PREMARIN(r) TABLETS

WARNING

Endometrial Cancer Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding (see PRECAUTIONS, Malignant Neoplasms, Endometrial Cancer). Cardiovascular and other risks. Oestrogens with or without progestogens should not be used for the prevention of cardiovascular disease or dementia (see CLINICAL TRIALS and PRECAUTIONS, Cardiovascular Risk and Dementia). The oestrogen-alone substudy of the Women's Health Initiative (WHI) study reported increased risks of stroke and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with conjugated oestrogens (0.625 mg) relative to placebo (see CLINICAL TRIALS and PRECAUTIONS, Cardiovascular Risk). The oestrogen plus progestogen substudy of the WHI reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with conjugated oestrogens (0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL TRIALS and PRECAUTIONS, Cardiovascular Risk and Malignant Neoplasms, Breast Cancer). The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with conjugated oestrogens alone and during 4 years of treatment with conjugated oestrogens combined with medroxyprogesterone acetate, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women (see CLINICAL TRIALS and PRECAUTIONS, Dementia and Use in Geriatrics). Other doses of conjugated oestrogens and medroxyprogesterone acetate, and other combinations and dosage forms of oestrogens and progestogens were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, oestrogens with or without progestogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

NAME OF THE MEDICINE

PREMARIN Conjugated oestrogens 0.3mg tablets Conjugated oestrogens 0.625mg tablets

DESCRIPTION

PREMARIN (conjugated oestrogens), is a mixture of natural oestrogens (of equine origin) composed principally of the sodium salts of water-soluble sulphate esters of oestrone, equilin, and 17 a-dihydroequilin, together with smaller amounts of 17 a-oestradiol, equilenin, and 17 a-dihydroequilenin, 17 b-dihydroequilin, 17 b-dihydroequilenin, 17 b-oestradiol and d 8, 9- dihydroestrone. Each tablet contains lactose, hypromellose, magnesium stearate, macrogol 400, sucrose, microcrystalline cellulose, powdered cellulose, hydroxypropylcellulose, calcium phosphate, carnauba wax, and Opacode monogramming ink NS- white. The colouring agent in PREMARIN 0.3 mg tablets is Opadry 152B21511 Green, the colouring agent in PREMARIN 0.625 mg Tablets is Opadry 03B16083 Maroon.

PHARMACOLOGY

Pharmacodynamics

Oestrogen production occurs primarily in the ovarian follicles in women from the menarche to the menopause and is important in the development and maintenance of the female urogenital system and secondary sex characteristics. During the menopause the ovarian-oestrogen production decreases and in postmenopausal women, when the ovaries have ceased to function, only a small amount of oestrogen is still produced. This decrease and eventual cessation of oestrogen production in perimenopausal and postmenopausal women, respectively, may result in vasomotor symptoms (sweating, hot flushes) and atrophic vaginitis. In addition to relieving or eliminating these disorders, oestrogen replacement therapy has also been demonstrated to retard or halt the post- menopausal bone mass loss (osteoporosis). The pharmacological effects of conjugated oestrogens are similar to those of endogenous oestrogens.

Pharmacokinetics

Conjugated oestrogens are water-soluble and are well absorbed from the gastrointestinal tract after release from the drug formulation. The PREMARIN tablet releases conjugated oestrogens slowly over several hours. Table 1 summarises the mean pharmacokinetic parameters for conjugated oestrogens following the administration of 1 x 0.625 mg tablets to healthy postmenopausal women.

Metabolism and inactivation occur primarily in the liver. Some oestrogens are excreted into the bile; however, they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water soluble oestrogen conjugates are strongly acidic and are ionised in body fluids, which favours excretion through the kidneys since tubular reabsorption is minimal.

CLINICAL TRIALS

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of oral conjugated oestrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (CE 0.625 mg/MPA 2.5 mg) compared to placebo. The primary endpoint was the incidence of coronary heart disease (CHD) (non-fatal myocardial infarction (MI), silent MI and CHD death). The primary safety endpoint was the incidence of invasive breast cancer. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in CE/MPA), colorectal cancer, hip fracture, and death due to other causes. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

Oestrogen-alone Substudy

The oestrogen-alone substudy included 10,739 women (average age of 63 years, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), who were followed-up on average for 7.1 years. The oestrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of oestrogen alone in predetermined primary endpoints. Results of the substudy are presented in Table 2 below. The confidence intervals are unadjusted for multiple looks and multiple comparisons.

a: Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. b: Results are based on centrally adjudicated data for an average follow-up of 7.1 years. c: Results are based on an average follow-up of 6.8 years.

d: Not included in global index

e: All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease. f: A subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or

death due to other causes.

For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE alone were 12 more strokes while the absolute risk reduction per 10,000 women-years was seven fewer hip fractures. The absolute excess risk of events included in the "global index" was a non- significant two events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality (see BOXED WARNING and PRECAUTIONS). Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with placebo (see Table 2). Centrally adjudicated results for stroke events, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE alone compared to placebo. Oestrogen alone increased the risk of ischaemic stroke, and this excess was present in all subgroups of women examined (see Table 2).

Oestrogen-Progestogen Substudy

The oestrogen plus progestogen substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other), was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years (RR 1.15, 95% nCI 1.03-1.28). For those outcomes included in the WHI "global index", that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were six more CHD events, seven more strokes, ten more PEs, and eight more invasive breast cancers, while the absolute risk reductions per 10,000 women- years were seven fewer colorectal cancers and five fewer hip fractures (see BOXED WARNING and PRECAUTIONS). Results of the oestrogen plus progestogen substudy are presented in Table 3 below. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

a: Results are based on centrally adjudicated data. Mortality data was not part of the adjudicated data, however data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95% nCI 0.82-1.18).

b: Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

c: Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.

Women's Health Initiative Memory Study

The oestrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were age 65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to evaluate the effects of CE 0.625 mg daily on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 5.2 years, 28 women in the oestrogen-alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the oestrogen- alone group was 1.49 (95% CI, 0.83 to 2.66) compared to placebo. The most common classification of probable dementia in the treatment group and placebo group was Alzheimer's disease. Since the substudy was conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see BOXED WARNING, PRECAUTIONS - Dementia and Use in Geriatrics). The oestrogen plus progestogen WHIMS substudy, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47%, age 65 to 69 years; 35%, 70 to 74 years; 18%, 75 years of age and older) to evaluate the effects of CE/MPA 0.625 mg conjugated oestrogens/ 2.5 mg medroxyprogesterone acetate on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of four years, 40 women in the oestrogen plus progestogen group (45 per 10,000 woman-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the oestrogen plus progestogen group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. When the data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women (see BOXED WARNING, and PRECAUTIONS- Dementia and Use in Geriatrics).

CONTRAINDICATIONS

Known or suspected pregnancy Known, suspected or past cancer of the breast Known or suspected oestrogen-dependent neoplasia (e.g., endometrial cancer, endometrial hyperplasia) Undiagnosed abnormal genital bleeding Active or history of confirmed venous thromboembolism (such as deep venous thrombosis, pulmonary embolism) Active or history of arterial thromboembolic disease (e.g., stroke, myocardial infarction) Severe uncontrolled hypertension Other undiagnosed breast pathology Active or chronic liver dysfunction or disease Known thrombophilic disorders (e.g., protein C, protein S or antithrombin deficiency) Known or suspected hypersensitivity to any ingredients contained in PREMARIN.

PRECAUTIONS

The benefits and risks of oestrogen therapy must always be carefully weighed, including consideration of the emergence of risks as therapy continues. Oestrogen therapy or hormone therapy should not be initiated or continued to prevent cardiovascular disease or dementia.

Combined Oestrogen and Progestogen Therapy

There are additional and /or increased risks that may be associated with the use of combination oestrogen-progestogen therapy compared with using oestrogen-alone regimens. These include an increased risk of myocardial infarction, pulmonary embolism, invasive breast cancer and ovarian cancer (see CLINICAL TRIALS).

Cardiovascular Risk

An increased risk of stroke and deep vein thrombosis (DVT) has been reported with oestrogen-alone therapy. An increased risk of stroke, DVT, pulmonary embolism, and myocardial infarction has been reported with oestrogen-progestogen therapy. The physician should be aware of the possibility of thrombotic disorders (including thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism) during oestrogen therapy and alert to their earliest manifestations. Should any of these events occur or be suspected, oestrogens with or without progestogens should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolaemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

Stroke

In the oestrogen-alone substudy of the WHI, a statistically significant increased risk of stroke was observed in women receiving CE 0.625 mg daily compared to women receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was observed in year one and persisted. Should a stroke occur or be suspected, oestrogens should be discontinued immediately (see CLINICAL TRIALS). In the oestrogen plus progestogen substudy of the WHI, a statistically significant increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5 mg daily compared to women receiving placebo (31 vs. 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted (see CLINICAL TRIALS). Patients who are at risk of developing migraines with aura may be at risk of ischemic stroke and should be kept under careful observation.

Coronary Heart Disease

In the oestrogen-alone substudy of the WHI, no overall effect on CHD events (defined as nonfatal MI, silent MI, or death due to CHD) was reported in women receiving oestrogen alone compared to placebo (see CLINICAL TRIALS). In the oestrogen plus progestogen substudy of the WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo (39 vs. 33 per 10,000 women-years). An increase in the relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5.

Venous Thromboembolism

In the oestrogen-alone substudy of the WHI study, the risk of VTE (DVT and PE) was reported to be increased for women taking conjugated oestrogens (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years. Should a VTE occur or be suspected, oestrogens should be discontinued immediately (see CLINICAL TRIALS). In the oestrogen plus progestogen substudy of WHI, a statistically significant 2-fold greater rate of VTE was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. If feasible, oestrogens should be discontinued at least four to six weeks before surgery of the type associated with increased risk of thromboembolism or during periods of prolonged immobilisation.

Malignant Neoplasms

Breast Cancer

Studies involving the use of oestrogens by postmenopausal women have reported inconsistent results on the risk of breast cancer. The most important randomised clinical trial providing information about this issue is the WHI. In the oestrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04) (see CLINICAL TRIALS). In the oestrogen plus progestogen substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer. In this substudy, prior use of oestrogen alone or oestrogen plus progestogen combination hormone therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24 (95% nCI 1.01-1.54), and the absolute risk was 41 vs. 33 cases per 10,000 women-years, for oestrogen plus progestogen compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for oestrogen plus progestogen compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women- years for oestrogen plus progestogen compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the oestrogen plus progestogen group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histological subtype, grade and hormone receptor status did not differ between the groups (see CLINICAL TRIALS). Some observational studies have reported an increased risk of breast cancer for oestrogen- alone therapy after several years of use. The risk increased with duration of use, and appeared to return to baseline within approximately five years after stopping treatment (only the observational studies have substantial data on risk after stopping). The observational Million Women Study in Europe reported an increased risk of mortality due to breast cancer among current users of oestrogens alone or oestrogens plus progestogens compared to never users, while the oestrogen plus progestogen sub-study of WHI showed no effect on breast cancer mortality with a mean follow-up of 5.6 years. The use of oestrogen-alone and oestrogen plus progestogen has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Endometrial Cancer

The use of unopposed oestrogens in women with an intact uterus has been associated with an increased risk of endometrial cancer (see Exacerbation of Other Conditions). The reported endometrial cancer risk among unopposed oestrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on oestrogen dose. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after oestrogen therapy is discontinued. Clinical surveillance of all women taking oestrogen or oestrogen plus progestogen combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural oestrogens results in a different endometrial risk profile than synthetic oestrogens of equivalent oestrogen dose. Adding a progestogen to postmenopausal oestrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Addition of a Progestogen when a Woman has not had a Hysterectomy

Studies of the addition of a progestogen for 10 or more days of a cycle of oestrogen administration or daily with oestrogen in a continuous regimen, have reported a lower incidence of endometrial hyperplasia than would be induced by oestrogen treatment alone. There are, however, possible risks that may be associated with the use of progestogens with oestrogens compared to oestrogen alone regimens. These include: a possible increased risk of breast cancer; adverse effects on lipoprotein metabolism (e.g. lowering HDL, raising LDL) and impairment of glucose tolerance (see CLINICAL TRIALS and PRECAUTIONS - Combined Oestrogen and Progestogen Therapy).

Ovarian Cancer

In some epidemiological studies, use of oestrogen-only products has been associated with an increased risk of ovarian cancer over multiple years of use. Other epidemiological studies have not found these associations. The oestrogen plus progestogen substudy of WHI reported that after an average follow-up of 5.6 years, the relative risk for ovarian cancer for oestrogen plus progestogen vs. placebo was 1.58 (95% nCI 0.77 - 3.24) but was not statistically significant. The absolute risk of oestrogen plus progestogen vs. placebo was 4.2 vs. 2.7 cases per 10,000 women-years.

Dementia

In the oestrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomised women aged 65 to 79 years was randomised to CE (0.625.mg daily) or placebo. In the oestrogen plus progestogen WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years was randomised to CE/MPA (0.625 mg/2.5 mg daily) or placebo. In the oestrogen-alone substudy, after an average follow-up of 5.2 years, 28 women in the oestrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE alone vs. placebo was 1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for CE alone vs. placebo was 37 vs. 25 cases per 10,000 women-years (see CLINICAL TRIALS). In the oestrogen plus progestogen substudy, after an average follow-up of four years, 40 women in the oestrogen plus progestogen group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for oestrogen plus progestogen vs. placebo was 2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for CE/MPA vs. placebo was 45 vs. 22 cases per 10,000 women-years (see CLINICAL TRIALS). When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see BOXED WARNING and PRECAUTIONS, Use in Geriatrics).

Physical Examination

A complete medical and family history should be obtained prior to initiating or reinstating any oestrogen therapy. Pretreatment and subsequent physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs including histological endometrial assessment, when indicated and Papanicolaou Smear. Before starting treatment pregnancy should be excluded. Periodic check-ups and careful benefit/risk evaluations should be undertaken in women treated with oestrogen therapy.

Gallbladder Disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving oestrogens has been reported.

Uterine Bleeding

Certain patients may develop abnormal uterine bleeding (see Endometrial Cancer).

Fluid Retention

Because oestrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when oestrogens are prescribed.

Exacerbation of Other Conditions

Oestrogen therapy may cause an exacerbation of asthma, epilepsy, migraine with or without aura, diabetes mellitus, otosclerosis, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Endometriosis may be exacerbated with administration of oestrogen therapy. Malignant transformation of residual endometrial implants have been reported in women treated post- hysterectomy with oestrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestogen should be considered.

Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to oestrogens. In a large, randomised, placebo-controlled clinical trial, a generalised effect of oestrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals during oestrogen use.

Impaired Liver Function and Past History of Cholestatic Jaundice

Oestrogens may be poorly metabolised in patients with impaired liver function (see CONTRAINDICATIONS). For patients with a history of cholestatic jaundice associated with past oestrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.

Angioedema

Exogenous oestrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

Hypercalcaemia

Oestrogen administration may lead to severe hypercalcaemia in patients with breast cancer and bone metastases. If hypercalcaemia occurs, use of the medication should be stopped and appropriate measures taken to reduce the serum calcium level.

Hypocalcaemia

Oestrogens should be used with caution in patients with severe hypocalcaemia.

Hypothyroidism

Oestrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are receiving oestrogens may require increased doses of their thyroid hormone replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Visual Abnormalities

Retinal vascular thrombosis has been reported in patients receiving oestrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilloedema or retinal vascular lesions, oestrogens should be discontinued.

Hypertriglyceridaemia

In patients with pre-existing hypertriglyceridaemia, oestrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Consider discontinuation of treatment if pancreatitis occurs. In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with PREMARIN 0.625 mg, 0.45 mg and 0.3 mg compared with placebo were 34.3, 30.2, 25.1 and 10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0, and 5.5 respectively.

Other

PREMARIN is not an oral contraceptive, nor will it restore fertility. If it is administered, with or without a progestogen, to a woman of child bearing potential she should be advised to use non-hormonal methods of contraception.

Use in Pregnancy

Australian Pregnancy Category D

PREMARIN should not be used during pregnancy (see CONTRAINDICATIONS). Oestrogens are ineffective in the prevention or treatment of threatened or habitual abortion when given in the first trimester of pregnancy. If a woman becomes pregnant while using PREMARIN, it should be discontinued immediately.

Use in Lactation

Oestrogen administration to nursing mothers has been shown to decrease the quantity and quality of breast milk. Detectable amounts of oestrogens have been identified in the milk of mothers receiving the drug. Lactating mothers should not use oestrogens.

Carcinogenicity

Studies suggest that combination oestrogen and progestogen increases the risk of breast cancer, ovarian cancer and endometrial cancer in women in a time dependant manner (see PRECAUTIONS). Long-term, continuous administration of natural and synthetic oestrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina and liver.

Paediatrics Use

See INDICATIONS. Safety and effectiveness in paediatric use has not been established. Oestrogen treatment of prepubertal girls induces premature breast development and vaginal cornification, and may induce uterine bleeding. Since large and repeated doses of oestrogen over an extended time period have been shown to accelerate epiphyseal closure, hormonal therapy should be started only with caution before epiphyseal closure has occurred in order not to compromise final height.

Use in the Elderly

The oestrogen-alone substudy of the WHI reported an increased risk of stroke compared with placebo in postmenopausal women 70 years of age or older. Of the total number of subjects in the oestrogen-alone substudy of the Women's Health Initiative study, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and over. There was a higher relative risk (CE vs. placebo) of stroke in women less than 75 years of age compared to women 75 years and over (see PRECAUTIONS - Cardiovascular Risk). In the oestrogen plus progestogen substudy of the WHI, there was a higher relative risk (CE/MPA vs. placebo) of non-fatal stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age. In women greater than 75, the increased risk of non-fatal stroke and invasive breast cancer observed in the oestrogen plus progestogen combination group compared to the placebo group was 75 vs. 24 per 10,000 women-years and 52 vs. 12 per 10,000 women-years respectively. A substudy of the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI conducted in women aged 65-79, reported an increased risk of developing probable dementia when compared with placebo (see PRECAUTIONS - Dementia and CLINICAL TRIALS). Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both treatment groups and placebo groups was Alzheimer's disease. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see BOXED WARNING and PRECAUTIONS, Dementia). With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilising PREMARIN to determine whether those over 65 years of age differ from younger subjects in their response to PREMARIN.

Effect on Laboratory Tests

Pathologists should be advised that a patient is receiving oestrogen therapy when relevant specimens are submitted. Certain endocrine and liver function tests may be affected by administration of oestrogens: Accelerated prothrombin time, partial thromboplastin time and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 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 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 are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-trypsin, ceruloplasmin). Impaired glucose tolerance. The response to metyrapone test may be reduced. Increased plasma HDL and HDL2 cholesterol sub-fraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels. The results of these tests should not be regarded as reliable until oestrogen use has been discontinued for 1-2 months. Abnormal tests should then be repeated. Gonadotropin levels. Plasma cortisol levels. Increased plasma oestrogen levels.

INTERACTIONS WITH OTHER MEDICINES

Data from a drug-drug interaction study involving conjugated oestrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both medicines is not altered when the medicines are co-administered. Other clinical drug-drug interaction studies have not been conducted with conjugated oestrogens.

In vitro and in vivo studies have shown that oestrogens are metabolised partially by cytochrome P450 3A4 (CYP3A4). Therefore, CYP3A4 inducers or inhibitors may affect drug metabolism. Inducers of CYP3A4, such as St John's Wort (Hypericum perforatum) preparations, phenobarbitone, phenytoin, carbamazepine, rifampicin and dexamethasone may reduce plasma concentrations of oestrogens. This may lead to a decreased effect and/or changes in the uterine bleeding profile. CYP3A4 inhibitors such as cimetidine, erythromycin, clarithromycin, cyclosporin, grapefruit juice, ketoconazole, itraconazole, and ritonavir may increase plasma concentrations of oestrogens and may result in side effects. Hot flushes and vaginal bleeding have been reported in patients taking oestrogens and St John's Wort (Hypericum perforatum). The following drug interactions may occur during oestrogen use: alteration of the effectiveness of antihypertensive agents, theophyllines, phenothiazines, corticosteroids, tricyclic antidepressants, diazepam and caffeine, by either potentiating/enhancing their pharmacological effect or by decreasing their clearance.

DOSAGE AND ADMINISTRATION

Continuous daily administration of PREMARIN is generally recommended. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary. See the statements in the BOXED WARNING, particularly when considering PREMARIN for long-term usage. For women with an intact uterus, when indicated for climacteric symptoms or prevention of postmenopausal osteoporosis, it is recommended that a progestogen is administered (see PRECAUTIONS - Malignant Neoplasms). For continuous PREMARIN administration, a progestogen should be added for at least 10-14 consecutive days each month. In some cases, hysterectomised women with a history of endometriosis may need a progestogen (see PRECAUTIONS - Exacerbation of other Conditions). If PREMARIN is administered cyclically (i.e. 21 days out of 28 days), it is recommended that the progestogen is added for the last 10-14 days of the oestrogen course.

Usual Dosage Ranges:

Climacteric Symptoms

For treatment of moderate-to-severe vasomotor symptoms and atrophic vaginitis associated with the menopause, the lowest dose that will control symptoms should be chosen. Vasomotor Symptoms: 0.3 mg to 1.25 mg daily. Atrophic Vaginitis: 0.3 mg to 1.25 mg daily, depending upon the tissue responses of the individual patient.

For prevention of postmenopausal osteoporosis

0.3mg - 0.625mg daily. The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated pharmacological therapy. Postmenopausal women require an adequate daily intake of elemental calcium. Therefore when not contraindicated, calcium supplementation may be helpful for women with sub-optimal dietary intake. Vitamin D supplementation may also be required to ensure adequate daily intake in postmenopausal women.

Hypoestrogenism due to:

Female Hypogonadism

2.5 to 7.5 mg daily, in divided doses for 20 days, followed by a rest period of 10 days duration. If bleeding does not occur by the end of this period, the same dosage schedule is repeated. The number of courses of oestrogen therapy necessary to produce bleeding may vary depending on the responsiveness of the endometrium. If bleeding occurs before the end of the 10-day period, begin a 20-day oestrogen-progestogen cyclic regimen with PREMARIN, 2.5 to 7.5 mg daily in divided doses. During the last five days of oestrogen therapy, give an oral progestogen. If bleeding occurs before this regimen is concluded, therapy is discontinued and may be resumed on the fifth day of bleeding.

Female Castration and Primary Ovarian Failure

0.3 mg to 1.25 mg daily. Adjust dosage according to severity of symptoms and response of the patient.

OVERDOSAGE

Symptoms of overdosage of oestrogen-containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment, if necessary, should be symptomatic. Contact the Poisons Information Centre on 13 11 26 for advice on the management of an overdose.

PRESENTATION AND STORAGE CONDITIONS

Presentation

The 0.3 mg tablets: are dark green and marked "0.3". The 0.625 mg tablets are maroon in colour and marked "0.625. PREMARIN 0.3 mg tablets and PREMARIN 0.625 mg tablets are presented in blister packs of 1x28, 2 x 28, 3x28, and 4x28 tablets. PREMARIN 0.3 mg tablets are also available in blister packs of 7 tablets. Not all pack sizes are marketed.

Storage Conditions

Store below 25oC.

NAME AND ADDRESS OF THE SPONSOR

Pfizer Australia Pty Ltd ABN 50 008 422 348 38-42 Wharf Road WEST RYDE NSW 2114

POISONS SCHEDULE

S4, PRESCRIPTION ONLY MEDICINE.

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG)

30 March 1995.

DATE OF MOST RECENT AMENDMENT

26 August 2013. (r) Registered Trade Mark.