ESTRADIOL VALERATE AND NORGESTREL TABLETS USP TAJ PHARMA

ESTRADIOL VALERATE AND NORGESTREL TABLETS USP TAJ PHARMA

1. NAME OF THE MEDICINAL PRODUCT
   Estradiol Valerate and Norgestrel Tablets USP Taj Pharma
2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Calendar-pack containing:
11 white tablets of:
Estradiol valerate                        2 mg
10 colored tablets of:
Estradiol valerate                        2 mg
Norgestrel                                   0.5 mg

3. PHARMACEUTICAL FORM

Coated tablets.

4. CLINICAL PARTICULARS

Therapeutic indication

Two phase preparation for climacteric and cycle disturbances.

Posology and method of administration

Estradiol Valerate and Norgestrel Tablets is a cyclic HRT product.  One tablet is to be taken orally once a day for 21 days, followed by a 7 day tablet free interval. Therefore, each new pack is started after a 28 day cycle. The white tablets should be taken from days 1 to 11 followed by the brown tablets from days 12 to 21. It is recommended that the tablets are taken at the same time every day

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

For women still having periods, the first tablet should be taken on the 5th day of their menstrual period. If menstruation has stopped, or is infrequent or sporadic, then the first tablet can be taken any time

If the patient is being transferred from a continuous HRT product, the patient may start Estradiol Valerate and Norgestrel Tablets on any convenient day. For those transferring from a cyclic or sequential product, Progylton should be started following completion of the previous regimen

If a tablet is missed, it should be taken as soon as possible, unless it is more than 12 hours late. In this case the missed tablet should be left in the pack and the next tablet taken at the right time. Missing a dose may result in breakthrough bleeding or spotting

Unless there is a previous diagnosis of endometriosis, it is not recommended that progestagen-containing HRT be given to hysterectomised women

Children and adolescents

Estradiol Valerate and Norgestrel Tablets is not indicated for use in children and adolescents

Geriatric patients

There are no data suggesting a need for dosage adjustment in women aged 65 years or (older (see section 4.4 Special warnings and precautions for use

Patients with hepatic impairment

Estradiol Valerate and Norgestrel Tablets has not been specifically studied in patients with hepatic impairment. (see 4.3 (Contraindications

Patients with renal impairment

Estradiol Valerate and Norgestrel Tablets has not been specifically studied in renally impaired patients. Available data do not suggest a need for dosage adjustment in this patient population.

Contraindications Pregnancy and lactation Undiagnosed vaginal bleeding

Known, past or suspected cancer of the breast

Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer) Untreated endometrial hyperplasia

Active or recent arterial thromboembolic disease (e.g. angina, myocardial infraction)- Previous 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)

Known hypersensitivity to any of the components of Estradiol Valerate and Norgestrel Tablets

Acute liver disease or a history of liver disease unless liver function tests have

returned to normal

Porphyria

Special warnings and special 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 risks 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 examination (including pelvic and breast) should be guided by this and by the contraindications (section 4.3) and warnings for use (section 4.4). 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.

Before starting treatment, pregnancy should be excluded. If withdrawal bleeding fails to occur at about 28-day intervals, the possibility of pregnancy should be considered in peri- menopausal women.

The patient may experience blood loss after completing each pack.

Conditions that 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 monitored. It should be taken into account that these conditions may recur or may be aggravated during treatment with Estradiol Valerate and Norgestrel Tablets, 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 chorea minor

a history of endometrial hyperplasia (see below) epilepsy

asthma otosclerosis

hereditary angioedema

Close medical supervision (including periodic measurement of prolactin levels) is necessary if the patient suffers from prolactinoma.

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the following situations: significant increase in blood pressure pregnancy jaundice or deterioration in liver function. migrainous headaches occur for the first time

Endometrial Hyperplasia

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 progestagen for 10 days per cycle in non-hysterectomised women reduces, but does not eliminate, this risk.

Breakthrough bleeding and spotting may occur during the first few months of treatment, but if this occurs after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated. This may include an endometrial biopsy to exclude endometrial malignancy.

Breast Cancer

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

Combined oestrogen-progestagen therapy

The randomised placebo-controlled trial the (Women’s Health Initiative study), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen 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-progestagen 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-progestagen 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. Long-term (at least 5-10 years) use of oestrogen–only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk (see section 4.8).

Venous Thromboembolism (VTE)

HRT is associated with a 1.3-3fold 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 (section 4.8).

Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI >30kg/m2) pregnancy/postpartum 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 to 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.

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a 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.

Women already on chronic anticoagulant 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 leg, sudden pain in chest, dyspnoea)

Coronary Arterial 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- progestagen or oestrogen only HRT.

Combined oestrogen-progestagen therapy

The relative risk of CAD during use of combined oestrogen+progestagen 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+progestagen 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-progestagen 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).

Liver tumor

In rare cases benign, and even more rarely, malignant liver tumors have been observed after the use of hormonal substances such as those contained in HRT products. In isolated cases, these tumors led to life-threatening intra-abdominal hemorrhage. A hepatic tumor should be considered in the differential diagnosis if upper abdominal pain, enlarged liver, or signs of intra-abdominal hemorrhage occur.

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 of Estradiol Valerate and Norgestrel Tablets may increase.

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).

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 and Norgestrel Tablets cannot be used as a contraceptive.

Hormonal contraception should be stopped when treatment with Estradiol Valerate and Norgestrel Tablets is started and the patient should be advised to take non-hormonal contraceptive precautions.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Lactose

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

Interaction with other medicinal and other forms of interaction

The metabolism of oestrogens and progestagens 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

.oestrogens and progestagens

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased efficacy and changes in uterine bleeding profile

The requirement for oral antidiabetics or insulin can change.

Pregnancy and lactation

Estradiol Valerate and Norgestrel Tablets  is not indicated for use during pregnancy or lactation. If pregnancy occurs during medication with Estradiol Valerate and Norgestrel Tablets , treatment should be discontinued immediately.

No data on exposed pregnancies are available. Studies in animals have not shown reproductive toxicity.

The results of most epidemiological studies to-date, relevant to inadvertent foetal exposure to combinations of oestrogens and progestagens indicate no teratogenic or foetotoxic effect.

Effects on ability to drive and use machines

No observed effects.

Undesirable effects

During the first few months treatment, breakthrough bleeding, spotting and breast tenderness or enlargement can occur. These are usually temporary and normally disappear after continued treatment.

The most appropriate MedDRA term (version 8.0) to describe a certain reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema (see section Special Warnings and special precautions for use).

Other reactions have also been reported in association with oestrogen/progestagen treatment:

Oestrogen-dependent neoplasms benign and malignant, e.g. breast* (see below) and endometrial** (see below) 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

Probable dementia (see Section 4.4)

–           In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Breast Cancer

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

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

For oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen- progestagen combined HRT was 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) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

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

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

The MWS has estimated, from the known

average incidence of breast cancer in developed countries, that:

• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.
• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be
• For users of       oestrogen-only        replacement        therapy   between    0     and     3     (best     estimate     =     1.5)     for     5     years’     use     between 3 and 7 (best estimate = 5) for 10 years’ use.
• For users of   oestrogen    plus    progestagen    combined    HRT,    between     5     and     7     (best     estimate     =     6)     for     5     years’      use      between 18 and 20 (best estimate = 19) for 10 years’ use.

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

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

• For 1000 women in the placebo group, about 16 cases of invasive breast cancer would be diagnosed in 5 years.
• For 1000 women who used oestrogen + progestagen combined HRT (CEE + MPA), the number of additional cases           would  be between 0 and 9 (best estimate = 4) for 5 years’ use.

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

Endometrial Cancer

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

Overdose

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

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

The estrogen in Estradiol Valerate and Norgestrel Tablets  is estradiol valerate, a prodrug of the natural human 17ß- estradiol. Synthetic 17 β-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. The constituent norgestrel is a synthetic progestogen.

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

With the composition and the sequential regimen of Estradiol Valerate and Norgestrel Tablets , including an estrogen monophase for 11 days, an estrogen-progestogen combination for 10 days and a treatment- free interval of 7 days, a menstrual cycle is established in women with an intact uterus, provided the preparation is taken regularly.

Hormone replacement therapy (HRT) alleviates many of the symptoms of estradiol deficiency in menopausal woman such as hot flushes, excessive sweating, urogenital atrophy with symptoms of vaginal dryness and dyspareunia.

Relief of menopausal symptoms was achieved by the third cycle after initiation of treatment. In a clinical trial 314 subjects were enrolled and treated with 2 mg EV/0.5 mg NG, 235 subjects completed the study. 93.3% of the subjects who completed showed a reduction of the mean number of hot flushes per week of at least 50% after 3 cycles of treatment. 61.1% of subjects had no hot flushes any more at cycle 3. In another clinical trial one third of the subjects was free of vasomotor symptoms after one treatment cycle.

The Kupperman Index, related to the most common menopausal complaints which are weighted according to their importance, significantly decreased from baseline at cycle 3.

Data from clinical trials indicate that regular monthly withdrawal bleeding occurred in approximately 90% of women. The mean duration of withdrawal bleeding was 3.8 days. Withdrawal bleeding starts on average 3.1 days after the last pill of the progestagen phase. The amenorrhea rate (no bleeding or spotting) is less than 5%.

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 progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

Pharmacokinetic properties

Estradiol valerate

Absorption

Estradiol valerate is rapidly and completely absorbed. The steroid ester is cleaved into estradiol and valeric acid during absorption and the first liver passage. At the same time, estradiol undergoes extensive further metabolism, e.g. into estrone, estriol and estrone sulfate. Only about 3 % of estradiol becomes bioavailable after oral administration of estradiol valerate. Food does not affect the bioavailability of estradiol.

Distribution

Following single administration of 2mg estradiol valerate, maximum concentrations of estradiol in serum of approx. 25-30 pg/ml are generally reached between 4-9 hours after tablet intake. Within 24 hours after tablet intake, serum levels of estradiol declined to concentrations of about 15 pg/ml. Estradiol binds to albumin and the sex hormone binding globulin (SHBG). However, the binding to SHBG is lower than that of levonorgestrel. The unbound fraction of estradiol in serum is about 1-1.5 % and the SHBG- bound fraction is in the range of 30-40 %.

The apparent volume of distribution of estradiol after single intravenous administration is about 1 l/kg.

Metabolism

After the ester cleavage of the exogenously administered estradiol valerate, the metabolism of the drug follows the biotransformation pathways of endogenous estradiol. Estradiol is mainly metabolized in the liver but also extrahepatically e.g. in gut, kidney, skeletalmuscles and target organs. These processes involve the formation of estrone, estriol, catecholestrogens and sulfate and glucuronide conjugates of these compounds, which are all distinctly less estrogenic or even nonestrogenic.

Elimination

The total serum clearance of estradiol following single intravenous administration, shows high variability in the range of 10-30 ml/min/kg. A certain proportion of estradiol metabolites are excreted in the bile and undergo a so-called enterohepatic circulation. Ultimately estradiol metabolites are mainly excreted as sulfates and glucuronides with the urine.

Steady state conditions

In relation to the single dose, approximately two times higher serum levels of estradiol are observed after multiple administration. On average, the concentration of estradiol varies between 30 (minimum levels) and 60 pg/ml (maximum levels). Estrone, as a less estrogenic metabolite, reaches about 8-times higher concentrations in serum, estrone sulfate reaches approximately 150-times higher concentrations. After stopping the treatment with

Estradiol Valerate and Norgestrel Tablets , pre-treatment levels of estradiol and estrone are reached within 2-3 days. No distinct difference in the estrogen levels is observed between the treatment phase with estradiol valerate alone or in combination with norgestrel.

Norgestrel

Absorption

After oral administration, norgestrel is absorbed rapidly and completely. The active component of the racemate norgestrel is levonorgestrel which becomes completely bioavailable from the racemate and accounts for about half of the dose of norgestrel.

Distribution

On an average, maximum concentrations of levonorgestrel in serum of 7-8 ng/ml are already reached within 1-1.5 hours after a single administration of Estradiol Valerate and Norgestrel Tablets .

Subsequently, serum levels of levonorgestrel decline biphasically with a mean terminal half-life of 27 hours and reach minimum concentrations of about 1 ng/ml 24 hours post dose.

Levonorgestrel binds to albumin and SHBG. Only about 1-1.5 % of the total levonorgestrel concentration in serum is not protein-bound. The relative fractions of free, albumin- and SHBG- bound levonorgestrel are strongly dependent on the concentration of SHBG in serum. After induction of the binding proteins, the fraction bound to SHBG increases whereas the unbound fraction and that bound to albumin decreases. At the end of the estrogen monophase of the Estradiol Valerate and Norgestrel Tablets  treatment cycle, the concentration of SHBG reaches the highest levels in serum which then decreases to the lowest levels at the end of the combination phase.

Accordingly, the free fraction of levonorgestrel amounts to about 1 % at the beginning and about 1.5 % at the end of the combination phase. The corresponding fractions of levonorgestrel bound to SHBG are 70 and 65 %, respectively.

Biotransformation

Norgestrel is completely metabolized. Biotransformation of the active substance levonorgestrel follows the known pathways of steroid metabolism. Pharmacologically active metabolites are not known.

Elimination

The total clearance rate of levonorgestrel from serum is 1 ml/min/kg.

With a half-life of about 1 day, approximately the same proportions of the metabolites of norgestrel are excreted with the urine and the bile.

Steady-state conditions

Based on the elimination half-life of levonorgestrel in serum of about 24 hours, an accumulation of the active substance in serum would be expected. Accordingly, elevated trough levels ofabout 1 ng/ml are observable after repeated administration. However, due to the simultaneous change in the protein binding capacity during treatment (decrease in SHBG concentration), the area under the serum levels-time course of levonorgestrel does not really differ between the beginning and the end of the 10-day treatment phase with the estrogen/progestogen combination. Thus, no accumulation of levonorgestrel in serum is observed after multiple administration of Estradiol Valerate and Norgestrel Tablets .

Preclinical safety data

None

PHARMACEUTICAL PARTICULARS

list of exicipients

Lactose monohydrate, maize starch, polyvidone 25000, talc, magnesium stearate, sucrose, polyvidone 700000, macrogol 6000, calcium carbonate, glycerol 85%, titanium dioxide, ferric oxide yellow, ferric oxide red , montanglycol wax

Incompatabilitis

None known

Shelf life

5 years

Special precautions for storage

Do not store above 25°C.

Nature and contents of container

Each pack consists of aluminium foil and PVC and contains 21 tablets.

Instructions for use and handling (and disposal)

No special requirements for disposal.

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 AND NORGESTREL TABLETS USP TAJ PHARMA  

Read the entire leaflet carefully before using the medicine.

This leaflet contains concise information about the medicine. If you have further questions, refer to the doctor or pharmacist.

This medicine was prescribed for you. Do not pass it on to others. It can harm them even if it seems to you that their medical condition is similar.

WHAT IS THE MEDICINE INTENDED FOR?

A hormonal medicine in two phases to treat irregularities of the menstrual cycle and menopause-related disturbances. Each tablet has a small amount of two female hormones: estrogen (estradiol valerate) and progestogen (norgestrel).

During menopause, and in the period preceding it, estrogen production by the woman’s body gradually gets less, which may cause menstrual cycle irregularities, hot flushes, night sweats, mood swings and dryness in the vagina. Over a long time, thinning of the bones (osteoporosis) may also occur. Estradiol Valerate and Norgestrel Tablets serves as a replacement of estrogen during menopause and in the period preceding it and thereby improves the symptoms which may appear. The additional hormone in Estradiol Valerate and Norgestrel Tablets is progestogen, which contributes to regulation of the bleeding and lowers the chance of developing uterine cancer, in comparison to women treated with estrogen alone.

Therapeutic group: Hormone Replacement Therapy (HRT) estrogen and progestogen.

BEFORE USING THE MEDICINE

Special warnings regarding use of the medicine Before treatment with Estradiol Valerate and Norgestrel Tablets , tell the doctor if

any of the following conditions apply to you or have applied to you in the past:

Risk factors for cancer, such as if any of your close

relatives had cancer.

Risk factors for blood clotting problems.

Risk factors for angina pectoris, a stroke or heart disease.

• If you have elevated levels of blood
• If you are suffering from endometriosis, from uterine
• fibroids or from endometrial hyperplasia.
• If you are suffering, or have suffered in the past, from a change in skin color known as “pregnancy patches” (chloasma), especially in the face or In such a case, avoid exposure to the sun or to ultraviolet light.
• If you are suffering from hypertension, diabetes, gallstones, migraine or severe headaches, asthma, epilepsy or systemic lupus erythematosus (SLE).
• If you are suffering from hereditary angioedema. Preparations which contain estrogen may cause or worsen the Refer to the doctor immediately if symptoms of angioedema develop, including swelling of the hands, legs, face, tongue and/or throat and/ or difficulty swallowing or urticaria and difficulty breathing.
• If you are suffering from
• If you are suffering from a neurological disease known as chorea minor.
• If you are suffering from premature
• If you are suffering from adenoma of the pituitary
• Aside from the benefits of HRT, there are also some risks. You may wish to discuss this with your doctor when you have to decide whether to start HRT, or whether to continue treatment.

Effect on the heart and circulation Heart disease

HRT is not recommended for women who are suffering or have recently suffered from a heart disease. If you have ever suffered from heart disease, consult with the doctor as to whether it is recommended that you take HRT.

HRT will not help to prevent heart disease.

Studies that were conducted on one type of HRT (containing conjugated estrogen and medroxyprogesterone acetate) have shown that women may be at slightly higher risk of developing heart disease during the first year of treatment. For other types of HRT, the risk may be similar, although this has not yet been established.

Stroke

Recent research studies suggest that HRT slightly increases the risk of having a stroke. Other risk factors that increase the risk of stroke are:

• Older age
• High blood pressure
• Smoking
• Excessive drinking of alcohol
• An irregular heart rate

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

• Of 1000 women in their 50s who are not taking HRT – on average, 3 may have a stroke over a 5-year period.
• Of 1000 women in their 50s who are taking HRT – on average, 4 may have a stroke over a 5-year period.
• Of 1000 women in their 60s who are not taking HRT – on average, 11 may have a stroke over a 5-year period.
• Of 1000 women in their 60s who are taking HRT – on average, 15 may have a stroke over a 5-year period.

Thrombosis (blood clots)

HRT may increase the risk of blood clots in the veins (deep vein thrombosis), especially during the first year of taking it.

These blood clots are not always serious, but if a blood clot travels to the lungs, it can cause chest pain, breathlessness, collapse or even death. This condition is called pulmonary embolism. Deep vein thrombosis and pulmonary embolism are examples of a condition called venous thromboembolism.

The risk of blood clots increases if:

• you are seriously overweight
• you had a blood clot in the past
• any of your close relatives had blood clots
• you have had one or more miscarriages
• you have a blood clotting problem that needs treatment with a medicine such as warfarin
• you have to be off your feet for a long time because of a surgery, injury or illness

• you have systemic lupus erythematosus (SLE).

If any of these conditions apply to you, talk to your doctor to see if it is recommended that you take HRT. Your doctor will present to you the benefits versus the risks of taking Estradiol Valerate and Norgestrel Tablets .

• Of 1000 women in their 50s who are not taking HRT – on average, 3 may have a blood clot over a 5-year period.
• Of 1000 women in their 50s who are taking HRT – on average, 7 may have a blood clot over a 5-year period.
• Of 1000 women in their 60s who are not taking HRT – on average, 8 may have a blood clot over a 5-year period.
• Of 1000 women in their 60s who are taking HRT – on average, 17 may have a blood clot over a 5-year period.

Surgery

If you have to undergo surgery, be hospitalized, if you were involved in a serious accident or if you are off your feet for a long time, you should tell the doctor in advance that you are taking HRT. You may need to stop treatment with the medicine for about 4-6 weeks before the operation, to reduce the risk of a blood clot. The doctor will decide when treatment can be resumed.

Effect on the risk of developing cancer
Breast cancer

Breast cancer

HRT is not recommended for women who have or who have had breast cancer.

Taking HRT slightly increases the risk of breast cancer; as does having a late menopause, alcohol intake, obesity, a relative (mother, sister, grandmother) who is sick or has been sick with breast cancer.

The risk of breast cancer in menopausal women who are taking estrogen-only HRT for 5 years is similar to that of women of the same age who are still having periods over this time and are not taking HRT.

The risk of breast cancer in women taking estrogen plus progestogen HRT is higher than the risk in women taking estrogen-only HRT, but estrogen-only HRT is less effective in preventing endometrial cancer (see section “Endometrial cancer”).

For all kinds of HRT, the extra risk of breast cancer goes up the longer you take it, but returns to normal within 5 years after stopping the treatment.

– Of 1000 women in their 50s who are not taking HRT – on average, 32 will be diagnosed with breast cancer by the time they reach the age of 65.

– Of 1000 women in their 50s who started taking estrogenonly HRT and took it for 5 years – on average, 33-34 will be diagnosed with breast cancer by the time they reach the age of 65.

If they take estrogen-only HRT for 10 years, then the average is 37 women.

– Of 1000 women in their 50s who started taking estrogen plus progestogen HRT and took it for 5 years – on average, 38 will be diagnosed with breast cancer by the time they reach the age of 65.

If they take estrogen plus protestogen HRT for 10 years, then the average is 51 women.

Refer to the doctor immediately if you notice any changes in the breasts, such as: dimpling of the skin, changes in the nipple, a lump that can be seen or felt.

Endometrial cancer

Taking estrogen-only HRT for a long time may increase the risk of endometrial cancer, but adding progestogen in addition to the estrogen helps to lower this extra risk.

If you have not undergone a hysterectomy, the doctor will usually prescribe estrogen and also progestogen, separately, or as a combined hormonal treatment.

If you have had your womb removed, consult the doctor regarding the safety of taking estrogen alone without progestogen.

If your womb has been removed because of endometriosis, any endometrium left in your body may be at risk. Therefore, the doctor will prescribe HRT that contains a progestogen in addition to estrogen.

Estradiol Valerate and Norgestrel Tablets contains progestogen.

– Of 1000 women with a womb who are not taking HRT –

on average, 5 will be diagnosed with endometrial cancer between the ages of 50 and 65.

– In women who are taking estrogen-only HRT, the number of women will be 2 to 12 times higher, depending on the dosage and how long it was taken.

– Addition of progestogen to estrogen-only HRT, substantially reduces the risk of endometrial cancer.

If you get breakthrough bleeding or spotting, there is usually nothing to worry about, especially during the first few months of taking HRT.

If the bleeding or spotting:

• carries on for more than the first few months from the start of treatment,
• starts after you have been on HRT for a while,
• carries on even though you have stopped taking HRT, refer to the doctor; this may be a sign of that the endometrium is becoming thicker.

Ovarian cancer

Ovarian cancer is serious and very rare. This cancer can be difficult to diagnose because there are sometimes no obvious signs of the disease.

Some studies have indicated that taking estrogen-only HRT for more than 5 years may increase the risk of ovarian cancer. It is not yet known whether other kinds of HRT increase the risk to the same degree.

Dementia

HRT will not prevent memory loss. In a study of women who started using combined HRT after the age of 65, a small increase in the risk of dementia was observed.

Liver tumors

During or after the use of hormones such as those contained in Estradiol Valerate and Norgestrel Tablets , benign liver tumors have been observed rarely, and malignant liver tumors even more rarely. In isolated cases, bleeding from such tumors into the abdominal cavity has endangered life. Although such events are improbable, you should consult the doctor if you feel any unusual feelings in the upper abdomen that do not disappear within a short time. If you are taking or have recently taken other medicines, including non-prescription medicines and nutritional supplements, inform the doctor or pharmacist. It is especially important to inform the doctor or pharmacist if you are taking:

• Medicines to treat epilepsy (such as: phenytoin, phenobarbital); Antibiotics (such as: rifampicin, rifabutin);
• Medicines of the protease inhibitor type to treat the AIDS virus (HIV);
• Medicines of the transcriptase inhibitor type to treat the AIDS virus (HIV) (such as: nevirapine, efavirenz);
• Herbal preparations containing the herb St. John’s Wort (Hypericum)
• Medicines to treat diabetes (such as: insulin); Contraception
• Estradiol Valerate and Norgestrel Tablets is not a contraceptive. If you are using a contraceptive, consult the doctor. Estradiol Valerate and Norgestrel Tablets may interfere with the activity of the contraceptive.

Pregnancy and breast-feeding

Do not use the medicine if you are pregnant or breastfeeding.

If you become pregnant whilst taking the medicine, stop taking it immediately and

refer to the doctor.

Driving and using machines

The medicine may cause dizziness. If this occurs, do not drive or operate dangerous machinery.

Important information regarding some of the components of the medicine

The medicine contains sugar. If you suffer from an intolerance to some sugars, refer to the doctor before beginning treatment with the medicine.

HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions. Check with the doctor or pharmacist if you are unsure.

• The usual dosage is to take one whole tablet with water every day at a set hour, for a period of 21 days.
• Swallow the medicine with water.
• Do not crush/halve/chew the tablet for fear that the dosage will not be accurate.
• One package of Estradiol Valerate and Norgestrel Tablets contains 21 tablets. The package includes 7 strips of weekly labels, each one marked with 7 days. Choose the weekly label strip that begins with the day you start taking the tablets.

For example, if you start on Wednesday, choose the strip that begins with “Wednesday”. Paste it on the appropriate place, so that the tablet that will be taken on the first day will be the tablet marked “1”. In this way, the day of the week will be marked above each tablet. Start by taking the tablet that is marked by the relevant day of the week. The arrows show you which way to progress.

Take the tablets in the direction of the arrows until the package is finished.

This means that one white tablet daily should be taken for the first 11 days, then one brown tablet daily for the next 10 days.

After 21 days of taking the tablets, take a 7-day break.

During the 7-day break, bleeding similar to menstrual bleeding may occur; this is normal.

Start taking tablets from the next package on the eighth day, even if the bleeding continues. In this way, you will start a new package each month on the same day of the week.

When to start taking for the first time?

• If you have regular periods, start taking the medicine on the fifth day of the period.
• If you do not have regular periods, you can start taking the medicine at any time that you choose.
• If you are taking another HRT that causes you to have a period, complete the treatment course and start taking
• Estradiol Valerate and Norgestrel Tablets on the next day.
• If you are taking another HRT that does not cause you to have a period, you can start taking Estradiol Valerate and Norgestrel Tablets at any time that you choose.
• Tests and check-ups
• While using the medicine, you must regularly and independently check your breasts and take note of any changes in the breast. If you notice dimpling of the skin, changes in the nipple, a lump that can be seen or felt, refer to the doctor as soon as possible.
• You must regularly go for breast screenings.
• You must regularly go for cervical smear tests (PAP Smear).
• You must go for a gynecological check-up at least once a year. During the check-up, your doctor will discuss with you the benefits and risks of continuing to take Estradiol Valerate and Norgestrel Tablets.
• If you accidentally take too high a dosage
• If you took an overdose, or if a child has accidentally swallowed the medicine, refer immediately to the doctor or hospital emergency room and bring the package of the medicine with you.
• If you forget to take Estradiol Valerate and Norgestrel Tablets
• If the delay in taking the tablet is less than 12 hours, take the tablet as soon as possible, and continue taking the rest of the tablets as usual, in the direction of the arrow and at the regular time.
• If the delay in taking the tablet is more than 12 hours, leave the forgotten tablet in the package, and continue taking the rest of the tablets as usual, in the direction of the arrow, at the set time.
• Bleeding may occur if you have missed a tablet. This is normal.The expected bleeding pattern when taking Estradiol Valerate and Norgestrel Tablets
• The amount of bleeding can vary from woman to woman.
• Your bleeding pattern may change when taking the medicine.

The following may occur:

• Bleeding in the first three weeks of starting the tablets.
• Consult the doctor.
• Heavier bleeding. You may notice this mainly if your periods had become shorter or lighter before you started treatment with Estradiol Valerate and Norgestrel Tablets. This is normal.
• Bleeding in the break period between two packages. This is normal.
• If after several months of starting treatment you are still getting spotting or breakthrough bleeding, or if you are worried about the bleeding, refer to the doctor.
• Do not take medicines in the dark! Check the label and the dose each time you take medicine. Wear glasses if you need them.

 SIDE EFFECTS

As with any medicine, use of Estradiol Valerate and Norgestrel Tablets may cause side effects in some users. Do not be alarmed when reading the list of side effects. You may not suffer from any of them.

Stop using the medicine and refer immediately to a doctor if you notice any of the following symptoms:

• Chest pain that spreads to the arm or neck
• Sudden numbness or confusion
• Difficulty breathing
• Severe rash that might blister
• Sudden pain and swelling in the leg
• Yellowing of the skin or eyes
• Severe or prolonged headache, possibly with disturbed vision for the first time.

Refer to the doctor immediately

• If you notice any change in the breasts, such as, dimpling in the skin, changes in the nipple, a lump that can be seen or felt,
• If bleeding or spotting carries on for more than the first few months from the start of treatment, or starts after you have been taking the tablets for a while,
• If bleeding or spotting carries on even though you have stopped taking HRT,
• If there are suspicious signs of a severe allergic reaction or hereditary angioedema, such as: swelling in the hands, legs, face, lips, mouth, tongue and/or throat and/or difficulty swallowing or appearance of rash (urticaria) with breathlessness.

Additional side effects

Women taking different types of HRT, reported the following symptoms, which may or may not have been caused by HRT, and which, in some cases, may be symptoms of menopause.

Occurring often: weight gain or loss, headache, abdominal pain, nausea, rash, itching, vaginal bleeding including spotting (irregularities in bleeding pattern, usually subside during continued treatment).

Occurring infrequently: allergies (hypersensitivity reaction), depression, dizziness, visual disturbances, palpitations, indigestion, erythema nodosum (a skin condition characterized by reddish painful skin nodules), urticaria (hives), breast pains, breast tenderness, edema.

Occurring rarely: anxiety, decreased or increased libido, migraine, contact lens intolerance, bloating, vomiting, excessive hair growth, acne, muscle cramps, painful periods,

vaginal discharge, pre-menstrual-like syndrome, swollen breasts, fatigue.

If any of the side effects gets serious, or if you suffer from a side effect not listed in this leaflet, consult the doctor.

HOW SHOULD THE MEDICINE BE STORED?

• Avoid poisoning! This medicine and all medicines must be kept in a closed place out of the reach of children and/or infants to avoid poisoning. Do not induce vomiting unless explicitly instructed to do so by the doctor.
• Do not use the medicine beyond the expiry date (exp. date) that appears on the package. The expiry date refers to the last day of that month.
• Do not store at a temperature exceeding 25℃.

Further INFORMATION

• In addition to the active ingredients, the brown tablets also contain:

Lactose monohydrate, maize starch, polyvidone 25000, talc, magnesium stearate, sucrose, polyvidone 700000, macrogol 6000, calcium carbonate, glycerol 85%, titanium dioxide, ferric oxide pigment – yellow, ferric oxide pigment – red, montanglycol wax.

In addition to the active ingredients, the white tablets also contain:

Lactose monohydrate, maize starch, polyvidone 25000, talc, magnesium stearate, sucrose, polyvidone 700000, macrogol 6000, calcium carbonate, montanglycol wax.

• What does the medicine look like and what are the contents of the package?

In a Estradiol Valerate and Norgestrel Tablets package, there are 10 brown tablets and 11 white tablets.

The tablets come in blisters, in packages of 21 tablets.

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