Kliofem® film-coated tablets.

Excipient: lactose monohydrate.

For a full list of excipients, see 6.1.

Film-coated tablet for oral administration.

1 Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women with more than 1 year since last menses.

2 Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

(See also section 4.4).

The experience of treating women older than 65 years is limited.

Kliofem 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.

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 amenorrhea and not taking HRT or women transferring from another continuous combined HRT product, treatment with Kliofem may be started on any convenient day. In women transferring from a sequential HRT regimens, treatment should start as soon as their withdrawal bleeding has ended.

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

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.

• 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 any of the excipients

• Porphyria.

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

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 contra-indications 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 and modified 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 Kliofem, 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. 1st degree heredity for breast cancer

• Hypertension

• Liver disorders (e.g. liver adenoma)

• Diabetes mellitus with or without vascular involvement

• Cholelithiasis

• Migraine or (severe) headache

• Systemic lupus erythematosus

• 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

• Pregnancy

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 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 progestogen 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-progestogen, 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-progestogen HRT (see Section 4.8).

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

HRT, especially oestrogen-progestogen 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 thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

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 oestrogens and progestogen or oestrogen-only HRT.

The relative risk of CAD during use of combined oestrogen-progestogen 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-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Ischaemic stroke

Combined oestrogen-progestogen 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 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.

− 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 (TGB), 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-1-antitrypsin, 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.

- Kliofem 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.

The metabolism of oestrogens and progestogens 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, carbamezapine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir 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 progestogens.

Clinically, an increased metabolism of oestrogens and progestogens 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 Kliofem.

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.

Kliofem is not indicated during pregnancy. If pregnancy occurs during medication with Kliofem, treatment should be withdrawn immediately.

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

The results of most of epidemiological studies to-date have not indicated a teratogenic or foetotoxic effect when combinations of oestrogens with progestogens at dose levels relevant for Kliofem were taken inadvertently during pregnancy.

Lactation

Kliofem is not indicated during lactation.

No effects known.

Clinical experience:

The most frequently reported adverse events in the clinical trials with Kliofem 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 Kliofem or similar HRT products as compared to placebo and which on an overall judgement were considered as 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 by an overall judgement considered possibly related to Kliofem 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 re-occurrence

− Skin and subcutaneous tissue disorder: Seborrhoea, rash, angioneurotic oedema

− Reproductive system and breast disorders: Hyperplasia endometrial, vulvovaginal pruritus

− Investigations: Weight decreased, blood pressure increased

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

• Skin and subcutaneous tissue 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-progestogen 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-progestogen 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 progestogen 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-progestogen 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-progestogen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen-progestogen 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.

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

Pharmacotherapeutic group: Oestrogen and progestagen for continuous combined hormone replacement therapy, ATC code: G03FA01.

Estradiol: The active ingredient, synthetic 17 beta-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 progestogen 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 progestogen 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.

Kliofem 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 months 10-12 of treatment. Bleeding and/or spotting appeared in 30% of the women during the first three 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-analysed trials shows that current use of HRT, alone or in combination with a progestogen – 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 Kliofem on bone mineral density were examined in a 2-year, randomised, double-blind, placebo-controlled trial in postmenopausal women (n=327, including 48 on Kliofem). All women received calcium supplementation 1,000 mg daily. Kliofem 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 Kliofem 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 Kliofem was 91% after 2 years of treatment.

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 5-8 hours after intake of 1 Kliofem tablet. The half life of 17β-estradiol is about 12-14 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 sulphates and glucuronides. Oestrogens are excreted by the bile, where they are hydrolysed and reabsorbed (enterohepatic circulation), and mainly 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 0.5 - 1.5 hours after intake of 1mg. The terminal half-life of NET is about 8-11 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 sulphate or glucuronide conjugates.

The pharmacokinetic properties in the elderly have not been studied.

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

In experimental animals estradiol and estradiol valerate displayed an embryolethal effect at relatively low doses; malformations of the urogenital tract and feminisation of male foetuses was observed.

Norethisterone, like other progestogens, caused virilisation of female foetuses in rats and monkeys. After high 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 SPC.

Tablet core:

Lactose monohydrate

Maize starch

Hydroxypropylcellulose

Talc

Magnesium stearate

Film-coating:

White tablets

Hypromellose

Triacetin

Talc

None known.

48 months

Do not refrigerate. Keep the container in the outer carton in order to protect from light.

Polypropylene/polystyrene calendar dial pack containing 28 tablets. Calendar dial packs (3 x 28 tablets) are contained within outer carton.

No special requirements.

Novo Nordisk Limited

Broadfield Park, Brighton Road

Crawley, West Sussex, RH11 9RT

PL 3132/0080

18/06/2008

30/03/2012

POM.