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Data Sheet

PREMARIN® TABLETS

(Conjugated oestrogens USP tablets)

NAME OF DRUG

PREMARIN Tablets.

DESCRIPTION

PREMARIN (conjugated oestrogens), is a mixture of natural oestrogens (of equine origin) composed principally of the sodium salts of water-soluble sulfate esters of oestrone, equilin, and 17 alpha-dihydroequilin, together with smaller amounts of 17 alpha-oestradiol, equilenin, and 17 alpha-dihydroequilenin, 17 beta-dihydroequilin, 17 beta-dihydroequilenin, 17 beta-oestradiol and delta 8, 9-dihydroestrone.

Each tablet contains lactose, methylcellulose, magnesium stearate, shellac solution, macrogol 20000, glyceryl mono-oleate, calcium sulfate, sucrose, microcrystalline cellulose, titanium dioxide, carnauba wax, stearic acid and edible ink.

The colouring agent in PREMARIN 0.3mg tablets is Opalux Green, which contains sodium benzoate, iron oxide yellow (CI 77492), indigo carmine (CI 73015), methyl hydroxybenzoate and propyl hydroxybenzoate.

The colouring agent in PREMARIN 0.625 mg Tablets is Opalux Maroon, which contains sodium benzoate, erythrosine (CI 45430), sunset yellow FCF (CI 15985), titanium dioxide and indigo carmine (CI 73015).

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 postmenopausal bone mass loss (osteoporosis).

The pharmacological effects of conjugated oestrogens are similar to those of endogenous oestrogens.

Pharmacokinetics

Conjugated oestrogens are soluble in water and are well absorbed from the gastrointestinal tract. 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 sub-studies to assess the risks and benefits of conjugated oestrogen [0.625 mg daily] alone or in combination with medroxyprogesterone acetate (MPA) [0.625 mg/2.5 mg daily] compared to placebo. The primary endpoint was incidence of coronary heart disease (CHD), i.e. non-fatal myocardial infarction (MI), silent MI and coronary death. The primary safety endpoint was incidence of invasive breast cancer. The study did not evaluate the effects of hormone replacement therapy on menopausal symptoms.

The oestrogen alone (ET) 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 ET substudy, which 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) after an average follow-up of 6.8 years are presented in the table below.

In the ET substudy of WHI there was no significant overall effect on the relative risk (RR) of CHD (RR 0.95, 95% nominal confidence interval [nCI] 0.79- 1.16); a slightly elevated RR of CHD was reported in the early follow-up period and diminished over time. There was no significant effect on the RR of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04) or colorectal cancer (RR 1.08, 95% nCI 0.75-1.55) reported. Oestrogen use was associated with a statistically significant increased risk of stroke (RR 1.37, 95% nCI 1.09-1.73) and deep vein thrombosis (DVT) (RR 1.47, 95% nCI 1.06-2.06). The RR of pulmonary embolism (PE) (RR 1.37, 95% nCI 0.90-2.07) was not significantly increased. A statistically significant reduced risk of hip, vertebral and total fractures was reported with oestrogen use (RR 0.61, 95% nCI 0.41-0.91), (RR 0.62, 95% CI 0.42-0.93), and (RR 0.70, 95% nCI 0.63-0.79), respectively. The ET substudy did not report a statistically significant effect on death due to other causes (RR 1.08, 95% nCI 0.88-1.32) or an effect on overall mortality risk (RR 1.04, 95% nCI 0.88-1.22). These confidence intervals are unadjusted for multiple looks and multiple comparisons.

RELATIVE AND ABSOLUTE RISK SEEN IN THE OESTROGEN ALONE
SUBSTUDY OF WHI
Event Relative Risk
ET vs. Placebo
(95% nCIa)		 Placebo
n = 5,429		 ET
n = 5,310
    Absolute risk per 10,000 Person-years
CHD eventsb 0.95 (0.79-1.16) 56 53
Non-fatal MIb 0.91 (0.0.73-1.14) 43 40
CHD deathb 1.01 (0.71-1.43) 16 16
Strokec 1.37 (1.09-1.73) 33 45
Deep vein thrombosisb 1.47 (1.06-2.06) 15 23
Pulmonary embolismb 1.37 (0.90-2.07) 10 14
Invasive breast cancerb 0.80 (0.62-1.04) 34 28
Colorectal cancerc 1.08 (0.75-1.55) 16 17
Hip fracturec 0.61 (0.41-0.91) 17 11
Vertebral fracturesc 0.62 (0.42 - 0.93) 17 11
Total fracturesc 0.70 (0.63-0.79) 195 139
Death due to other causesc,d 1.08 (0.88-1.32) 50 53
Overall mortalityc 1.04 (0.88-1.22) 78 81

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 All deaths, except from breast or colorectal cancer, definite/probable CHD, PE, or cerebrovascular disease.

Final adjudicated results for CHD events from the oestrogen alone substudy, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) in women receiving conjugated oestrogens compared with placebo.

The WHI oestrogen plus progestogen (HT) substudy 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, at that time, exceeded the specified benefits (such as the reduction of colorectal cancer and hip fracture). Results of the HT substudy of the WHI, 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) for an average follow-up of 5.6 years are presented in the table below. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

In the WHI HT substudy, an increase in CHD risk was associated with combined hormone therapy (RR 1.24, 95% nCI 1.00-1.54). This was most apparent in the first year of the study (RR 1.81, 95% nCI 1.09-3.01). The RR of invasive breast cancer (RR 1.24, 95% nCI 1.01-1.54) was increased in women on combined hormone therapy. The substudy also reported a statistically significant increased RR of overall stroke (RR 1.31, 95% nCI 1.02-1.68), ischaemic stroke (RR 1.44, 95% nCI 1.09-1.90), DVT (RR 1.95, 95% nCI 1.43-2.67), and PE (RR 2.13, 95% nCI 1.45-3.11). Oestrogen plus progestogen was found to increase bone mineral density vs. placebo (3.7% vs. 0.14%, P<0.001) after three years. A statistically significant reduced RR of hip (RR 0.67, 95% nCI 0.47-0.96), vertebral (RR 0.65, 95% nCI 0.46-0.92), lower arm/wrist (RR 0.71, 95% nCI 0.59-0.85), and total fractures (RR 0.76, 95% nCI 0.69-0.83) was associated with oestrogen plus progestogen use.

Oestrogen plus progestogen use was associated with a statistically significant decreased risk of invasive colorectal cancer (RR 0.56, 95% nCI 0.38-0.81) although when colorectal cancers were diagnosed in combined hormone users, they were more advanced. Additional analyses showed no statistically significant differences in relative risk of endometrial (RR 0.81, 95% nCI 0.48-1.36) or cervical (RR 1.44, 95% nCI 0.47-4.42) cancers in patients on combined hormone replacement vs. placebo. After an average of 5.2 years of follow-up, the HT substudy did not report a statistically significant effect on death due to other causes (RR 0.92, 95% nCI 0.74-1.14), and there was no effect on overall mortality risk (RR 0.98, 95% nCI 0.82-1.18). These confidence intervals are unadjusted for multiple looks and multiple comparisons.

RELATIVE AND ABSOLUTE RISK SEEN IN THE OESTROGEN
PLUS PROGESTOGEN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSa
Event Relative Risk
HT vs. placebo
at 5.6 Years
(95% nCIb)		 Placebo
n = 8,102		 HT
n = 8,506
    Absolute Risk per 10,000 Person-years
CHD events 1.24 (1.00-1.54) 33 39
Non-fatal MI 1.28 (1.00-1.63) 25 31
CHD death 1.10 (0.70-1.75) 8 8
All Strokes 1.31 (1.02-1.68) 24 31
Ischaemic Stroke 1.44 (1.09-1.90) 18 26
Deep vein thrombosis 1.95 (1.43-2.67) 13 26
Pulmonary embolism 2.13 (1.45-3.11) 8 18
Invasive breast cancerc 1.24 (1.01-1.54) 33 41
Invasive colorectal cancer 0.56 (0.38-0.81) 16 9
Endometrial cancer 0.81 (0.48-1.36) 7 6
Cervical cancer 1.44 (0.47 - 4.42) 1 2
Hip fracture 0.67 (0.47-0.96) 16 11
Vertebral fractures 0.65 (0.46-0.92) 17 11
Lower arm/wrist fractures 0.71 (0.59-0.85) 62 44
Total fractures 0.76 (0.69-0.83) 199 152

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

In the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, one population of 4,532 women aged 65 to 79 years was randomised to conjugated oestrogens plus MPA (0.625 mg/2.5 mg daily) or placebo. In a second population of WHIMS 2,947 hysterectomised women, aged 65-79 years, were randomised to conjugated oestrogens (0.625 mg daily) or placebo. After an average follow-up of four years, a relative risk of 2.05 (95% CI 1.21-3.48) for probable dementia was reported in the oestrogen plus progestogen group compared to placebo. In the oestrogen alone group, after an average follow-up of 5.2 years, a relative risk of 1.49 (95% CI 0.83-2.66) for probable dementia was reported 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). Since this study was conducted in women aged 65-79 years, it is unknown whether these findings apply to younger postmenopausal women (see PRECAUTIONS - Dementia).

INDICATIONS

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.

  1. PREMARIN is indicated as replacement therapy for oestrogen deficiency states associated with climacteric manifested by:
  2. Moderate to severe vasomotor symptoms associated with the oestrogen deficiency in natural and surgical menopause (sweating, hot flushes).
  3. Atrophic vaginitis.

    When prescribing solely for the treatment of symptoms of vaginal atrophy, topical vaginal products should be considered.

    There is no evidence that oestrogens are effective for anxiety or depression without associated vasomotor symptoms, and they should not be used to treat such conditions.
  4. For the prevention of postmenopausal osteoporosis.

    When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis, in whom non-oestrogen medications are not considered appropriate.
  5. Hypoestrogenic states e.g. female hypogonadism, primary ovarian failure or female castration.

See the statements in bold under PRECAUTIONS, particularly when considering PREMARIN for long-term usage.

CONTRAINDICATIONS

PRECAUTIONS

Oestrogen therapy and hormone therapy should not be initiated or continued to prevent or treat cardiovascular disease or dementia (see PRECAUTIONS - Cardiovascular Risk and PRECAUTIONS - Dementia).

The benefits and risks of HT must always be carefully weighed, including consideration of the emergence of risks as therapy continues. In most circumstances, the risks of long-term HT treatment outweigh the benefits. 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. In the absence of comparable data, the risks of HT should be assumed to be similar for all oestrogens and oestrogen/progestogen combinations.

ET and HT have been associated with increased risks of certain cancers and cardiovascular diseases. The use of unopposed oestrogen in women with an intact uterus is associated with an increased risk of endometrial cancer.

If prescribing hormone replacement therapy for prevention of osteoporosis, the potential for increased cardiovascular, thrombotic and neoplastic adverse events must be considered.

Combined hormone replacement therapy should not be used for the long-term maintenance of general health, including the primary or secondary prevention of cardiovascular disease. Oestrogen or oestrogenic compounds must not be used alone as hormone therapy in women who have not had a hysterectomy.

Cardiovascular Risk

ET has been associated with an increased risk of stroke and deep vein thrombosis.

HT has been associated with an increased risk of myocardial infarction as well as stroke, venous thrombosis and pulmonary embolism (PE). Patients who have risk factors for thrombotic disorders should be kept under careful observation.

Stroke

In the oestrogen alone substudy of the WHI, a statistically significant increased risk of stroke was reported in women receiving oestrogen alone compared to women receiving placebo (45 vs. 33 per 10,000 person-years). The increase in risk was observed during year one and persisted.

In the oestrogen-plus-progestogen substudy of WHI, a statistically significant increased risk of stroke was reported in women receiving the oestrogen plus progestogen combination compared to women receiving placebo (31 vs. 24 per 10,000 person-years). The increase in risk was demonstrated after the first year and persisted.

Coronary Heart Disease

In the oestrogen alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or death due to CHD) was reported in women receiving oestrogen alone compared to placebo.

In the oestrogen plus progestogen substudy of WHI, no statistically significant increase of CHD events was reported in women receiving the oestrogen/progestogen combination compared to women receiving placebo (39 vs. 33 per 10,000 person-years). An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5.In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/progestin Replacement Study; HERS), treatment with oral conjugated oestrogens plus medroxyprogesterone acetate demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with oral conjugated oestrogens plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the hormone-treated group than in the placebo group in year one, but not during the subsequent years.

Venous Thromboembolism

In some studies, women on ET, given alone or in combination with a progestogen, have been reported to have an increased risk of thrombophlebitis, and /or thromboembolic disease.

In the oestrogen alone substudy of WHI (see CLINICAL TRIALS - Women's Health Initiative) the risk of VTE (deep vein thrombosis (DVT) and pulmonary embolism), was reported to be increased for women taking conjugated oestrogens (30 vs. 22 per 10,000 person-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 person-years). The increase in VTE risk was observed during the first two years.

In the oestrogen and progestogen substudy of WHI a statistically significant 2-fold greater rate of VTE was reported in women receiving the oestrogen/progestogen combination, compared to women receiving placebo (35 vs. 17 per 10,000 person-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 person-years) and PE (18 vs. 8 per 10,000 person-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted.

Recognised risk factors for VTE include, but are not limited to, a personal history or family history of VTE, obesity and systemic lupus erythematosus.

The physician should be aware of the possibility of thrombotic disorders (including thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism) during hormone replacement therapy and alert to their earliest manifestations. Should any of these occur or be suspected; hormone therapy should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation.

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

In some studies use of oestrogens as well as concomitant oestrogen and progestogen use is associated with an increased risk of breast cancer.

In the oestrogen alone substudy of WHI, after an average of 7.1 years of follow-up, conjugated oestrogens (0.625 mg per day) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04).

In the oestrogen plus progestogen substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of invasive breast cancer (RR 1.24, 95% nCI 1.01-1.54); invasive breast cancers were larger and diagnosed at a more advanced stage in the active therapy group compared to those in the placebo group. The absolute risk was 41 vs. 33 cases per 10,000 person-years, for oestrogen plus progestogen compared with placebo, respectively. Metastatic disease was rare with no apparent difference between groups. Other prognostic factors such as histological subtype, grade and hormone receptor status did not differ between groups.

Epidemiological studies (not necessarily including PREMARIN) have reported an increased risk of breast cancer in women taking oestrogens or oestrogen/progestogen combinations for HT for several years. The excess risk increases with duration of use and seems to return to baseline in the course of about 5 years after stopping treatment. These studies also suggest that the risk of breast cancer is greater and becomes apparent earlier with oestrogen/progestogen combination therapy as compared to the use of oestrogens alone.

Studies evaluating various HT formulations did not show significant variation in the relative risk of breast cancer among formulations regardless of the oestrogen/progestogen components, doses, regimens, or route of administration.

According to epidemiological studies, about 32 women in every 1,000 women who have never used HT are expected to have breast cancer diagnosed between the ages of 50 and 65 years. Among 1,000 current or recent users of oestrogen-only preparations, it is estimated that 5 and 10 years of use beginning at age 50 result in 1.5 (95% confidence interval (CI), 0-3) and 5 (95% CI, 3-7), respectively, additional breast cancers diagnosed by age 65 years. The corresponding numbers for those using oestrogen/progestogen combinations are 6 (95% CI, 5-7) and 19 (95% CI, 18-20), respectively.

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 healthcare 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.

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. Most studies show no significant increased risk associated with use of oestrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after ET is discontinued.

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 ET has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer (see Addition of a Progestogen when a Woman has not had a Hysterectomy).

In a subset of WHI (see CLINICAL TRIALS - Women's Health Initiative) no increased risk of endometrial cancer after an average of 5.6 years of treatment with the oestrogen/progestogen combination compared to placebo was observed.

Clinical surveillance of all women taking ET/HT 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. Where no pathological cause is found, alteration in the dose or cycling may be indicated (see DOSAGE AND ADMINISTRATION).

NOTE: In perimenopausal patients where the endometrium is still proliferative, persistence of the endometrial proliferation may occur during administration of hormone replacement therapy. An endometrial biopsy may be performed at the discretion of the attending physician.

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.

In a subset of WHI (see CLINICAL TRIALS - Women's Health Initiative) no increased risk of endometrial cancer after an average of 5.2 years of treatment with the estrogen/progestogen combination compared to placebo was observed.

There are, however, possible risks that may be associated with the use of progestogens in oestrogen replacement regimens compared to oestrogen alone regimens. These include (a) an increased risk of breast cancer (see PRECAUTIONS - Malignant Neoplasms - Breast Cancer); (b) adverse effects on lipoprotein metabolism (e.g. lowering HDL, raising LDL); and (c) impairment of glucose tolerance.

Ovarian Cancer

In some epidemiological studies, the use of oestrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiological studies have not found these associations. The analysis of the WHI data suggested that oestrogen plus progestogen therapy may increase the risk of ovarian cancer.

Dementia

In the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, one population of 4532 women aged 65 to 79 years was randomised to conjugated oestrogens plus MPA (0.625 mg/2.5 mg daily) or placebo. In a second population of WHIMS 2947 hysterectomised women, aged 65-79 years were randomised to conjugated oestrogens (0.625 mg daily) or placebo. After an average follow-up of four years, a relative risk of 2.05 (95% CI 1.21-3.48) for probable dementia was reported in the oestrogen plus progestogen group compared to placebo. In the oestrogen alone group, after an average follow-up of 5.2 years, a relative risk of 1.49 (95% CI 0.83-2.66) for probable dementia was reported compared to placebo. When data from the two populations was 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 this study was conducted in women aged 65-79 years, it is unknown whether these findings apply to younger postmenopausal women (see Use in Geriatrics).

Therefore, in older women, the use of PREMARIN for the prevention of osteoporosis should only be considered for those who have failed on, or were intolerant of, non-oestrogen medication.

Physical Examination

A complete medical and family history should be obtained prior to initiating or reinstating any oestrogen therapy and all prospective and current users of ET should be advised of the risks and benefits of oestrogens (see PRECAUTIONS). Pretreatment and subsequent physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs including histological endometrial assessment and/or Papanicolaou Smear. Before starting treatment pregnancy should be excluded. Periodic check-ups and careful benefit/risk evaluations should be undertaken in women treated with ET/HT (see Endometrial Cancer).

Gallbladder Disease

Women receiving PREMARIN should be monitored for gall-bladder disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving ET/HT has been reported.

Uterine Bleeding

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

Fluid Retention

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

Exacerbation of Other Conditions

ET/HT may cause an exacerbation of asthma, epilepsy, migraine, diabetes mellitus with or without vascular involvement, 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 ET/HT. Addition of a progestogen should be considered in women who have undergone hysterectomy but are known to have residual endometriosis, since malignant transformation after oestrogen only therapy has been reported.

Elevated Blood Pressure

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

Impaired Liver Function

Oestrogens may be poorly metabolised in patients with impaired liver function and they should be administered with caution in such patients.

Jaundice

If jaundice develops in any patient receiving oestrogen, the medication should be discontinued while the cause is investigated.

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, PREMARIN should be discontinued.

Hypercalcaemia

PREMARIN should be used with caution in patients with metabolic bone disease that is associated with hypercalcaemia or in patients with renal insufficiency.

Hypocalcaemia

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

Hypothyroidism

Patients dependent on thyroid replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range (see Laboratory Test Interactions).

Visual Abnormalities

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

Hypertriglyceridaemia

Caution should be exercised in patients with pre-existing hypertriglyceridaemia since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this population, Women with pre-existing hypertriglyceridaemia should be followed closely during ET/HT.

Other

PREMARIN is not an oral contraceptive, nor will it restore fertility. If it is administered together 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 Paediatrics

Although oestrogen replacement therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay, safety and effectiveness in paediatric patients have not otherwise been established. Oestrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding.

Since large and repeated doses of oestrogen over an extended time period have been shown to accelerate epiphyseal closure, hormonal therapy should not be started before epiphyseal closure has occurred in order not to compromise final growth.

Use in Geriatrics

Of the total number of subjects in the oestrogen alone substudy of the WHI 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.

Of the total number of subjects in the oestrogen plus progestogen subset of WHI, 44% (n=7,320) were 65-74 years of age, while 6.6% (n=1,095) were 75 and over (see CLINICAL TRIALS). There was a higher relative risk of non-fatal stroke and invasive breast cancer in women 75 years and over compared to younger subjects. In women greater than 75 years, the increased risk of non-fatal stroke and invasive breast cancer observed in the oestrogen plus progestogen group compared to the placebo group was 75 vs. 24 per 10,000 person-years and 52 vs. 12 per 10,000 person-years, respectively.

In WHIMS, 2947 hysterectomised women, aged 65-79 years, were randomised to conjugated oestrogens (0.625 mg daily) or placebo; 81% (n=2,383) were 65 to 74 while 19% (n=564) were 75 and over. Approximately 50% of the women had no prior oestrogen therapy use. After an average follow-up of 5.2 years, the absolute risk of developing probable dementia with oestrogen alone was 37 cases per 10,000 person-years compared to 25 cases per 10,000 person-years with placebo (RR 1.49, 95% CI 0.83-2.66). (see PRECAUTIONS: Dementia).

The second population of WHIMS, including 4,532 women 65 years of age and older, followed-up for an average of four years, 82% were 65-74 (n=3,729) while 18% (n=803) were 75 and over. Most women (80%) had no prior hormone therapy use. After an average follow-up of 4 years, the absolute risk of developing probable dementia with oestrogen plus progestogen was 45 cases per 10,000 person-years compared to 22 cases per 10,000 person-years with placebo (RR 2.05, 95% CI 1.21-3.48) (see PRECAUTIONS: Dementia).

Alzheimer's disease was the most common classification of probable dementia in the treatment groups and placebo groups. Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 years for the oestrogen alone group, and 82% of the cases of probable dementia occurred in women that were older than 70 years in the oestrogen plus progestogen group (see PRECAUTIONS - Dementia).

When data from the two populations were pooled, the absolute risk of developing probable dementia with either oestrogen alone or oestrogen plus progestogen was 41 cases per 10,000 person-years compared to 23 cases per 10,000 person-years with placebo (RR 1.76, 95% CI 1.19-2.60).

Use in Pregnancy

Category D

Oestrogens should not be used during pregnancy.

Use during Lactation

Lactating mothers should not use PREMARIN.

Carcinogenic Potential

Studies suggest that combination HT 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.

Interactions with Other Drugs

Data from a drug-drug interaction study involving PREMARIN 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 PREMARIN.

In vitro and in vivo studies have shown that 17β-oestradiol, one of the components of conjugated oestrogens, is metabolised partially by cytochrome P450 3A4 (CYP3A4). Therefore, strong CYP3A4 inducers such as phenobarbitone, phenytoin, carbamazepine, rifampicin and dexamethasone may reduce plasma concentrations of 17β-oestradiol. This may lead to a decreased effect and/or changes in the uterine bleeding profile. CYP3A4 inhibitors such as cimetidine, erythromycin, cyclosporin, grapefruit juice and ketoconazole may increase plasma concentrations of 17β-oestradiol and may result in side effects.

Hot flushes and vaginal bleeding have been reported in patients taking ET/HT and St John's wort (Hypericum perforatum). St. John's wort may induce hepatic microsomal enzymes, which theoretically may result in reduced efficacy of ET/HT.

Laboratory Test Interactions

Pathologists should be made aware that a patient is receiving HT when relevant specimens are submitted.

Certain endocrine and liver function tests may be affected by administration of PREMARIN:

  1. 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.
  2. 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.
  3. 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).
  4. Impaired glucose tolerance.
  5. The response to metyrapone test may be reduced.
  6. Increased plasma HDL and HDL2 cholesterol sub-fraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.
  7. 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.
  8. Gonadotropin levels.
  9. Plasma cortisol levels
  10. Increased plasma oestrogen levels.

ADVERSE REACTIONS

The most serious adverse reactions associated with the use of PREMARIN are indicated under PRECAUTIONS. The following adverse reactions have been reported and are listed in the table in CIOMS frequency categories:

Adverse reactions are listed in the Table in CIOMS frequency categories:

Very Common: ≥10%
Common: ≥1% and <10%
Uncommon: ≥0.1% and <1%
Rare: ≥0.01% and <0.1%
Very Rare: ≥0.01%

System Organ Class Adverse Reaction

Immune System Disorders

Rare: Urticaria, angioedema, anaphylactic/anaphylactoid reactions

Reproductive System and Breast Disorders

Common: Breakthrough bleeding/spotting, breast pain, tenderness, enlargement, discharge
Uncommon: Change in menstrual flow, change in cervical ectropion and secretion
Rare: Dysmenorrhoea, galactorrhoea, increased size of uterine leiomyomata
Very Rare: Endometrial hyperplasia

Gastrointestinal Disorders

Uncommon: Nausea, bloating, abdominal pain
Rare: Vomiting, pancreatitis

Hepato-biliary Disorders

Uncommon: Gallbladder disease
Very Rare: Cholestatic jaundice

Infections and Infestations

Uncommon: Vaginitis including vaginal candidiasis

Neoplasms benign and malignant (including cysts and polyps)

Rare: Breast cancer, ovarian cancer, fibrocystic breast changes
Very Rare: Endometrial cancer, enlargement of hepatic hemangiomas

Musculoskeletal, Connective Tissue and Bone Disorders

Common: Arthralgias, leg cramp

Psychiatric Disorders

Uncommon: Changes in libido, mood disturbances, depression, dementia
Rare: Irritability

Skin and Subcutaneous Tissue Disorders

Common: Alopecia
Uncommon: Chloasma/melasma, hirsutism, pruritis, rash,
Very Rare: Erythema multiforme, erythema nodosum

Cardiac Disorders

Rare: Myocardial infarction

Vascular Disorders

Uncommon: Venous thrombosis
Rare: Superficial thrombophlebitis, pulmonary embolism

Respiratory, Thoracic and Mediastinal Disorders

Rare: Exacerbation of asthma

General Disorders and Administration Site Conditions

Uncommon: Oedema

Metabolism and Nutrition Disorders

Rare: Glucose intolerance
Very Rare: Exacerbation of porphyria, hypocalcaemia

Eye Disorders

Uncommon: Intolerance to contact lenses
Very Rare: Retinal vascular thrombosis

Nervous System Disorders

Uncommon: Dizziness, headache, migraine, nervousness
Rare: Cerebrovascular accident/stroke, exacerbation of epilepsy
Very Rare: Exacerbation of chorea

Investigations

Common: Changes in weight (increase or decrease), increased triglycerides
Very Rare: Increase in blood pressure

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 bold under PRECAUTIONS, particularly when considering PREMARIN for long-term usage.

For women with an intact uterus, it is recommended that a progestogen is administered (see PRECAUTIONS). For continuous PREMARIN administration, a progestogen should be added for at least 10-14 consecutive days each month.

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:

  1. 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.
  2. For prevention of postmenopausal osteoporosis

    The minimum effective dose is 0.625mg daily for most patients.

    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.
  3. 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.

PRESENTATION

Tablets:
0.3 mg (dark green, marked 0.3): 1 x 28's
0.625 mg (maroon, marked 0.625): 1 x 28's;

MEDICINE CLASSIFICATION

Prescription Medicine

NAME AND ADDRESS

Pharmacy Retailing (NZ) Limited
Trading as Healthcare logistics
58 Richard Pearce Drive
Airport Oaks
Auckland

For all enquiries please contact:
Wyeth Australia Pty Limited
17-19 Solent Circuit
Baulkham Hills NSW 2153
AUSTRALIA

Toll free telephone number: 0800 447 400 or email medinfo@wyeth.com

DATE OF PREPARATION

20 March 2008