Kliogest 2 mg/1 mg film-coated tablets

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 26/05/17

files-icon(Click to Download)

XPIL

Summary of Product Characteristics last updated on medicines.ie: 22/3/2016
print

Print ViewKeyword Search SmPC

Novo Nordisk Limited

Novo Nordisk Limited

Company Products

Medicine NameActive Ingredients
Medicine Name Activelle Active Ingredients Estradiol Hemihydrate, Norethisterone acetate
Medicine Name Actrapid 100 international units/ml, Solution for injection in a vial Active Ingredients Human Insulin
Medicine Name Estrofem 2mg Active Ingredients Estradiol Hemihydrate
Medicine Name Fiasp 100 units-mL solution for injection in Cartridge Penfill Active Ingredients Insulin aspart
Medicine Name Fiasp 100 units-mL solution for injection in pre-filled FlexTouch pen Active Ingredients Insulin aspart
Medicine Name Fiasp 100 units-mL solution for injection in vial Active Ingredients Insulin aspart
Medicine Name GlucaGen HypoKit 1 mg powder and solvent for solution for injection Active Ingredients Glucagon hydrochloride
Medicine Name Insulatard 10 ml Vial Active Ingredients Human Insulin
Medicine Name Insulatard InnoLet Active Ingredients Human Insulin
Medicine Name Insulatard Penfill Active Ingredients Human Insulin
Medicine Name Insulatard, Insulatard Penfill, Insulatard InnoLet Active Ingredients Human Insulin
Medicine Name Kliogest 2 mg/1 mg film-coated tablets Active Ingredients Estradiol Hemihydrate, Norethisterone acetate
Medicine Name Levemir FlexPen (Insulin detemir) 100 units/ml solution for injection in pre-filled pen Active Ingredients insulin detemir
Medicine Name Levemir InnoLet (Insulin detemir) 100 units/ml solution for injection in pre-filled pen Active Ingredients insulin detemir
Medicine Name Levemir Penfill (Insulin detemir) 100 units/ml solution for injection in cartridge Active Ingredients insulin detemir
Medicine Name Norditropin FlexPro 10 mg/1.5 ml solution for injection in pre-filled pen Active Ingredients Somatropin
Medicine Name Norditropin FlexPro 15 mg/1.5 ml solution for injection in pre-filled pen Active Ingredients Somatropin
Medicine Name Norditropin FlexPro 5 mg/1.5 ml solution for injection in pre-filled pen Active Ingredients Somatropin
Medicine Name Norditropin SimpleXx 10 mg/1.5 ml, solution for injection Active Ingredients Somatropin
Medicine Name Norditropin SimpleXx 15 mg/1.5 ml, solution for injection Active Ingredients Somatropin
Medicine Name Norditropin SimpleXx 5 mg/1.5 ml, solution for injection in cartridge Active Ingredients Somatropin
Medicine Name Novofem film-coated tablets Active Ingredients Estradiol Hemihydrate, Norethisterone acetate
Medicine Name NovoMix 30 FlexPen Active Ingredients Insulin aspart
Medicine Name NovoMix 30 Penfill Active Ingredients Insulin aspart
Medicine Name NovoNorm 0.5 mg, 1 mg and 2 mg tablets Active Ingredients Repaglinide
1 - 0 of 40 items.Total: Infinity pages

When a pharmaceutical company changes any document, 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.

Updated on 26 May 2017 PIL

Reasons for updating

  • Change to section 2 - excipient warnings
  • Change to section 6 - what the product contains
  • Change to section 6 - date of revision
  • Change to other sources of information section
  • Change to information for healthcare professionals

Updated on 26 May 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 23 March 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 22 March 2016 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 22 March 2016 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

            November 2015March 2016

Updated on 9 November 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to instructions about overdose
  • Change to side-effects
  • Change to date of revision

Updated on 9 November 2015 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

……

 

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 at least more than 10 years.

 

……

            In women with no personal history of VTE but with a first degree relative with a history of VTEvenous thromboembolism 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 VTE venous thromboembolism 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.

           

……

 

Hypothyroidism

 

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.

 

Angioedema

 

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

 

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.

……

 

4.5     Interaction with other medicinal products and other forms of interaction

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 anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz, telaprevir).

……

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

 

……

 


4.8     Undesirable effects

 

……

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

 

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

 

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

 

        Dry eyes

 

        Tear film composition changes.

 

……

4.9       Overdose

Symptoms of over dosage with oral oestrogens are breast tenderness, nausea, vomiting and/or metrorrhagia. Over dosage of progestagens may lead to a depressive mood, fatigue, acne and hirsutismOverdose may be manifested by nausea and vomiting. Treatment should be symptomatic.

……

 

6.6              Special precautions for disposal and other handling

 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

……

 

10.       Date of revision of the text

 

            August 2014November 2015

 

Updated on 14 August 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Addition of information on reporting a side effect.

Updated on 14 August 2014 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

... 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:.

 

 

System organ class

Very common >1/10

Common >1/100; <1/10

Uncommon >1/1,000; <1/100

Rare >1/10,000; <1/1,000

Infections and infestations

 

Genital candidiasis or vaginitis, see also Reproductive system and breast disorders

 

 

Immune system disorders

 

 

Hypersensitivity, see also Skin and subcutaneous tissue disorders

 

Metabolism and nutrition disorders

 

Fluid retention, see also General disorders and administration site conditions

 

 

Psychiatric disorders

 

Depression or depression aggravated

Nervousness

 

Nervous system disorders

 

Headache, migraine or migraine aggravated

 

 

Vascular disorders

 

 

Thrombophlebitis superficial

Pulmonary embolism

Thrombophlebitis deep

Gastrointestinal disorders

 

Nausea

Abdominal pain, abdominal distension or abdominal discomfort

Flatulence or bloating

 

Skin and subcutaneous tissue disorders

 

 

Alopecia, hirsutism or acne

Pruritus or Urticaria

 

Musculoskeletal, connective tissue and bone disorders

 

Back pain

Leg cramps

 

 

Reproductive system and breast disorders

Breast pain or breast tenderness

Vaginal haemorrhage

Breast oedema or breast enlargement

Uterine fibroids aggravated or uterine fibroids re-occurrence or uterine fibroids

 

 

General disorders and administration site conditions

 

Oedema peripheral

Drug ineffective

 

Investigations

 

Weight increased

 

 

 

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

 

Age range (years)

IncidenceAdditional cases per 1,000 never-users of HRT over a 5 -years period*

Risk ratio and 95% CI**

Additional cases per 1,000 HRT users over 5 years’ use (95% CI)

Oestrogen-only HRT

50-65

9-12

1.2

1-2 (0-3)

Combined oestrogen-progestagen

50-65

9-12

1.7

6 (5-7)

* 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 proportionatelly.

 

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

 

Age range (years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio and 95% CI

Additional cases per 1,000 HRT users over 5 years’ use (95% CI)

CEE oestrogen-only

50-79

21

0.8 (0.7-1.0)

-4 (-6-0)*

CEE+MPA oestrogen-progestagen**

50-79

174

1.2 (1.0-1.5)

4 (0-9)

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

** 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.

 

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

 

Age range (years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio and 95% CI

Additional cases per 1,000 HRT users over 5 years’ use (95% CI)

Oral oestrogen-only*

50-59

7

1.2 (0.6-2.4)

1 (-3-10)

Oral combined oestrogen-progestagen

50-59

4

2.3 (1.2-4.3)

5 (1-13)

* 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 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

 

Age range (years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio and 95% CI

Additional cases per 1,000 HRT users over 5 years’ use (95% CI)

50-59

8

1.3 (1.1-1.6)

3 (1-5)

* 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

 

Updated on 25 September 2012 PIL

Reasons for updating

  • Change to MA holder contact details

Updated on 18 November 2011 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4 - Clinical particulars
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5 - Pharmacological properties
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6 - Pharmaceutical particulars
  • Change to section 6.1 - List of excipients
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 2: Lactose monohydrate 36.3 mg per tablet
Section 4.2 Amended sentences:
Kliogest is a continuous combined hormone replacement 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.
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.
Section 4.3: Addition
Known, past or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency (see section 4.4))
Section 4.4: Additions
Extensive additions to this section.
Section 4.5: Additions
meprobamate, phenylbutazone
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.
Section 4.8 Additions
Extensive additions to this section.
Section 5.1 Amendments
Pharmacotherapeutic group: progestagens and oestrogens, fixed combination, ATC code: G03FA01.
Norethisterone acetate: Synthetic progestagen with actions similar to those of progesterone, a natural female sex hormone.

Updated on 18 November 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to instructions about missed dose
  • Change to storage instructions
  • Change to side-effects
  • Change to drug interactions
  • Change to information about pregnancy or lactation
  • Change to date of revision

Updated on 3 June 2011 PIL

Reasons for updating

  • Change of inactive ingredient

Updated on 5 August 2010 SmPC

Reasons for updating

  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

PREVIOUS WORDING

NEW WORDING

4.4  Special Warnings and Precautions for Use

 

4.4  Special warnings and precautions for use

(formatted to lower case)

Ovarian cancer

 

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

 

Ovarian cancer

 

Use of oestrogen alone and oestrogen plus progestogen therapies for at least 5 or 10 years has been associated with an increased risk of ovarian cancer in some epidemiological studies

 

4.6  Pregnancy and Lactation

 

4.6    Pregnancy and lactation

 

(formatted to lower case)

4.7  Effects on Ability to Drive and Use Machines

 

 

4.7    Effects on ability to drive and use machines

 

(formatted to lower case)

 

4.8    Undesirable Effects

 

4.8    Undesirable effects

 

(formatted to lower case)

 

 

5.2  Pharmacokinetic Properties

 

 

5.2    Pharmacokinetic properties

 

(formatted to lower case)

5.3  Preclinical Safety Data

 

 

5.3    Preclinical safety data

(formatted to lower case)

 

6.1  List of Excipients

 

Gelatin

 

6.1    List of excipients

(formatted to lower case)

Hydroxypropylcellulose

6.4  Special Precautions for Storage

 

 

6.4    Special precautions for storage

(formatted to lower case)

 

6.6  Special Precautions for Disposal and other handling

 

 

6.6    Special precautions for disposal of a medicinal product or waste materials derived from such medicinal product and other handling of the product

(p and s formatted to lower case)

9.       Date of Authorisation/renewal of authorisation

Date of first authorisation: 18th November 1987

Date of last renewal: 18th November 2007.

 

 

 

9.      DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 18 November 1987

Date of last renewal: 18 November 2007.

 

10.  DATE OF REVISION OF THE TEXT

October 2009

 

10.    DATE OF REVISION OF THE TEXT

July 2010

 

Updated on 19 March 2010 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change in the revision date of text from Aug 2008 to Oct 2009

Updated on 10 February 2010 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 19 January 2010 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 29 October 2008 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 4.4    Special warnings and precautions for use

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

 This heading has to be changed to: 6.6    Special Precautions for Disposal and other handling
 

Updated on 3 March 2008 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 6.4 - Special precautions for storage
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

Updated on 6 December 2004 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.1 - List of excipients
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 18 August 2003 SmPC

Reasons for updating

  • Improved electronic presentation

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 30 June 2003 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)