Harmogen 1.5 mg

Each tablet contains Estropipate USP (piperazine estrone sulphate) equivalent to 0.93 mg estrone.

For excipients, see 6.1

Tablets for oral administration

Hormone Replacement Therapy (HRT) for estrogen deficiency symptoms in post- and peri-menopausal women.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis, (See also Section 4.4).

Harmogen is an estrogen-only product for oral use.

Adults and the Elderly:

Post-menopausal osteoporosis: 1.5 mg daily.

Estrogen-deficiency symptoms: 1.5 mg 3.0 mg daily taken as a single or divided dose.

For initiation and continuation of treatment of peri- and postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.

Dosage Schedule (for both indications):

Therapy may start at any time in women with established amenorrhoea or who are experiencing long intervals between spontaneous menses. In women who are menstruating, it is advised that therapy starts within five days of the start of bleeding. Patients changing from a cyclical or continuous sequential preparation should complete the cycle, and after a withdrawal bleed, may then change to Harmogen 1.5mg. Patients changing from a continuous combined preparation may start therapy at any time if amenorrhoea is established, or otherwise start within five days of the start of bleeding.

Harmogen should be given continuously and, in women with an intact uterus, a progestogen is recommended and should be added for at least 12-14 days each cycle. The benefits of the lower risk of endometrial hyperplasia and endometrial cancer, due to adding progestogen, should be weighed against the increased risk of Breast cancer, (See Sections 4.4 and 4.8). Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

If a tablet is missed it should be taken within a few hours of when normally taken, otherwise the forgotten tablet should be discarded, and the usual tablet should be taken at the next scheduled time. If one extra tablet is taken inadvertently, the usual tablet should be taken at the next scheduled time. There is an increased likelihood of break-through bleeding and spotting when a dose is missed.

Known, past or suspected breast cancer;

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

Undiagnosed genital bleeding;

Untreated endometrial hyperplasia;

Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism);

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

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

Known hypersensitivity to the active substances or to any of the excipients;

Porphyria.

For the treatment of menopausal 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

Medical Examination/Follow Up

Assessment of each woman prior to taking hormone replacement therapy (and at regular intervals thereafter) should include a personal and family medical history. Physical examination should be guided by this and by the contraindications (see Section 4.3) and warnings (see Section 4.4) for this product. During assessment of each individual woman, clinical examination of the breasts and pelvic examination should be performed where clinically indicated rather than as a routine procedure. Women should be encouraged to participate in the national breast screening programme (mammography) and the national cervical screening programme (cervical cytology) as appropriate for their age. Breast awareness should also be encouraged and women advised to report any changes in their breasts to their doctor or nurse, (see “Breast Cancer” below).

Conditions which need supervision:

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

Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer (see below);

Diabetes mellitus with or without vascular involvement;

Migraine or (severe) headache;

Epilepsy;

A history of, or risk of factors for, thromboembolic disorders (see below);

Systemic lupus erythematosus, SLE;

Liver disorders (e.g. liver adenoma);

Leiomyoma (uterine fibroids) or endometriosis;

Otosclerosis;

Cholelithiasis;

A history of endometrial hyperplasia (see below);

Hypertension;

Asthma.

Reasons for immediate withrawal of therapy:

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

- Jaundice or deterioration in liver function

- Significant increase in blood pressure

- New onset of migraine-type headache

- Pregnancy

Endometrial Hyperplasia

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods, (see Section 4.8). The addition of progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk (See Section 4.8).

The endometrial safety of added progestogen has not been studied for Harmogen 1.5mg.

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 in 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 premalignant 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).

Breast Cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

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

Venous Thromboembolism

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI >30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

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

Coronary Artery Disease

There is no evidence from randomised controlled trials of cardiovasular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS, i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and medroxyprogesterone acetate. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and medroxyprogesterone acetate for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian Cancer

Long-term (at least 5 to 10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.

Other Conditions

Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Harmogen 1.5 mg tablets is increased.

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

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. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

In rare cases benign, and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Harmogen 1.5mg. If severe upper abdominal complaints, enlarged liver or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.

Women who may be at risk of pregnancy should be advised to adhere to nonhormonal contraceptive methods.

The requirement for oral anti-diabetics or insulin can change as a result of the effect on glucose tolerance.

The metabolism of estrogen may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's Wort (Hypericum Perforatum) may induce the metabolism of estrogens.

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

Some laboratory tests can be influenced by estrogens such as tests for thyroid function (see Section 4.4).

Pregnancy

Harmogen 1.5 mg is not indicated during pregnancy. If pregnancy occurs during medication with Harmogen 1.5 mg treatment should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetoxic effects.

Lactation

Harmogen 1.5mg is not indicated during lactation.

None known

The following adverse reactions have been reported with Harmogen 1.5 mg estrogen therapy:

1. Genito-urinary tract: Endometrial neoplasia*, intermenstrual bleeding, increase in the size of uterine fibromyomata, endometrial proliferation or aggravation of endometriosis, changes in cervical eversion and excessive production of cervical mucus, candidal infections, thrush;

2. Breast: Tenderness, pain, enlargement or secretion, breast cancer*

3. Gastro-intestinal tract: Nausea, vomiting, abdominal cramp, bloating;

4. Cardiovascular system: Hypertension, thrombosis, thrombophlebitis, venous thromboembolism*, myocardial infarction* and stroke*;;

5. Liver/biliary system: In rare cases benign, and in even rarer cases malignant liver tumours, cholelithiasis, cholestatic jaundice, gall bladder disease;

6. Skin: Chloasma which may persist when the drug is discontinued, erythema multiforme, erythema nodosum, , vascular purpura, rash, loss of scalp hair, hirsutism;

7. Eyes: Steepening of corneal curvature, intolerance to contact lenses;

8. CNS: Headache, migraine, dizziness, mood changes (elation or depression), chorea, probable dementia (see Section 4.4);

9. Miscellaneous: Sodium and water retention, reduced glucose tolerance, change in body weight, muscle cramps, aggravation of porphyria, changes in libido.

* See sections 4.3, Contraindications and Section 4.4 Special Warnings and Special Precautions for Use.

Breast cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95% CI 1.21 – 1.49) and 1.30 (95% CI 1.21 – 1.40), respectively.

For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95% CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95% CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see Section 4.4).

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestogen to estrogen-only therapy greatly reduces this increased risk.

Overdosage is unlikely to cause serious problems, although the following symptoms may be present, i.e. nausea and withdrawal bleeding in women. However gastric lavage or emesis may be used when considered appropriate.

Pharmacotherapeutic group: Natural and semisynthetic estrogens, plain.

ATC Code G03C A

Estropipate is a semi-synthetic estrogen conjugate, sulphate ester of estrone. This substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectemy.

Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

Women with an increased risk of osteoporosis include those suffering from an early menopause, receiving recent prolonged corticosteroid therapy, having a family history of osteoporosis, of small frame, who are thin, smokers and those with an excess alcohol intake.

Estropipate is metabolised in the liver, so any form of liver impairment will result in reduced metabolism.

Gastro-intestinal absorption of orally administered (tablets) estrogens is usually prompt and complete, inactivation of estrogens in the body occurs mainly in the liver. During cyclic passage through the liver, estrogens in the body are degraded to less active estrogenic compounds and conjugated with sulphuric and glucuronic acids. Estrone is 50-80% bound as it circulates in the blood, primarily as a conjugate with sulphate.

No additional information is available.

Lactose (monohydrate) NF

Lactose (anhydrous) NF

Dibasic potassium phosphate USP

Tromethamine USP

Hydroxypropyl cellulose NF

Sodium starch glycollate NF

Microcrystalline cellulose NF

Colloidal silicon dioxide NF

Magnesium stearate NF

Hydrogenated vegetable oil wax

Dye E110

Purified water USP

Alcohol 200 proof

None known

Three years

None

The containers comprise an HDPE container with tamper-evident cap or securitainer holding 100 estropipate tablets or a PVC/Aluminium foil blister pack, holding 28 tablets, which, together with a Patient Information Leaflet are packed in a carton.

No special instructions

Pharmacia Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

UK

PL 0032/0252

7^th June 2001/7^th June 2003

April 2008

POM

Ref: HA 5_0