Climaval

1. NAME OF THE MEDICINAL PRODUCT

Climaval® 2 mg, film coated tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet of Climaval 2 mg contains 2 mg estradiol valerate.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Blue tablet, coded OD on one side, CG on the other.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Hormone replacement therapy for estrogen deficiency symptoms in postmenopausal women who have been hysterectomised.

The experience treating women older than 65 years is limited.

4.2 Posology and method of administration

1 mg to 2 mg daily. Dosage may be adjusted according to severity of symptoms or clinical response. Climaval may be taken continuously in hysterectomised patients. For the treatment of postmenopausal symptoms, the lowest effective dose should be used. HRT should only be continued as long as the benefit in alleviation of severe symptoms outweighs the risks of HRT.

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women

Missed tablet

If a tablet is missed it should be taken within 12 hours of when normally taken; otherwise the tablet should be discarded, and the usual tablet should be taken the following day.

Use in children

Not to be used in children.

Use in the elderly

In the elderly, Climaval should only be used for the control of post-menopausal symptoms.

4.3 Contraindications

• Known, past or suspected breast cancer

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

• Undiagnosed genital bleeding

• Untreated endometrial hyperplasia

• Severe renal disease

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

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

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

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

• Porphyria.

4.4 Special warnings and precautions for use

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. Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified according to the clinical needs of the individual. A careful appraisal of the risks and benefits should be undertaken over time in women treated with hormone replacement therapy.

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 Climaval, in particular:

• Endometriosis

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

• Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer

• Hypertension

• Liver disorders (eg liver adenoma) – patients with mild chronic disease should have their liver function checked every 8-12 weeks

• Diabetes mellitus with or without vascular involvement

• Cholelithiasis

• Migraine or (severe) headache

• Systemic lupus erythematosus

• A history of endometrial hyperplasia (see below)

• Epilepsy

• Asthma

• Otosclerosis.

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contraindication is discovered and in the following situations:

• Jaundice or deterioration in liver function

• Significant increase in blood pressure

• New onset of migraine-type headache, or any other symptoms that are a possible prodromata of vascular occlusion.

Endometrial hyperplasia

Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy is recommended in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis.

Breast cancer

Randomised controlled studies and epidemiological studies have reported an increased risk of breast cancer in women taking estrogens or estrogen-progestogen combinations for HRT for several years (see section 4.8). The excess risk increases with duration of intake of HRT and seems to return to baseline in the course of about five years after stopping treatment. Women using estrogen-progestogen combined HRT had a similar or possibly higher risk as compared with women who used estrogens alone.

From epidemiological studies, breast cancers diagnosed in current or recent users of HRT were less likely to have spread outside the breast than those found in non-users. Women whose breast cancers developed after HRT tended to have less aggressive tumour characteristics compared with women with breast cancer who had not received HRT. The increased risk was found mostly for women with a lean or normal body build. Although obese women are at an increased risk of having breast cancer, HRT did not further increase this risk.

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 2-3 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 (Body Mass Index> 30kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the 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 post-operative 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 four to six 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).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens 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.

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 estrogens and 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 estrogens 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.

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 Climaval is increased.

Women with pre-existing hypertriglyceridemia 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 corticosteroidsand sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

4.5 Interaction with other medicinal products and other forms of Interaction

The metabolism of estrogens 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.

4.6 Pregnancy and lactation

Not applicable, because Climaval is only indicated in women without a uterus.

4.7 Effects on ability to drive and use machines

No adverse effects on the ability to drive or operate machines have been recorded.

4.8 Undesirable effects

The following have been reported during treatment: Dyspepsia, flatulance, nausea, vomiting, abdominal pain and bloating, weight gain, breast tension and pain, palpitations, cardiac symptoms, changes in libido, headaches, dizziness, vertigo, epistaxis, biliary stasis, hypertension, urticaria and other rashes, thrombophlebitis, mucous vaginal discharge, general pruritus, oedema, aolopecia, depressive mood and decrease in glucose tolerance and breast cancer*

*The risk of breast cancer and increases with the number of years of HRT usage. According to data from epidemiological studies - 51 epidemiological studies performed during 1970s to the early 1990s and reported in a re-analysis, and from more recent studies - the best estimate of the risk is that for women not using HRT, in total about 45 women in every 1000 women are expected to have breast cancer diagnosed over the period from ages 50 to 70 years. It is estimated that among those with current or recent use of HRT, the total number of additional cases during the corresponding period will be between 1 and 3 (best estimate = 2) extra cases per 1000 for those using HRT for 5 years, between 3 and 9 (best estimate = 6 extra cases per 1000 for using HRT for 10 years between 5 and 20 (best estimate = 12) per 1000 treated women for those using HRT for 15 years (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 (only between the ages of 45 and 65).

Other adverse reactions have been reported in association with estrogen/progestogen treatment:

• estrogen-dependent neoplasms benign and malignant

(e.g. endometrial cancer)

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

• myocardial infarction and stroke

• gall bladder disease

• skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

4.9 Overdose

There have been no reports of ill-effects from overdose. There are no specific antidotes, and further treatment should be symptomatic.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The active ingredient, synthetic 17 beta-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.

Estradiol valerate is used in estrogen deficiency states.

After the menopause the protective effects which endogenous estrogens appear to have on the female cardiovascular system are lost, therefore the risk of women developing cardiovascular disease rises to become similar to that of men.

5.2 Pharmacokinetic properties

Estradiol valerate, like most natural estrogens, is readily and fully absorbed from the GI tract, is 50% bound to plasma proteins and is rapidly metabolised in the liver to oestriol and oestrone. When given orally in doses of 1 - 2 mg, peak levels of estradiol are generally observed 3 - 6 hours after ingestion, but by 24 hours (range 6 - 48 hours) concentrations have returned to baseline (i.e. pre-treatment concentrations). The average half-life of estradiol in plasma is about one hour.

Estradiol undergoes first-pass effect in the liver. There is some enterohepatic recycling. It is excreted via the kidney in the urine as sulphate and glucuronide esters together with a small proportion of unchanged oestradiol. Other metabolites have been identified.

5.3 Preclinical safety data

Acute toxicity of estrogens is low. Because of marked differences between animal species and between animals and humans, preclinical results possess a limited predictive value for the application of estrogens in humans.

Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential revealed no particular human risks beyond those discussed in other sections of the SmPC.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipient(s)

Tablet core:

Lactose monohydrate, maize starch, FD & C blue no. 2 lake (E132), povidone (grade 30), purified water, talc (sterilised, white), magnesium stearate.

Tablet coat:

Hypromellose, propylene glycol, Opaspray blue M-1-6517 (E171, E464, E132).

6.2 Incompatibilities

No incompatibilities have been described.

6.3 Shelf-life

3 years

6.4 Special precautions for storage

Do not store above 25oC. Store in the original package.

6.5 Nature and contents of container

Blister strips of 28 tablets packed in cardboard cartons. Two sizes are available; cartons containing one blister strip or three blister strips.

Blister consists of 20 μm layer of aluminium foil on a 250μm UPVC blister.

6.6 Instructions for use and handling

The pack was designed to help patients take the tablets correctly. The arrows on the foil should be followed and the tablets taken on the days shown.

7. MARKETING AUTHORISATION HOLDER

Novartis Pharmaceuticals UK Limited
Trading as Sandoz Pharmaceuticals
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR

8. MARKETING AUTHORISATION NUMBER(S)

PL 0101/0308

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25 March 1997.

10. DATE OF REVISION OF THE TEXT

August 2003

LEGAL CATEGORY]

POM


Home Forum Anti-Androgens Contraceptives Estrogens Progestins Testosterone Aerodiol Climaval Elleste Solo Estraderm TTS Estrofem Ethinylestradiol Hormonin Evorel Oestradiol Implant Oestrogel Premarin Progynova Zumenon	1. NAME OF THE MEDICINAL PRODUCT Climaval® 2 mg, film coated tablet 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet of Climaval 2 mg contains 2 mg estradiol valerate. For excipients, see 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet Blue tablet, coded OD on one side, CG on the other. 4. CLINICAL PARTICULARS *4.1 Therapeutic indications* Hormone replacement therapy for estrogen deficiency symptoms in postmenopausal women who have been hysterectomised. The experience treating women older than 65 years is limited. *4.2 Posology and method of administration* 1 mg to 2 mg daily. Dosage may be adjusted according to severity of symptoms or clinical response. Climaval may be taken continuously in hysterectomised patients. For the treatment of postmenopausal symptoms, the lowest effective dose should be used. HRT should only be continued as long as the benefit in alleviation of severe symptoms outweighs the risks of HRT. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women Missed tablet If a tablet is missed it should be taken within 12 hours of when normally taken; otherwise the tablet should be discarded, and the usual tablet should be taken the following day. Use in children Not to be used in children. Use in the elderly In the elderly, Climaval should only be used for the control of post-menopausal symptoms. *4.3 Contraindications* • Known, past or suspected breast cancer • Known or suspected estrogen-dependent malignant tumours. (e.g. endometrial cancer) • Undiagnosed genital bleeding • Untreated endometrial hyperplasia • Severe renal disease • Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal • Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism) • Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) • Known hypersensitivity to the active substance or to any of the excipients • Porphyria. 4.4 Special warnings and precautions for use 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. Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified according to the clinical needs of the individual. A careful appraisal of the risks and benefits should be undertaken over time in women treated with hormone replacement therapy. 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 Climaval, in particular: • Endometriosis • A history of, or risk factors for, thromboembolic disorders (see below) • Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer • Hypertension • Liver disorders (eg liver adenoma) – patients with mild chronic disease should have their liver function checked every 8-12 weeks • Diabetes mellitus with or without vascular involvement • Cholelithiasis • Migraine or (severe) headache • Systemic lupus erythematosus • A history of endometrial hyperplasia (see below) • Epilepsy • Asthma • Otosclerosis. Reasons for immediate withdrawal of therapy: Therapy should be discontinued in case a contraindication is discovered and in the following situations: • Jaundice or deterioration in liver function • Significant increase in blood pressure • New onset of migraine-type headache, or any other symptoms that are a possible prodromata of vascular occlusion. Endometrial hyperplasia Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy is recommended in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis. Breast cancer Randomised controlled studies and epidemiological studies have reported an increased risk of breast cancer in women taking estrogens or estrogen-progestogen combinations for HRT for several years (see section 4.8). The excess risk increases with duration of intake of HRT and seems to return to baseline in the course of about five years after stopping treatment. Women using estrogen-progestogen combined HRT had a similar or possibly higher risk as compared with women who used estrogens alone. From epidemiological studies, breast cancers diagnosed in current or recent users of HRT were less likely to have spread outside the breast than those found in non-users. Women whose breast cancers developed after HRT tended to have less aggressive tumour characteristics compared with women with breast cancer who had not received HRT. The increased risk was found mostly for women with a lean or normal body build. Although obese women are at an increased risk of having breast cancer, HRT did not further increase this risk. 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 2-3 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 (Body Mass Index> 30kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the 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 post-operative 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 four to six 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). Coronary artery disease (CAD) There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens 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. 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 estrogens and 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 estrogens 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. 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 Climaval is increased. Women with pre-existing hypertriglyceridemia 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 corticosteroidsand sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). 4.5 Interaction with other medicinal products and other forms of Interaction The metabolism of estrogens 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. 4.6 Pregnancy and lactation Not applicable, because Climaval is only indicated in women without a uterus. *4.7 Effects on ability to drive and use machines* No adverse effects on the ability to drive or operate machines have been recorded. *4.8 Undesirable effects* The following have been reported during treatment: Dyspepsia, flatulance, nausea, vomiting, abdominal pain and bloating, weight gain, breast tension and pain, palpitations, cardiac symptoms, changes in libido, headaches, dizziness, vertigo, epistaxis, biliary stasis, hypertension, urticaria and other rashes, thrombophlebitis, mucous vaginal discharge, general pruritus, oedema, aolopecia, depressive mood and decrease in glucose tolerance and breast cancer* The risk of breast cancer and increases with the number of years of HRT usage. According to data from epidemiological studies - 51 epidemiological studies performed during 1970s to the early 1990s and reported in a re-analysis, and from more recent studies - the best estimate of the risk is that for women not using HRT, in total about 45 women in every 1000 women are expected to have breast cancer diagnosed over the period from ages 50 to 70 years. It is estimated that among those with current or recent use of HRT, the total number of additional cases during the corresponding period will be between 1 and 3 (best estimate = 2) extra cases per 1000 for those using HRT for 5 years, between 3 and 9 (best estimate = 6 extra cases per 1000 for using HRT for 10 years between 5 and 20 (best estimate = 12) per 1000 treated women for those using HRT for 15 years (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 (only between the ages of 45 and 65). Other adverse reactions have been reported in association with estrogen/progestogen treatment: • estrogen-dependent neoplasms benign and malignant (e.g. endometrial cancer) • venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use. • myocardial infarction and stroke • gall bladder disease • skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura. 4.9 Overdose* There have been no reports of ill-effects from overdose. There are no specific antidotes, and further treatment should be symptomatic. *5. PHARMACOLOGICAL PROPERTIES* *5.1 Pharmacodynamic properties* The active ingredient, synthetic 17 beta-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estradiol valerate is used in estrogen deficiency states. After the menopause the protective effects which endogenous estrogens appear to have on the female cardiovascular system are lost, therefore the risk of women developing cardiovascular disease rises to become similar to that of men. *5.2 Pharmacokinetic properties* Estradiol valerate, like most natural estrogens, is readily and fully absorbed from the GI tract, is 50% bound to plasma proteins and is rapidly metabolised in the liver to oestriol and oestrone. When given orally in doses of 1 - 2 mg, peak levels of estradiol are generally observed 3 - 6 hours after ingestion, but by 24 hours (range 6 - 48 hours) concentrations have returned to baseline (i.e. pre-treatment concentrations). The average half-life of estradiol in plasma is about one hour. Estradiol undergoes first-pass effect in the liver. There is some enterohepatic recycling. It is excreted via the kidney in the urine as sulphate and glucuronide esters together with a small proportion of unchanged oestradiol. Other metabolites have been identified. *5.3 Preclinical safety data* Acute toxicity of estrogens is low. Because of marked differences between animal species and between animals and humans, preclinical results possess a limited predictive value for the application of estrogens in humans. Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential revealed no particular human risks beyond those discussed in other sections of the SmPC. *6. PHARMACEUTICAL PARTICULARS* *6.1 List of excipient(s)* Tablet core: Lactose monohydrate, maize starch, FD & C blue no. 2 lake (E132), povidone (grade 30), purified water, talc (sterilised, white), magnesium stearate. Tablet coat: Hypromellose, propylene glycol, Opaspray blue M-1-6517 (E171, E464, E132). *6.2 Incompatibilities* No incompatibilities have been described. *6.3 Shelf-life* 3 years *6.4 Special precautions for storage* Do not store above 25oC. Store in the original package. *6.5 Nature and contents of container* Blister strips of 28 tablets packed in cardboard cartons. Two sizes are available; cartons containing one blister strip or three blister strips. Blister consists of 20 μm layer of aluminium foil on a 250μm UPVC blister. *6.6 Instructions for use and handling* The pack was designed to help patients take the tablets correctly. The arrows on the foil should be followed and the tablets taken on the days shown. *7. MARKETING AUTHORISATION HOLDER* Novartis Pharmaceuticals UK Limited Trading as Sandoz Pharmaceuticals Frimley Business Park Frimley Camberley Surrey GU16 7SR *8. MARKETING AUTHORISATION NUMBER(S)* PL 0101/0308 *9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION* 25 March 1997. *10. DATE OF REVISION OF THE TEXT* August 2003 *LEGAL CATEGORY]* POM
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