SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Premique Cycle® 0.625 mg/10 mg Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Conjugated estrogens* and medroxyprogesterone acetate (MPA).

14 tablets containing 0.625mg conjugated estrogens and 14 combination tablets containing

0.625mg conjugated estrogens and 10mg MPA.

*Conjugated estrogens contain sodium estrone sulfate, sodium equilin sulfate, 17a-dihydroequilin, 17a-estradiol, equilenin, 17a-dihydroequilenin, 17^-dihydroequilin, 17^-dihydroequilenin, 17^-estradiol and 8,9-dehydro-oestrone.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Premique Cycle is available for oral administration as conjugated estrogens 0.625mg tablets and conjugated estrogens/MPA (0.625 mg/10mg) combination tablets. Conjugated estrogens 0.625mg tablets are white, oval, biconvex sugar-coated tablets marked "0.625". Conjugated estrogens/MPA (0.625mg/10mg) combination tablets are green, oval, biconvex sugar-coated tablets marked "0.625/10".

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hormone replacement therapy for estrogen deficiency symptoms in menopausal and postmenopausal women

• 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.

4.2 Posology and method of administration

Posology

Adults:

Premique Cycle is available use in a sequential regimen for treatment of women with a uterus. That is, for the first 14 days of each cycle (days 1-14), one white tablet containing conjugated estrogens 0.625mg is taken daily, and for the last 14 days (days 15-28), one green tablet containing conjugated estrogens 0.625mg and MPA 10mg is taken daily. There should be no break between packs.

For most post-menopausal women, therapy may be commenced at any convenient time, although if the patient is still menstruating, commencement on the first day of bleeding is recommended. In women transferring from another sequential hormone replacement therapy regimen, treatment should begin the day following completion of the prior regimen.

Patients should be advised that a regular withdrawal bleed will usually occur at the end of one cycle of Premique Cycle and the beginning of the next.

For treatment of postmenopausal symptoms: Conjugated estrogens 0.625mg daily for the first 14 days of each cycle, followed by conjugated estrogens/MPA (0.625mg/10mg) combination tablet daily on days 15 to 28.

For prevention and treatment of osteoporosis associated with estrogen deficiency:

Conjugated estrogens 0.625mg daily for the first 14 days and conjugated estrogens/MPA (0.625mg/10mg) combination tablet taken daily on days 15 to 28 (see section 5.1).

Maintenance/Continuation/Extended Treatment:

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see section 4.4) should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.

The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding a progestogen should be weighed against the increased risk of breast cancer (see sections 4.4 and 4.8).

Forgotten tablet: If a tablet is forgotten, it should be taken as soon as the patient remembers, therapy should then be continued as before. If more than one tablet has been forgotten only the most recent tablet should be taken. The patient should not take double the usual dose to make up for the missed tablet.

Missed pills may cause breakthrough bleeding.

Elderly:

There are no special dosage requirements for elderly patients, but, as with all medicines, the lowest effective dose should be used.

Paediatric population:

Not recommended.

Method of administration Premique Cycle is taken orally.

4.3 Contraindications

1.    Hypersensitivity to the active substances or to any of the excipients of Premique Cycle listed in section 6.1.

2.    Known, past or suspected breast cancer.

3.    Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer).

4.    Undiagnosed genital bleeding.

5.    Untreated endometrial hyperplasia.

6.    Previous or current venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism).

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

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

9.    Acute liver disease or history of liver disease where the liver function tests have failed to return to normal.

10.    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 Premique Low Dose, in particular:

-    Leiomyoma (uterine fibroids) or endometriosis

-    Risk factors for thromboembolic disorders (see below)

-    Risk factors for estrogen 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) headaches

-    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 estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

The addition of a progestogen for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (see ‘Breast cancer’ below and section 4.8).

Break-through bleeding and spotting may occur during the first months of treatment. If breakthrough 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 estrogen-progestogen and possibly also estrogen-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, including the Million Women Study (MWS), are consistent in finding an increased risk of breast cancer in women taking estrogen-progestogen combinations for HRT that becomes apparent after about 3 years (see section 4.8).

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

HRT, especially estrogen-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.

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

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

Venous thromboembolism

Hormone replacement therapy (HRT) is associated with a 1.3-3 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 a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition.

Generally recognised risk factors for VTE include, use of estrogens, 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 scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4-6 weeks earlier, if this is possible. Treatment should not be restarted until the woman is completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

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

If venous thromboembolism develops after initiating therapy the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of potential thromboembolic symptoms (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 MPA.

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

Ischaemic stroke

Combined estrogen-progestogen and estrogen-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

•    Estrogens/progestogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Premique Low Dose is increased.

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

•    The use of estrogen may influence the laboratory results of certain endocrine tests and liver enzymes.

Estrogens 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 usually 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 usually unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in 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 estrogen-only HRT after the age of 65.

•    There is an increase in the risk of gallbladder disease in women receiving HRT (see conditions that need supervision).

•    A worsening of glucose tolerance may occur in some patients on estrogen/progestogen therapy and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.

•    This product contains lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

•    Estrogens should be used with caution in individuals with severe hypocalcaemia.

4.5 Interaction with other medicinal products and other forms of interaction

The metabolism of estrogens and progestogens 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 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 estrogens and progestogens.

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

The response to metyrapone may be reduced.

Aminogluthimide administered concomitantly with MPA may significantly depress the bioavailability of MPA.

4.6 Fertility, pregnancy and lactation

Pregnancy:

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

Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of MPA on the foetus.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens and progestogens indicate no teratogenic or foetotoxic effect.

Breast-feeding:

Premique Cycle is not indicated during lactation.

4.7 Effects on ability to drive and use machines

Premique Cycle should not affect the ability to drive or use machines.

4.8 Undesirable effects

See also section 4.4.

Adverse drug reactions (ADRs)

The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects. Breast pain is a very common adverse event reported in > 10% of patients.

			Uncommon ADRs	Rare ADRs	Very Rare ADRs
System Organ	Very	Common	(>1/1000, <1/100)	(>1/10000,	(<1/10000),
Class	Common ADRs	ADRs (>1/100, < 1/10)		<1/1000)	isolated reports
	(>1/10)

Infections and infestations		Vaginitis	Vaginal candidiasis
Neoplasms benign and malignant (including cysts and polyps)				Fibrocystic breast changes; Ovarian cancer	Enlargement of hepatic hemangiomas
Immune system disorders				Anaphylactic/ anaphylactoid reactions, including urticaria and angioedema
Metabolism and nutrition disorders				Glucose intolerance	Exacerbation of porphyria; Hypocalcaemia
Psychiatric disorders		Depression	Changes in libido; Mood disturbances	Irritability
Nervous system disorders			Dizziness; Headache; Migraine; Anxiety	Stroke; Exacerbation of epilepsy	Exacerbation of chorea
Eye disorders			Intolerance to contact lenses	None	Retinal vascular thrombosis
Cardiac disorders				Myocardial infarction
Vascular disorders			Pulmonary embolism	Superficial thrombophlebitis
Respiratory, thoracic and mediastinal disorders				Exacerbation of asthma
Gastrointestinal disorders			Nausea; Bloating; Abdominal pain	Vomiting; Pancreatitis
Hepatobiliary disorders			Gallbladder disease	None	Cholestatic jaundice
Skin and subcutaneous tissue disorders			Alopecia; Acne; Pruritus	Chloasma/melas ma; Hirsutism; Pruritus; Rash
Musculoskeleta l, connective tissue and bone disorders		Arthralgias; Leg cramps
Reproductive system & breast disorders	Breast pain	Breakthrough bleeding/ spotting; Dysmenorrhea; Breast	Change in menstrual flow; Change in cervical ectropion and secretion	Galactorrhoea; Increased size of uterine leiomyomata

		tenderness, enlargement, discharge
General disorders and administration site conditions			Oedema
Investigations		Changes in weight (increase or decrease); Increased triglycerides			Increase in blood pressure

Breast cancer risk

•    An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.

•    Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-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.

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 & 95%CI#	Additional cases per 1000 HRT users over 5 years (95%CI)
		estrogen only HRT
50-65	9-12	1.2	1-2 (0-3)
		Combined estrogen-progestogen
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.

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

Age range (yrs)	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 estrogen-only
50-79	21	0.8 (0.7 - 1.0)	-4 (-6 - 0)**
		CEE+MPA estrogen & progestogen{
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.

*Taken from baseline incidence rates in developed countries

**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 estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of estrogen-only use and estrogen 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 progestogen to estrogen-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

Use of estrogen-only or combined estrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer 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, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-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 HT (see section 4.4). Results of the WHI studies are presented:

WHI Studies - Additional risk of VTE 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
Oral estrogen-only*
50-59	7	1.2 (0.6-2.4)	1 (-3 - 10)
Oral combined estrogen-progestogen
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 estrogen-progestogen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of estrogen-only and estrogen + 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 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 reported in association with estrogen/progestogen treatment including

Premique:

•    Estrogen-dependent neoplasms benign and malignant, e.g. endometrial hyperplasia, endometrial cancer

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

•    Myocardial infarction

•    Stroke

•    Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura

•    Probable dementia (see section 4.4)

•    Exacerbation of otosclerosis

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 the Yellow

Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdosage of estrogen-containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females. There is no specific antidote, and further treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Progestagens and estrogens, fixed combinations, ATC Code: GO3F A12

Conjugated Estrogens

The active ingredients are primarily the sulfate esters of estrone, equilin sulfates, 17a-estradiol and 17^-estradiol. These substitute for the loss of estrogen production in menopausal women, and alleviate menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

Progestogen:

As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces but does not eliminate the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Relief of estrogen-deficiency symptoms

In a 1-year clinical trial (n=2,808), vasomotor symptoms were assessed for efficacy during the first 12 weeks of treatment in a subset of symptomatic women (n=241) who had at least 7 moderate or severe hot flushes daily or 50 moderate to severe hot flushes during the week before randomisation. Premique 0.625mg/2.5mg (conjugated estrogens/medroxyprogesterone acetate) was shown to be statistically better than placebo at weeks 4, 8 and 12 for relief of both frequency and severity of moderate to severe vasomotor symptoms.

In two clinical trials, the incidence of amenorrhoea (no bleeding or spotting) increased over time in women treated with Premique 0.625mg/2.5mg. Amenorrhoea was seen in 68% of women at cycle 6 and 77% of women at cycle 12. Breakthrough bleeding and/or spotting appeared in 48% during the first 3 months, and in 24% of women during months 10-12 of treatment.

Prevention of osteoporosis

Epidemiological studies suggest a number of individual risk factors which contribute to the development of post-menopausal osteoporosis. These include: early menopause; family history of osteoporosis; thin, small frame; cigarette use; recent prolonged systemic corticosteroid use.

Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens 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 help prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

After 3 years of treatment with Premique 0.625mg/2.5mg, the increase in lumbar spine bone mineral density (BMD) was 4.87% ± 0.66. The percentage of women who maintained (less than 1% BMD loss per year) or gained BMD in lumbar zone during treatment was 92%.

Premique 0.625mg/2.5mg also had an effect on hip BMD. The increase after 3 years was 1.94% ± 0.44 at total hip. The percentage of women who maintained (less than 1% BMD loss per year) or gained BMD in hip zone during treatment was 88%.

5.2 Pharmacokinetic properties

Absorption

Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. However Premique contains a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. MPA is well absorbed from the gastrointestinal tract. Table 1 summarises the mean pharmacokinetic parameters for unconjugated and conjugated estrogens, and medroxyprogesterone acetate following administration of 2 Premique 0.625/2.5mg and 2 Premique 0.625/5mg tablets to healthy postmenopausal women.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. MPA is approximately 90% bound to plasma proteins but does not bind to SHBG.

Biotransformation

Exogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.

Elimination

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are extracted as glucuronide conjugates with only minor amounts secreted as sulfates.

Table 1 - Pharmacokinetic parameters for Premique

Pharmacokinetic parameters for unconjugated and conjugated estrogens (CE) and medroxyprogesterone acetate (MPA)

Drug	2 x 0.625mg CE/2.5mg MPA Combination Tablets (n=54)	2 x 0.625mg CE/5mg MPA Combination Tablets (n=51)
PK Parameter	Cmax tmax t1/2 AUC	Cmax tmax t1/2 AUC

PK Parameter Arithmetic Mean (%CV)	C v-/max (pg/mL)	tmax (h)		t1/2 (h)	AUC (pg.h/mL )	C v-/max (pg/mL)	tmax (h)	t1/2 (h)	AUC (pg.h/mL )
Conjugated Estrogens Total 6.6(38) 6.1(28) Estrone			20.7(34)		116(59)	6.3(48)	9.1(29)	23.6(36)	151(42)
BA*- Total 6.4(39) 6.1(28) Estrone			15.4(34)		100(57)	6.2(48)	9.1(29)	20.6(35)	139(40)
Total Equilin 5.1(45) 4.6(35)			11.4(25)		50(70)	4.2(52)	7.0(36)	17.2(131)	72(50)
PK Parameter Arithmetic Mean (%CV)	C '-/max (pg/mL)	tmax (h)		t1/2 (h)	AUC (pg.h/mL )	C '-/max (pg/mL)	tmax (h)	t1/2 (h)	AUC (pg.h/mL )
Medroxyprogesterone acetate MPA 1.5(40) 2.8(54)			37.6(30)		37(30)	4.8(31)	2.4(50)	46.3(39)	102(28)

BA* = Baseline adjusted

T_1/2 = apparent terminal phase disposition half-life (0.693/X_z)

5.3 Preclinical safety data

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina and liver.

In a two-year oral study in which female rats were exposed to MPA dosages of up to 5000pg/kg/day in their diets (50 times higher - based on AUC values - than the level observed in women taking 10mg of MPA), a dose-related increase in pancreatic islet cell tumours (adenomas and carcinomas) occurred. Pancreatic tumour incidence was increased at 1000 and 5000pg/kg/day, but not at 200pg/kg/day.

The cortisol activity of MPA at these high doses is thought to increase serum glucose in rats which reactively stimulates the beta cells of the pancreatic islets to produce insulin. This repeated stimulation is thought to cause the tumours in rats. Similar lesions are not likely to occur in humans since the endocrine system of rats is more sensitive to hormones than that of women. When MPA is combined with estrogen, MPA binds to fewer glucocorticosteriod receptors and thus has less effect on plasma glucose. In humans, the diabetogenic response to MPA at therapeutic doses is slight. Moreover, an extensive literature search revealed no evidence that MPA causes pancreatic tumours in humans.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

White (conjugated estrogens) tablets:

Calcium phosphate tribasic

Calcium sulfate

Carnauba wax

Microcrystalline cellulose

Glyceryl mono-oleate

Lactose monohydrate

Magnesium stearate

Methylcellulose

Macrogol

Shellac

Sucrose

Titanium dioxide (E171)

Edible printing ink (Opacode S-8-2774l-Black).¹’

Green (conjugated estrogens/MPA) combination tablets

Calcium phosphate tribasic Calcium sulfate Carnauba wax Microcrystalline cellulose Glyceryl mono-oleate Lactose monohydrate Magnesium stearate Methylcellulose Methyl hydroxybenzoate Macrogol Povidone

Propyl hydroxybenzoate Shellac

Sodium benzoate Sucrose

Indigo carmine (E132)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Edible printing ink.

⁺ contains iron oxide black (E172), shellac, propylene glycol, ethanol, ethyl acetate, N-Butyl alcohol, purified water, ammonia solution.

6.2 Incompatibilities

None known

6.3 Shelf life 2 years.

6.4 Special precautions for storage

Do not store above 25^oC. Keep blister in outer carton to protect from light.

6.5 Nature and contents of container

Polyvinylchloride (PVC)/Aluminium foil blister pack.

Cartons containing 3 blisters (84 tablets). Each blister contains 14 conjugated estrogen tablets 0.625mg and 14 conjugated estrogen 0.625mg/MPA 10mg tablets.

6.6 Special precautions for disposal

No special instructions.

7    MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent

CT13 9NJ United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 00057/1287

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/07/2011

10 DATE OF REVISION OF THE TEXT

27/04/2016