the liver.

Some laboratory tests may be influenced by oestrogen therapy, such as tests for glucose tolerance or thyroid function.

4.6     Fertility, pPregnancy and lactation

          Pregnancy

Kliogest is not indicated during pregnancy.

If pregnancy occurs during medication with Kliogest, 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.

The results of most epidemiological studies to -date, relevant to inadvertent foetal exposure to combinations of oestrogens and progestagens, indicate no teratogenic or foetotoxic effect.

Lactation

Kliogest is not indicated during lactation.

4.7     Effects on ability to drive and use machines

Kliogest has no known effects on the ability to drive or use machines.

4.8     Undesirable effects

Clinical experience

The most frequently reported adverse events in the clinical trials with Kliogest were vaginal bleedings and breast pain/tenderness, reported in approximately 10% to 30% of patients. Vaginal bleedings usually occurred in the first months of treatment. Breast pain usually disappears after a few months of therapy. All adverse events observed in the randomised clinical trials with a higher frequency in patients treated with Kliogest or similar HRT products as compared to placebo, and which on an overall judgement are possibly related to treatment, are presented in the table below:.

Post-marketing experience

In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported, and are by an overall judgement considered possibly related to Kliogest treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (< 1/10,000, not known (cannot be estimated from the available data)). Post-marketing experience is subject to underreporting especially with regard to trivial and well-known adverse drug reactions. The presented frequencies should be interpreted in that light:

–        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

–        Vascular disorders: Hypertension aggravated

–        Cardiac disorders: Myocardial infarction

–        Gastrointestinal disorders: Dyspepsia, vomiting

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

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

–        Reproductive system and breast disorders: EHyperplasia 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).

Breast cancer risk

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 below:.

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

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

Endometrial cancer risk

The endometrial cancer risk is about 5 in every 1,000 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 epidemiological studies varied from between 5 and 55 extra cases diagnosed in every 1,000 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 5 years of combined (sequential or continuous) HRT did not increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer risk

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 2,500 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 below:.

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

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 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.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

.

4.9       Overdose

Overdosage may be manifested by nausea and vomiting. Treatment should be symptomatic.

5.         Pharmacological Properties

5.1       Pharmacodynamic pProperties

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

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

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

Kliogest is a continuous combined HRT given with the intention of avoiding the regular withdrawal bleeding associated with cyclic or sequential HRT. Amenorrhoea (no bleeding and spotting) was seen in 94% of the women during month 10-12 of treatment. Bleeding and/or spotting was observedappeared in 30% of the women during the first three3- months of treatment and in 6% during months 10-12 of treatment.

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

Evidence from the WHI trial and meta-analysised of trials shows that current use of HRT, oestrogen alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

The effects of Kliogest on bone mineral density were examined in a 2-year, randomised, double- blind, placebo-controlled clinical trial in postmenopausal women (n=327, including 48 on Kliogest). All women received calcium supplementation 1,000 mg daily. Kliogest significantly prevented bone loss at the lumbar spine, total hip, distal radius and total body in comparison with calcium supplemented placebo-treated women. In early postmenopausal women (1 to 5 years since last menses), the percentage change from baseline in bone mineral density at lumbar spine, femoral neck and femoral trochanter after 2 years of treatment with Kliogest was 5.4±0.7%, 2.9±0.8% and 5.0±0.9%, respectively. The percentage of women who maintained or gained bone mineral density during treatment with Kliogest was 91%, after 2 years of treatment.

5.2     Pharmacokinetic properties

Following oral administration of 17β-estradiol in micronised 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 44 pg/ml (range 30-53 pg/ml) within 6 hours after intake of 1 Kliogest tablet. The half-life of 17β-estradiol is about 18 hours. It circulates bound to SHBG (37%) and to albumin (61%), while only approximately 1-2% is unbound. 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 sulphfates 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.

After oral administration norethisterone acetate is rapidly absorbed and transformed to norethisterone (NET). It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration of approximately 9 ng/ml (range 6-11 ng/ml) within 1 hour after intake of 1 mg. The terminal half- life of NET is about 10 hours. NET binds to SHBG (36%) and to albumin (61%). The most important metabolites are isomers of 5α-dihydro-NET and of tetrahydro-NET, which are excreted mainly in the urine as sulphfate or glucuronide conjugates.

The pharmacokinetics of estradiol is not influenced by norethisterone acetate.

The pharmacokinetic properties in the elderly have not been studied.

5.3     Preclinical safety data

The toxicity profiles of estradiol and norethisterone acetate are well-known. There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPCsummary of product characteristics.

6.       Pharmaceutical particulars

...

6.4       Special precautions for storage

Store below 25ºC. Do not refrigerate. Keep the container in the outer carton in order to protect it from light.

...

10.       Date of revision of the text

            Nov 2011August 2014

SmPC changes for Kliogest

Gelatine Substitution

Note – 1) formatting changed from TrueFrutigerLight to Times New Roman throughout SmPC

              2) All main headers have change from upper & lower case to all UPPER

Ovarian cancer

 The following text has been deleted: 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

 The following text has been added: Use of estrogen alone and estrogen plus progestogen therapies for at least 5 or 10 years has been associated with an increased risk of ovarian cancer in some epidemiological studies.

 Other conditions

Kliogest tablets contain lactose.

 Monohydrate has been added to the text above to read: Kliogest tablets contain lactose monohydrate.

 4.8    Undesirable Effects

Editorial changes at the top of the table

5.1    Pharmacodynamic properties

ATC code G03F A01

Oestrogen and progestogen for continuous combined hormone replacement therapy (HRT).

 The text above has been replaced with the following text: Pharmacotherapeutic group: Oestrogen and progestogen for continuous combined hormone replacement therapy, ATC code: G03F A01

 6.4    Special Precautions for Storage

 Keep the container in the outer carton. Do not store above 25C. Do not refrigerate or freeze.

 The text above has been replaced with the following text: Do not store above 25C. Do not refrigerate. Keep the container in the outer carton in order to protect from light.

 6.6    Instructions for Use

Kliogest 2mg/1mg Film-coated Tablets (IE)

Changes to Summary of Product Characteristics resulting from MA renewal application and lactose warning resubmission.

Section 1, Name of medicinal product

Kliogest film-coated tablet
changed to
Kliogest 2m/1mg Film-coated Tablets

Section 2, Qualitative and quantitative composition

For excipients, see 6.1
changed to
Excipient: Lactose monohydrate 37.4 mg per tablet.
For full list of excipients see section 6.1.

Section 6.4, Special precautions for storage

Store below 25¢ªC.
changed to
Do not store above 25¢ªC.

Do not refrigerate.
changed to
Do not refrigerate or freeze.

Section 4.4, Special warnings and precautions for use

Additional warning in subsection ¡®Other conditions¡¯:
Kliogest tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Section 10: Date of Revision

from
October 2004.
changed to
 February 2008