Estradiol Valerate  2mg Tablets Taj Pharma

1. Name of the medicinal product

Estradiol Valerate  1mg Tablets Taj Pharma
Estradiol Valerate  2mg Tablets Taj Pharma

2. Qualitative and quantitative composition

a) Each film-coated tablet contains:
Estradiol valerate USP                            1mg
Excipients                                                q.s
Colours: Indigo carmine and Titanium Dioxide USP

b) Each film-coated tablet contains:
Estradiol valerate USP                            2mg
Excipients                                                q.s
Colours: Indigo carmine and Titanium Dioxide USP

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

White sugar coated tablet for oral administration.

4. Clinical particulars

4.1 Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in peri- and postmenopausal 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.

4.2 Posology and method of administration

• Posology

Estradiol valerate is an oestrogen-only product.

One tablet of Estradiol valerate 2 mg to be taken daily. It does not matter at what time of day the woman takes her tablet, but once she has selected a particular time she should keep to it every day. Treatment is continuous, which means that the next pack follows immediately without a break.

For initiation and continuation of treatment of menopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used. Treatment to control menopausal symptoms should be initiated with Estradiol valerate 1 mg. If considered necessary, Estradiol valerate 2 mg should be used. Once treatment is established the lowest effective dose necessary for relief of symptoms should be used.

For prevention of postmenopausal osteoporosis one tablet of Estradiol valerate 2 mg is to be taken daily.

In women with an intact uterus, a progestogen should be added to Estradiol valerate for at least 12 – 14 days each month/28 day cycle. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

• How to start Estradiol valerate 2 mg

If the woman has an intact uterus and is still menstruating, a combination regimen with Estradiol valerate and a progestogen, commencing with the oestrogen phase, should begin on the first day of bleeding. If the menstrual periods are very infrequent or if amenorrhoea is established, she may start at any time provided, if appropriate, pregnancy has been excluded (see section 4.6).

In women transferring from a continuous combined HRT product, treatment with Estradiol valerate may be started on any day.

In women transferring from cyclic or continuous sequential HRT regimens, the woman should complete the cycle and then change to Estradiol valerate without a break in therapy.

• Missed or lost tablets

If the woman forgets to take a tablet at the usual time, she may take it within the following 12 hours. If the woman is more than 12 hours late the forgotten tablet should not be taken and the remaining tablets taken at the usual time on the right days. A missed dose may lead to breakthrough bleeding or spotting.

Paediatric population

Not recommended for children

Method of administration

The tablets can be taken with or without food. The tablets should be swallowed whole with a glass of water or milk. The tablets should be taken at the same time each day.

4.3 Contraindications

– Known, past or suspected breast cancer

– Known or suspected oestrogen-dependent malignant tumours e.g. endometrial cancer

– Undiagnosed genital bleeding

– Untreated endometrial hyperplasia

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

– Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4)

– 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

– Hypersensitivity to the active substances or to any of the excipients listed in section 6.1

– Porphyria

4.4 Special warnings and precautions for use

• For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risk and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.
• Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

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). Investigations, including appropriate imaging tools, e.g mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

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 Estradiol valerate, in particular:

– Leiomyoma (uterine fibroids) or endometriosis

– Risk factors for, thromboembolic disorders (see below)

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

– Hypertension

– Liver disorders (e.g. liver adenoma)

– 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

– Hereditary angioedema.

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

– Pregnancy.

Endometrial hyperplasia and carcinoma

• In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see Section 4.8). After stopping treatment risk may remain elevated for at least 10 years.
• The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.
• For oral doses of estradiol > 2mg, conjugated equine oestrogens> 0.625 mg and patches > 50 micrograms/day the endometrial safety of added progestogens has not been demonstrated.
• 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, if they are known to have residual endometriosis.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestogen therapy

• The randomised placebo-controlled trial the Women’s Health Initiative study (WHI) , and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestogen for HRT that becomes apparent after about 3 years (see Section 4.8).

Oestrogen-only therapy

• The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestogen combinations (see Section 4.8).
• The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.
• HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

• Ovarian cancer is much rarer than breast cancer.
• Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
• Some other studies including the WHI trial suggest that the use of combined HRTs may be associated with a similar, or slightly smaller, risk (see Section 4.8).

Venous thromboembolism

• HRT is associated with a 1.3- to 3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see Section 4.8).
• Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30kg/m²), pregnancy/post-partum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
• Patients with known thromboembolic states have an increased risk of VTE. HRT may add to this risk. HRT is therefore contraindicated in these patients (see Section 4.3).
• In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
• Those women already on anti-coagulant treatment require careful consideration of the benefit-risk of use of HRT.
• 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 protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT.

Combined oestrogen-progestogen therapy

The relative risk of CAD during use of combined oestrogen-progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Oestrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

Ischaemic stroke

Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.8).

Other conditions

• Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed..
• Women with pre-existing hypertriglyceridaemia 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).
• Chloasma may occasionally occur, especially in women with a history of chloasmagravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.
• HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
• Estradiol valerate is not suitable as a contraceptive. If appropriate, contraception should be practised with non-hormonal methods.
• Patients with rare hereditary problems of fructose intolerance, glucose-galactosemalabsorption or sucrose-isomaltase insufficiency should not take this medicine.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactosemalabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Note: The prescribing information of concomitant medication should be consulted to identify potential interactions.

Effects of other medicinal products on Estradiol valerate

Substances increasing the clearance of sex hormones (diminished efficacy by enzyme-induction), e.g.:

The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. barbiturates, phenytoin, primidone, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John’s Wort (Hypericumperforatum).

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

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After cessation of drug therapy enzyme induction may be sustained for about 4 weeks.

Substances with variable effects on the clearance of sex hormones:

When co-administered with sex hormones, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors including combinations with HCV inhibitors, can increase or decrease plasma concentrations of oestrogen. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations.

Substances decreasing the clearance of sex hormones (enzyme inhibitors):

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the oestrogen.

Other forms of interaction

Laboratory tests

The use of sex steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range. For more information see section 4.4 “Other conditions”.

4.6 Fertility, pregnancy and lactation

• Pregnancy

Estradiol valerate is not indicated during pregnancy. If pregnancy occurs during medication with Estradiol valerate treatment should be withdrawn immediately.

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

• Breast-feeding

Estradiol valerate is not indicated during breast-feeding.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of Estradiol valerate.

4.8 Undesirable effects

The following undesirable effects have been reported in users of Estradiol valerate and other oral HRT preparations.

Neoplasms benign, malignant and unspecified

Breast cancer*, Endometrial cancer*

Immune system disorders

Hypersensitivity reaction, Exacerbation of hereditary angioedema

Metabolism and nutrition disorder

Porphyria aggravated, Increased or decreased weight, Increased appetite, Carbohydrate tolerance decreased

Psychiatric disorders

Anxiety/depressive symptoms, Decreased or increased libido

Nervous system disorders

Migraine, Headache, Dizziness, Fatigue, Chorea, Stroke*

Eye disorders

Visual disturbances, Intolerance to contact lenses

Cardiac disorders

Palpitations, Myocardial infarction*

Vascular disorders

Hypertension, Thrombophlebitis, Venous Thromboembolism*

Respiratory, thoracic and mediastinal disorders

Epistaxis

Gastrointestinal disorders

Dyspepsia, Abdominal pain, Vomiting, Nausea, Bloating, Flatulence

Hepatobiliary disorders

Gall bladder disease including Cholestasis

Skin and subcutaneous tissue disorders

Rashes, various Skin disorders (including Pruritus, Eczema, Urticaria, Acne, Hirsutism, Hair loss, Erythema nodosum, Erythema multiforme, Rash hemorrhagic, Chloasma (see section 4.4)

Musculoskeletal and connective tissue disorders

Muscle cramps, Leg pain

Renal and urinary disorders

Cystitis-like symptom

Reproductive system and breast disorders

Increased size of uterine fibroids, Vaginal candidosis, Uterine cervical erosions, Changes in vaginal bleeding pattern and abnormal bleeding or flow, Breakthrough bleeding, Spotting (bleeding irregularities usually subside during continued treatment), Dysmenorrhoea, Changes in vaginal secretion, Premenstrual-like syndrome, Breast secretion, Breast tenderness, enlargement or pain.

General disorders and administration site conditions

Oedema

* Please see further information below.

Breast cancer risk

• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years.
• Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestogen combinations.
• The level of risk is dependent on the duration of use (see section 4.4).
• Results of the largest randomised placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented.

Million Women Study – estimated additional risk of breast cancer after 5 years of use

US WHI studies – additional risk of breast cancer after 5 years of use

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with an uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed diagnosed (see Section 4.4). A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3 – 3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:

WHI Studies – additional risk of VTE over 5 years of use

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen-progestogen therapy is associated with an up to 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined – Additional risk of ischaemicstroke^a over 5 years of use

a No differentiation was made between ischaemic and haemorrhagic stroke.

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

– Gall bladder disease.

– Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura

– Probable dementia over the age of 65 (see section 4.4)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

Overdose may cause nausea and vomiting and withdrawal bleeding may occur in some women. There are no specific antidotes and treatment should be symptomatic.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, natural and semisynthetic oestrogens, plain,

• Estradiol/estradiol valerate:

Estradiol valerate contains estradiol valerate, (the valeric-acid ester of the endogenous female oestrogen, estradiol.

The active ingredient estradiol valerate, a prodrug of the synthetic 17ß-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

Ovulation is not inhibited during the use of Estradiol valerate, and the endogenous production of hormones is hardly affected.

Clinical trial information

Relief of oestrogen-deficiency symptoms and bleeding patterns

– During the climacteric, the reduction and finally loss of ovarian estradiol secretion can result in instability of thermoregulation, causing hot flushes associated with sleep disturbance and excessive sweating, and urogenital atrophy with symptoms of vaginal dryness, dyspareunia and urinary incontinence. Less specific but often mentioned as part of the climacteric syndrome are symptoms like anginal complaints, palpitations, irritability, nervousness, lack of energy and concentration abilities, forgetfulness, loss of libido and joint and muscle pain. HRT alleviates many of these symptoms of estradiol deficiency in the menopausal woman.

– Relief of menopausal symptoms was achieved during the first few weeks of treatment.

– The addition of a progestogen to an oestrogen replacement regimen like Estradiol valerate for at least 10 days per cycle is recommended in women with an intact uterus. It reduces the risk of endometrial hyperplasia and the attendant risk of adenocarcinoma in these women. The addition of a progestogen to an oestrogen replacement regimen has not been shown to interfere with the efficacy of oestrogen for its approved indications.

Prevention of osteoporosis

– Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.

– The effect of oestrogens 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 progestogen – 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.

Observational studies and the WHI trial on conjugated equine oestrogens (CEE) plus medroxyprogesterone acetate (MPA) suggest a reduction of colon cancer morbidity in postmenopausal women taking HRT. In the WHI trial on CEE mono-therapy a risk reduction was not observed. It is unknown whether these findings also extend to other HRT products.

• Progestogen:

As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

5.2 Pharmacokinetic properties

Absorption

After oral administration estradiol valerate is quickly and completely absorbed.

Distribution

Already after 0.5 – 3 hours peak plasma levels of estradiol, the active drug substance, are measured. As a rule, after 6 – 8 hours a second maximum appears, possibly indicating an entero-hepatic circulation of estradiol.

In plasma, estradiol is mainly found in its protein-bound form. About 37% are bound to SHBG and 61% to albumin. Cumulation of estradiol after daily repetitive intake of Estradiol valerate does not need to be expected.

The absolute bioavailability of estradiol amounts to 3 – 5% of the oral dose of estradiol valerate.

Biotransformation

Esterases in plasma and the liver quickly decompose estradiol valerate into estradiol and valeric acid. Further decomposition of valeric acid through β-oxidation leads to C₂-units and results in CO₂ and water as end products. Estradiol itself undergoes several hydroxylating steps. Its metabolites as well as the unchanged substance are finally conjugated. Intermediate products of metabolism are estrone and estriol, which exhibit a weak oestrogenic activity of their own, although this activity is not so pronounced as with estradiol. The plasma concentration of conjugated estrone is about 25 to 30 fold higher than the concentration of unconjugated estrone. In a study using radioactive labelled estradiol valerate about 20% of radioactive substances in the plasma could be characterised as unconjugated steroids, 17% as glucuronized steroids and 33% as steroid sulphates. About 30% of all substances could not be extracted from the aqueous phase and, therefore, probably represent metabolites of high polarity.

Elimination

Estradiol and its metabolites are mainly excreted by the kidneys (relation of urine:faeces = 9:1). Within 5 days about 78 – 96% of the administered dose are excreted with an excretion half-life of about 27 hours.

5.3 Preclinical safety data

There are no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

6. Pharmaceutical particulars

6.1 List of excipients

Lactose monohydrate, Maize Starch, Povidone, Talc, Magnesium Stearate, Sucrose, Povidone, Macrogol, Calcium Carbonate, Glycol montanate, Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

None.

6.5 Nature and contents of container

Container consists of aluminium foil and PVC blister strips packed in a cardboard carton

Presentation: Carton containing memo-packs of either 1 x 28 tablets or 3 x 28 tablets.

6.6 Special precautions for disposal and other handling

None.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Estradiol valerate 1mg Taj Pharma
Estradiol valerate 2mg Taj Pharma

Package leaflet: Information for the user

Due to regulatory changes, the content of the following Patient Information Leaflet may vary from the one found in your medicine pack. Please compare the ‘Leaflet prepared/revised date’ towards the end of the leaflet to establish if there have been any changes.

If you have any doubts or queries about your medication, please contact your doctor or pharmacist.

Estradiol valerate 2 mg Tablets Taj Pharma

Estradiol valerate

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1  What estradiol valerate is and what it is used for
2. What you need to know before you take estradiol valerate
3. How to take estradiol valerate
4. Possible side effects
5. How to store estradiol valerate
6. Contents of the pack and other information

1. WHAT ESTRADIOL VALERATE IS AND WHAT IT IS USED FOR

What Estradiol valerate is

Estradiol valerate is a Hormone Replacement Therapy (HRT). It contains the female hormone, oestrogen. Your ovaries gradually make less of this hormone as you get older and will no longer produce it after you have been through the menopause. Estradiol valerate can be used in peri- and postmenopausal women.

What Estradiol valerate is used for

Relief of symptoms occurring after menopause

During the menopause, the amount of the oestrogen produced by a woman’s body drops. This can cause symptoms such as hot face, neck and chest (“hot flushes”). Estradiol valerate alleviates these symptoms after menopause. You will only be prescribed Estradiol valerate if your symptoms seriously hinder your daily life.

Prevention of osteoporosis

After the menopause some women may develop fragile bones (osteoporosis). You should discuss all available options with your doctor.

If you are at an increased risk of fractures due to osteoporosis and other medicines are not suitable for you, you can use Estradiol valerate to prevent osteoporosis after menopause.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE ESTRADIOL VALERATE

Medical history and regular check-ups

The use of HRT carries risks which need to be considered when deciding whether to start taking it, or whether to carry on taking it.

The experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited. If you have a premature menopause the risks of using HRT may be different. Please talk to your doctor.

Before you start (or restart) HRT, your doctor will ask about your own and your family’s medical history. Your doctor may decide to perform a physical examination. This may include an examination of your breasts and/or an internal examination, if necessary.

Once you have started on Estradiol valerate, you should see your doctor for regular check-ups (at least once a year). At these check-ups, discuss with your doctor the benefits and risks of continuing to take Estradiol valerate.

Be sure to:

• go for regular breast screening and cervical smear tests, as recommended by your doctor.
• regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel.

Do not take Estradiol valerate:

If any of the following applies to you. If you are not sure about any of the points below, talk to your doctor before taking Estradiol valerate,

Do not take Estradiol valerate

• If you have or have ever had breast cancer, or if you are suspected of having it
• If you have cancer which is sensitive to oestrogens, such as cancer of the womb lining (endometrium) or if you are suspected of having it
• If you have any unexplained vaginal bleeding
• If you have excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated
• If you have or have ever had a blood clot in a vein (thrombosis) such as in the legs (deep vein thrombosis) or the lungs (pulmonary embolism)
• If you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency)
• If you have or recently have had a disease caused by blood clots in the arteries, such as a heart attack, stroke or angina
• If you have or have ever had a liver disease, and your liver function tests have not returned to normal
• If you have a rare blood problem called “porphyria” which is passed down in families (inherited)
• If you are allergic to estradiol valerate or any of the other ingredients of this medicine (listed in section 6)
• If you have been told to avoid lactose, that you have a rare hereditary condition called Lapp lactase deficiency or glucose-galactosemalabsorption
• If you have any reason to believe that you either are, or may be, pregnant, or if you are producing milk (lactating) and breast-feeding. (See also the ‘Pregnancy and breast-feeding’ section of this leaflet)

• If any of the above conditions appear for the first time while taking Estradiol valerate, stop taking it at once and consult your doctor immediately.

Warnings and precautions

Talk to your doctor or pharmacist before taking Estradiol valerate

Tell your doctor if you have ever had any of the following problems, before you start the treatment, as these may return or become worse during treatment with Estradiol valerate. If so, you should see your doctor more often for check-ups:

• fibroids inside your womb
• growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia)
• increased risk of developing blood clots (see “Blood clots in a vein (thrombosis)”)
• increased risk of getting an oestrogen-sensitive cancer (such as mother, sister or grandmother who has had breast cancer)
• high blood pressure
• a liver disorder, such as a benign liver tumour
• diabetes
• gallstones
• migraine or severe headaches
• a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
• epilepsy
• asthma
• a disease affecting the eardrum and hearing (otosclerosis)
• a very high level of fat in your blood (triglycerides)
• fluid retention due to cardiac or kidney problems

Stop taking Estradiol valerate and see a doctor immediately

If you notice any of the following when taking HRT:

• any of the conditions mentioned in the ‘DO NOT take Estradiol valerate’ section
• yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease
• a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness).
• migraine-like headaches which happen for the first time.
• if you become pregnant
• if you notice signs of a blood clot, such as:
  • painful swelling and redness of the legs
  • sudden chest pain
  • difficulty in breathing

for more information, see ‘Blood clots in a vein (thrombosis)’

Note: Estradiol valerate is not a contraceptive. If it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your doctor for advice.

HRT and cancer

Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)

Taking oestrogen-only HRT will increase the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer).

Taking a progestogen in addition to the oestrogen for at least 12 days of each 28 day cycle protects you from this extra risk.

If you still have your womb, your doctor will prescribe a progestogen separately.

If you have had your womb removed (a hysterectomy), discuss with your doctor whether you can safely take this product without a progestogen.

If you’ve had your womb removed because of endometriosis, any endometrium left in your body may be at risk. So your doctor may prescribe HRT that includes a progestogen as well as an oestrogen.

Compare

In women who still have a womb and who are not taking HRT, on average, 5 in 1000 will be diagnosed with endometrial cancer between the ages of 50 and 65.

For women, aged 50 to 65, who still have a womb and who take oestrogen-only HRT, between 10 and 60 women in 1000 will be diagnosed with endometrial cancer (i.e. between 5 and 55 extra cases), depending on the dose and how long it is taken.

Breast cancer

Evidence suggests that taking combined oestrogen-progestogen and possibly also oestrogen-only HRT increases the risk of breast cancer. The extra risk depends on how long you take HRT. The additional risk becomes clear within a few years. However, it returns to normal within a few years (at most 5) after stopping treatment.

For women who have had their womb removed and who are using oestrogen-only HRT for 5 years, little or no increase in breast cancer risk is shown.

Your risk of breast cancer is also higher:

• if you have a close relative (mother, sister or grandmother) who has had breast cancer
• if you are seriously overweight

Compare

Women aged 50 to 79 who are not taking HRT, on average, 9 to 17 in 1000 will be diagnosed with breast cancer over a 5-year period. For women aged 50 to 79 who are taking oestrogen-progestogen HRT over 5 years, there will be 13 to 23 cases in 1000 users (i.e. an extra 4 to 6 cases).

Regularly check your breasts. See your doctor if you notice any changes in your breast such as:

• dimpling of the skin
• changes in the nipple
• any lumps you can see or feel

Additionally, you are advised to join mammography screening programs when offered to you. For mammogram screening, it is important that you inform the nurse/healthcare professional who is actually taking the x-ray that you use HRT, as this medication may increase the density of your breasts which may affect the outcome of the mammogram. Where the density of the breast is increased, mammography may not detect all lumps.

Ovarian cancer

Ovarian cancer (cancer of the ovaries) is rare – much rarer than breast cancer. It can be difficult to diagnose because there are often no obvious signs of the disease. The use of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period. For women who have been taking HRT for 5 years, there will be about 3 cases per 2000 users (i.e. about 1 extra case).

Effects of HRT on heart or circulation

Blood clots in a vein (thrombosis)

The risk of blood clots in the veins (also called deep vein thrombosis, or DVT) is about 1.3 to 3–times higher in HRT users than non-users, especially during the first year of taking it.

Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death. This condition is called pulmonary embolism, or PE.

DVT and PE are examples of a condition called venous thromboembolism, or VTE.

You are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. Inform your doctor if any of these situations apply to you:

• you are unable to walk for a long time because of major surgery, injury or illness (see also section 3, “If you need to have surgery”)
• you are seriously overweight (BMI >30 kg/m²)
• you have any blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots
• any of your close relatives has ever had a blood clot in the leg, lung or any other organ
• you have had one or more miscarriages
• you have systemic lupus erythematosus (SLE)
• you have cancer

For signs of a blood clot, see “Stop taking Estradiol valerate and see a doctor immediately”.

Compare

Looking at women in their 50s who are not taking HRT, on average, over a 5-year period, 4 to 7 in 1000 would be expected to get a blood clot in a vein.

For women in their 50s who are taking oestrogen-progestogen HRT, for over 5 years, there will be 9 – 12 cases in 1000 (i.e. an extra 5 cases).

For women in their 50s who have had their womb removed and have been taking oestrogen-only HRT for over 5 years, there will be 5 to 8 cases in 1000 users (i.e. 1 extra case).

Heart disease (heart attack)

There is no evidence that HRT will prevent a heart attack.

HRT is not recommended for women who have heart disease, or have had heart disease recently. If you have ever had heart disease, talk to your doctor to see if you should be taking HRT.

Women over the age of 60 years who use oestrogen-progestogen HRT are slightly more likely to develop heart disease than those not taking any HRT.

For women who have had their womb removed and are taking oestrogen-only therapy there is no increased risk of developing a heart disease.

If you get:

• a pain in your chest that spreads to your arm or neck

• See a doctor as soon as possible and do not take any more HRT until your doctor says you can. This pain could be a sign of heart disease.

Stroke

The risk of getting a stroke is about 1.5–times higher in HRT users than in non–users. The number of extra cases of stroke due to HRT use will increase with age.

Other things that can increase the risk of stroke include:

• high blood pressure
• smoking
• drinking too much alcohol
• an irregular heartbeat

If you are worried about any of these things, or if you have had a stroke in the past, talk to your doctor to see if you should take HRT.

Compare

Looking at women in their 50s who are not taking HRT, on average, 8 in 1000 would be expected to have a stroke over a 5-year period. For women in their 50s who are taking HRT, there will be 11 cases in 1000 users, over 5 years (i.e. an extra 3 cases).

Other conditions

• HRT will not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start using HRT after the age of 65. Speak to your doctor for advice.
• If you have heart or kidney problems, your doctor should examine you carefully as oestrogens may cause fluid retention resulting in swelling.
• If you have pre-existing elevated triglycerides (a type of blood fat) your doctor should monitor you closely during oestrogen replacement therapy or HRT. Rare cases of large increases of plasma triglycerides (hypertriglyceridemia) leading to inflammation of the pancreas (pancreatitis) have been reported with oestrogen replacement therapy.
• If you have a tendency to develop blotchy brown patches (chloasma) on the face you should avoid exposure to the sun or ultraviolet light whilst using Estradiol valerate.
• Your doctor will monitor you carefully if you have terminal kidney insufficiency as the blood levels of the active substances in Estradiol valerate will probably increase

Other medicines and Estradiol valerate

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Some medicines may interfere with the effect of Estradiol valerate. This might lead to irregular bleeding. This applies to the following medicines:

• medicines for epilepsy (such as barbiturates, phenytoin, primidone,carbamazepine and possibly oxcarbazepine, topiramate and felbamate)
• medicines for tuberculosis (such as rifampicin, rifabutin)
• medicines for HIV and Hepatitis C Virus infections (so-called protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as nevirapine, efavirenz, ritonavir and nelfinavir)
• herbal remedies containing St. John’s wort (Hypericumperforatum)
• Medicines for treatment of fungal infections (such as griseofulvin, fluconazole, itraconazole, ketoconazole and voriconazole)
• Medicines for treatment of bacterial infections (such as clarithromycin and erythromycin)
• Medicines for treatment of certain heart diseases, high blood pressure (such as verapamil and diltiazem)
• Grapefruit juice

Laboratory tests

If you need a blood test, tell your doctor or the laboratory staff that you are taking Estradiol valerate, because this medicine can affect the results of some tests.

Pregnancy and breast-feeding

Estradiol valerate is for use in post-menopausal women only. Do not take if you are pregnant or breast-feeding.

If you become pregnant, stop taking Estradiol valerate immediately and contact your doctor.

Driving and using machines

No effects on ability to drive and use machines have been observed in users of Estradiol valerate.

Estradiol valerate contains lactose monohydrate and sucrose

Estradiol valerate contains lactose and sucrose (types of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. HOW TO TAKE ESTRADIOL VALERATE

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is one tablet of Estradiol valerate 2 mg to be taken daily.

Use in children and adolescents

Estradiol valerate is not for use in adolescents or children.

Your doctor will aim to prescribe the lowest dose to treat your symptom for as short as necessary. Speak to your doctor if you think this dose is too strong or not strong enough.

About the pack

This pack is designed to help you remember to take your medicine. Each tablet is placed in a section marked with the day of the week on which it should be taken. The arrows between tablets show the order in which they must be taken. Your doctor may tell you when to start (see “when to start” for further information).

On the day you start, take your first tablet from the top row of tablets marked with the correct day. For instance, if you start on a Tuesday, press out the tablet from the blister marked ‘TUE’.

Take one tablet each day, following the directions of the arrows, until you have finished all 28 tablets in the memo strip. When you have finished each memo strip, start the next memo strip on the following day. Do not leave a break between memo strips. It is best to take your tablet at the same time each day. You can take Estradiol valerate with or without food. The tablet should be swallowed whole with a glass of water or milk.

Your doctor may prescribe the hormone progestogen in addition to Estradiol valerate for at least 12 – 14 days each month:

• if you still have your womb
• if you have a history of endometriosis

When to start

If you have been taking other HRT preparations: carry on until you have finished your current pack and have taken all the tablets for that month. Take your first Estradiol valerate tablet the next day. Do not leave a break between your old tablets and the Estradiol valerate tablets.

If this is your first HRT treatment and you are still having regular periods: start your Estradiol valerate tablets on the first day of bleeding

If this is your first HRT treatment and your periods have become very infrequent or have stopped completely: you can start your Estradiol valerate tablets at any time if you are sure you are not pregnant.

If you take more Estradiol valerate than you should

Overdose may cause nausea and vomiting and irregular bleeding. No specific treatment is necessary but you should consult your doctor or pharmacist if you are concerned.

If you forget to take Estradiol valerate

If you forget to take a tablet at your usual time and you are less than 12 hours late, take it as soon as possible. Take the next tablet at the usual time.

If you are more than 12 hours late, leave the forgotten tablet in the pack. Continue to take the rest of the tablets at the usual time every day. You may experience breakthrough bleeding.

If you stop taking Estradiol valerate

You may begin to feel the usual symptoms of menopause again, which may include hot flushes, trouble sleeping, nervousness, dizziness or vaginal dryness. Consult your doctor or pharmacist if you want to stop taking Estradiol valerate tablets.

If you need to have surgery

If you are going to have surgery, tell the surgeon that you are taking Estradiol valerate. You may need to stop taking Estradiol valerate about 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, “Blood clots in a vein (thrombosis)”). Ask your doctor when you can start taking Estradiol valerate again.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following diseases are reported more often in women using HRT compared to women not using HRT:

Serious side effects

• breast cancer
• abnormal growth or cancer of the lining of the womb (endometrial hyperplasia or cancer)
• ovarian cancer
• blood clots in the veins of the legs or lungs (venous thromboembolism)
• heart disease
• stroke
• probable memory loss if HRT is started over the age of 65

For more information about these side effects see section 2.

Other side effects that have been linked to the use of Estradiol valerate and other oral hormone replacement therapies:

• During the first few months of treatment you may experience some vaginal bleeding at unexpected times (breakthrough bleeding and spotting). These symptoms normally lessen with continued treatment. If they don’t, contact your doctor (see section 2 ‘HRT and cancer/ Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)’ for more information)
• breast pain, tenderness or enlargement, breast discharge
• painful periods, changes in vaginal secretions, pre-menstrual symptoms, increased size of fibroids in the womb, thrush, changes to the neck of the womb
• indigestion, a feeling of being bloated, passing wind, feeling or being sick, abdominal pain, gall bladder disease
• skin rashes or discolouration, itching, eczema, acne, unusual hair loss or hair growth, increased skin pigment especially on the face (chloasma – see section 2 ‘other conditions’ for more information), some rare skin problems
• headache, migraine, dizziness, anxiety or depressive symptoms, fatigue
• fast or irregular heartbeat (palpitations), high blood pressure, inflammation of veins usually in the legs
• fluid retention leading to swelling of parts of the body
• changes in body weight and sex drive, increased appetite
• muscle cramps, leg pains
• nose bleeds, visual disturbances (such as blurred vision), discomfort with contact lenses, allergic-type reactions, a worsening of glucose tolerance, bladder inflammation, rare disorders (porphyria, chorea)

The following side effects have been reported with other HRTs:

• various skin disorders:
  • painful reddish skin nodules (erythema nodosum)
  • rash with target-shaped reddening or sores (erythema multiforme)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. HOW TO STORE ESTRADIOL VALERATE

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Estradiol valerate contains

The active substance is estradiol valerate.

The other ingredients are lactose monohydrate, maize starch, povidone, talc, magnesium stearate, sucrose, povidone, macrogol, calcium carbonate, glycol montanate, purified water.

What Estradiol valerate looks like and contents of the pack

Estradiol valerate 2mg tablets are film-coated tablets.

They are supplied in a blister pack containing 28 tablets with the days of the week printed on the blister.

Not all pack sizes may be marketed.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com