Ethinyloestradiol Tablets BP 10 mcg, 50mcg and 1mg

Ethinylestradiol 10.5 mcg, 52.5mcg or 1.048mg

For excipients see 6.1.

White uncoated tablets for oral administration

Post menopausal symptoms due to oestrogen deficiency.

Second line therapy for 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.

Palliative treatment of prostatic cancer.

Hormone replacement therapy for failure of ovarian development e.g. in patients with gonadal dysgenesis where initial oestrogen therapy is later followed by combined oestrogen/progestogen therapy.

Disorders of menstruation, given in conjunction with a progestogen.

Ethinyloestradiol Tablets is an oestrogen-only preparation of hormone replacement therapy (HRT) for oral administration.

Post menopausal symptoms due to oestrogen deficiency including prevention of postmenopausal osteoporosis: the lowest dose that will control symptoms should be chosen. The usual dose range is 10 to 50 micrograms daily, usually on a cyclical basis (e.g., 3 weeks on and 1 week off).

For women without a uterus, who did not have endometriosis diagnosed, it is not recommended to add a progestogen.

In women with an intact uterus (or in endometriosis when endometrial foci may be present despite hysterectomy), where a progestogen is necessary, it should be added for at least 12-14 days every month/28 day cycle to reduce the risk to the endometrium.

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).

Therapy with Ethinyloestradiol Tablets 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 on the first day of bleeding. As Ethinyloestradiol Tablets are usually taken on a cyclical basis direct switching from other oestrogen-only HRT preparations taken cyclically is possible.

HRT should only be continued as long as the benefit in alleviation of severe symptoms outweighs the risks of HRT.

Palliative treatment of prostatic cancer: 150 micrograms to 1.5 mg daily. Larger dose Ethinyloestradiol Tablets are available.

Hormone replacement therapy for failure of ovarian development e.g. in patients with gonadal dysgenesis: 10 to 50 micrograms daily, usually on a cyclical basis. Initial oestrogen therapy should be followed by combined oestrogen/progestogen therapy.

Disorders of menstruation: 20 to 50 micrograms daily from day 5 to day 25 of each cycle. A progestogen is given daily in addition, either throughout the cycle or from days 15 to 25 of the cycle.

If a dose is forgotten it should be taken as soon as it is remembered. If it is nearly time for the next dose then the patient should wait until then. Two doses should not be taken together. Forgetting a dose may increase the likelihood of break-through bleeding and spotting.

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

Current or previous idiopathic venous thromboembolism (deep venous thrombosis, pulmonary embolism)

Known, past or suspected breast cancer or other known or suspected oestrogen dependent tumours (e.g. endometrial cancer)

Untreated endometrial hyperplasia

Undiagnosed genital bleeding

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

Porphyria

Known hypersensitivity to the active substance or to any of the excipients

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigation, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual. A careful appraisal of the risks and benefits should be undertaken at least annually in women treated with hormone replacement therapy.

In women with an intact uterus, the benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding a progestogen should be weighed against the increased risk of breast cancer (see below and Section 4.8).

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 ethinyloestradiol tablets, in particular:

Risk factors for oestrogen dependent tumours e.g. 1st degree heredity for breast cancer

Leimyoma (uterine fibroids) or endometriosis

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

Hypertension

Liver disorders (e.g. liver adenoma)

Diabetes Mellitus with or without vascular involvement

Cholelithiasis

Otosclerosis

Asthma

Migraine or (severe) headache and epilepsy

Systemic Lupus erythematosis

Hyperplasia of the endometrium (see below)

Reasons for immediate withdrawal of therapy

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 oestrogens are administered alone for prolonged periods. The addition of a progestogen for at least 12 days of the cycle in non-hysterectomised women reduces, but may not eliminate, this risk (see section 4.8).

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)

Break-through bleeding and spotting may occur during the first months of treatment. If break-through 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 oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis (but see above).

Breast cancer

Randomised controlled trials and epidemiological studies have reported an increased risk of breast cancer in women taking oestrogens or oestrogen-progestogen combinations for HRT for several years (see section 4.8). An observational study of almost 829,000 women has shown that, compared to never-users, use of oestrogen-progestogen combined HRT is associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40). In this study the magnitude of the increase in breast cancer risk was similar for all oestrogen-only preparations, irrespective of the type, dose or route of administration of the oestrogen (oral, transdermal and implanted). Likewise the magnitude of the increased risk was similar for all oestrogen plus progestogen preparations, irrespective of the type of progestogen or the number of days of addition per cycle. For all HRT, an excess risk becomes apparent within 1-2 years of starting treatment and increases with duration of use of HRT but begins to decline when HRT is stopped and by 5 years reaches the same level as in women who have never taken HRT.

The increase in risk applies to all women studied, although the relative risk was significantly higher in those with a lean or normal body build (body mass index or BMI of < 25kg/m2) compared to those with a BMI of 25kg/m2.

At present the effect of HRT on the diagnosis of breast tumours remains unclear – all women should be encouraged to report any changes in their breasts to their doctor or nurse.

Ovarian Cancer

Long-term (at least 5 to 10 years) use of oestrogen-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 oestrogen-only products.

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 three fold 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 further to this risk. Personal or strong family history of recurrent 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 doctors immediately when they are aware of a potential thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnoea).

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of stroke in healthy women during treatment with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). 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 oestrogens and MPA 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.

Coronary Artery Disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens and MPA. Large clinical trials showed a possible increased risk of cardiovascular morbidity in the first year of use and no benefit thereafter. For other HRT products there are as yet no randomised controlled trials to date examining benefit in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Other conditions

Oestrogens 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 Ethinyloestradiol Tablets is increased.

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

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 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 biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

Patients with rare hereditary problems of galactose intolerance, the Lapp-lactose deficiency, or glucose-galactose malabsorption should not take this medicine.

The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug metabolising enzymes, specifically cytochrome P450 enzymes, such as anti-convulsants (e.g. phenobarbitol, 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 Johns Wort (Hypericum Perforatum) may induce the metabolism of oestrogens.

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

Ethinyloestradiol doses greater than 50 micrograms per day may cause imipramine toxicity in patients on concomitant therapy.

Through its effects on the coagulation system, ethinyloestradiol may reduce the effects of anticoagulants such as warfarin, phenindione or nicoumalone.

The doses of insulin or hypoglycaemic drugs may need to be adjusted due to the mild diabetogenic effect of ethinyloestradiol.

Ethinyloestradiol may inhibit the metabolism of theophylline and reduce its clearance.

Ethinyloestradiol Tablets are not indicated during pregnancy. If pregnancy occurs during medication with Ethinyloestradiol Tablets treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent fetal exposure to oestrogens indicate no teratogenic or fetotoxic effects.

Ethinyloestradiol Tablets are not indicated during lactation.

None stated

Breast cancer

The risk of breast cancer increases with the number of years of HRT usage. According to data from a recent epidemiological study in about 829,000 postmenopausal women, the best estimate of the risk is that for women not using HRT, in total about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 65 years. Among those with current or recent use of oestrogen-only replacement therapy, it is estimated that the total number of additional cases during the corresponding period will be between 0 and 3 (best estimate = 1.5) per 1000 for 5 years' use and between 3 and 7 (best estimate = 5) per 1000 for 10 years' use (see table) Among those with current or recent use of oestrogen plus progestogen combined HRT, it is estimated that the total number of additional cases will be between 5 and 7 (best estimate = 6) per 1000 for 5 years' use and between 18 and 20 (best estimate = 19) per 1000 for 10 years' use (see section 4.4). The number of additional cases of breast cancer is broadly similar for women who start HRT irrespective of age at start of HRT use (between the ages of 45 and 65).

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens and is substantially reduced by the addition of a progestogen (see section 4.4). According to the data from epidemiological studies, the best estimate of the risk of endometrial cancer 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. It is estimated that, among those who use oestrogen-only replacement therapy, there will be 4 additional cases per 1000 after 5 years' use and 10 additional cases per 1000 after 10 years' use. Adding a progestogen to oestrogen-only therapy substantially reduces, but may not eliminate, this increased risk.

Other adverse reactions have been reported in association with oestrogen treatment;

Genito-urinary tract: endometrial neoplasia, endometrial cancer, intermenstrual bleeding, increase in the size of uterine fibromyomata, endometrial proliferation or aggravation of endometriosis, excessive production of cervical mucus.

Breast: tenderness, pain, enlargement, secretion.

Gastro-intestinal tract: nausea, vomiting, cholelithiasis, cholestatic jaundice.

Cardiovascular system: hypertension, thrombosis, thrombophlebitis, thromboembolism, myocardial infarction, stroke.

Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

Skin: erythema nodosum, erythema multiforme, vascular purpura, rash, chloasma.

Eyes: corneal discomfort if contact lenses are used.

CNS: headache, migraine, mood changes (elation or depression).

Metabolic: sodium and water retention, reduced glucose tolerance and change in body weight, hypercalcaemia.

In men: feminisation, gynaecomastia, testicular atrophy and impotence.

Acute overdose of ethinyloestradiol may cause nausea and vomiting and may result in withdrawal bleeding in females.

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. Therefore, if possible, treatment for prevention of osteoporosis should start as soon as possible after the onset of menopause in women with increased risk for future osteoporotic fractures. The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued.

The active ingredient, ethinyloestradiol, is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

The main therapeutic use of exogenous oestrogens is replacement in deficiency states.

Ethinyloestradiol is rapidly and completely absorbed from the gut but it undergoes some first pass metabolism in the gut wall.

Ethinyloestradiol is rapidly distributed throughout most body tissues with the largest concentration found in adipose tissue. It distributes into breast milk in low concentrations. More than 80% of ethinyloestradiol in serum is conjugated as the sulphate and almost all the conjugated form is bound to albumin.

Ethinyloestradiol is metabolised in the liver. Hydroxylation appears to be the main metabolic pathway. 60% of a dose is excreted in the urine and 40% in the faeces. About 30% is excreted in the urine and bile as the glucuronide or sulphate conjugate.

The rate of metabolism of ethinyloestradiol is affected by several factors, including enzyme-inducing agents, antibiotics and cigarette smoking.

After oral administration, an initial peak occurs in plasma at 2 to 3 hours, with a secondary peak at about 12 hours after dosing; the second peak is interpreted as evidence for extensive enterohepatic circulation of ethinyloestradiol.

The elimination half-life of ethinyloestradiol ranges from 5 to 16 hours.

None stated

Lactose

Starch Maize

Magnesium Stearate

IMS 99%

Purified water

None stated

36 months

Store below 25° C

Pigmented polypropylene container fitted with a tamper evident closure containing 21, 28, 100, or 500 tablets. All pack sizes may not be marketed.

Not applicable

UCB Pharma Ltd

208 Bath Road

Slough

Berkshire

SL1 3WE

10mcg: PL 00039/0548

50mcg: PL 00039/0549

1mg: PL 00039/0550

4 July 2005

July 2005