PREMARIN 0.3 MG COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

2.  QUALITATIVE AND QUANTITATIVE COMPOSITION

3 PHARMACEUTICAL FORM

4.   CLINICAL PARTICULARS

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.

1. 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 women. 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.

2. Conditions that 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 Premarin, in particular:

– Leiomyoma (uterine fibroids) or endometriosis

– Risk factors for thromboembolic disorders (see below)

– Risk factors for estrogen dependent tumours (e.g. first 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

3. Reasons for immediate withdrawal of therapy

Therapy should be discontinued if 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

4. 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.

For oral doses of conjugated equine estrogens >0.625 mg the endometrial safety of added progestogens has not been demonstrated. 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).

Breakthrough 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.

Unopposed estrogen stimulation may lead to pre-malignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis (but see above).

5. Breast Cancer

The overall evidence shows an increased risk of breast cancer in women taking combined estrogen-progestogen or estrogen-only HRT, that is dependent on the duration of taking HRT.

The Women’s Health Initiative trial (WHI) found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of estrogen-progestogen combinations (see section 4.8).

Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

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

6. 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).

7. 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 (Body Mass Index >30kg/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. If prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs 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 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 potential thromboembolic symptoms (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

8. 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 estrogen-progestogen or estrogen-only HRT. Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.

9. 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).

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) compared to women receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).

Other Conditions

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

11. 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 unaltered.

grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.

Interference with Laboratory and Other Diagnostic Tests

Laboratory test interactions

Increased platelet count decreased levels of antithrombin III, and increased plasminogen antigen and activity.

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 radioimmunoassay or T3 levels by radioimmunoassay. 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., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations may be decreased.

Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.

Impaired glucose tolerance.

The response to metyrapone may be reduced.

4.6 Fertility, pregnancy and lactation

Pregnancy

Premarin is not indicated during pregnancy.

For women with a uterus

If pregnancy occurs during medication with Premarin treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.

Breast-feeding

Premarin is not indicated during lactation.

4.7 Effects on ability to drive and use machines

No studies on the effect of ability to drive or use machines have been performed.

4.8 Undesirable effects

See also section 4.4.

The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects.

Breast Cancer

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.

The increased risk in users of estrogen-only therapy is 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).

Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological studies- Estimated additional risk of breast cancer after 5 years’ use in women with BMI 27 (kg/m2)

Estimated additional risk of breast cancer after 10 years’ use in women with BMI 27 (kg/m2)

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

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

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-progestogen 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 1.311.56). 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

*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

*no differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions reported in association with estrogen/proges­togen treatment including Premarin:

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 non-users. For further information, see sections 4.3 and 4.4.

Myocardial infarction

Gallbladder disease

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

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

Exacerbation of otosclerosis

Gynecomastia in males

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

5.1 Pharmacodynamic properties

ATC Code: G03C A57

Conjugated Estrogens

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

Mechanism of Action

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle.

After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal wo­men.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal wo­men.

In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2,805 postmeno­pausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups, receiving either placebo or conjugated estrogens, with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate-to-severe hot flushes daily, or at least 50 moderate-to-severe hot flushes during the week before randomisation. With conjugated estrogens 0.3 mg tablets, the relief of both the frequency and severity of moderate-to-severe vasomotor symptoms was shown to be statistically improved compared with placebo at weeks 4 and 12.

Table 1 shows the observed mean number of hot flushes in the CE 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.

Standard errors based on assumption of equal variances.

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. Premarin tablets release conjugated estrogens slowly over several hours. Maximum plasma concentrations are achieved approximately 6–10 hours following administration. The estrogens are generally eliminated in near-parallel fashion, with half-lives ranging from 10–20 hours, when corrected for endogenous concentrations as needed.

The pharmacodynamic profile of unconjugated and conjugated estrogens following doses of 3 × 0.3mg and 2 × 0.625mg is provided in Table 1.

Table 1 – Pharmacokinetic parameters for Premarin

Pharmacokinetic profile for unconjugated estrogens following a dose of 3 × 0.3mg or 2 × 0.625mg

Pharmacokinetic profile for conjugated estrogens following a dose of 3 × 0.3mg or 2 × 0.625mg

* ti/2 = terminal-phase disposition half-life (0.693/y)

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.

Biotransformation

Exogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in 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 following reabsorption. In post-menopausal 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.

Elimination

Estriol, estrone and estradiol are excreted in the urine along with glucuronide and sulfate conjugates.

Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

5.3 Preclinical safety data

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Monohydrate (Spray Dried)

Microcrystalline Cellulose

Hypromellose 2208, K100M (100,000 cps)

Magnesium Stearate

Sucrose

Microcrystalline Cellulose

Hydroxypropyl Cellulose

Hypromellose, 2910, E6 (6 cps)

Hypromellose, 2910, E15 (15 cps)

Polyethylene Glycol 400

Opadry® Green 15B21511#

Hypromellose, 2910, E6 (6 cps)

Carnauba Wax

Opacode® WB NS-78–18011, White Ink##

#The colorant Opadry® Green 15B21511 contains: HPMC 2910/ Hypromellose, 3 cP, HPMC 2910/ Hypromellose 2910, 6 cP, Quinoline Yellow Aluminium Lake (E104), Macrogol/ PEG 400, FD&C Blue #2/ Indigo Carmine Aluminium Lake (E132), Titanium Dioxide and Polysorbate 80.

## The white branding ink Opacode® WB NS-78–18011 contains: Titanium Dioxide, Propylene Glycol and Hypromellose 2910, 3 cPs.

6.2 Incompati­bilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Blister pack, consisting of a polyvinyl chloride PVC/Aclar®/PVC and a hard tempered aluminium foil lid containing 28 tablets. One carton contains 3 blisters.

6.6 Special precautions for disposal and other handling

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00057/1284

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

21/07/2011