SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Climagest 1 mg film-coated tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

16 tablets each containing 1 mg oestradiol valerate (equivalent to 0.764 mg oestradiol), 12 tablets each containing 1 mg oestradiol valerate and 1 mg norethisterone.

This product contains lactose monohydrate.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Oestradiol valerate 1mg tablets: grey-blue tablet, coded OC on one side, CG on the other.

Combination tablets: white tablet, coded OE on one side, CG on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women.

The experience treating women older than 65    years is limited.

4.2    Posology and method of administration

Climagest provides continuous oestrogen and sequential progestagen to women.

Treatment commences with one grey-blue tablet daily for the first 16 days followed by one white tablet daily for the next 12 days, as directed on the 28 day calendar pack. Women not menstruating may start therapy at any time. However, if the patient is menstruating regularly it is advised that the patient starts therapy on the first day of bleeding. Menstrual bleeding during initial Climagest therapy may be irregular. Pregnancy should be excluded before starting therapy. For the initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.

Climagest may be taken continuously by women with an intact uterus as it provides both oestrogen and progestagen to reduce endometrial hyperstimulation.

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

Patients changing from another continuous sequential or cyclical preparation should complete the cycle and may then change to Climagest without a break in therapy. Patients changing from a continuous combined preparation may start therapy at any time if amenorrhoea is established, or otherwise start on the first day of bleeding.

Missed tablet: If a tablet is missed it should be taken within 12 hours of when normally taken; otherwise the tablet should be discarded, and the usual tablet should be taken the following day. Forgetting or missing a dose may increase the likelihood of breakthrough bleeding.

Use in the elderly

Climagest should only be used in the elderly for the indications listed. Use in children

Climagest should not be used in children.

4.3 Contraindications

•    Known, past or suspected breast cancer,

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

•    Undiagnosed genital bleeding,

•    Untreated endometrial hyperplasia,

•    Severe renal disease,

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

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

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

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

•    Known hypersensitivity to the active substances or to any of the excipients,

•    Porphyria.

4.4 Special warnings and precautions for use

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 contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast cancer’ below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

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

-    leiomyoma (uterine fibroids) or endometriosis,

-    risk factors for thromboembolic disorders (see below),

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

-    hypertension,

-    liver disorders (e.g. liver adenoma),

-    diabetes mellitus with or without vascular involvement,

-    cholelithiasis,

-    migraine or (severe) headache,

-    systemic lupus erythematosus (SLE),

-    a history of endometrial hyperplasia (see below),

-    epilepsy,

-    asthma,

-    otosclerosis.

Reasons for immediate withdrawal of therapy:

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

-    jaundice or deterioration in liver function,

-    significant increase in blood pressure,

-    new onset of migraine-type headache,

-    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 greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years. The addition of a 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.

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

Breast cancer

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

Combined oestrogen-progestagen therapy

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

Oestrogen-only therapy

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

The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) 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.

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).

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

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

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

As in all post-operative patients prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery, temporarily stopping HRT four to six 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 young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

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

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRT.

Combined oestrogen-progestagen therapy

The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.

Oestrogen-only

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

Ischaemic stroke

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5 to 10 years) use of oestrogen-only HRT has been associated with a slightly increased risk of ovarian cancer (see section 4.8).

Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk (see section 4.8).

Other conditions

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

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.

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 biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

Thyroid function should be monitored regularly in patients who require thyroid hormone replacement therapy and who are also taking oestrogen in order to ensure that thyroid hormone levels remain within an acceptable range.

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.

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

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

4.5 Interactions 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).

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.

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

4.6 Pregnancy and lactation

Pregnancy

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

Data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than normally used in Oral Contraceptives and HRT formulations, masculinisation of the female foetus 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 effects.

Lactation

Climagest is not indicated during lactation.

4.7 Effects on ability to drive and use machines

No adverse effects on the ability to drive or operate machines have been recorded.

4.8 Undesirable Effects

Table 1 represents adverse drug reactions from legacy clinical trials combined with adverse drug reactions from post-marketing experience. The adverse drug reactions are listed according to the system organ class in MedDRA and the frequency is not known.

Table 1 Adverse drug reactions

Neoplasms benign, malignant and unspecified (including cysts and polyps)	Breast cancer.
Immune system disorders	Hypersensitivity.
Psychiatric disorders	Depression, depressed mood, libido increased.
Nervous system disorders	Dizziness, vertigo, headache.
Cardiac disorders	Palpitations.
Vascular disorders	Embolism, thrombophlebitis, hypertension, migraine, epistaxis.

Gastrointestinal disorders	Vomiting, abdominal pain, dyspepsia, flatulence, nausea, abdominal distention.
Hepatobiliary disorders	Cholestasis.
Skin and subcutaneous tissue disorders	Urticaria, rash, pruritus generalised, alopecia.
Musculoskeletal and connective tissue disorders	Pain in extremity.
Reproductive system and breast disorders	Endometrial hyperplasia, uterine leiomyoma, breast discomfort, breast pain, breast tenderness. During the first few months of therapy metrorrhagia or vaginal haemorrhage may occur; this is usually transient, vaginal discharge.
Investigations	Glucose tolerance decreased, liver function test abnormal, weight increased.
General disorders and administration site conditions	Oedema.

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.

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

Age range (years)	Additional cases per 1000 never-users of HRT over a 5 year period*	Risk ratio#	Additional cases per 1000 HRT users over 5 years (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)
#Overall risk ratio. The risk ratio 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 proportionately.

* Taken from baseline incidence rates in developed countries.

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

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 HRT users over 5 years (95%CI)
		CEE oestrogen-only
50 - 79	21	0.8 (0.7 - 1.0)	-4 (-6 - 0)*
		CEE+MPA oestrogen & progestagen{
50 - 79	17	1.2 (1.0 - 1.5)	+4 (0 - 9)

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

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

Endometrial cancer risk

Postmenopausal women with a uterus

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

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

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

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

Ovarian cancer

Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.

Risk of venous thromboembolism

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

Risk of coronary artery disease

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

Risk of ischaemic stroke

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

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

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

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio and 95%CI	Additional cases per 1000 HRT users over 5 years
50 - 59	8	1.3 (1.1 - 1.6)	3 (1 - 5)

* No differentiation was made between ischaemic and haemorrhagic stroke.

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

-    gall bladder disease,

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

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

-    jaundice cholestatic,

-    cholelithiasis,

-    diarrhoea,

-    dry eyes,

-    tear film composition changes.

4.9    Overdose

There have been no reports of adverse effects from overdosage. There are no specific antidotes, and if further treatment is required it should be symptomatic.

5    PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group : progestagens and oestrogens, ATC code: G03F B05.

Oestradiol

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

Oestradiol valerate is used in oestrogen deficiency states. Treatment with oestrogens relieves menopausal vasomotor symptoms. Oestrogens cross the placenta.

Progestagen

As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of progestagen greatly reduces the oestrogen induced risk of endometrial hyperplasia in non hysterectomised women.

Norethisterone is a progestagen added to prevent endometrial hyperplasia and increased risk of endometrial carcinoma which can be induced by unopposed oestrogen use.

5.2 Pharmacokinetic properties

Oestradiol

Absorption

Oestradiol valerate, like most natural oestrogens, is readily and fully absorbed from the gastrointestinal (GI) tract. When given orally in doses of 1 to 2 mg, peak plasma concentrations of oestradiol are generally observed 3 to 6 hours post dose. Oestradiol is also known to undergo enterohepatic re-circulation.

Distribution

In the systemic circulation, oestradiol is approximately 52% bound to plasma albumin and 45-46% to sex hormone binding globulin. Only 2% is free and biologically active.

Metabolism

Oestradiol undergoes extensive first-pass metabolism. Oestradiol is metabolised primarily in the liver to oestrone, then later to oestriol, epioestriol and catechol oestrogens, which are then conjugated to sulphates and glucuronides. Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyse the hydroxylation of oestradiol, forming oestriol. Oestriol is glucuronidated by UGT1A1 and UGT2B7 in humans. Oestradiol metabolites are subject to enterohepatic circulation. Other metabolites (e.g. 2-methoxy, 2-hydroxy-3-methoxy and 4-methoxy estradiol) have been identified.

Elimination

The elimination half life of oestradiol is approximately 1 hour. Systemic concentrations of oestradiol returned to baseline (e.g. pre-treatment concentrations) in 24 hours (range 6 to 48 hours) post dose. Oestradiol is excreted via the kidney in the urine as sulphate and glucuronide esters while a small proportion is excreted as unchanged oestradiol.

Norethisterone acetate

Absorption

Norethisterone is absorbed from the GI tract and its effects last for at least 24 hours. When a dose of 1 mg is given, there are wide variations in serum norethisterone levels at any particular time point after dosing (100 to 1700 pg/mL). Norethisterone undergoes first pass effect with a resulting loss of 36% of the dose. When injected, it is detectable in the plasma after 2 days and is not completely excreted in the urine after 5 days. There are large intersubject variations in bioavailability.

Distribution

In plasma, norethindrone is bound approximately 35% to sex hormone-binding globulin (SHBG) and 61% to albumin. Only 4% is free and biologically active.

Metabolism

The most important metabolites are several isomers of 5- alpha -dihydronorethisterone and of tetrahydronorethisterone ,which are further metabolised to glucuronides.

Elimination

The elimination half-life of norethisterone is reported to be 6 to 8 hours, and is eliminated primarily in urine as glucuronides of metabolites. There are large inter-subject variations in elimination half-life.

5.3 Preclinical safety data

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

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

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

Long-term, continuous administration of natural and synthetic oestrogens and norethisterone in some animal species increases the frequency of tumours in certain hormone dependent tissues.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Oestradiol only tablets:

Tablet core:

Lactose monohydrate Maize starch Povidone Talc

Magnesium stearate FD&C blue no.2 lake (E132)

Purified water Tablet coat:

Hypromellose Propylene glycol

Opaspray blue M-1-6516 (E171, E464, E132) Purified water

Combination tablets:

Tablet core:

Lactose monohydrate Maize starch Povidone Talc

Magnesium stearate Purified water Tablet coat:

Hypromellose Propylene glycol

Opaspray white M-1-7-111B (E171 and E464 ) Purified water

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5    Nature and Contents of Container

UPVC blister strips with aluminium foil.

Packs contain 28 or 84 tablets. Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

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

7.    MARKETING AUTHORISATION HOLDER

Novartis Pharmaceuticals UK Limited

Trading as Sandoz Pharmaceuticals

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

PL 0101/0328

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/11/2006

DATE OF REVISION OF THE TEXT

30/07/2014